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Am J Physiol Regul Integr Comp Physiol 287: R1101-R1109, 2004. First published July 15, 2004; doi:10.1152/ajpregu.00063.2004
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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Osmoregulation of atrial myocytic ANP release: osmotransduction via cross-talk between L-type Ca2+ channel and SR Ca2+ release

Jing Yu Jin, Jin Fu Wen, Dan Li, and Kyung Woo Cho

Department of Physiology, Institute for Medical Sciences, Jeonbug National University Medical School, Jeonju 561–180, Republic of Korea

Submitted 29 January 2004 ; accepted in final form 12 July 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Hyperosmolality has been known to increase ANP release. However, its physiological role in the regulation of atrial myocytic ANP release and the mechanism by which hyperosmolality increases ANP release are to be defined. The purpose of the present study was to define these questions. Experiments were performed in perfused beating rabbit atria. Hyperosmolality increased atrial ANP release, cAMP efflux, and atrial dynamics in a concentration-dependent manner. The osmolality threshold for the increase in ANP release was as low as 10 mosmol/kgH2O (~3%) above the basal levels (1.55 ± 1.71, 17.19 ± 3.11, 23.15 ± 5.49, 54.04 ± 11.98, and 62.00 ± 13.48% for 10, 20, 30, 60, and 100 mM mannitol, respectively; all P < 0.01). Blockade of sarcolemmal L-type Ca2+ channel activity, which increased ANP release, attenuated hyperosmolality-induced increases in ANP release (–13.58 ± 4.68% vs. 62.00 ± 13.48%, P < 0.001) and cAMP efflux but not atrial dynamics. Blockade of the Ca2+ release from the sarcoplasmic reticulum, which increased ANP release, attenuated hyperosmolality-induced increases in ANP release (13.44 ± 7.47% vs. 62.00 ± 13.48%, P < 0.01) and dynamics but not cAMP efflux. Blockades of Na+-K+-2Cl– cotransporter, Na+/H+ exchanger, and Na+/Ca2+ exchanger had no effect on hyperosmolality-induced increase in ANP release. The present study suggests that hyperosmolality regulates atrial myocytic ANP release and that the mechanism by which hyperosmolality activates ANP release is closely related to the cross-talk between the sarcolemmal L-type Ca2+ channel activity and sarcoplasmic reticulum Ca2+ release, possibly inactivation of the L-type Ca2+ channels.

atrial natriuretic peptide; L-type calcium channels; sarcoplasmic reticulum calcium release; hyperosmolality

ACUTE INCREASE in osmolality increases ANP release in vitro and in vivo. Hyperosmolality accentuates ANP release in rat atrial block (4, 32), atrial slice (48), dispersed atrial myocytes (19), and beating or nonbeating atria (40). In humans, moderate or marked acute hyperglycemia increases plasma levels of ANP (5, 10, 31). Some of these reports show that hyperosmolality by about 9–13% of basal levels accentuates ANP release (4, 19). Although the mechanism by which hyperglycemia increases plasma levels of ANP is difficult to differentiate from its effect induced by hypervolemia, these findings suggest that hyperosmolality may be a stimulant to increase atrial ANP release.

Hypertonicity by high extracellular osmolality results in a shrinkage of cardiomyocytes (14). Hyperosmolality has been known to induce an activation of Na+-K+-2Cl–1 cotransporter (NKCC) in rabbit ventricular myocytes (14) and Na+/H+ exchanger (NHX) in rabbit heart (17), which may result in an increase in intracellular Na+ concentration ([Na+]i). An increase in [Na+]i is related to an increase in intracellular Ca2+ concentration ([Ca2+]i) via reverse mode of Na+/Ca2+ exchanger (NCX). It was also shown that hyperosmolality increases [Na+]i (25) and [Ca2+]i (3, 23, 25, 42) in cardiac ventricular myocytes.

The change in atrial volume has been considered the most important physiological factor in the regulation of ANP release (8, 13, 27). There have also been reported various modulating factors for ANP release (35). Ca2+ has been known to have diverse effects on atrial ANP release, i.e., an increase or a decrease in ANP release. Many reports indicate that increase in Ca2+ influx via L-type Ca2+ channel activation increases ANP secretion in perfused hearts (36, 38), isolated beating atria (39), and contracting cultured atrial myocytes (30). Similarly, sarcolemmal (SL) L-type Ca2+ channel blocker inhibits ANP secretion in perfused hearts (38), isolated beating atria (39), and contracting atrial myocytes (30). In contrast, some reports, including ours, indicate that Ca2+ is negatively involved in the regulation of ANP release in perfused hearts (20, 37) and isolated beating atria (12, 47).

The increase in plasma osmolality has been shown to elevate plasma levels of ANP in marine fishes (15, 45). Especially, cardiac atrium has been shown to act as an osmoregulator secreting ANP in euryhaline eels (45). The purpose of the present study was to answer the following questions. 1) What is the physiological role of hyperosmolality in the regulation of ANP release and threshold to detect changes in osmolality in beating rabbit atria? 2) What is the mechanism by which hyperosmolality activates atrial myocytic ANP release?


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Beating perfused atrial preparation. New Zealand White rabbits were used. An isolated perfused atrial preparation was prepared by the method described previously (7, 11), which allowed atrial pacing and measurements of changes in atrial volume during contraction (stroke volume), pulse pressure, transmural extracellular fluid (ECF) translocation, cAMP efflux, and ANP secretion. Briefly, the hearts were removed and placed in oxygenated warm saline. The left atrium was then dissected. A calibrated transparent atrial cannula (8 cm long, 4 mm OD) containing two small catheters within it was inserted into the left atrium through the atrioventricular orifice. The cannula was secured by ligatures around the atrioventricular sulcus. The outer tip of the atrial cannula was open to allow for outflow from the atrium. One of the two catheters located in the atrium was for inflow. The other catheter was used to record pressure changes in the atrium. The cannulated atrium was then transferred to an organ chamber containing buffer at 36.5°C. The pericardial space of the organ chamber was open to the air so as not to restrict atrial dynamics. The atrium was perfused with HEPES-buffered solution by means of a peristaltic pump (1 ml/min). The composition of the buffer was as follows (mM): 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 25 NaHCO3, 10.0 glucose, and 10.0 HEPES (with NaOH, pH 7.4) and 0.1% bovine serum albumin (osmolality, 300.4 ± 2.6 mosmol/kgH2O) (n = 12). Soon after setup of the perfused atrium, transmural electrical field stimulation with a luminal electrode was started at 1.3 Hz (duration, 0.3 ms; voltage, 2 times threshold intensity, 20–30 V; 6.1-cmH2O distension). The perfusate was prewarmed to 36.5°C by passage through a water bath and equilibrated with oxygen by passage through silicone tubing in a gas mixing chamber. The buffer in the organ chamber was oxygenated by passing oxygen through silicone tubing coils located inside the chamber. Perfusate gas and pH were monitored via periodic sampling and measured with a pH/blood gas analyzer. The changes in atrial stroke volume were monitored by reading the lowest level of the water column in the calibrated atrial cannula during end diastole. Atrial pulse pressure was measured via a pressure transducer connected to the intra-atrial catheter and recorded on a physiograph. To estimate transendocardial ECF translocation, transmural atrial clearance of [3H]inulin was measured. Radioactivity in the atrial perfusate and pericardial buffer solution was measured with a liquid scintillation system, and the amount of ECF translocated through the atrial wall was calculated as follows: ECF translocated (µl·min–1·g atrial wt–1) = [total radioactivity in the perfusate (cpm/min) x 1,000]/[radioactivity in the pericardial reservoir (cpm/µl) x atrial wet wt (mg)].

Experimental protocols. The atria were perfused for 60 min to stabilize ANP secretion. The atria were paced at 1.3 Hz. [3H]inulin was introduced to the pericardial fluid 20 min before the start of the sample collection (7). The perfusate was collected at 2-min intervals at 4°C for analyses. Experiments were carried out by using six groups of atria to define the concentration-dependent effects of mannitol (Fig. 1). Control cycles (four 12-min periods) were followed by mannitol (6 mM, group 1, n = 3; 10 mM, group 2, n = 9; 20 mM, group 3, n = 9; 30 mM, group 4, n = 6; 60 mM, group 5, n = 5; 100 mM, group 6, n = 8; vehicle, group 26, n = 9). To define the role of SL L-type Ca2+ channel activity in the hyperosmolality-induced responses, three cycles (36 min) of nifedipine (1 µM), an L-type Ca2+ channel-selective inhibitor, were followed by an administration of mannitol (100 mM) or vehicle for three cycles in the presence of nifedipine (group 8, n = 10; nifedipine alone, group 9, n = 10). Three cycles of mannitol (100 mM) were also followed by nifedipine or vehicle for three cycles in the presence of mannitol (group 10, n = 6; mannitol alone, group 11, n = 6). To define the role of the Ca2+ release from the sarcoplasmic reticulum (SR) in the hyperosmolality-induced responses, three cycles of combined infusion of ryanodine (1 µM), a SR Ca2+ release-selective inhibitor, and thapsigargin (1 µM), a SR Ca2+ ATPase-selective inhibitor, were followed by an administration of mannitol (100 mM) or vehicle for three cycles in the presence of the prior agent (group 12, n = 8; thapsigargin plus ryanodine, group 13, n = 7). To analyze the role of the NKCC, NHX, and NCX, three cycles of selective inhibitor for the transporter were followed by an administration of mannitol (100 mM) or vehicle in the presence of the prior agent. The following inhibitors were used: 1) NKCC inhibitor, bumetanide (10 µM, group 14, n = 9; bumetanide alone, group 15, n = 6); 2) NHX inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 10 µM, group 16, n = 6; EIPA alone, group 17, n = 3); 3) NCX inhibitor, KB-R7943 (KB-R, 10 µM, group 18, n = 6; KB-R alone, group 19, n = 5) and 2',4'-dichlorobenzamil (DCB, 30 µM, group 20, n = 8; DCB alone, group 21, n = 4). In another series of experiments, to define involvement of p38 mitogen-activated protein (MAP) kinase or protein kinases, three cycles of infusion of SB-203580 (SB, 20 µM, group 22, n = 8; SB alone, group 23, n = 3) or staurosporine (0.1 µM, group 24, n = 6; staurosporine alone, group 25, n = 3) were followed by an infusion of mannitol (100 mM) or vehicle in the presence of the prior agent. The effects were evaluated after two cycles (24 min) of administration of the agent. For the time-matched or modulating-agent control, vehicle was introduced, and values obtained during the periods corresponding to the control and experimental observations were compared. The concentrations of inhibitors for Ca2+, ion channels, and protein kinases were in the range of doses used previously (11, 18, 28, 29, 33, 34, 46).



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  		Fig. 1. Protocols for experiments with isolated beating rabbit atria. Atria were paced at 1.3 Hz. Cont, control period. Inhibitors (Inhi): nifedipine (Nife), thapsigargin, ryanodine, bumetanide (Bumet), 5-(N-ethyl-N-isopropyl)amiloride (EIPA), KB-R7943 (KB-R), 2',4'-dichlorobenzamil (DCB), SB-203580 (SB), staurosporine (Stauro). Mann, mannitol. See Experimental protocols for details.

 
Radioimmunoassay of ANP. Immunoreactive ANP in the perfusate was measured by a specific radioimmunoassay as described previously (7). The secreted amount of immunoreactive ANP was expressed as nanograms of ANP per minute per gram of atrial tissue. The molar concentration of immunoreactive ANP in terms of the ECF translocation reflects the concentration of ANP in the interstitial space of the atrium and, therefore, indicates the rate of myocytic release of ANP into the surrounding paracellular space (7). It was calculated as ANP released (in µM) = immunoreactive ANP (in pg·min–1·g–1)/ECF translocated (in µl·min–1·g–1)·3,063 [molecular weight of ANP-(1–28)]. Most of the ANP secreted is processed ANP (7).

Radioimmunoassay of cAMP. cAMP was measured by equilibrated radioimmunoassay as described previously (11). Briefly, standards and samples were taken up in a final volume of 100 µl of 50 mM sodium acetate buffer (pH 4.8) containing theophylline (8 mM), and then 100 µl of diluted cAMP antiserum (Calbiochem-Novabiochem, San Diego, CA) and iodinated 2'-O-monosuccinyl-adenosine 3',5'-cyclic monophosphate tyrosyl methyl ester were added and incubated for 24 h at 4°C. For the acetylation reaction, 5 µl of a mixture of acetic anhydride and triethylamine was added to the assay tube before the addition of antiserum and tracer. The amount of cAMP efflux was expressed as picomoles cAMP per minute per gram atrial tissue. The molar concentration of cAMP efflux in terms of the ECF translocation reflects the concentration of cAMP in the interstitial space of the atrium. It was calculated as cAMP efflux concentration (in µM) = cAMP (in pmol·min–1·g–1)/ECF translocated (in µl·min–1·g–1). For the preparation of perfusates, 100 µl of the perfusate were treated with trichloroacetic acid for a final concentration of 6% for 15 min at room temperature and were centrifuged at 4°C. The supernatant was transferred to a polypropylene tube, extracted with water-saturated ether, and then dried by using a SpeedVac concentrator (Savant, Farmingdale, NY). The dried samples were resuspended with sodium acetate buffer.

Statistical analysis. Significant difference was compared by using repeated-measures ANOVA followed by Bonferroni's multiple-comparison test (see Figs. 2, 4, 5, and 7). Student's t-test for unpaired data (see Figs. 3, 6, 8, and 9) was also applied. Statistical significance was defined as P < 0.05. The results are given as means ± SE.



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  		Fig. 2. A: effects of mannitol (30 mM) on atrial natriuretic peptide (ANP) secretion (Aa), extracellular fluid (ECF) translocation (Ab), ANP concentration in terms of ECF translocation (Ac), cAMP efflux (Ad), cAMP concentration (Ae), atrial stroke volume (Af), and pulse pressure (Ag) in perfused beating rabbit atria (1.3 Hz; n = 6). B: time-matched control for the same parameters (Ba–Bg) was stable during the period corresponding to mannitol infusion (n = 9). Values are means ± SE. +P < 0.05, +++P < 0.001 vs. control period.

 


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  		Fig. 4. A: effects of nifedipine (Nife; 1 µM) on ANP concentration in terms of ECF translocation (Aa), cAMP concentration (Ab), atrial stroke volume (Ac), and pulse pressure (Ad) in perfused beating rabbit atria (1.3 Hz; n = 10). B: effects of mannitol (100 mM) in the presence of nifedipine on ANP concentration (Ba), cAMP concentration (Bb), atrial stroke volume (Bc), and pulse pressure (Bd) (n = 10). C: A and B are superimposed for comparison. Values are means ± SE. **P < 0.01, ***P < 0.001 vs. control. +++P < 0.01 vs. nifedipine.

 


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  		Fig. 5. A: effects of mannitol (100 mM) on ANP concentration (Aa), cAMP concentration (Ab), atrial stroke volume (Ac), and pulse pressure (Ad) in perfused beating rabbit atria (1.3 Hz; n = 6). B: effects of nifedipine (1 µM) in the presence of mannitol on ANP concentration (Ba), cAMP concentration (Bb), atrial stroke volume (Bc), and pulse pressure (Bd) (n = 6). C: A and B are superimposed for comparison. Values are means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control. +++P < 0.01 vs. mannitol.

 


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  		Fig. 7. A: effects of mannitol (100 mM) on ANP concentration (Aa), cAMP concentration (Ab), atrial stroke volume (Ac), and pulse pressure (Ad) in perfused beating rabbit atria (1.3 Hz; n = 8). B: effects of mannitol in the presence of thapsigargin (T, 1 µM) plus ryanodine (R, 3 µM) on ANP concentration (Ba), cAMP concentration (Bb), atrial stroke volume (Bc), and pulse pressure (Bd) (n = 8). C: effects of thapsigargin plus ryanodine for the same parameters (Ca–Cd). Values are means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control or thapsigargin plus ryanodine.

 


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  		Fig. 3. Concentration-dependent effects of mannitol on the changes ({Delta}) in ANP concentration (concn), atrial stroke volume, pulse pressure, and cAMP efflux concentration. Responses were compared with differences of mean values of 2 fractions before (fraction numbers 23 and 24) and after 3 cycles (fraction numbers 41 and 42) of mannitol or vehicle. No. of experiments: 6 mM mannitol, n = 3; 10 mM mannitol, n = 9; 20 mM mannitol, n = 9; 30 mM mannitol, n = 6; 60 mM mannitol, n = 5; 100 mM mannitol, n = 8; control, n = 9. Data for mannitol (30 and 100 mM) and control were derived from Figs. 2 and 7A. Values are means ± SE. *P < 0.05, +P < 0.01 vs. control.

 


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  		Fig. 6. A: comparison of effects of nifedipine (Nif; 1 µM, n = 20; middle column; data from Fig. 4, A and B) and mannitol (100 mM, n = 12; right column; data from Fig. 5, A and B) on the changes in ANP concentration, atrial stroke volume, pulse pressure, and cAMP efflux concentration. The responses were compared with differences of mean values of 2 fractions before (fraction numbers 5 and 6) and after 3 cycles (fraction numbers 23 and 24) of nifedipine, mannitol, or vehicle. Data for nifedipine, mannitol, and control were derived from Fig. 4, A and B; 5, A and B; and 2B, respectively. **P < 0.01, ***P < 0.001 vs. control. B: effects of mannitol in the presence of nifedipine (n = 10; middle column; data from Fig. 4B) and effects of nifedipine in the presence of mannitol (n = 6; right column; data from Fig. 5B) on the changes in ANP concentration, atrial stroke volume, pulse pressure, and cAMP efflux concentration. The responses were compared with differences of mean values of 2 fractions before (fraction numbers 23 and 24) and after 3 cycles (fraction number 41 and 42) of mannitol, nifedipine, or vehicle. Data for effects of mannitol in the presence of nifedipine, effects of nifedipine in the presence of mannitol, and control were derived from Figs. 4B, 5B, and 2B, respectively. Values are means ± SE. **P < 0.01, ***P < 0.001.

 


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  		Fig. 8. Effects of combined treatment of thapsigargin (1 µM) and ryanodine (3 µM) on mannitol (100 mM)-induced changes in ANP concentration, atrial stroke volume, pulse pressure, and cAMP efflux concentration. The responses were compared with differences of mean values of 2 fractions before (fraction numbers 23 and 24) and after 3 cycles (fraction numbers 41 and 42) of mannitol, thapsigargin plus ryanodine. Three cycles before mannitol, vehicle or thapsigargin plus ryanodine was administered. Data were derived from Figs. 2B and 7. Values are means ± SE. *P < 0.05, **P < 0.01, ***P < 0.001.

 


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  		Fig. 9. Comparison of effects of inhibitors for Na+-K+-2Cl– cotransporter (NKCC; Bumet), Na+/H+ exchanger (NHX; EIPA), Na+/Ca2+ exchanger (NCX; KB-R, DCB), p38 MAP kinase (SB), and protein kinases (Stauro) on mannitol (M) (100 mM)-induced increases in ANP concentration and atrial stroke volume. Responses were compared with differences of mean values of 2 fractions before (fraction numbers 23 and 24) and after 3 cycles (fraction numbers 41 and 42) of mannitol. Three cycles before mannitol, vehicle or inhibitor was administered. No. of experiments: mannitol alone (M, 100 mM, n = 8; data derived from Fig. 7A); Bumet (10 µM) + M (n = 9); KB-R (10 µM) + M (n = 6); DCB (30 µM) + M (n = 8); EIPA (10 µM) + M (n = 6); SB (20 µM) + M (n = 8); Stauro (0.1 µM) + M (n = 6). Values are means ± SE.

 

   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hyperosmolality activates atrial myocytic ANP release in a concentration-dependent manner. ANP secretion, ECF translocation, and the concentration of ANP in terms of the ECF translocation, which reflects the rate of atrial myocytic ANP release, were stable during the control periods (Fig. 2, Aa–Ac and Ba–Bc). cAMP efflux, the concentration of cAMP in perfusate in terms of the ECF translocation and atrial dynamics, atrial stroke volume, and pulse pressure were also steady and stable (Fig. 2, Ad–Ag and Bd–Bg). Hyperosmotic solution (30 mM mannitol added to regular HEPES buffer) increased ANP secretion, the concentration of ANP, cAMP efflux, and atrial stroke volume and pulse pressure (Fig. 2A). Hyperosmolality-induced increases in ANP concentration and cAMP efflux concentration continuously progressed. Hyperosmolality-induced increase in atrial dynamics showed a peak and waned.

Hyperosmolality-induced increase in ANP release was significant at a concentration as low as ~10 mosmol/kgH2O above the basal level (315.8 ± 0.7 mosmol/kgH2O, n = 8, 10 mM mannitol added vs. 304.4 ± 1.4 mosmol/kgH2O, n = 8, regular buffer). Hyperosmolality (10 mosmol/kgH2O) significantly increased ANP concentration at the third cycle of infusion (1.55 ± 1.71%, n = 9, for hyperosmolality vs. –6.13 ± 1.76%, n = 9, for time-matched control; P < 0.05; Fig. 3). Hyperosmolality (10 mM) significantly increased cAMP efflux concentration at the third cycle of infusion (38.21 ± 11.43%, n = 7, for hyperosmolality vs. 3.43 ± 3.88%, n = 9, for time-matched control; P < 0.01). Hyperosmolality (10 mM)-induced increase in atrial dynamics was not significant. As shown in Fig. 3, hyperosmolality increased atrial myocytic ANP release, atrial stroke volume and pulse pressure, and cAMP efflux in a concentration-dependent manner. Hyperosmotic solution containing glucose increased ANP release with equal potency (17.85 ± 2.36%, n = 3, and 55.63 ± 10 18%, n = 4, for 30 and 60 mM, respectively).

L-type Ca2+ channel inhibition with nifedipine blocks hyperosmolality-induced activation of atrial myocytic ANP release. To define the mechanism by which hyperosmolality activates atrial myocytic ANP release, the role of the SL L-type Ca2+ channels was tested. Blockade of L-type Ca2+ channel activity with nifedipine increased ANP secretion and atrial myocytic ANP release concomitantly with a decrease in atrial stroke volume and pulse pressure (see Figs. 4, A and B, and 6A, middle column). Nifedipine had no effect on cAMP efflux (see Figs. 4, Ab and Bb, and 6A, middle column). The effects of nifedipine maintained after the third cycle of infusion. These results indicate that Ca2+ entry via L-type channel activation decreases atrial myocytic ANP release. In the presence of nifedipine, hyperosmolality (100 mM mannitol added) failed to activate myocytic ANP release (ANP concentration 62.00 ± 13.48%, n = 8, for mannitol vs. –6.13 ± 1.76%, n = 9, for time-matched control, P < 0.001; –13.58 ± 4.68%, n = 10, for nifedipine plus mannitol vs. –12.02 ± 5.28%, n = 10, for nifedipine alone, P > 0.05; see Figs. 4Ba, 6B, middle, and 7Aa). Nifedipine failed to block hyperosmolality-induced increase in atrial dynamics (for atrial stroke volume: 13.31 ± 4.57%, n = 8, for mannitol vs. –2.04 ± 1.21%, n = 9, for time-matched control, P < 0.01; 200.99 ± 56.57%, n = 10, for nifedipine plus mannitol vs. –42.62 ± 6.31%, n = 10, for nifedipine alone, P < 0.001; for atrial pulse pressure: 11.49 ± 1.59%, n = 8, for mannitol vs. –1.73 ± 1.23%, n = 9, for control, P < 0.001; 48.01 ± 9.29%, n = 10, for nifedipine plus mannitol vs. –21.46 ± 3.27%, n = 10, for nifedipine alone, P < 0.001; see Figs. 4, Bc and Bd, and 6B, middle column). Hyperosmolality-induced increase in cAMP efflux concentration was not observed in the presence of nifedipine (65.78 ± 15.84%, n = 8, for mannitol vs. 3.43 ± 3.88%, n = 9, for time-matched control, P < 0.01; 30.34 ± 8.60%, n = 10, for nifedipine plus mannitol vs. 17.76 ± 6.11%, n = 10, for nifedipine alone, P > 0.05; see Figs. 4Bb and 6B, middle column). These results indicate that hyperosmolality-induced activation of atrial myocytic ANP release is closely related to the L-type Ca2+ channel activity (Fig. 4C).

To further define the effects of mannitol, the effects of nifedipine were tested in the presence of mannitol. Hyperosmolality (100 mM mannitol added) increased atrial myocytic ANP release (Figs. 5 Aa and 6A, right column). Hyperosmolality-induced increase in ANP release showed a peak and waned (Figs. 5Aa and 6B, right column). Hyperosmolality induced increases in atrial stroke volume and pulse pressure, and cAMP efflux was maintained (Figs. 5, Ab–Ad, and 6A, right column). In the presence of hyperosmolality, nifedipine failed to activate atrial ANP release (Figs. 5Ba and 6B, right column). In the presence of hyperosmolality, nifedipine decreased atrial stroke volume and pulse pressure without changes in hyperosmolality-induced increase in cAMP efflux (Figs. 5, Bb–Bd, and 6B, right column). These results indicate that hyperosmolality interferes with nifedipine-induced increase in ANP release (Fig. 5C).

Inhibition of SR Ca2+ release with ryanodine plus thapsigargin attenuates hyperosmolality-induced activation of atrial myocytic ANP release. Because cross-talk between the SL L-type Ca2+ channels and SR Ca2+ release has a fundamental importance in the regulation of cardiac [Ca2+]i homeostasis, the role of the SR function in the hyperosmolality-induced activation of atrial ANP release was tested. Blockade of the SR Ca2+ release by combined treatment with ryanodine and thapsigargin slightly but not significantly increased atrial ANP release concomitantly with a decrease in atrial stroke volume and pulse pressure (Fig. 7, B and C). The results indicate that the SR Ca2+ release is negatively involved in the regulation of ANP release. In the blockade of the SR Ca2+ release, hyperosmolality failed to increase atrial myocytic ANP release and atrial stroke volume and pulse pressure (Figs. 7, Ba, Bc, and Bd, and 8). In the blockade of the SR Ca2+ release, hyperosmolality increased cAMP efflux (Figs. 7Bb and 8). Effects of thapsigargin plus ryanodine were stable during the corresponding periods (Figs. 7C and 8). These results indicate that hyperosmolality-induced increase in ANP release is closely related to the SR Ca2+ release.

Inhibition of NKCC, NHX, and NCX has no effect on hyperosmolality-induced activation of atrial myocytic ANP release. Because hyperosmolality has been shown to activate NKCC (14), NHX (17) and possibly NCX in the heart (25), the role of these functions in the hyperosmolality-induced increase in ANP concentration (release) was tested (Fig. 9). Blockade of NKCC with bumetanide decreased ANP release by 16.39 ± 3.50% up to the third cycle of infusion. Bumetanide failed to block the hyperosmolality-induced increases in atrial ANP release and stroke volume. Blockade of NHX with EIPA decreased ANP release by 34.63 ± 4.6% up to the third cycle. EIPA failed to block hyperosmolality-induced increases in ANP release and stroke volume. Blockade of reverse mode of the NCX with KB-R decreased atrial ANP release by 38.42 ± 5.38% up to third cycle. KB-R failed to modify the hyperosmolality-induced increases in ANP release and stroke volume. Similarly, blockade of NCX with DCB failed to block hyperosmolality-induced increases in atrial ANP release and stroke volume. Neither bumetanide nor DCB alone showed significant changes in ANP release during the period corresponding to mannitol infusion compared with time-matched control. EIPA (–34.60 ± 8.86%, n = 3, vs. –6.13 ± 1.76%, n = 9, P < 0.001) and KB-R (–37.41 ± 6.23%, n = 5, vs. –6.13 ± 1.76%, n = 9, P < 0.001) alone decreased ANP release during the corresponding period.

Protein kinase inhibition with SB or staurosporine has no effect on hyperosmolality-induced activation of atrial myocytic ANP release. It was shown that hyperosmolality activates p38 MAP kinase signaling pathways (2). To define the role of p38 MAP kinase in the hyperosmolality-induced increase in ANP release, the effect of SB was tested (Fig. 9). Blockade of p38 MAP kinase with SB decreased ANP release by 39.44 ± 3.43% up to third cycle. SB had no significant effect on the hyperosmolality-induced increase in ANP release. Staurosporine decreased ANP release by 13.44 ± 3.43% up to the third cycle. Staurosporine had no effect on the hyperosmolality-induced increase in ANP release (Fig. 9). SB but not staurosporine alone decreased ANP release during the period corresponding to mannitol infusion compared with time-matched control (–28.87 ± 10.09%, n = 3, vs. –6.13 ± 1.76%, n = 9, P < 0.01).


   DISCUSSION
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 REFERENCES
 
The present study explores the role of hyperosmolality on the regulation of atrial myocytic ANP release.

Osmoregulation of atrial myocytic ANP release. The present study indicates that an increase in extracellular osmolality is a powerful stimulant to induce an increase in atrial myocytic ANP release, cAMP production, and atrial dynamics. Hyperosmotic stimulation with mannitol or glucose increased ANP release with equal potency. The responses were concentration dependent up to 100 mosmol/kgH2O above the basal levels of osmolality. The responses to the changes in osmolality were fairly sensitive to detect it at levels as low as 3% above basal levels. Mannitol (10 mM) significantly increased atrial ANP release. These results indicate that the cardiac atrium is sensitive to detect changes in fluid osmolality and to respond by increasing atrial myocytic ANP release. This suggests that the changes in fluid osmolality as well as volume could be one of the physiological stimulants in the regulation of atrial myocytic ANP release. Therefore, it is possible to hypothesize that the cardiac atrium has a role in the regulation of body fluid osmolality as well as fluid volume and hydrostatic pressure balance as an osmoregulator.

The heart is involved in the osmoregulation in marine fishes (15, 45). However, in mammals it was not tested that the changes in fluid osmolality could be a regulator to control the ANP release in the physiological ranges. Hyperosmolality (9–12.9% above the basal osmolality) has been shown to activate atrial ANP release (4, 19). The response was also observed by a much higher increase in osmolality in rat atrial block (32, 48) and atria (40).

Both the L-type Ca2+ channels and SR Ca2+ release are involved in the hyperosmolality-induced increase in atrial myocytic ANP release. Ca2+ entry via SL L-type Ca2+ channel activation decreases atrial myocytic ANP release (22, 47). It was shown that SR Ca2+ release was positively (9, 21, 24, 26, 30, 39) or negatively (29) involved in the regulation of ANP release. Because SR Ca2+ release is under the control of SL Ca2+ entry mainly via L-type Ca2+ channel activation (Ca2+-induced Ca2+ release, CICR, Ref. 16), it is possible to hypothesize that cross-talk between the SL Ca2+ entry and SR Ca2+ release is involved in the control of atrial myocytic ANP release. Especially the role of inactivation of L-type Ca2+ channels in the regulation of atrial ANP release has yet to be defined.

L-type Ca2+ channel blockade attenuated hyperosmolality-induced increase in atrial myocytic ANP release. Previously, it was shown that L-type Ca2+ channel activation with Bay K 8644 decreased and inhibition with inhibitors increased atrial ANP release in beating rabbit atria (47). This means that the Ca2+ entry via L-type Ca2+ channels inhibits atrial myocytic ANP release. Taken together with the present data, hyperosmolality-induced increase in ANP release is related with the L-type Ca2+ channel activity but not with the Ca2+ entry per se (Fig. 10). Therefore, it is possible to postulate that inactivation of the channels is involved in the hypertonicity-induced activation of atrial ANP release. To define this hypothesis the SR Ca2+ release was modulated. Blockade of the SR Ca2+ release attenuated hyperosmolality-induced increase in atrial ANP release. This suggests that the Ca2+ release from the SR is related to the hyperosmolality-induced increase in ANP release. However, Ca2+ release from the SR per se decreases atrial ANP release in the present and our previous data (29).



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  		Fig. 10. Hypothetical model for the hyperosmolality-induced activation of atrial myocytic ANP release in beating atria. Exocytotic ANP-pit close to as well as far from the L-type Ca2+ channel is negatively regulated by entry of Ca2+ via the channel, the former directly and the latter indirectly via Ca2+ release from the sarcoplasmic reticulum (SR). Ca2+ in the microdomain between the sarcolemma (SL) and SR is related to the inhibition of ANP release as well as inactivation of L-type Ca2+ channel and activation of myocytic length changes. Shrinkage of the gap between the SL and SR by hyperosmolality accentuates the rate of Ca2+ accumulation in the microdomain. Inactivation of the L-type Ca2+ channel is accentuated by the shrinkage of the microdomain and relieves the inhibitory Ca2+ of ANP release, which results in an increase in ANP release. Accentuation of Ca2+-induced Ca2+ release may also be related to the hyperosmolality-induced increase in atrial dynamics. RyR, ryanodine receptor; SERCA, sarcoplasmic reticulum Ca2+-ATPase; +, activation; –, inhibition.

 
Hyperosmolality-induced activation of ANP release may be related to the changes in the [Ca2+]i in the Ca2+ microdomain (1, 41) between the SL L-type Ca2+ channels and subsarcolemmal SR. Increase in SR Ca2+ release or the rate of Ca2+ accumulation (44) may be accentuated by shrinkage of the cytoplasm of the Ca2+ microdomain, which results in an accentuation of Ca2+-induced Ca2+ current inactivation (1, 41, 44) and a relief of the Ca2+-induced inhibition of ANP release and then activation of ANP release (Fig. 10). It was shown in the skeletal muscle that hypertonicity decreased the tiny gap between the SL and subsarcolemmal SR (6). From this notion, it is possible to hypothesize that enhanced inactivation of L-type Ca2+ channels is related to the hyperosmolality-induced increase in ANP release (Fig. 10).

The hyperosmolality-induced increase in ANP release was accompanied by increases in atrial dynamics and cAMP production. The changes in cAMP production and atrial dynamics were closely related to the function of the L-type Ca2+ channel activity and SR Ca2+ release, respectively. Blockade of the SR function attenuated hyperosmolality-induced increase in atrial dynamics but not cAMP production. Also, blockade of L-type Ca2+ channels attenuated increase in cAMP production but not atrial dynamics. Hyperosmolality-induced increase in atrial dynamics may be related to the accentuation of the SR Ca2+ release (Fig. 10).

The present data indicate that the change in cAMP production is not directly related to the hypertonicity-induced increase in ANP release. This contrasts the previous reports showing that histamine- or forskolin-induced decrease in ANP release is related to the increase in cAMP production (11, 28). This finding suggests that cAMP is compartmentalized in the regulation of hyperosmolality-induced ANP release. The present data also show that hyperosmolality-induced increase in atrial dynamics is not related to an activation of ANP release.

NKCC, NHX, NCX, and some protein kinases are not involved in the hyperosmolality-induced increase in atrial ANP release. NKCC blockade had no significant effects on the hyperosmolality-induced increases in ANP release and atrial dynamics. Similarly, blockades of NHX and NCX had no significant effect on the hyperosmolality-induced increase in ANP release. Previously, it was shown that the SL Ca2+ entry involved in the Ca2+ release from the SR by CICR was mainly L-type Ca2+ channels (1, 41). The present finding that Na+ or Ca2+ entry via NKCC, NHX, or NCX is not involved in the hyperosmolality-induced increase in ANP release is relevant to this notion. Previously, Schiebinger et al. (40) reported that NCX is involved in the hyperosmolality-induced increase in ANP release. The present study contrasts to the report.

The present finding suggests that staurosporine-sensitive protein kinase(s) or p38 MAP kinase is not involved in the hyperosmolality-induced increase in ANP release.

It is possible that neurotransmitters released from nerve endings (35, 43) may be involved in the hyperosmolality-induced increase in ANP release. However, it may not be the case. In our experimental model, an activation of adrenoceptors decreased ANP release. Also, acetylcholine showed a transient but little ANP effect with a decrease in atrial dynamics (unpublished data).

In summary, cardiac atrium has a role for the regulation of osmolality as well as volume of the body fluid via ANP release. The present study suggests that the cross-talk between the SL L-type Ca2+ channels and SR Ca2+ release, possibly inactivation of the L-type Ca2+ channels, is involved in the osmotransduction to activate ANP release.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by research grants from the Korea Science and Engineering Foundation (R01–2003-000–10507-0) and Korea Research Foundation (2003–002-E00013).


   ACKNOWLEDGMENTS
 
We thank He Xiu Quan for the computer-generated figures. We also thank Kyong Sook Kim for secretarial work.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. W. Cho, Dept. of Physiology, Jeonbug National Univ. Medical School, 2–20 Keum-Am-Dong-San, Jeonju 561–180, Republic of Korea (E-mail: kwcho{at}chonbuk.ac.kr)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Adachi-Akahane S, Cleemann L, and Morad M. Cross-signaling between L-type Ca2+ channels and ryanodine receptors in rat ventricular myocytes. J Gen Physiol 108: 435–454, 1996.[Abstract/Free Full Text]
  2. Aggeli IKS, Gaitanaki C, Lazou A, and Beis I. Hyperosmotic and thermal stresses activate p38-MAPK in the perfused amphibian heart. J Exp Biol 205: 443–454, 2002.[Abstract/Free Full Text]
  3. Allen DG and Smith GL. The effects of hypertonicity on tension and intracellular calcium concentration in ferret ventricular muscle. J Physiol 383: 425–439, 1987.[Abstract/Free Full Text]
  4. Arjamaa O and Vuolteenaho O. Sodium ion stimulates the release of atrial natriuretic polypeptides (ANP) from rat atria. Biochem Biophys Res Commun 132: 375–381, 1985.[CrossRef][Web of Science][Medline]
  5. Boehlen L, Ferrari P, Papiri M, Allemann Y, Shaw S, and Weidmann P. Atrial natriuretic factor increases in response to acute glucose load. J Hypertens 12: 803–807, 1994.[Web of Science][Medline]
  6. Chawla S, Skepper JN, Hockaday AR, and Huang CLH. Calcium waves induced by hypertonic solutions in intact frog skeletal muscle fibres. J Physiol 536: 351–359, 2001.[Abstract/Free Full Text]
  7. Cho KW, Kim SH, Kim CH, and Seul KH. Mechanical basis of atrial natriuretic peptide secretion in beating atria: atrial stroke volume and ECF translocation. Am J Physiol Regul Integr Comp Physiol 268: R1129–R1136, 1995.[Abstract/Free Full Text]
  8. Cho KW, Seul KH, Ryu H, Kim SH, and Koh GY. Characteristics of distension-induced release of immunoreactive atrial natriuretic peptide in isolated perfused rabbit atria. Regul Pept 22: 333–345, 1988.[CrossRef][Web of Science][Medline]
  9. Church DJ, Rebsamen MC, Morabito D, Van der Bent V, Vallotton MB, and Lang U. Role of cell contractions in cAMP-induced cardiomyocyte atrial natriuretic peptide release. Am J Physiol Heart Circ Physiol 278: H117–H125, 2000.[Abstract/Free Full Text]
  10. Clark BA, Sclater A, Epstein FH, and Elahi D. Effect of glucose, insulin, and hypertonicity on atrial natriuretic peptide levels in man. Metabolism 42: 224–228, 1993.[CrossRef][Web of Science][Medline]
  11. Cui X, Wen JF, Jin JY, Xu WX, Kim SZ, Kim SH, Lee HS, and Cho KW. Protein kinase-dependent and Ca2+-independent cAMP inhibition of atrial ANP release in beating rabbit atria. Am J Physiol Regul Integr Comp Physiol 282: R1477–R1489, 2002.[Abstract/Free Full Text]
  12. De Bold ML and De Bold AJ. Effect of manipulations of Ca2+ environment on atrial natriuretic factor release. Am J Physiol Heart Circ Physiol 256: H1588–H1594, 1989.[Abstract/Free Full Text]
  13. Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol Regul Integr Comp Physiol 247: R1093–R1096, 1984.[Abstract/Free Full Text]
  14. Drewnowska K and Baumgarten CM. Regulation of cellular volume in rabbit ventricular myocytes: bumetanide, chlorothiazide, and ouabain. Am J Physiol Cell Physiol 260: C122–C131, 1991.[Abstract/Free Full Text]
  15. Evans DH. An emerging role for a cardiac peptide hormone in fish osmoregulation. Annu Rev Physiol 52: 43–60, 1990.[CrossRef][Web of Science][Medline]
  16. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol Cell Physiol 245: C1–C14, 1983.[Abstract/Free Full Text]
  17. Falck G, Skarra S, and Jynge P. Cardiac contractile function and electrolyte regulation during hyperosmolal stress: An experimental study in the isolated rabbit heart. Pharmacol Toxicol 84: 174–180, 1999.[Web of Science][Medline]
  18. Fujita S and Endoh M. Influence of Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+ exchange inhibitor KB-R7943 and their combination on the increases in contractility and Ca2+ transient induced by angiotensin II in isolated adult rabbit ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol 360: 575–584, 1999.[CrossRef][Web of Science][Medline]
  19. Gibbs DM. Noncalcium-dependent modulation of in vitro atrial natriuretic factor release by extracellular osmolality. Endocrinology 120: 194–197, 1987.[Abstract/Free Full Text]
  20. Ito T, Toki Y, Siegel N, Gierse JK, and Needleman P. Manipulation of stretch-induced atriopeptin prohormone release and processing in the perfused rat heart. Proc Natl Acad Sci USA 85: 8365–8369, 1988.[Abstract/Free Full Text]
  21. Katoh S, Toyama J, Aoyama M, Miyamoto N, Seo H, Matsui N, Kodama I, and Yamada K. Mechanisms of atrial natriuretic peptide (ANP) secretion in rat hearts perfused in vitro—Ca2+-dependent signal transduction for ANP release by mechanical stretch. Jpn Circ J 54: 1283–1294, 1990.[Medline]
  22. Kim SH, Cho KW, Chang SH, Kim SZ, and Chae SW. Glibenclamide suppresses stretch-activated ANP secretion: involvements of K+ATP channel and L-type Ca2+ channel modulation. Pflügers Arch 434: 362–372, 1997.[CrossRef][Web of Science][Medline]
  23. Kotsanas G, Holroyd SM, Wendt IR, and Gibbs CL. Intracellular Ca2+, force and activation heat in rabbit papillary muscle: effects of 2,3-butanedione monoxime. J Mol Cell Cardiol 25: 1349–1358, 1993.[CrossRef][Web of Science][Medline]
  24. Kuroski-De Bold ML and De Bold AJ. Stretch-secretion coupling in atrial cardiocytes. Dissociation between atrial natriuretic factor and mechanical activity. Hypertension 18, Suppl III: III169–III178, 1991.[Medline]
  25. Lado MG, Sheu SS, and Fozzard HA. Effects of tonicity on tension and intracellular sodium and calcium activities in sheep heart. Circ Res 54: 576–585, 1984.[Abstract/Free Full Text]
  26. Laine M, Weckstrom M, Vuolteenaho O, and Arjamaa O. Effect of ryanodine on atrial natriuretic peptide secretion by contracting and quiescent rat atrium. Pflügers Arch 426: 276–283, 1994.[CrossRef][Web of Science][Medline]
  27. Lang RE, Thoelken H, Ganten D, Luft FC, Ruskoaho H, and Unger T. Atrial natriuretic factor: a circulating hormone stimulated by volume loading. Nature 314: 264–266, 1985.[CrossRef][Medline]
  28. Li D, Wen JF, Jin JY, Jin H, Ann HS, Kim SZ, Kim SH, Lee HS, and Cho KW. Histamine inhibits atrial myocytic ANP release via H2 receptor-cAMP-protein kinase signaling. Am J Physiol Regul Integr Comp Physiol 285: R380–R393, 2003.[Abstract/Free Full Text]
  29. Li D, Wen JF, Jin JY, Kim SZ, Kim SH, Lee HS, and Cho KW. Calcium release from sarcoplasmic reticulum decreases atrial myocytic ANP release (Abstract). Kor J Physiol Pharmacol 7, SupplI: 121, 2003.
  30. McDonough PM, Stella SL, and Glembotski CC. Involvement of cytoplasmic calcium and protein kinases in the regulation of atrial natriuretic factor secretion by contraction rate and endothelin. J Biol Chem 269: 9466–9472, 1994.[Abstract/Free Full Text]
  31. McKenna K, Smith D, Tormey W, and Thompson CJ. Acute hyperglycaemia causes elevation in plasma atrial natriuretic peptide concentrations in type 1 diabetes mellitus. Diabet Med 17: 512–517, 2000.[CrossRef][Web of Science][Medline]
  32. Naruse K, Naruse M, Obana K, Brown AB, Shibasaki T, Demura H, Shizume K, and Inagami T. Right and left atrium share a similar mode of secreting atrial natriuretic factor in vitro in rats. J Hypertension 4, Suppl 6: S497–S499, 1986.
  33. Rafiee P, Shi Y, Kong X, Pritchard KA Jr, Tweddell JS, Litwin SB, Mussatto K, Jaquiss RD, Su J, and Baker JE. Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection. Circulation 106: 239–245, 2002.[Abstract/Free Full Text]
  34. Ramasamy R, Payne JA, Whang J, Bergmann SR, and Schaefer S. Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2Cl– cotransporter. Am J Physiol Heart Circ Physiol 281: H515–H522, 2001.[Abstract/Free Full Text]
  35. Ruskoaho H. Atrial natriuretic peptide: synthesis, release, and metabolism. Pharmacol Rev 44: 479–601, 1992.[Web of Science][Medline]
  36. Ruskoaho H, Toth M, Ganten D, Unger Th, and Lang RE. The phorbol ester induced atrial natriuretic peptide secretion is stimulated by forskolin and Bay K 8644 and inhibited by 8-bromo-cyclic GMP. Biochem Biophys Res Commun 139: 266–274, 1986.[CrossRef][Web of Science][Medline]
  37. Ruskoaho H, Vuolteenaho O, and Leppaluoto J. Phorbol esters enhance stretch-induced atrial natriuretic peptide secretion. Endocrinology 127: 2445–2455, 1990.[Abstract/Free Full Text]
  38. Saito Y, Nakao K, Morii N, Sugawara A, Shiono S, Yamada T, Itoh H, Sakamoto M, Kurahashi K, Fujiwara M, an Imura H. Bay K 8644, a voltage sensitive calcium channel agonist, facilitates secretion of atrial natriuretic peptide from isolated perfused rat hearts. Biochem Biophys Res Commun 138: 1170–1176, 1986.[CrossRef][Web of Science][Medline]
  39. Schiebinger RJ. Calcium, its role in isoproterenol-stimulated atrial natriuretic peptide secretion by perfused rat atria. Circ Res 65: 600–606, 1989.[Abstract/Free Full Text]
  40. Schiebinger RJ, Joseph CM, Li Y, and Cragoe EJ Jr. Mechanism of hyperosmolality stimulation of ANP secretion: its dependence on calcium and sodium. Am J Physiol Endocrinol Metab 268: E476–E483, 1995.[Abstract/Free Full Text]
  41. Sham JSK, Cleemann L, and Morad M. Functional coupling of Ca2+ channels and ryanodine receptors in cardiac myocytes. Proc Natl Acad Sci USA 92: 121–125, 1995.[Abstract/Free Full Text]
  42. Smogorzewski M, Galfayan V, and Massry SG. High glucose concentration causes a rise in [Ca2+]i of cardiac myocytes. Kidney Int 53: 1237–1243, 1998.[CrossRef][Web of Science][Medline]
  43. Sonnenberg H, Krebs RF, and Veress AT. Release of atrial natriuretic factor from incubated rat heart atria. IRCS Med Sci Lib Compend 12: 783–784, 1984.
  44. Sun H, Leblanc N, and Nattel S. Mechanisms of inactivation of L-type calcium channels in human atrial myocytes. Am J Physiol Heart Circ Physiol 272: H1625–H1635, 1997.[Abstract/Free Full Text]
  45. Takei Y and Hirose S. The natriuretic peptide system in eels: a key endocrine system for euryhalinity? Am J Physiol Regul Integr Comp Physiol 282: R940–R951, 2002.[Abstract/Free Full Text]
  46. Watano T, Kimura J, Morita T, and Nakanishi H. A novel antagonist, No. 7943, of the Na+/Ca2+ exchange current in guinea-pig cardiac ventricular cells. Br J Pharmacol 119: 555–563, 1996.[Web of Science][Medline]
  47. Wen JF, Cui X, Ahn JS, Kim SH, Seul KH, Kim SZ, Park YK, Lee HS, and Cho KW. Distinct roles for L- and T-type Ca2+ channels in regulation of atrial ANP release. Am J Physiol Heart Circ Physiol 279: H2879–H2888, 2000.[Abstract/Free Full Text]
  48. Zongaso MA, Carayon A, Masson F, Maistre G, Noe E, Eurin J, Barthelemy C, Komajda M, and Legrand JC. Effects of arginine vasopressin and extracellular osmolarity on atrial natriuretic peptide release by superfused rat atria. Eur J Pharmacol 209: 45–55, 1991.[CrossRef][Web of Science][Medline]



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