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Lovelace Respiratory Research Institute, Albuquerque 87108; and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We tested the hypothesis that the cellular mechanisms mediating hypoxic vasoconstriction (HVC) in frog skin, an important vertebrate respiratory organ, are similar to those mediating HVC in the pulmonary vasculature of mammals. An accepted hypothesis in the lung is that alveolar hypoxia alters the redox potential in vascular smooth muscle cells of arterial vessels. This decreases membrane K+ conductance, causing depolarization. Depolarization increases the open probability of L-type Ca2+ channels, facilitating Ca2+ entry into the cell, which leads to vascular smooth muscle contraction and vasoconstriction. We studied the cutaneous microcirculation of the frog (Xenopus laevis) web by enclosing the web in a transparent chamber that was ventilated with different gas mixtures. Arteriolar and venular diameters were measured by video microscopy. Drugs were applied topically or intravascularly. A dose-dependent constriction to hypoxia occurred in arterioles but not venules, although both vessel types constricted to similar degrees to the thromboxane mimetic U-46619. The magnitude of HVC was not associated with arteriolar size. Constriction of arterioles with 4-amino pyridine, a K+-channel antagonist, was blocked by the L-type Ca2+-channel blocker nifedipine. Nifedipine also antagonized HVC and hypercapnic vasoconstriction. Bay K 8664, a drug that increases the open probability of L-type Ca2+ channels, augmented HVC. These data support our hypothesis that the cellular mechanisms mediating HVC are similar in frog skin and mammalian lungs. This similarity between amphibain and mammalian tissues suggests that the mechanisms of HVC may have arisen relatively early in vertebrate evolution. In addition, because of its structural simplicity and easy accessibility, frog skin may be a useful tissue for studying this general phenomenon in vivo.
hypoxic pulmonary vasoconstriction; amphibia; cutaneous respiration; cutaneous blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MANY RESPIRATORY ORGANS (e.g., vertebrate lungs, fish gills, and amphibian skin) regulate local blood flow to match local O2 availability at the respiratory surface (3, 7, 11, 14). Hypoxic vasoconstriction (HVC), a blood flow reduction in response to low respiratory surface PO2, is the primary mechanism matching blood flow to O2 availability. HVC facilitates O2 uptake efficiency and blood oxygenation by diverting blood away from poorly oxygenated gas-exchange regions to better oxygenated ones.
In contrast to other respiratory organs, the mechanisms mediating HVC in mammalian lungs have been well studied. An accepted hypothesis is that alveolar hypoxia alters the redox potential in the vascular smooth muscle cell. This decreases membrane K+ conductance, causing depolarization. Depolarization increases the open probability of L-type Ca2+ channels, facilitating Ca2+ entry into the cell, which leads to vascular smooth muscle contraction and vasoconstriction (19). Although both pulmonary arteries and veins are vasoactive, HVC occurs primarily in the arterial pulmonary circulation. This appears to be due to the presence of L-type Ca2+ channels in arterial vascular smooth muscle but not in the pulmonary venous circulation (18).
Amphibian skin is another important respiratory organ that displays HVC (10, 11). In contrast to the pulmonary microcirculation, the cutaneous microcirculation can be readily studied in vivo with little or no surgical intervention (8). The purpose of this study was to test the hypothesis that the mechanism mediating HVC in amphibian skin is similar to that in mammalian lung.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Albino Xenopus laevis (Xenopus I, Ann Arbor, MI) were used because their unpigmented skin allows excellent visualization of the cutaneous microcirculation (10). They were kept in aquaria at
22°C at least 2 wk before experimental use and fed
crickets twice per week.
Experimental Setup
All experiments were performed at room temperature (22°C).
Frogs were anesthetized with methohexital Na+
(Brevital-Na+, Eli Lilly; 40 mg/kg im). This barbiturate
was used because it rapidly produces anesthesia lasting 1-2 h,
and barbiturates have no effect on pulmonary hypoxic vasoconstriction
in mammals (1). After anesthesia was induced, the frog was
placed supine on a wire mesh, and the foot was positioned in a round
plastic chamber (1.4 cm high; 8.5 cm radius) constructed from a Petri
dish. The foot web was spread loosely by pinning the distal ends of the toes on each side of the foot to modeling clay within the chamber. Moist gauze was placed between the most posterior part of the leg. This
created a seal that allowed the web to be exposed to different chamber
gases while the rest of the aminal was exposed to the atmosphere. The
chamber had gas inflow and outflow ports and a hole in the top for
topical administration of drug solutions. The hole could be covered by
a glass coverslip. The gas ports allowed the chamber to be ventilated
with different gas mixtures. Chamber ventilation was 1 liter/min
causing a change in chamber gas composition of >99% in 1 min when the
inflow gas was changed. The web chamber was placed beneath a microscope
(Nikon Optiphot) and transilluminated. Magnified images of the web
microcirculation were recorded by video microscopy (video camera,
Dage-MTI, model CCD-72; video monitor, Hitachi, VM-1220U; and video
recorder, Panasonic, AG-1950). Magnification from skin to
monitor was ×670 with a ×20 objective.
In experiments testing the effects of 4-amino pyridine (4-AP) on vessel diameter, its vehicle (frog Ringer solution with 0.1% DMSO) and a combination of 4-AP and nifedipine were directly infused into the web circulation. Intravascular infusion was necessary because topical application of 4-AP caused slight muscle twitching in the foot, making microvascular measurements impossible. In these experiments, a small arterial vessel in the distal gastrocnemius muscle was cannulated occlusively with tapered PE-10 tubing. Infusate then traveled into the main artery perfusing the foot web.
Microcirculatory Measurements
Vessels were chosen on the basis of visual clarity. Good visual clarity was necessary to accurately measure vessel diameters. This selection criterium may have biased our results if there was any association between visual clarity and responsiveness of the vessels. Vessel diameters were determined from the videotapes. The external diameters of arterioles and venules were measured from printed video images by a naive technician. Measurements were made every 30 s.Drugs
All drugs were dissolved in DMSO (Sigma Chemical), then diluted 1:1,000 in distilled water for topical application or in frog Ringer solution for intravascular administration. The Ringer solution contained (in mM): 76.1 NaCl, 30.7 NaHCO3, 1.4 NaH2PO4, 2.5 KCl, 3.1 MgSO4, 4.0 CaCl2, and 5.6 glucose. PCO2 of the Ringer solution was12 Torr. DMSO diluted 1:1,000 had no effect on
vascular dimensions. The drugs were: nifedipine (Research Biochemicals
International), 4-AP (Sigma Chemical), U-46619 (Cayman Chemicals), and
S(
)-Bay K 8644 (Research Biochemicals International). The
drug doses chosen for testing were based on doses used in previous lung
experiments (18).
Experimental Protocols
1. Site of hypoxic vasoconstriction. The effect of N2 was tested on arterioles and venules by exposing the web to 10 min of air, then 10 min of N2, followed by 10 min of air. One arterial and one venous vessel were tested per frog. Responding vessels, the arterioles, constricted during the N2 exposure and relaxed to initial normoxic levels during the second air period. The percent change in arteriolar diameter after 10 min of N2 exposure was plotted against the vessel diameter 1 min before N2 was administered to the web. In addition, arteriolar data from 44 additional frogs used in other protocols that were treated with 10 min of air followed by 10 min of N2 were plotted. A correlation between the N2 response and initial vessel diameter would indicate a size dependence of hypoxic responsiveness.
2. General vasoactivity of arterioles and venules. Only arterioles responded to N2, suggesting that either hypoxia selectively affects the arterioles or that frog web venules do not have the ability to constrict. To assess these possibilities, we applied U-46619, a thromboxane mimetic that constricts both arterial and venous vessels in the lung (18). If U-46619 constricted both arterioles and venules in the web, as it does in the lung, we could conclude that hypoxia specifically affects arterioles in the web. Three doses of U-46619 (0.01, 0.1, and 1.0 µM) and of vehicle were applied topically (120 µl) to the web under normoxic conditions. Ten minutes after application of U-46619 or vehicle, vessel diameters were measured. Different animals were used for each dose tested. Adjacent arterioles and venules were measured in each animal.
3. Dose-response relationship of arterioles to O2. We then tested whether the response to O2 was dose dependent. The web chamber was initially ventilated with air (21% O2) for 10 min. Then the web was exposed to four different O2 concentrations for 10 min each in a random order. The vessel diameters at the end of 10-min periods were analyzed and compared with the diameters measured at the end of the initial normoxic period. The O2 concentrations tested after the initial air exposure were 0, 8, 21, and 100%.
4. Effect of time on HVC. The effect of time on HVC was tested by exposing the web to consecutive 10-min periods of air and N2. The response to N2 was tested three times in succession. Values obtained at the end of the air periods were compared with the values obtained at the end of the subsequent hypoxic period. In another experiment, we characterized the response of arteriolar diameter to 40 min of continuous N2 to assess the duration of HVC in frog skin.
5. Effects of 4-AP and 4-AP + nifedipine on HVC. 4-AP blocks voltage-sensitive K+ channels, and nifedipine inhibits the activity of L-type Ca2+ channels. Because topical application of 4-AP caused slight muscle twitching in the foot, drugs in this experiment were applied intravascularly, as described above. During air exposure, arteriolar diameter was measured for 10 min, then vehicle (frog Ringer solution with 0.1% DMSO) was infused (0.1 ml over 1 min). Ten minutes later, either 4-AP (10 µM), 4-AP (10 µM) + nifedipine (10 µM), or vehicle was infused in exactly the same manner. Vessel diameters were measured every 30 s. Diameter values obtained just before infusion were compared with the largest change in diameter observed after infusion. Different animals were used for the three different treatments. Vasoconstriction by 4-AP and reversal of 4-AP-induced constriction by nifedipine would support our hypothesis that a reduction in membrane potassium conductance leads to cell depolarization, subsequent increased membrane conductance of Ca2+ through L-type Ca2+ channels, and vascular constriction.
6. Effects of nifedipine on HVC. The effects of nifedipine on HVC were tested by exposing the web to 10-min periods of air, N2, then air. Nifedipine (120 µl) was then applied to the skin surface. Ten minutes later, the web was exposed to N2 for 10 min. Each concentration of nifedipine (10 µM and 100 µM) was tested in a separate group of animals. Values 1 min before nifedipine or vehicle application and values at the end of the 10-min hypoxic period were used in the statistical analysis. In preliminary experiments, longer normoxic nifedipine periods had no significant effect on the response to the subsequent hypoxic period.
7. Effects of Bay K 8644 on arterioles and venules during normoxia and hypoxia. Bay K 8644 increases the open probability of L-type Ca2+ channels. Bay K 8644 (50 µM; 120 µl) or vehicle (120 µl) was applied topically to the web under normoxic conditions. Ten minutes after Bay K 8644 or vehicle application, the web was exposed to air, 8% O2, and 0% O2. The order of gas exposures was randomized. Diameters of both an arteriole and venule were measured simultaneously in each animal tested with Bay K 8664 and vehicle. Values 1 min before Bay K 8664 or vehicle application and at the end of each succeeding 10-min period were analyzed. Enhancement of HVC by Bay K 8644 would support the involvement of L-type Ca2+ channels in HVC. Venules were studied to test the possibility that venule unresponsiveness to hypoxia is due to L-type Ca2+ channels that have an unusually low open probability at hypoxic membrane potentials or that hypoxia has a relatively small effect on smooth muscle membrane potential. Either of these possibilities would be supported if venular HVC occurred in the presence of Bay K 8644.
8. Effects of nifedipine on hypercapnia- and hypercapnia plus hypoxia-induced arteriolar constriction. Hypercapnia at the gas-exchange surface reduces blood flow both in mammalian lungs (2) and in frog skin (10). To determine whether hypercapnic vasoconstriction may involve a mechanism similar to that for HVC, the effects of nifedipine on local hypercapnia (5% CO2-95% air) and on a combination of hypercapnia and hypoxia (5% CO2-95% N2) were investigated as described in the protocol testing the effects of nifedipine on HVC. Attenuation of the hypercapnic and hypercapnic plus hypoxic responses by nifedipine would indicate that L-type Ca2+ channels are involved in HVC as well as in hypercapnic vasoconstriction.
Statistical analysis. Because vessels of different sizes were studied, diameter changes were expressed as a percent change from control-period diameters. To assess the significance of these values, an arcsin square-root transformation was performed to distribute the data normally before statistical testing. Paired t-tests, unpaired t-tests, and 1- and 2-way repeated-measures ANOVA were used where appropriate. Multiple comparisons of sample means were performed with either a Dunnett's test or Neuman-Keuls test. The specific test used is indicated in RESULTS or figure legends. Statistical significance was set at a level of P = 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Site of HVC.
During the initial air periods, the arterioles and venules had mean
(±SD) diameters of 44 ± 12 and 51 ± 13 µm, respectively. Exposure of the foot web to 100% N2 constricted arterioles
by 42 ± 5% (mean ± SE; P < 0.001) but had
no significant effect on venules (P = 0.095; Fig.
1). Among arterioles, there was no
correlation between initial vessel size and percent change in vessel
diameter during N2 exposure (r = 0.185;
P = 0.153; Fig. 2).
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2. General vasoactivity of arterioles and venules.
U-46619 constricted both arterioles (P < 0.05) and
venules (P < 0.05) in a dose-dependent manner (Fig.
3). There was no significant difference
in the percent change in vessel diameter between arterioles and venules
(P > 0.17).
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3. Dose-response relationship of arterioles to O2.
Hypoxic vasoconstriction of web arterioles was dose dependent (Fig.
4). Hyperoxia had no significant effect
on arteriolar diameter (P > 0.54).
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4. Effect of time on HVC.
Time had no significant effect on HVC during three consecutive 10-min
periods of air and N2 exposure (P > 0.357;
Fig. 5). HVC is not a brief, transient
response because time had little effect on HVC during a continuous
40-min N2 exposure (Fig. 6). The data in Fig. 6 also suggest that the response to N2 is
biphasic (larger during the first several minutes than at later times). We assessed that possibility by comparing arteriolar diameters after 2 min (the time when constriction appeared greatest) and 40 min.
Although there was a significant difference (P = 0.048; ANOVA), no significant difference existed between the 4- and 40-min values (P = 0.14; ANOVA).
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5. Effects of 4-AP and 4-AP plus nifedipine on HVC.
4-AP infused into the web circulation constricted web arterioles (Fig.
7). Coinfusion of nifedipine abolished
the response to 4-AP (P = 0.50; Fig. 7). The vehicle
had no effect on vessel diameters (P > 0.26; paired
t-test). In two experiments, intravascular infusion of
nifedipine alone had no apparent effect on vessel diameter (data not
shown).
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6. Effects of nifedipine on HVC.
Nifedipine significantly attenuated the arteriolar response to 100%
N2 (P < 0.012; Fig.
8). The magnitude of HVC inhibition by 10 µM nifedipine was not significantly different from inhibition by 100 µM nifedipine (P = 0.18).
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7. Effects of Bay K 8644 on arterioles and venules during normoxia
and hypoxia.
Bay K 8644 (50 µM) had no significant effect on arteriolar diameter
during air (P > 0.50; data not shown) or 8%
O2 exposure (P > 0.8) but potentiated the
constriction to 100% N2 (P < 0.001; Fig.
9). Bay K 8644 had no significant effect
on venular diameters during air, 8% O2, or 100%
N2 exposure (P > 0.33; Fig.
10).
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8. Effects of nifedipine on hypercapnia- and hypercapnia plus
hypoxia-induced arteriolar constriction.
Exposure of the foot web to N2, 5% CO2/95%
air, or to 5% CO2/95% N2 constricted
arterioles (P < 0.05). There was no significant difference in the degree of constriction among the three gas treatments (P > 0.05; Fig.
11). Nifedipine significantly
attenuated the arteriolar responses to the different gas mixtures
(P < 0.05). During nifedipine treatment, there was no
significant effect of gas treatment (P > 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypoxic vasoconstriction occurs in a variety of species and respiratory organs. The present study illustrates that this response in amphibian skin exhibits numerous similarities to the more investigated response in the mammalian lung. For example, the sites of vasoconstriction in the skin are restricted to the arterial circulation, which is similar to hypoxic pulmonary vasoconstriction (5). Unlike the rabbit lung (5), however, we observed no difference in hypoxic responsiveness between arterioles of different sizes, although the range in vessel size studied was only between ~20 and 75 µm initial diameter. The lack of venous responsiveness to hypoxia is not due to a general inability of veins to constrict, because arterioles and venules both responded similarly to the vasoconstrictor thromboxane mimetic U-46619. Similar observations have been made in isolated, perfused rat lungs (18). In addition, hypoxic vasoconstriction in this preparation appears to be PO2 dependent, because N2 elicited greater vasoconstriction than did 8% O2. Thus the segmental profile of hypoxic vasoconstriction and its PO2 dependence are similar between amphibian skin and mammalian lungs.
In addition to similarities in the sites of the response to hypoxia, data from the frog web strongly suggest that a common mechanism of hypoxic vasoconstriction exists between this bed and the mammalian lung. In the mammalian pulmonary circulation, it has been proposed that hypoxic vasoconstriction is a contractile response of vascular smooth muscle cells to increased calcium influx secondary to membrane depolarization. This response has been observed in isolated pulmonary vascular myocytes (9, 15) and is associated with decreased voltage-dependent potassium currents in these cells (15). Thus it has been postulated that hypoxia reduces potassium efflux, eliciting depolarization and calcium entry through voltage-sensitive L-type calcium channels. Data from the present study strongly suggest that a similar mechanism exists in the frog cutaneous vasculature. For example, hypoxic vasoconstriction was greatly blunted following topical application of the L-type calcium-channel blocker nifedipine. Similar attenuation of hypoxic pulmonary vasoconstriction has been observed with L-type calcium-channel blockers in the mammalian lung (13). Also, consistent with earlier experiments on the pulmonary circulation (4, 15), we observed that administration of the voltage-sensitive potassium-channel blocker 4-AP produced vasoconstriction similar to that seen with hypoxia and that this response was also inhibited by nifedipine. Our observation that the L-type channel activator BAY K 8644 greatly potentiates hypoxic vasoconstriction further supports a role for this pathway of calcium influx in the response. The lack of effect of BAY K 8644 on resting tone suggests that the vascular smooth muscle cells are relatively hyperpolarized under normoxic conditions, because this dihydropyridine acts to shift the voltage-activation curve to the left for calcium influx (16). Once again, the enhancement of hypoxic vasoconstriction in frog skin by BAY K 8664 parallels findings in the mammalian lung (12, 17). Although nifedipine consistently attenuated hypoxic vasoconstriction, blockade of the response was not complete even with higher doses of the antagonist. It is unclear whether this residual response represents limitations of the delivery of the antagonist by topical application or whether additional parallel vasoconstrictor pathways contribute to the hypoxic response similar to those suggested in studies of lungs from other species. Thus the characteristics of the vascular responses to hypoxia in amphibian skin and the mammalian lung are strikingly similar and suggest a shared conserved mechanism in these anatomically distinct respiratory organs.
In addition to the response to hypoxia, we examined the response to hypercapnia in our preparation. Consistent with our earlier work (10), we observed cutaneous vasoconstriction in response to 5% CO2 and determined that this response is also sensitive to nifedipine. These data suggest that hypercapnia and hypoxia may share the same signaling pathway to elicit vasoconstriction. This hypothesis is further supported by the observation that the response to the two stimuli were not additive and were inhibited to a similar degree by L-type Ca+2-channel blockade. The mechanism of hypercapnic vasoconstriction in mammalian lungs is not well studied; however, a recent study by Gao et al. (2) showed that the response occurs primarily in small arteries of the isolated rat lung and that it is prevented by preconstriction of the lung with KCl. These data suggest that, similar to the response to hypoxia, the mechanism of hypercapnic vasoconstriction in the rat lung involves potassium channels and alterations in membrane potential. Interestingly, hypercapnia-induced arteriolar constriction has also been observed in the amphibian lung (6); however, the mechanism of this response has not been studied.
In contrast to what is found in the pulmonary circulation of mammals (3), hypercapnia did not potentiate the hypoxic response of frog skin arterioles. The reason for this difference is not known. However, it is possible that both 100% N2 and 5% CO2 alone produce a maximal vasoconstriction in the skin so that the combination of these gases cannot reduce vessel diameter further.
We speculate that the mechanism mediating HVC arose early in vertebrate evolution because the hypoxic vascular responses in amphibian skin and mammalian lung appear to share mechanistic similarities. Additional studies on other species would be needed to assess further this possibility.
The response of the skin to environmental PO2 will act to match cutaneous blood flow to O2 availability. This is probably beneficial for many amphibians because there are large PO2 variations in bodies of fresh water. Surface water PO2 can vary between near 0 Torr at night to several hundred Torr during the day, whereas lake bottoms are often anoxic for periods of weeks to months. Reducing cutaneous blood flow in severe aquatic hypoxia or anoxia will minimize O2 loss from the blood to the environment. Increasing skin perfusion in hyperoxic water will augment cutaneous O2 uptake. Local responses to PO2 will also distribute blood flow within the skin to match regional PO2. Local variations in skin surface PO2 can exist when animals are partially submerged or when the ventral surface contacts the ground.
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ACKNOWLEDGEMENTS |
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We acknowledge the excellent technical assistance of Michelle Duran, Lisa Roberts, and Yvonne Villalobos.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grants HL-38942 (G. M. Malvin), HL-07758 (G. M. Malvin) and HL-58124 (B. R. Walker).
Address for reprint requests and other correspondence: B. R. Walker, Dept. of Cell Biology and Physiology, Univ. of New Mexico School of Medicine, 915 Camino de Salud, Albuquerque, NM 87131 (E-mail: bwalker{at}salud.unm.edu).
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.
Received 24 July 2000; accepted in final form 11 December 2000.
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REFERENCES |
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
REFERENCES
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