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NEUROHUMORAL CONTROL OF CIRCULATION AND HYPERTENSION
in normal rats
Departments of 1Internal Medicine and 2Psychology, University of Iowa; and 3Veterans Affairs Medical Center, Iowa City, Iowa 52242
Submitted 17 January 2003 ; accepted in final form 13 August 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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. This study aimed to determine whether DOCA, a precursor of aldosterone, acts centrally to stimulate TNF- production in normal rats. DOCA (5 mg sc daily for 8 days) induced a progressive increase in TNF- beginning on day 3 and increased tissue TNF- in hypothalamus, pituitary, and heart but not in other brain and peripheral tissues harvested on day 9. A continuous intracerebroventricular infusion of SL (100 ng/h) blocked the plasma TNF- response. Oral SL (1 mg/kg) blocked the plasma and tissue TNF- responses. Thus DOCA increases TNF- in brain, heart, and blood in normal rats. Activation of brain MR appears to account for the increase in plasma TNF-. These findings have important implications for the understanding of pathophysiological states (e.g., HF, hypertension) characterized by high circulating levels of aldosterone. aldosterone; deoxycorticosterone acetate; spironolactone; brain; heart
Excessive stimulation of MR in the brain increases sodium ingestion (8) and sympathetic excitation (23). In a rat model of ischemia-induced heart failure, we found that blockade of central MR with spironolactone had a beneficial effect to reduce sodium consumption and sympathetic drive (16). Furthermore, central MR blockade caused an unexpected reduction in the circulating level of the proinflammatory cytokine TNF- in heart failure rats (15).
To our knowledge, the observation that central MR can regulate blood-borne TNF- is without precedent. Therefore, the present study was undertaken to determine whether stimulation of central MR can increase circulating TNF- levels in normal rats and, if so, to explore potential tissue sources of TNF- during chronic MR stimulation. The findings suggest a previously unknown central regulatory mechanism that may have important pathophysiological consequences in high Aldo states.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Rats were subjected to either one or three survival surgeries, using sterile technique. After each procedure, animals recovered from anesthesia under observation in the laboratory before returning to metabolic cages. Animals were treated postoperatively for pain with buprenorphine (0.1 mg/kg) at 12-h intervals for a day.
Procedures
Intracerebroventricular cannula implantation. The method for cannula implantation has been described before (15, 16). Briefly, rats under Equithesin anesthesia were secured to a stereotaxic apparatus. A stainless steel 23-gauge cannula (16 mm long) was implanted into the third ventricle at a 10° angle from the midline, using the stereotaxic coordinates of 1.0 mm caudal to bregma, 1.5 mm lateral and 8.7 mm below the dura. The cannula was fixed to the cranium using dental acrylic and small screws. Metal tubing (30 gauge) was used as an obturator to keep the cannula patent.
Jugular catheterization. The procedure for jugular catheterization has been described before (14). Briefly, under ketamine-xylazine anesthesia, a midline cervical incision was made and the jugular vein was isolated by blunt dissection. A Silastic catheter (Dow Corning, Midland, MD) was inserted into the jugular vein and held in position by sutures. The free end of the catheter was externalized to the base of the skull. The catheter was flushed every day with bacteriostatic saline containing heparin (100 U/ml) and sealed with a piece of blunt steel tubing to prevent clogging.
Implantation of osmotic minipumps. The procedure for implantation of osmotic minipumps has been described before (15, 16). Briefly, the pumps were primed, implanted into the neck region with the free end of the Silastic tubing connected to the intracerebroventricular cannula, and secured using dental acrylic.
Measurements of plasma TNF- levels and plasma renin activity. BLOOD COLLECTION. Blood samples (0.75 ml) were collected once daily into chilled EDTA tubes. The blood samples were centrifuged at 4°C and the plasma was separated and stored at -70°C until assayed for TNF- and plasma renin activity (PRA). After each collection, blood cells were reinfused with an equal volume of heparinized saline.
PRA. ANG I was measured and expressed as PRA using NEN Life Science Products (Boston, MA) ANG I radioimmunoassay kit. The procedure for PRA measurement has been described before (14, 17). Briefly, the accumulation of angiotensin is favored by allowing the endogenous substrate to react in the presence of reagents that inhibit both plasma converting enzymes and proteolysis by angiotensinases. The sensitivity of the assay is 6.0 pg/ml, and the intra- and interassay coefficients of variation were 5 and 10%, respectively.
PLASMA TNF- LEVELS. Plasma TNF- levels were measured using an ultrasensitive rat TNF- ELISA kit (Biosource International, Camarillo, CA) according to manufacturer instructions. The details of methodology were previously described (15). The minimum detectable concentration of TNF was <0.1 pg/ml.
Measurements of Tissue TNF- levels. TISSUE DISSECTION. Animals were decapitated under pentobarbital anesthesia, the trunk blood was collected to measure plasma levels of TNF-, and then the tissues were harvested from brain (cortex, hypothalamus, brain stem, and pituitary) and peripheral organs (liver, lung, kidney, adrenal gland, spleen, right and left ventricle of the heart). The tissues were finely minced using a razor blade and collected into Eppendorf tubes containing 500 µl lysis buffer. A 1:10 tissue to buffer ratio was used to extract protein from the sample for the measurement of TNF-.
TISSUE TNF- LEVELS. Tissue TNF- levels were measured as described in literature (29), with the following modification. Briefly, tissues were homogenized in 0.1 mM HEPES lysis buffer, containing a cocktail of protease inhibitor and detergent (21 mM leupeptin, 31 nM aprotonin, 10 nM PMSF, and 1% Triton X-100). The samples were centrifuged for 15 min at 12,000 rpm, and the supernatant was collected. The protein content of the sample was measured using a Bio-Rad Protein Assay (Bio-Rad Laboratories) with BSA as a standard. Samples were stored at -20°C until analyzed for TNF- using the Biosource ultrasensitive TNF- ELISA kit as described previously (15). TNF- levels in the tissue were expressed as picograms per milligram of protein.
Drugs
Spironolactone. Spironolactone (Sigma, St. Louis, MO) was dissolved in absolute ethanol and diluted with sterile water (Sigma) to a final concentration of 0.4 mg/ml. The final ethanol concentration used in vehicle-treated animals was 0.2% ethanol in 1 µl volume. Alzet miniosmotic pumps (model 2004, Alza, Palo Alto, CA) were filled with spironolactone or the ethanol vehicle and attached to a flow moderator to obtain a continuous infusion of the drug. The pumps had an average flow rate of 0.25 µl/h, and the final dose of drug infused intracerebroventricularly was 100 ng/h for a period of 8 days. This dose of intracerebroventricular SL was chosen because it attenuated fluid accumulation and sympathetic drive (16) and reduced plasma TNF- (15) in our previous studies of rats with congestive heart failure. For oral administration, SL was dissolved in 1% ethanol vehicle and was administered by gavage for a period of 8 days, at a dose of 1 mg/kg, daily. We have found that this oral dosage of SL attenuated renal sympathetic nerve activity in heart failure rats (unpublished observation).
DOCA. DOCA (Sigma) was used to activate MR receptors. DOCA is a precurser for Aldo and is commonly used to study the effects of stimulating MR on salt appetite (41) and myocardial fibrosis (3). In addition to stimulating MR, DOCA suppresses the production of both renin and Aldo (26, 40). In these studies, DOCA (5 mg/rat) or vehicle (sesame oil) was given subcutaneously daily for a period of 8 days. This dose of DOCA has been shown previously to induce salt appetite in rats (41).
Protocols
Study I. The effect of DOCA vs. oil on plasma TNF- levels and sodium ingestion was measured, without intervention. Rats were adapted to metabolic cages for a period of 7 days, during which they had access to water and a 1.8% sodium chloride. A jugular venous cannula was implanted on day 8 to facilitate blood collection. After collecting a baseline blood sample and measurement of sodium ingestion, the rats were treated with a daily subcutaneous injection of DOCA (5 mg) or sesame oil (oil) vehicle for a period of 8 days. Salt intake was measured daily, and a blood sample was collected daily for measurement of TNF-.
Study II. The effect of DOCA vs. oil on plasma TNF-, sodium ingestion, and PRA was measured during a continuous intracerebroventricular infusion of SL. The protocol was identical to study I, except that these animals were instrumented 1 wk before the study with a third-ventricular (intracerebroventricular) cannula for the continuous infusion of the MR antagonist SL the 1% ethanol vehicle. Central infusion of drug or vehicle and subcutaneous DOCA administration were begun concomitantly.
Study III. The effect of DOCA vs. oil on TNF- levels in selected brain and peripheral tissues was measured in the presence of systemically administered SL. The protocol was identical to study I, except that these animals did not undergo daily blood collection, and SL was administered by gavage. Tissue and plasma TNF- measurements were made only once, the day after the 8-day treatment protocol.
Verification of cannula placement and minipump function. At the end the second study protocol, brains were removed to check the site of intracerebroventricular cannula implantation. Only those animals in which the drug or vehicle was infused into the third ventricle were used in this study.
Statistical Analysis
Each value is expressed as a mean ± SE. Changes in salt intake, plasma TNF- levels, and PRA between the groups were analyzed by two-way repeated-measures ANOVA followed by post hoc Fischer's least significant difference (LSD) test. Tissue levels of TNF- were analyzed using ANOVA followed by post hoc Fischer's LSD test.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Induction of salt appetite. Figure 1 shows the expected effect of DOCA on salt appetite in rats. Daily DOCA treatment induced a progressive increase in the intake of 1.8% NaCl solution, which was first evident on day 2. In the vehicle (oil)-treated group, salt intake remained at or around baseline.
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Induction of plasma TNF-. Figure 2 shows the effect of daily injections of DOCA on plasma TNF- levels in rats. The pretreatment baseline levels of TNF- (pg/ml) in the DOCA (3.5 ± 1.2) and oil (3.8 ± 1.7) groups were not different (P > 0.05). TNF- levels in the vehicle-treated group remained at or around baseline throughout the study. In contrast, DOCA treatment produced a progressive increase in plasma TNF- levels that was evident by day 3.
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Study II: Effects of Central MR Blockade on DOCA-Induced Responses
Induction of salt appetite. Figure 3 shows the effects of central SL on salt ingestion in rats. In rats treated with intracerebroventricular ethanol vehicle (ICVETH), the DOCA-induced increase in salt appetite was nearly identical to that seen in rats treated with DOCA alone (Fig. 1). Central infusion of SL (DOCA + ICV-SL) reduced but did not completely block the DOCA-induced salt appetite. In the rats treated with sesame oil and intracerebroventricular SL (oil + ICV-SL), salt appetite did not increase.
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Induction of plasma TNF-. Figure 4 shows the effect of DOCA on TNF- levels in rats treated with continuous central infusion of SL or ethanol vehicle. The pretreatment baseline levels of TNF- (pg/ml) were comparable (P > 0.05) across groups (DOCA + ICV-ETH, 3.48 ± 1.2; DOCA + ICV-SL, 3.47 ± 1.2, oil + ICV-SL, 3.79 ± 1.7). In DOCA-treated rats receiving intracerebroventricular ethanol vehicle (DOCA + ICV-ETH), TNF- increased as early as day 3 after treatment (13.31 ± 2.7), a result similar to treatment with DOCA alone (Fig. 3). In the DOCA-treated rats receiving intracerebroventricular SL (DOCA + ICV-SL), this rise in plasma TNF- did not occur. In the control rats treated with subcutaneous sesame oil and intracerebroventricular SL (oil + ICV-SL), TNF- levels remained at or around baseline throughout the study.
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PRA. Figure 5 shows the effect of DOCA treatment on PRA. The pretreatment baseline PRA levels in the three groups studied were not different (DOCA + ICVSL, 2.57 ± 0.33; DOCA + ICV-ETH, 2.32 ± 0.21; oil + ICV-SL, 2.31 ± 0.23). The PRA levels were dramatically reduced in both DOCA-treated groups as early as day 1. There was no difference in this response between the DOCA-treated rats receiving central SL vs. ethanol infusion. SL had no significant effect on PRA levels in the rats treated with subcutaneous oil vehicle instead of DOCA. PRA remained at baseline levels in this group.
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Study III: Effects of DOCA on Tissue Levels of TNF-
In this study, the plasma TNF- level (pg/ml) in DOCA-treated rats was 24.6 ± 3.9 at the completion of the protocol. In contrast, the plasma TNF- level in rats treated with DOCA + oral SL did not differ from that of rats treated with vehicle (2.1 ± 1.0 vs. 2.2 ± 0.3).
DOCA treatment resulted in substantial increases in TNF- (pg/mg protein) in hypothalamic and pituitary tissues in the brain but not in cortex or in brain stem (Fig. 6). In the peripheral tissues (Fig. 7), DOCA increased TNF- in myocardium but had no effect on lung, adrenal, kidney, liver, or spleen tissues.
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The DOCA-induced increases in tissue levels of TNF- in brain and in peripheral tissues were completely blocked by oral administration of SL. Treatment with the both vehicles simultaneously (oil + ethanol) had no effect on brain or peripheral tissue levels of TNF-.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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levels in normal rats. In addition, we demonstrate here for the first time that this DOCA-induced increase in plasma TNF- is dependent on activation of MR in the central nervous system. The present findings are consistent with our previously reported data describing the effects of central MR blockade in rats with heart failure (15, 16). It is important to recognize, however, that central neural mechanisms are dysfunctional in the heart failure rat (11, 31, 45, 49), likely due at least in part to excessive activity of the renin-angiotensin system, proinflammatory cytokines, and other neuroactive peptides. Thus an effect of manipulating central MR in the heart failure model, in which they appear to contribute substantially to augmented sympathetic nerve activity and circulating TNF-, may not be representative of their usual influence. In the present study, we have eliminated those confounding variables and demonstrate a direct effect of central MR stimulation on plasma TNF- in otherwise normal rats.
Several questions arise from this study. How does MR stimulation effect an increase in plasma TNF-? What is the primary tissue source of plasma TNF- in DOCA-treated rats? Does DOCA affect production of TNF-, its release from tissue, or both? These issues are addressed at least in part by the results of this study, but additional work will be needed before definitive answers can be provided.
The production of TNF-, in response to an appropriate stimulus, is ubiquitous. Major sources of cytokine production include macrophages and other lymphoid tissues, the heart (29), the kidneys (37), and the brain (33). Proinflammatory cytokine production in the brain can increase substantially in response to circulating endotoxin or peripheral tissue injury (43). For example, we have shown that myocardial tissue injury induced by coronary artery ligation increases TNF- production in the hypothalamus within 60 min (13) and that this increase can be blocked by denervating the ischemic area (18). In the present study, we demonstrate that MR stimulation by systemically administered DOCA also elicits an increase in TNF- in hypothalamus and pituitary. In contrast, other brain regions examined—the brain stem and the cortex—showed no change in TNF- level in response to DOCA. An increase in brain cytokine production has been shown to result in an increase in blood-borne cytokines (39), although the mechanism is not known. Because the hypothalamic-pituitary connection is a well-recognized pathway by which neuropeptides produced in the brain effect stress responses (e.g., vasopressin, corticotropin-releasing factor), it is tempting to speculate that cytokines produced in the hypothalamus might migrate to the pituitary and gain entry to the systemic circulation via the pituitary portal system. Of course, other mechanisms for cytokine release from brain tissue are certainly possible (39).
DOCA treatment also induced an increase in myocardial TNF-. Although all peripheral tissues were not sampled in this study, this appeared to be a rather selective effect—for example, not manifest in liver and spleen, which are other important sources during infection or injury. Because our DOCA-treated rats had access to sodium, and their salt intake increased, it may be pertinent in this regard that the combination of DOCA and salt is a potent stimulus for myocardial fibrosis, and this effect can also be blocked by SL (44). Work by others (21) shows that myocardial injury begins early after DOCA-salt treatment. Thus in our study, DOCA-salt-induced myocardial injury may have contributed to the increased TNF- level measured in the heart. It is of interest, however, that both central and systemically administered SL normalized plasma TNF-, suggesting that the central nervous system MR play the dominant role in regulating plasma TNF-.
A superficial consideration of these data might suggest the brain as the source of the DOCA-induced increased in plasma TNF-, because there was no rise in plasma TNF- in the rats treated concomitantly with a central infusion of the MR antagonist SL. Before accepting such a conclusion, however, it is important to consider alternative mechanisms by which mineralocorticoids might act centrally to affect peripheral mechanisms influencing plasma TNF-. It is known, for example, that the stimulation of central MR increases the mRNA for angiotensin type I receptors in the same hypothalamic regions that mediate the sympathetic responses to ANG II (25). MR stimulation augments sympathetic drive in normal rats (23), and SL blockade reduces the heightened sympathetic drive observed in rats with ischemia-induced heart failure (16). Furthermore, the proinflammatory cytokine production within the hypothalamus elicited by MR stimulation may further augment sympathetic drive. The proinflammatory cytokines can induce the local production of prostaglandin E2 (PGE2) (9, 27) in brain, as well as stimulating entry of PGE2 from the periphery (7). PGE2 excites hypothalamic neurons and sympathetic drive (47). In addition, both ANG II (24) and the cytokines (28) induce the production of reactive oxygen species that have an excitatory influence on cardiovascular functions (48). Thus DOCA treatment favors a general state of sympathoexcitation, which can be shown to emanate at least in part from the hypothalamus (6, 38). Because augmented adrenergic overactivity may contribute further to cardiac injury (4) induced by DOCA-salt and may also influence the cardiac production of proinflammatory cytokines (36), it is at least conceivable that the heart itself and perhaps other peripheral tissues not examined here might contribute to the increase in plasma TNF- in the DOCA-treated rats.
A peripheral tissue source of TNF- therefore seems at least as compatible with our data as a central source. This issue is rendered more complex by the acquisition of our data at only one time point, 9 days after initiation of DOCA treatment, thereby precluding an assessment of a potential differential time of onset of TNF- production in brain and heart. Unpublished data from our laboratory (18) indicate that cardiac denervation prevents brain TNF- production after coronary ligation with myocardial injury; thus it may be that DOCA-salt-induced myocardial injury also affects brain TNF- production via a neural mechanism. Furthermore, because one effect of the proinflammatory cytokines is to promote further cytokine production (5), it is likely that one of these sites may be dependent on the other or, alternatively, that DOCA-stimulated production of TNF- by another tissue site altogether might account for the increased TNF- in blood, heart, and brain. Clearly, more detailed studies are required before such questions can be answered.
Finally, we have attributed the plasma TNF- response in this study to stimulation of MR within the central nervous system. Implicit in this interpretation are the assumptions that peripherally administered DOCA acted on the receptors in the central nervous system and that centrally administered SL did not have a substantial peripheral effect. With regard to the former assumption, we demonstrated a centrally mediated behavioral response—increased salt ingestion—in response to the same dose of DOCA that elicited the TNF- response. Sodium ingestion, like the TNF- response, was attenuated by centrally administered SL, albeit to a lesser degree. This observation might be explained as a higher threshold effect for blocking sodium appetite, perhaps due to the engagement of more MR receptors in that response. In addition, the site of DOCA action on salt appetite may be more remote from the third ventricle (i.e., amygdala) (30) than the site mediating the TNF- effect.
With respect to possible peripheral effects of the centrally administered SL, we have previously administered the same dose of SL both centrally and peripherally to heart failure rats (19). In those studies, we observed an early reduction in sympathetic drive and sodium appetite to centrally administered drug but no effect of peripheral administration on these variables over the first 2 wk. In the same model of heart failure, TNF- was reduced to negligible levels by centrally administered SL (11, 15).
The measurement of PRA emphasizes the difference between the present study and our previous observations in the heart failure rat. As expected, PRA was reduced in the DOCA-treated animals. Thus, while increased circulating ANG II may have factored into the centrally mediated TNF- increase in the heart failure rats, the effect of MR stimulation in normal rats occurred in a low-renin state. Notably, the increases in tissue and plasma TNF- we measured occurred early with respect to the onset of DOCA-induced hypertension.
The present findings may have important implications for both DOCA-salt and high-renin forms of hypertension. High Aldo levels are associated with cardiac fibrosis (2), left ventricular mass (34), and vascular and renal fibrosis (20). In addition to the known deleterious direct effects of Aldo on peripheral tissues (42) and its effects to promote sympathetic drive and autonomic dysfunction (23), our data indicate that Aldo also induces the release of yet another cardiovascular toxin, TNF-. In studies of high-renin hypertension, the adverse cardiovascular effects of increased TNF- (12) may need to be considered.
In summary, we have demonstrated that DOCA-salt treatment of normal rats increases TNF- levels in plasma, brain, and heart. These increases occurred in a low-renin state and were blocked by the MR antagonist SL. The effect of DOCA to increase circulating TNF- in normal rats appears to be mediated entirely by its effects on MR at the central nervous system level. Although the precise mechanism for this effect remains to be determined, the findings may have major clinical implications. If central MR modulates the release of TNF-, then blocking Aldo at the central nervous system level may help prevent the detrimental peripheral effects of blood-borne TNF- in hypertension and heart failure.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol 284: R916-R927, 2003.This article has been cited by other articles:
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  A. A. Elmarakby, J. E. Quigley, J. D. Imig, J. S. Pollock, and D. M. Pollock TNF-{alpha} inhibition reduces renal injury in DOCA-salt hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R76 - R83. [Abstract] [Full Text] [PDF]
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 A. Guggilam, M. Haque, E. K. Kerut, E. McIlwain, P. Lucchesi, I. Seghal, and J. Francis TNF-{alpha} blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H599 - H609. [Abstract] [Full Text] [PDF]
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 Y. Yu, Y.-M. Kang, Z.-H. Zhang, S.-G. Wei, Y. Chu, R. M. Weiss, and R. B. Felder Increased Cyclooxygenase-2 Expression in Hypothalamic Paraventricular Nucleus in Rats With Heart Failure: Role of Nuclear Factor {kappa}B Hypertension, March 1, 2007; 49(3): 511 - 518. [Abstract] [Full Text] [PDF]
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 Y.-M. Kang, Z.-H. Zhang, R. F. Johnson, Y. Yu, T. Beltz, A. K. Johnson, R. M. Weiss, and R. B. Felder Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure Circ. Res., September 29, 2006; 99(7): 758 - 766. [Abstract] [Full Text] [PDF]
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Z.-H. Zhang, Y.-M. Kang, Y. Yu, S.-G. Wei, T. J. Schmidt, A. K. Johnson, and R. B. Felder 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity in Hypothalamic Paraventricular Nucleus Modulates Sympathetic Excitation Hypertension, July 1, 2006; 48(1): 127 - 133. [Abstract] [Full Text] [PDF]
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 E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links Cardiovasc Res, June 1, 2006; 70(3): 434 - 445. [Abstract] [Full Text] [PDF]
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J. Francis, Z.-H. Zhang, R. M. Weiss, and R. B. Felder Neural regulation of the proinflammatory cytokine response to acute myocardial infarction Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H791 - H797. [Abstract] [Full Text] [PDF]
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J. Francis, Y. Chu, A. K. Johnson, R. M. Weiss, and R. B. Felder Acute myocardial infarction induces hypothalamic cytokine synthesis Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2264 - H2271. [Abstract] [Full Text] [PDF]
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P < 0.05, DOCA + ICV-ETH vs. DOCA + ICV-SL; 
P < 0.05, DOCA + ICV-SL vs. oil + ICV-SL.
