PubMed · 9509053
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C W Owens, B R Graham, B N Prichard. Beta-blocking agents.. https://pubmed.ncbi.nlm.nih.gov/9509053/
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BACKGROUND: Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury. METHODS AND RESULTS: Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine. CONCLUSIONS: The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.
Multiple models explaining the pathogenesis of heart failure have been put forth during the past 5 decades. These models were modified as clinical evidence supported or refuted their assumptions. During the past 2 decades, heart failure models emphasized the importance of neurohormonal systems in heart failure progression. The positive impact that angiotensin-converting enzyme inhibitors have had on mortality from heart failure has bolstered the neurohormonal theory. Attention recently has turned to the sympathetic nervous system and its potential deleterious effects on the cardiovascular system in heart failure. The sympathetic nervous system can negatively impact the cardiovascular system in heart failure in several ways, including down-regulating beta1-receptors, exerting direct toxic effects on the myocardium, and contributing to myocardial remodeling and life-threatening arrhythmias. Beta-adrenergic blockers have shown promise for reducing morbidity and mortality in heart failure, but definitive reductions in mortality remain to be shown by future investigations.
We tested the hypothesis that the post-hypoxia frequency decline of phrenic nerve activity following brief, isocapnic hypoxic episodes in rats is diminished by prior hypoxic episodes and alpha2-adrenoreceptor antagonism. Anesthetized (urethane), artificially ventilated (FIO2=0.50) and vagotomized rats were presented with two or three, 5 min episodes of isocapnic hypoxia (FIO2 approximately 0.11), separated by 30 min of control, hyperoxic conditions. Phrenic nerve discharge, end-tidal CO2, and arterial blood gases were measured before during and after hypoxia. The average maximum frequency decline, measured 5 min after the first hypoxic episode, was 26+/-7 bursts/min below pre-hypoxic baseline values (a 70+/-16% decrease). By 30 min post-hypoxia, frequency had returned to baseline. Two groups of rats were then administered either: (1) saline (sham) or (2) the alpha2-receptor antagonist, RX821002 HCl (2-[2-(2-Methoxy-1,4-benzodioxanyl)] imidazoline hydrochloride; 0.25 mg/kg, i.v.). Isocapnic hypoxia was repeated 10 min later. In sham rats, the post-hypoxia frequency decline (PHFD) was significantly attenuated relative to the initial (control) response. However, PHFD was attenuated significantly more in RX821002-treated vs. sham rats (-3+/-3 bursts/min vs. -12+/-4 bursts/min @ 5 min post hypoxia for RX821002 and sham-treated, respectively; p<0.05). We conclude that the magnitude of PHFD is dependent on the prior history of hypoxia and that alpha2 adrenoreceptor activation plays a role in its underlying mechanism.