Effect of ACE-inhibitor ramiprilat and AT1-receptor antagonist candesartan on cardiac norepinephrine release: comparison between ischemic and nonischemic conditions.
ACE-inhibitors and AT -receptor antagonists may exert part of their pharmacological actions by interference with angiotensin-and/or bradykinin-mediated prejunctional stimulation of cardiac norepinephrine release. As endogenous formation of angiotensin and bradykinin is increased in ischemia, we investigated the effects of the ACE-inhibitor ramiprilat and the AT -receptor antagonist candesartan on cardiac norepinephrine release in isolated perfused rat hearts, under nonischemic and stop-flow conditions. Exocytotic release of endogenous norepinephrine was induced by electrical field stimulation and measured by HPLC. Paired stimulations were applied in each heart to obtain an intraindividual comparison of the effect of the pharmacological agent on norepinephrine release with the release under baseline conditions. The ACE-inhibitor ramiprilat (0.1-10 nM) and the AT -receptor antagonist candesartan (1-100 nM) were studied during normal flow or in the fourth minute of stop-flow. Under nonischemic conditions, the ACE-inhibitor slightly reduced norepinephrine release at the highest concentration, while the AT -receptor antagonist did not influence norepinephrine release in normoxia. Conversely, both substances significantly increased norepinephrine release during ischemia. Augmentation of norepinephrine release in ischemia by ramiprilat and candesartan was blocked by the bradykinin B -receptor antagonist HOE 140 and, in case of candesartan, by the AT -receptor antagonist PD 123319. The ACE-inhibitor ramiprilat and AT -receptor antagonist candesartan enhance cardiac norepinephrine release selectively in ischemia by stimulating presynaptic bradykinin B -receptors. Regarding the AT -receptor antagonist, AT -receptor activation is also involved in bradykinin-mediated prejunctional stimulation.
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C052549:ramiprilat; D017257:Ramipril; C081643:candesartan; D009638:Norepinephrine