ramiprilat and candesartan

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.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Male; Myocardial Ischemia; Myocardium; Norepinephrine; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrazoles

The effects of the angiotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT(1)A reduce myocardial IS by a bradykinin-mediated process. It is unclear, however, whether the combination of ACEI and AT(1)A produces a more pronounced IS reduction than each of these drugs alone. Forty-six enflurane-anaesthetized pigs underwent 90 min low-flow ischaemia and 120 min reperfusion. Systemic haemodynamics (micromanometer), subendocardial blood flow (ENDO, microspheres) and IS (TTC-staining) were determined. The decreases in left ventricular peak pressure by ACEI (by 9+/-2 (s.e. mean) mmHg), AT(1)A (by 11+/-2 mmHg) or their combination (by 18+/-3 mmHg, P<0.05 vs ACEI and AT(1)A, respectively) were readjusted by aortic constriction prior to ischaemia. With placebo (n=10), IS averaged 20.0+/-3.3% of the area at risk. IS was reduced to 9.8+/-2.6% with ramiprilat (n=10) and 10.6+/-3.1% with candesartan (n=10). Combined ramiprilat and candesartan (n=10) reduced IS to 6.7+/-2.1%. Blockade of the bradykinin-B(2)-receptor with icatibant prior to ACEI and AT(1)A completely abolished the reduction of IS (n=6, 22.8+/-6.1%). The relationship between IS and ischaemic ENDO with placebo was shifted downwards by each ACEI and AT(1)A and further shifted downwards with their combination (P<0.05 vs all groups); icatibant again abolished such downward shift. The combination of ACEI and AT(1)A enhances the reduction of IS following ischaemia/reperfusion compared to a monotherapy by either drug alone; this effect is mediated by bradykinin.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Drug Therapy, Combination; Hemodynamics; Myocardial Infarction; Ramipril; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Swine; Tetrazoles