Protection of ischemic myocardium is an important unmet need in reperfusion therapy of acute myocardial infarction. Myocardial ischemia and reperfusion induce necrosis and apoptosis in cardiomyocytes. Caspase processing and activation are critical steps in most receptor and nonreceptor pathways of apoptosis. Caspase inhibitors have been shown to reduce ischemia reperfusion injury in cardiac muscle. Information about dose response and time of administration are needed to optimize the design of preclinical studies. We used isolated adult rabbit cardiomyocytes subjected to metabolic inhibition (MI) and recovery to examine the role of caspases and caspase inhibitors, the dose response, and the timing of administration. In vitro inhibitory concentrations (Ki) were determined for purified caspases. Cardiomyocytes subjected to MI were treated with peptidomimetic fluoromethyl ketone inhibitors of caspases before or during MI, or at recovery. Caspase inhibitors were most effective when added before MI and included throughout recovery, but were partially protective if added after MI. The optimal concentration of the inhibitors tested was approximately 10 microM. Protection was sustained when cells were allowed to recover for 4 or 24 h. These results suggest that caspase activation is an important component of myocyte injury mediated by MI and recovery. Low doses of caspase inhibitors were identified that reduce injury in this model system, and further investigations using in vivo models are warranted.

Ceranapril (SQ 29,852) is a new inhibitor of angiotensin I (AI) converting enzyme (ACE) belonging to the hydroxylphosphonate class. The purpose of the present report is to present the in vivo pharmacology of ceranapril in conscious animal models. In conscious, normotensive rats, ceranapril administered i.v. (ED50 = 63 nmol/kg) or p.o. (ED50 = 530 nmol/kg) inhibited an AI pressor response with potency equal to that of captopril. However, in conscious dogs, ceranapril was a relatively poor inhibitor of the AI pressor response after both i.v. (ED50 = 300 nmol/kg) and p.o. (ED50 = 18 mumol/kg) administration; in monkeys ceranapril was a good inhibitor of the AI pressor response after i.v. (ED50 = 60 nmol/kg) but not p.o. (ED50 = 18 mumol/kg) administration. In rats, the duration of ceranapril's inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranapril's blood pressure lowering effect had a longer duration than that of captopril. Ceranapril's ACE inhibitory effects were longer lasting in anephric rats than in sham rats, suggesting a renal route of excretion for ceranapril. Ceranapril administration to conscious female dogs resulted in significant increases in renal plasma flow and GFR. In SHR, doses of 23 and 68 mumol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 mumol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)