Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs

Abstract

1 In order to determine whether the renin-angiotensin system is involved in myocardial ischaemiareperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT,) antagonist, EXP3 174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion.2 EXP3174 (0.1 mg kg-', i.v. followed by 0.02mg kg-' h-l for 5.5 h) and enalaprilat (0.3 mg kg-', i.v. followed by 0.06 mg kg-' h-' for 5.5 h) were used in doses inducing a similar level of inhibition (87 ± 4 and 91 ± 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3 Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4 Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT, antagonist. 5 The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6 These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.

Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia

“…In this context, several studies investigated the effects of AT1R blockade in myocardial IR, but the results are not consistent across these studies. Losartan or its active metabolite EXP3174 did not reduce IS after myocardial IR in vivo in rabbits (Hartman, 1995), rats (Liu et al, 1996), or dogs (Richard et al, 1993). Moreover, Harada et al (1998) could not prove any IS reduction in AT1a receptor-deficient mice after IR injury.…”

EXP3174: The Major Active Metabolite of Losartan

“…This decrease was not accompanied by significant changes in cardiac output or heart rate. In this experiment, a decrease in mean arterial pressure was observed only at the highest dose of EXP3174 in nonfurosemide-treated anesthetized dogs (46,47). EXP3 174 also resulted in a dose-dependent reduction in mean arterial pressure in pentobarbital-anesthetized dogs with a renal artery stenosis (6).…”

Angiotensin II Type 1 Receptor Blockade Does Not Enhance Apoptotic Cell Death During Ischemia and Reperfusion in Humans In Vivo

“…15 However, preclinical studies addressing the effects of ARAs on IRI have been equivocal as results cover the entire range from beneficial to detrimental effects. [3][4][5]21,[38][39][40] This may represent differences in study drug, dosing regimens, ischemia-reperfusion protocols, and species studied. This study in a human in vivo setting does not support a modulating effect of ARAs on IRI in humans in vivo.…”