Angiotensin-Converting Enzyme Inhibition Preserves Endothelium-Dependent Coronary Microvascular Responses During Short-term Ischemia-Reperfusion

Abstract

Background Chronic angiotensin-converting enzyme (ACE) inhibition initiated days to weeks after acute myocardial infarction can reduce ventricular dilatation and improve patient survival. However, the effects on coronary vascular and myocardial function of very early ACE inhibitor therapy for acute myocardial infarction remain unresolved. Methods and Results Hemodynamics, segmental shortening, coronary blood flow, and in vitro coronary microvascular relaxation responses were studied in noninstrumented control pigs (n=8) and pigs subjected to 30 minutes of left anterior descending ischemia followed by administration of 30 mL IV normal saline (IR-saline, n=8), 5 mg/kg IV captopril (IR-captopril, n=6), or 1.5 mg/kg IV enalaprilat (IR-enalaprilat, n=6) before 1 hour of reperfusion. Hemodynamics were similar at baseline, end of ischemia, and end of reperfusion. However, coronary blood flow immediately on reperfusion was significantly enhanced in the IR-enalaprilat cohort (59±10 mL/min) compared with the IR-saline group (32±3 mL/min, P <.05). Segmental shortening in the dyskinetic ischemic region improved only minimally at the end of reperfusion to 1±2%, −7±3%, and −2±6% for the IR-saline, IR-captopril, and IR-enalaprilat groups, respectively ( P <.05, IR-captopril versus IR-saline). Arteriolar microvascular endothelium-dependent responses to ADP ( P <.01) and calcium ionophore A23187 ( P <.01) were impaired after ischemia-reperfusion, whereas bradykinin responses were preserved ( P =.95). Endothelium-dependent venular responses to ADP and serotonin were maintained despite ischemia-reperfusion. Endothelium-independent responses to sodium nitroprusside were unaltered in arterioles and venules. Either captopril or enalaprilat restored ADP and A23187 arteriolar responses to control levels and increased bradykinin responses above control levels. Conclusions Brief ischemia followed by reperfusion induces arteriolar microvascular endothelial dysfunction, while venular endothelial function is preserved in this porcine model. ACE inhibition enhances coronary blood flow at the time of reperfusion and can prevent impairment of endothelium-dependent arteriolar responses. However, ACE inhibition does not enhance ventricular segmental shortening acutely despite improved microvascular endothelial function and augmented postischemic coronary blood flow in this model of ischemia-reperfusion.