INTRACORONARY ADMINISTRATION OF THE ALPHA(1)-RECEPTOR AGONIST, METHOXAMINE, DOES NOT REPRODUCE THE INFARCT-LIMITING EFFECT OF ISCHEMIC PRECONDITIONING IN DOGS

Background: The cardioprotective effect of ischemic preconditioning ha s been hypothesized to occur through one or more signalling mechanisms which activate protein kinase C. Stimulation of alpha(1)-adrenergic r eceptors by catecholamines released during the preconditioning episode s of ischemia is one of these putative signalling mechanisms. Methods: To determine whether stimulation of alpha(1)-adrenergic receptors bef ore an ischemic challenge can mimic preconditioning, anesthetized dogs were treated with 4 intracoronary infusions of methoxamine HCl (10 mu g/kg/min; n = 8), each 5 min in duration and followed by 5 min of was hout. Control dogs (n = 10) were given similar infusions of 0.9% NaCl. A third group of dogs was preconditioned with 4 cycles of 5 min ische mia, each followed by 5 min of reperfusion (n = 8). All dogs then unde rwent 60 min of ischemia (circumflex coronary occlusion) followed by 3 h of reperfusion. Infarct size (expressed as % of area-at-risk) was m easured with TTC macrochemistery and analyzed (using analysis of covar iance [ANCOVA]) with respect to coronary collateral blood flow (measur ed using radioactive microspheres). Results: Methoxamine markedly incr eased systemic arterial and left atrial pressures prior to but not dur ing the ischemic challenge. Baseline predictors of infarct size were n ot different among the groups. Mean infarct size (adjusted from ANCOVA ) did not differ between control and methoxamine-treated groups, 28.3 +/- 2.8% vs. 29.7 +/- 3.2%, respectively (P = NS), but was only 12.7 /- 3.2% in the preconditioned group (P < 0.01 vs. control and methoxam ine). Conclusions: A series of methoxamine infusions before an ischemi c challenge did not affect infarct size. Thus, stimulation of alpha(1) -adrenergic receptors alone is insufficient to mimic the cardioprotect ive effect of ischemic preconditioning in this canine model.