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The objective was to analyze the mechanism of the protection induced by a nonalcoholic extract of red wine (RWE) on ischemia/reperfusion injury. Isovolumic perfused rat hearts were exposed after stabilization to a 20-min global ischemic period followed by 30 min of reperfusion in absence and presence of RWE infused prior to ischemia and early in reperfusion. In other hearts, 5-hydroxydecanoate (5-HD, 100 microM), a selective mitochondrial K(ATP) blocker, chelerythrine (1 microM), a protein kinase C blocker, or >L(G)-nitro->L-arginine methyl ester (>L-NAME), a nitric oxide synthase inhibitor, was administered prior to RWE infusion. Left ventricular developed pressure (LVDP), +dP/dtmax, and left ventricular end-diastolic pressure (LVEDP) were used to assess myocardial function. The lactate dehydrogenase release during reperfusion was measured. After the ischemic period, LVDP decreased to 61 +/- 4% and +dP/dtmax to 62 +/- 5% of baseline values at the end of reperfusion. The infusion of RWE resulted in a complete recovery of systolic function (LVDP = 102 +/- 4%; +dP/dtmax = 101 +/- 4%) and in an attenuation of the increase of LVEDP (20 +/- 3 mm Hg versus 42 +/- 4 mm Hg, p < 0.05). The treatment with RWE did not produce lactate dehydrogenase release during reperfusion. 5-HD and chelerythrine completely abolished the protection induced by RWE (mechanical and enzymatic). >L-NAME partially abolished the systolic improvement induced by RWE but returned lactate dehydrogenase loss to ischemic control values. The diastolic protection afforded by RWE was not altered by >L-NAME. These data are the first demonstration that mitochondrial K channels and nitric oxide are involved in the protection against ischemia/reperfusion conferred by a nonalcoholic RWE.

Chronic treatment with nifedipine induces up-regulation of functional active Ca2+ channels in cardiac muscle membranes. Adult male New Zealand White rabbits (NZW) were treated with nifedipine (20 mg/day) for 25 days. In isovolumic perfused hearts at constant coronary flow and heart rate (HR) the left ventricular developed pressure (LVDP) and its first derivative (dP/dt) were monitored. Basal contractility and contractility at different end-diastolic volumes (EDV) were higher in nifedipine-treated animals, with no changes in diastolic chamber stiffness. Dose response to nifedipine in pretreated animals showed less decrease in contractility than in controls [ED50 = 1.09 +/- 0.09 x 10-7 (control) and 1.55 +/- 0.17 x 10-7 M nifedipine (treated) (p < 0.05)]. Ca2+ channel density was assessed by specific binding at the dihydropyridine receptor with [methyl-3H]PN 200-110. In cardiac membranes, maximal binding capacity (Bmax) was 269 +/- 38 (n = 7, control) and 429 +/- 46 fmol/mg protein (n = 7, treated) (p < 0.05), without significant changes in dissociation constant. In addition, we noted no changes in dihydropyridine (DHP) binding sites in aortic membranes. Our results offer a possible explanation for the lack of decrease in contractility despite the persistent hypotensive effect in hypertensive patients during chronic treatment with nifedipine.