LOW-DOSE CALCIUM-ANTAGONISM COMPENSATES FOR IMPAIRED MYOCARDIAL BLOOD-SUPPLY RESULTING FROM DEFICIENT NITRIC-OXIDE SYNTHESIS

Coronary artery disease (CAD) has been documented to be usually associ ated with endothelial dysfunction. Thus, the present experiments were performed to investigate whether non-hypotensive doses of calcium anta gonists can compensate for the effects of deficient endogenous formati on of nitric oxide (NO) in the coronary vascular bed in vivo. In chron ically instrumented conscious dogs (n = 6) which were prepared for the measurement of coronary blood flow (CBF), coronary diameter of the le ft circumflex artery (LCX), mean arterial blood pressure (MAP) and hea rt rate (HR), continuous intravenous infusions of 0.2 mu g/kg/min niso ldipine (NI) or 2.0 mu g/kg/min diltiazem (DT) were performed after in tracoronary pretreatment with either vehicle or the inhibitor of NO sy nthesis NG-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg). NI dose-de pendently increased CBF up to a maximum of +74+/-7.5% from control, wh ile LCX diameter and HR were not significantly affected. MAP fell slig htly (-5+/-3 mmHg). The maximum CBF increase in response to diltiazem at 10-fold higher doses was +39+/-13% while MAP fell -12+/-2 mmHg at t he highest cumulative dose (100 mu g/kg). HR and LCX diameter remained unaltered. Pretreatment with L-NAME caused marked hypertension and br adycardia, associated with reduction in CBF (-34+/-16%) and LCX diamet er (-9.5+/-0.8%). Subsequent infusion of NI or DT increased CBF up to the control values obtained before L-NAME. In contrast, both calcium a ntagonists failed to reverse the effects on MAP or HR. These results s uggest that calcium antagonists at low doses restore normal myocardial perfusion during impaired synthesis of NO and may thus help to compen sate for an impaired coronary dilator capacity in diseases which are a ssociated with endothelial dysfunction.