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 associated with endothelial dysfunction. Thus, the present experiments were performed to investigate whether non-hypotensive doses of calcium antagonists can compensate for the effects of deficient endogenous formation of nitric oxide (NO) in the coronary vascular bed in vivo. In chronically instrumented conscious dogs (n = 6) which were prepared for the measurement of coronary blood flow (CBF), coronary diameter of the left circumflex artery (LCX), mean arterial blood pressure (MAP) and heart rate (HR), continuous intravenous infusions of 0.2 micrograms/kg/min nisoldipine (NI) or 2.0 micrograms/kg/min diltiazem (DT) were performed after intracoronary pretreatment with either vehicle or the inhibitor of NO synthesis NG-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg). NI dose-dependently increased CBF up to a maximum of +74 +/- 7.5% from control, while LCX diameter and HR were not significantly affected. MAP fell slightly (-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 the highest cumulative dose (100 micrograms/kg). HR and LCX diameter remained unaltered. Pretreatment with L-NAME caused marked hypertension and bradycardia, associated with reduction in CBF (-34 +/- 16%) and LCX diameter (-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 antagonists failed to reverse the effects on MAP or HR.(ABSTRACT TRUNCATED AT 250 WORDS)
Zanzinger
J
J
I. Physiologisches Institut, Universität Heidelberg, Germany.
Bassenge
E
E
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*
D002121:Calcium Channel Blockers; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester