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Low dose calcium-antagonism compensates for impaired myocardial blood supply resulting from deficient nitric oxide
1I. Physiologisches Institut, Universität Heidelberg, Germany.
Insights
Non-hypotensive doses of calcium antagonists like nisoldipine and diltiazem can restore coronary blood flow impaired by nitric oxide deficiency in dogs. These drugs improved blood flow but did not affect blood pressure or heart rate.
Area of Science:
- Cardiovascular Pharmacology
- Endothelial Function Research
- Nitric Oxide Signaling
Background:
- Coronary artery disease (CAD) is frequently linked to endothelial dysfunction.
- Endogenous nitric oxide (NO) plays a crucial role in regulating coronary vascular tone.
Purpose of the Study:
- To investigate if non-hypotensive doses of calcium antagonists can counteract impaired nitric oxide formation in the coronary vasculature.
- To assess the effects of nisoldipine and diltiazem on coronary blood flow (CBF) in the presence of nitric oxide synthase inhibition.
Main Methods:
- Conscious dogs with chronic instrumentation were used to measure CBF, coronary artery diameter (LCX), mean arterial blood pressure (MAP), and heart rate (HR).
- Intracoronary infusions of the nitric oxide synthesis inhibitor L-NAME were administered, followed by intravenous nisoldipine or diltiazem.
- Dose-response effects of calcium antagonists on hemodynamic and coronary parameters were evaluated.
Main Results:
- L-NAME administration significantly reduced CBF and LCX diameter while causing hypertension and bradycardia.
- Nisoldipine and diltiazem, at non-hypotensive doses, increased CBF towards pre-L-NAME levels.
- Neither calcium antagonist reversed the L-NAME-induced changes in MAP or HR.
Conclusions:
- Non-hypotensive calcium antagonists can compensate for reduced nitric oxide availability in the coronary vascular bed.
- These findings suggest a potential therapeutic role for specific calcium antagonists in conditions involving endothelial dysfunction and impaired NO production.
Abstract:
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)