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Comparative cardiac effects of milrinone and sodium nitroprusside in conscious rats
1Biopharmaceutics and Pharmacodynamics Division, Bureau of Drug Research, Health Protection Branch, Ottawa, Ontario, Canada.
Abstract:
The rat has been shown to be resistant to the inotropic action of milrinone. We compared in conscious rats, the effects of an i.v. infusion of milrinone (0.3 mg/kg/min), a phosphodiesterase (PDE) inhibitor to those of nitroprusside (50 micrograms/kg/min), a pure vasodilator, on blood pressure and dP/dtmax to determine whether or not an inherent positive inotropic effect of milrinone is offset by its powerful hypotensive action. For the first 10 min of infusion, we found no differences in dP/dtmax, (the first derivative of the left ventricular pressure (LVP), an index of contractility) for equihypotensive doses of milrinone or nitroprusside. A second objective of this study was to determine if milrinone-induced ventricular fibrillation (VF) is due to cardiac ischemia which could be associated with the profound hypotension induced by the drug. Milrinone infusion was accompanied by a significant QTc interval (QT corrected for heart rate) prolongation. VF and death occurred in 5/6 rats at total doses varying from 3.6 to 20.1 mg/kg infused over 12 to 67 min respectively. Premature ventricular contractions (PVCs) were noted in all 6 milrinone infused rats during the first min. of infusion. No arrhythmias were noted during the 2 hour i.v. infusion with nitroprusside. A direct action on the heart is postulated to explain, at least partially, the milrinone-induced VF since nitroprusside had a similar hypotensive action but no effect on the ECG. We conclude that the rat, in analogy to patients with severe cardiac failure, might be resistant to the inotropic action of milrinone but is sensitive to its vasodilatory and arrhythmogenic effects.
Insights
Rats are resistant to milrinone's inotropic effects but susceptible to its vasodilatory and arrhythmogenic actions, leading to ventricular fibrillation. Nitroprusside, a vasodilator, did not cause arrhythmias, suggesting a direct cardiac effect of milrinone.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Milrinone, a phosphodiesterase (PDE) inhibitor, exhibits inotropic and vasodilatory effects.
- Rats are reportedly resistant to milrinone's positive inotropic action.
Purpose of the Study:
- To investigate if milrinone's inotropic effect is masked by its hypotensive action in rats.
- To determine if milrinone-induced ventricular fibrillation (VF) is caused by cardiac ischemia due to hypotension.
- To assess milrinone's direct cardiac effects compared to nitroprusside.
Main Methods:
- Conscious rats received intravenous infusions of milrinone or nitroprusside at equihypotensive doses.
- Blood pressure and dP/dtmax (index of contractility) were monitored.
- Electrocardiogram (ECG) parameters, including QTc interval, and occurrence of arrhythmias were recorded.
Main Results:
- No significant difference in dP/dtmax between milrinone and nitroprusside during the initial 10 minutes.
- Milrinone infusion caused significant QTc interval prolongation and premature ventricular contractions (PVCs).
- Ventricular fibrillation (VF) and death occurred in 5/6 rats receiving milrinone, but not in nitroprusside-infused rats.
Conclusions:
- Rats may be resistant to milrinone's inotropic effects, similar to humans with severe heart failure.
- Milrinone exhibits potent vasodilatory and arrhythmogenic effects in rats.
- Milrinone-induced VF is likely due to a direct cardiac action, not solely ischemia from hypotension.