Effect of propranolol on the myocardial contractility of normotensive and spontaneously hypertensive rabbits: Relationship of pharmacokinetics and pharmacodynamics

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Abstract
Myocardial contractility of normotensive and spontaneously hypertensive rabbits was determined following an iv bolus injection of propranolol HCl. Left ventricular pressure and dimension were used to calculate the contractility parameters of (dP/dt) max ,maximum fiber shortening velocity V cf , and the slope of the end systolic pressure-end systolic volume line (ESP-ESV line). Hypertension was induced by a methoxamine HCl iv infusion which mimicked the cardiac effects seen in essential hypertension. Propanolol caused a significant decrease in all contractility parameters (pwithin 15min after administration, with a peak effect occurring after 30–35 mins. The pharmacokinetics and pharmacodynamics of propranolol were fit using Hill's equation in conjunction with the concentration of drug in the theoretical effect compartment. The normotensive group of rabbits had a calculated EC (50) of 12.7 ng/ml, while the hypertensive group had an EC 50 of 6.9 ng/ml,indicating that the hypertensive rabbits were much more sensitive to the propranolol than the normotensive group. In addition, the normotensive group of rabbits demonstrated a much different pharmacokinetic-pharmacodynamic relationship than that of the hypertensive group, indicating that the hypertensive state of the animal has a significant effect upon the concentration-effect relationship.