Tissue selectivity of propranolol derivatives in vivo. A confirmation of in vitro findings.
The beta-adrenergic antagonist activities of a p-toluidide and a p-trifluoromethylanilide derivative of propranolol were tested in intact rats to determine whether the unusual in vitro profiles on myocardium and adipose tissue were found in vivo. The relative potencies of p-toluidide derivatives studied in pithed rats were 1.3 for the rate of change in left ventricular pressure with respect to time (dP/dt) and 4.6 for heart rate (HR) compared to propranolol. The values for p-trifluoromethylanilide were 2.5 (dP/dt) and 4.6 (HR). The SR-isomer of the p-toluidide derivative was 81 times more potent than propranolol in inhibiting effects on dP/dt and 27 times more effective than propranolol on HR, whereas the SS-isomer was 0.17 times (dP/dt) and 0.16 times (HR) as potent as the parent compound. In fasted rats, infusion of isoproterenol resulted in an increase of 10.6 +/- 3.1 mg/dl in plasma non-esterified fatty acid (NEFA) and an increase of 46 +/- 9 mg/dl in glucose. Unlike propranolol, neither the p-toluidide nor the p-trifluoromethylanilide derivative blocked the increase in plasma NEFA, although they both blocked the increase in plasma glucose. It appeared that the p-toluidide and p-trifluoromethylanilide derivatives of propranolol were more selective for the beta 1-adrenergic receptors on the heart as opposed to the beta 1-like adrenoceptors on adipose tissue. These findings were qualitatively and generally quantitatively in agreement with our previous findings in vitro. Therefore, the in vitro data may be useful in predicting atypical and tissue selective in vivo effects of these types of compounds.
Zhu
Q M
QM
Department of Medicine (Division of Clinical Pharmacology), Stanford University School of Medicine, CA 94305.
Lee
C H
CH
Laughton
C
C
Khan
M M
MM
Melmon
K L
KL
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009928:Organ Specificity; D011433:Propranolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D011433:Propranolol; D007545:Isoproterenol