AN ANALYSIS OF THE HAEMODYNAMIC EFFECTS OF TOLBUTAMIDE IN CONSCIOUS DOGS

ABSTRACT

1. In conscious chronically instrumented dogs, tolbutamide (5–45 mg/kg) induced significant dose-related increases in mean arterial pressure and left ventricular enddiastolic pressure.

2. Cardiac output was descreased while heart rate, d(LVP)/dt, and regional myocardial performance at the left ventricle were not significantly affected. Computed total peripheral resistance was increased.

3. Pretreatment with the a-antagonist phentolamine (1–1.5 mg/kg) abolished the pressor response. Furthermore, the pressor response to norepinephrine (0.1 μg/kg) was enhanced by pretreatment with tolbutamide (45 mg/kg).

4. In an isolated tissue preparation using ring segments of canine femoral arteries, neither tolbutamide nor its major hepatic metabolites (carboxytolbutamide, p-toluenesulfonamide and p-toluenesulfonylurea) caused any smooth muscle contraction. However, pretreatment of these tissues with 10–⁴, 10–³, or 10–² mol/l tolbutamide potentiated the contractile response to norepinephrine by up to 19% and to phenylephrine by up to 8%.

5. It was concluded that the pressor effect of tolbutamide arises by potentiating the a-adrenoceptor mediated vasoconstrictor action of circulating endogenous catecholamines.