Potentiation of the pressor response to stress by tolbutamide in dogs

Abstract

Tolbutamide has previously been shown to amplify the pressor effects of “exogenous” catecholamines in conscious dogs, possibly due to sensitization of the α₁-adrenoreceptor-mediated vasoconstriction. The objective of this study was to examine if tolbutamide also amplifies the pressor effects of “endogenous” catecholamines released during psychological stress (classical Pavlovian aversive conditioning). Experiments were conducted in β-adrenoreceptor-blocked (propranolol, 1 mg/kg, i.v.) conscious dogs (n=4) trained in classical aversive conditioning. Conditioning was accomplished by following a tone (CS+) with a 1/2 second shock; another tone (CS-) was not followed by any shock and served as control. With saline pretreatment, aversive conditioning (i.e., CS+) increased mean arterial pressure (MAP) only by approximately 4.7% when compared to CS-, whereas with tolbutamide (45 mg/kg, i.v.) pretreatment, the increase in MAP induced by CS+ beyond what was induced by the CS- (approximately 6.2%) was significantly (p<0.05) larger than that with saline pretreatment. In isolated canine femoral arterial segments (n=4), the vasoconstrictor effect of phenylephrine (an α₁-agonist) at 5×10⁻⁶M (which was the EC₅₀ value) was amplified by 2×10⁻²M of tolbutamide from 54.0±2.0% to 66.9±2.1%. In conclusion, tolbutamide amplifies the pressor effects of “endogenous” catecholamines in conscious dogs, possibly by sensitization of the α₁-adrenoreceptor-mediated vasoconstriction. This mechanism of action is novel and has not been reported with other agents.