Central noradrenergic mechanisms and the cardiovascular effects of intracerebroventricular (+)- and (−)-propranolol in the conscious rabbit

Intracerebroventricular (?)-propranolol in the conscious rabbit produced a transient increase in mean arterial pressure followed by a prolonged depressor response. Pretreatment with intracisternal 6-hydroxydopamine diminished the rise in mean arterial pressure and abolished the late fall. Intravenous infusion of (+)-propranolol also produced a depressor response which could be attenuated by 6-hydroxydopamine pretreatment. The role of central noradrenergic neurones in these responses was further studied using the (+)-isomer which produces only the early pressor effect. Depletion of central noradrenaline by intracerebroventricular reserpine, blockade of Uptake₁ by intracerebroventricular desmethylimipramine and antagonism of alpha-adrenoceptor function by intracerebroventricular yohimbine reduced or abolished the pressor response and tachycardia following centrally administered (+)-propranolol. An increase in mean arterial pressure and heart rate was also observed when a second dose of (+)-propranolol was given 30 min after an initial intracerebroventricular injection of the drug. Central injection of desmethylimipramine also produced an increase in mean arterial pressure.These studies suggest that propranolol is taken up into central noradrenergic neurones via the Uptake₁ mechanism and causes the release of endogenous noradrenaline which exerts a pressor effect. These noradrenergic neurones may also mediate the late hypotensive response produced by the (?)-isomer.