Recent Views on Mechanisms for Lowering Sympathetic Tone

Abstract

A picture is gradually unfolding of the molecular structures at nerve endings which synthesize and store norepinephrine and release the amine onto sympathetic receptors. Norepinephrine is formed continuously regardless of sympathetic tone and is stored inside a lipoid membrane. The amine is present in two pools—a reserve pool in granules in equilibrium with a mobile pool which is maintained against a concentration gradient by active transport. MAO controls the amount of norepinephrine in the nerve ending so that at the steady-state level the amine does not freely diffuse onto receptor sites. In the absence of sympathetic tone, norepinephrine can leave the storage compartments by simple diffusion through the lipoid membrane onto MAO. After nerve stimulation the amine is released directly onto the receptor sites and reaches the blood stream in the form of bases. This model for the transducer helps to explain the action of a number of drugs. Amphetamine increases blood pressure by releasing a small amount of norepinephrine at peripheral sympathetic nerve endings. Reserpine lowers blood pressure by inhibiting the norepinephrine pump which maintains the amine in the mobile pool; as a result the peripheral stores of amine are depleted by an uncompensated diffusion of the amine onto MAO. Bretylium and a number of benzyl derivatives of guanidine lower blood pressure by preventing nerve impulses from releasing norepinephrine at sympathetic nerve endings. Guanethidine and a number of phenylethyl guanidine derivatives cause lowering of arterial pressure by depleting the peripheral stores of norepinephrine perhaps through a persistent activation of the physiologic release mechanism. Alpha-methyldopa, α-methyl-metatyrosine, and metaraminol may act in a similar way. Finally, considerable evidence suggests that MAO inhibitors lower blood pressure by exerting a bretylium-like action. They not only prevent guanethidine from releasing norepinephrine but like bretylium they appear to prevent nerve impulses from releasing norepinephrine onto receptors.