Rauwolfia and guanethidine: pharmacology and clinical use in treatment of hypertension.

B Y COINCIDENCE, reserpine, which is the oldest and weakest, and guanethidine, which is the latest and most potent of the modern antihypertensive drugs, share a common basic pharmacologic action. Both agents lead to depletion of the body stores of norepinephrine and thus, to varying degrees, interference with the function of the sympathetic nervous system.1-4 The precise mechanism by which they prevent the storage of norepinephrine is unknown, but evidence for its immediate release is seen in the transient rise in blood pressure and cardiac output after intravenous injection of guanethidineP Reserpine produces no such acute changes in man, but a similar release has been observed in animal preparations.“z6 Since both these agents lead to depletion of the sympathetic transmitter substance, the vascular smooth muscle retains its responsiveness to norepinephrine; indeed, an increased sensitivity is observed. The pressor effect of certain vasoconstrictor drugs, however, is diminished. These drugs-such as tyramine, amphetamine and ephedrine-depend for their action upon the presence of stored catecholamines in the tissue.? -g While guanethidine and reserpine share a similar mode of action, some important differences in their pharmacologic properties must be recognized. Guanethidine appears to produce actual blockade of adrenergic neurones in addition to depleting catecholamines. It does not cross the blood-brain barrier; hence its effects are confined to the peripheral sympathetic nervous system. Furthermore, in contrast to reserpine, it does not result in depletion of the catecholamine content of the adrenal medulla.1° Reserpine, on the other hand, crosses the bloodbrain barrier and depletes cerebral stores of norepinephrine” as well as those of hydroxytryptamine (serotinin).tZ To this may be attributed its sedative and psychologic and certain endocrine effects.‘” Therefore it was originally believed that the site of action of reserpine was a central one, probably in the l~ypothalamus.‘4 However, the observation that at lower doses of reserpine the peripheral stores of norepinephrine are more depleted than the central onesI has led to the conclusion that, as far as its hypotensive action is concerned, the main site of action of reserpine might be a peripheral one. While the pharmacologic mode of action of reserpine and guanethidine tend to be similar, their clinical effects are conspicuous by contrasts rather than by comparisons.