Abstract

Guanethidine given intravenously to normotensive dogs caused an initial, short-lived fall in arterial pressure and then a sustained rise that was succeeded by a late, prolonged fall to below control levels. The sustained rise was accompanied by a prominent vasoconstrictor response in the denervated, perfused hind limb and both responses were eliminate bypretreatment with phentolamine or reserpine; this suggests that they may be due to release of bound endogenous catecholamines.

Guanethidine caused prompt, prolonged inhibition of the reflex pressor response to occlusion of the common carotid arteries and to electric stimulation of the central end of a vagus or sciatic nerve, decrease of pressor responsiveness to tyramine and usually a small increase in response to angiotensin and norepinephrine. When guanethidine was given 24 hours before testing, or orally for several days or weeks, arterial pressures were lower than control values and responsiveness to angiotensin and norepinephrine increased progressively with time.

Reserpine caused moderate augmentation of response to angiotensin and norepinephrine but subsequent intravenous injection of guanethidine caused a striking, selective augmentation of response to norepinephrine. This combined action of reserpine and guanethidine on response to norepinephrine did not depend upon a functionally intact sympathetic nervous system but it could not be demonstrated in the denervated, perfused hind limb.

The vasoconstrictor response of the perfused hind limb to electric stimulation of the lumbar sympathetic trunk was eliminated both by reserpine and by guanethidine and was replaced by a vasodilator response that was blocked by atropine. Guanethidine reduced constrictor responses to tyramine and serotonin given directly into the perfusion circuit and caused those to serotonin to become Partly vasodilator.

Infusion of norepinephrine into dogs pretreated with guanethidine caused restoration of the depressed response to tyramine and depression of the enhanced response to norepinephrine but did not restore the vasoconstrictor response to sympathetic stimulation or the reflex response to occlusion of the cartoid arteries. Guanethidine caused vert prompt disappearance of cardiovascular reflexes and the vasoconstrictor response to sympathetic simulation, presumably long before depletion of endogenous amines could have produced a marked inhibitory effect. It is concluded, therefore, that the acute effects of guanethidine depend upon interference with vascular sympathetic effector systems primarily through an action at the sympathetic nerve terminals; the chronic effects of guanethidine may depend, in part, upon an ability to deplete stores of endogenous catecholamines.