Mechanism of sympathoinhibition by imidazolines

The aim of the present study is to characterize the cardiovascular effects of rilmenidine and moxonidine, two recently developed centrally acting antihypertensive drugs. Rilmenidine and moxonidine are alpha 2-adrenoceptor agonists and, in addition, possess affinity for imidazoline (I1)-receptors. To determine if alpha 2- or I1-receptors are involved in sympathoinhibition, rilmenidine and moxonidine were compared with UK 14304, an alpha 2-agonist devoid of affinity for I1-receptors, and antagonism by the "pure" alpha 2-adrenoceptor antagonists yohimbine, SK&F86466, and RX821002 was studied. When injected intravenously into conscious rabbits, rilmenidine and moxonidine, on the one hand, and UK 14304, on the other, elicited a similar pattern of effects. Thus, transient hypertension was followed by long-lasting hypotension accompanied by a decrease in heart rate, renal sympathetic nerve firing rate, and plasma norepinephrine concentration. The effects of rilmenidine, moxonidine, and UK 14304 were antagonized by intravenously administered yohimbine, SK&F86466, and RX821002. The effects of moxonidine and UK 14304 were also prevented by yohimbine injected into the cisterna magna. Altogether, the degree of antagonism of the effects of rilmenidine and moxonidine did not differ from the degree of antagonism of the effects of UK 14304. Rilmenidine, moxonidine, and UK 14304 were also given to pithed rabbits in which a constant sympathetic tone was maintained by electrical stimulation of the sympathetic nerves. At doses that caused sympathoinhibition in conscious rabbits, they lowered the plasma norepinephrine concentration markedly. Our experiments show by direct measurement of sympathetic nerve activity and plasma norepepinephrine concentration that rilmenidine, moxonidine, and UK 14304 cause sympathoinhibition. As a consequence, blood pressure and heart rate decrease. The simplest interpretation of the blockade of central sympathoinhibition by the selective alpha 2-adrenoceptor antagonists is that rilmenidine, moxonidine, and UK 14304 primarily activated alpha 2-adrenoceptors. The decrease in plasma norepinephrine in pithed rabbits indicates peripheral presynaptic alpha 2-adrenoceptor-mediated inhibition of norepinephrine release per action potential from postganglionic sympathetic axons and suggests a contribution of this mechanism to the overall reduction in sympathetic tone.