Imidazoline receptor mediated natriuresis: central and/or peripheral effect?

The ability of imidazoline agonists, such as moxonidine and rilmenidine, to lower blood pressure has been attributed to a central effect resulting in a decrease in peripheral sympathetic nerve activity. A similar decrease in sympathetic nerve activity to the kidney has been proposed to explain the increase in sodium excretion. The observed increase in sodium excretion following an intrarenal infusion of moxonidine or rilmenidine suggested the existence of a direct renal action. We therefore tested the hypothesis that direct renal infusions were acting at a central rather than a peripheral site. Thus, interventions which would decrease the natriuretic effects of central administered moxonidine would also block the effects of intrarenal administered moxonidine. Studies were performed in anesthetized Sprague-Dawley rats (280-320 g) which had undergone unilateral nephrectomy 7 to 10 days prior to the experiment. The interventions utilized resulted in minimal effects on blood pressure and creatinine clearance. Intracerebroventricular (icv) or intrarenal (ir) administration of moxonidine produced a significant increase in urine flow rate and sodium excretion. Intravenous (iv) prazosin was used to block the ability of the sympathetic nerves to alter sodium excretion secondary to alpha1-adrenoceptor stimulation. Prazosin prevented the natriuresis following icv moxonidine but only partially antagonized the effects of ir moxonidine. To determine if central imidazoline receptors mediated the effects of moxonidine, animals were pretreated with icv idazoxan. Following icv idazoxan, the effects of icv moxonidine were blocked, whereas the response to intrarenal moxonidine was only partially blocked. Peripheral (iv) administration of idazoxan blocked the actions of intrarenal moxonidine but left the response to icv moxonidine intact. Finally, chemical sympathectomy with reserpine did not alter the response to intrarenal moxonidine suggesting that this effect was independent of the sympathetic nervous system. In conclusion, these studies indicate the ability of central and peripheral moxonidine to increase urine flow rate through sodium excretion at two unique sites of action, one central and the other one peripheral, most conceivably within the kidney.