ABSTRACT
Adrenomedullin [AM] is a peptide with potent vasorelaxing and natriuretic properties originally isolated from human pheochromocytoma. It may function as a circulating hormone that is involved in the regulation of cardiovascular system, renal function and hormone secretion. It has been observed that the hypotensive effect of AM in the periphery is not matched by a similar effect when injected centrally. The mechanisms involved in the peripheral hypotensive and central hypertensive actions of AM in normal rats are controversial and diverse; moreover in hypertension the underlying mechanisms are not tackled till now. 120 male albino rats were used in this study to assess the mechanisms involved in the peripheral versus the central actions of AM in the rat model. Hypertension was induced in 90 rats using NG-nitro-L-arginine ester [L-NAME] and ten normal rats were used as a control group. The peripheral and central actions of AM were tested in the hypertensive rats and in another 20 normal rats. The 90 hypertensive rats were divided into nine equal groups. Peripherally, AM was either injected alone [group I-A] or following a two-weeks of oral administration of prazosin [0.55 mg/kg/day], propranolol [14.4 mg/kg/day], valsartan [14.4 mg/kg/day] or isosorbide dinitrate [10.4 mg/kg/day] [groups II-A to V-A respectively]. Centrally, AM was either injected intracerebroventricularly [icv] alone [group I-B] or following a bolus icv injection of saralain [10 micro g] [group II-B] or after a two-weeks of oral administration of prazosin [0.55 mg/kg/day] or clonidine [18 micro g/kg/day] [group III-B and IV-B respectively]. Mean arterial blood pressure [MABP], plasma renin activity [PRA] and aldosterone level values were compared before and after AM injection in the same rate of each group. A 40.6% drop in MABP was elicited in normal rats injected peripherally with AM. This drop was attenuated to 18.6% in L-NAME hypertensive rats. The percent age drop in MABP in hypertensive rats pretreated with isosorbide dinitrate [43.3%] was comparable to that observed in normal rats when AM was injected intravenously to both groups [p=0.999]. A significant decrease in PRA and aldosterone level was produced in hypertensive rats pretreated with various drugs following the peripheral administration of AM as compared to their pre-injection values. On the other hand, a significant further increase in MABP was obtained following the icv injection of AM to L-NAME hypertensive rats pretreated with saralazin [P=0.000]. The changes observed in MABP, PRA and aldosterone level after the central administration of AM to hyptertensive rats pretreated with either clonidine or prazosin were insignificant as compared to their pre-injection values. This study suggests that the peripheral vasodilator effect of AM is mediated partially via nitric oxide release or probably by other mechanisms. The central hypertensive response to AM in the L-NAME rat model is probably not mediated by angiotensin-II receptors. It could be through enhancing the central sympathetic discharge via an action on either alpha 1, alpha 2 or the suggested imidazoline receptors located centrally. Finally, AM is supposed to be involved in the physiological resetting of renin-angiotensin-aldosterone system possibly secondary to changes in either catecholamines discharge or nitric oxide level. These results were discussed