Nitric Oxide Inhibition and Renal Alterations

Acute and chronic administrations of L-arginine analogues are associated with renal functional and structural alterations that can be prevented or reversed by pharmacological blockade of other vasoactive systems. When given acutely, L-arginine derivatives have an antinatriuretic effect that is overridden by elevation of perfusion pressure and both endothelin and angiotensin II play an important role in the systemic and renal haemodynamic alterations associated with impaired nitric oxide availability. Long-term administration of L-arginine derivatives, mainly NG-nitro-L-arginine methylester (L-NAME), resulted in hypertension, intrarenal vascular, tubular and glomerular lesions and reduction in renal function. In prevention studies, blockade of the renin-angiotensin system markedly reduced hypertension and the renal morphological alterations associated with L-NAME administration. Although improvement in renal function may be achieved when arterial pressure is fully controlled, several reports indicate that the L-NAME-induced renal structural changes were independent of blood pressure and at least partly mediated by endothelin. In intervention studies, blockers of the renin-angiotensin system decreased but did not completely normalize arterial pressure, improved renal function and normalized albuminuria. Both the renin-angiotensin and the sympathetic nervous systems contribute to the sustained phase of chronic nitric oxide synthase inhibition, the adrenergic component being prominent with time. L-NAME hypertension can also be reversed by calcium antagonists, possibly via inhibition of angiotensin II-induced vasoconstriction, and the T-type antagonist had a greater effect than the L-type antagonist in reducing pre-glomerular resistance. The rat model of hypertension induced by chronic inhibition of nitric oxide generation has provided a useful tool to study both the development and the treatment of renal lesions resembling those found in human hypertension, a disease associated with early generalized impairment of endothelial function.