Renoprotective mechanisms of angiotensin II antagonism in experimental chronic renal failure.

We investigated angiotensin II and nitric oxide-cGMP pathway in the development of hypertension and renal damage in chronic experimental nephritis. Rats with autoimmune nephritis were treated for 12 weeks with AT1 receptor antagonist L-158,809 and/or ACE inhibitor captopril given in drinking water. Blood pressure, urinary albumin, and urinary excretion of cGMP were measured. Renal density of ACE, AT1 and AT2 receptors was determined by quantitative in vitro autoradiography. L-158,809, captopril, and their combination decreased blood pressure and normalised urinary albumin excretion rate in rats with nephritis. In L-158,809-treated rats, cGMP excretion was increased compared to the vehicle-treated nephritic group suggesting that the dysfunctional nitric oxide system may be activated by angiotensin antagonism. In nephritic rats, AT1 and AT2 receptor binding densities in renal medulla were decreased, cortical AT receptor expression remained unchanged. Following L-158,809 treatment, both AT1 and AT2 receptor binding was suppressed. Long-term blockade of AT1 receptors in chronic nephritis has beneficial effects both on albuminuria and blood pressure being as effective as ACE inhibition or their combination. The stimulatory effect of AT1 receptor antagonism on cGMP production was not mediated by AT2 receptor-dependent mechanisms suggesting that AT1 receptor blockade per se favours activation of humoral pathways that stimulate cGMP production and potentially contribute to renal protection in chronic nephritis.

Uhlenius N ，Miettinen A ，Vuolteenaho O ，Tikkanen I ... -  《KIDNEY & BLOOD PRESSURE RESEARCH》

Renin-angiotensin blockade improves renal cGMP production via non-AT(2)-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat.

Uhlenius N ，Vuolteenaho O ，Tikkanen I 《JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM》

Renoprotective effects of captopril in hypertension induced by nitric oxide synthase inhibition in experimental nephritis.

Uhlenius N ，Tikkanen T ，Miettinen A ，Holthöfer H ，Törnroth T ，Eriksson A ，Fyhrquist F ，Tikkanen I ... -  《NEPHRON》

Modulation of renal glomerular angiotensin II receptors by ace inhibition and AT1 receptor antagonism.

Haddad G ，Amiri F ，Garcia R 《regulatory peptides》

The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats.

Siragy HM ，Carey RM 《JOURNAL OF CLINICAL INVESTIGATION》