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Abstract
Aims: We investigated angiotensin II and nitric oxide-cGMP pathway in the development
of hypertension and renal damage in chronic experimental nephritis. Methods: 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. Results: 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. Conclusion: 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.