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Renin-angiotensin blockade improves renal cGMP production via non-AT2-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat

Minerva Foundation Institute for Medical Research, nina.uhlenius@ hel.f

Olli Vuolteenaho

Department of Physiology, University of Oulu

Ilkka Tikkanen

Minerva Foundation Institute for Medical Research, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

Background

To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS) blockade.

Methods

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT ₁-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP), urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.

Results

Captopril and L-158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT₁ -receptor binding in the kidney was inhibited to about 40% of the control value after administration of L-158,809. The AT₂-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.

Conclusion

Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT₁-receptor antagonism on cGMP production was not mediated by AT₂-receptor-dependent mechanisms, since renal AT₂-receptor binding density was suppressed following treatment with L-158,809. AT₁-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.

Key Words: angiotensin II • nitric oxide • cyclic GMP • hypertension • kidney

Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 4, 233-239 (2001)
DOI: 10.3317/jraas.2001.037


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