Renin-angiotensin blockade improves renal cGMP production via non-AT(2)-receptor mediated mechanisms in hypertension-induced by chronic NOS inhibition in rat.
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 AT1-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.


CONCLUSIONS
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 renalAT2-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.
Uhlenius
N
N
Minerva Foundation Institute for Medical Research, Biomedicum Helsink, Helsinki, Finland. nina.uhlenius@hel.f
Vuolteenaho
O
O
Tikkanen
I
I
D000419:Albuminuria / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D006152:Cyclic GMP / Q000652:urine*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C070967:L 158809; D009320:Atrial Natriuretic Factor; D002216:Captopril; D019001:Nitric Oxide Synthase; D012083:Renin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester