Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase.
Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.
Arnal
J F
JF
Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 367, Paris, France.
Warin
L
L
Michel
J B
JB
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D009599:Nitroprusside / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D009599:Nitroprusside; D009320:Atrial Natriuretic Factor; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester