Vascular endothelin-1 gene expression and effect on blood pressure of chronic ETA endothelin receptor antagonism after nitric oxide synthase inhibition with L-NAME in normal rats.
BACKGROUND
Vascular expression of the endothelin-1 gene may be associated with severe vascular hypertrophy. Because in rats, inhibition of NO synthase with the L-arginine analogue N omega-nitro-L-arginine methyl ester (L-NAME) induces blood pressure elevation associated with little cardiovascular hypertrophy, we studied vascular endothelin-1 gene expression in L-NAME-treated rats and the effects of chronic endothelin antagonism.


RESULTS
Sprague-Dawley rats received 100 mg.kg-1.d-1 L-NAME in their drinking water for 3 weeks. Systolic blood pressure rose to 189 +/- 3 mm Hg (P < .001 versus control rats). By Northern blot analysis, endothelin-1 mRNA levels were similar in aortas and mesenteric arteries of control and L-NAME-treated rats. The blood pressure of L-NAME hypertensive rats treated with the ETA-selective endothelin receptor antagonist A-127722 for 3 weeks at a low dose (10 mg.kg-1.d-1) and a high dose (30 mg.kg-1.d-1) was not different from that of rats receiving L-NAME but not the endothelin antagonist. Treatment with the ACE inhibitor cilazapril lowered the blood pressure of L-NAME-treated rats equally whether or not they were receiving the ETA antagonist.


CONCLUSIONS
These results indicate that the endothelin system does not participate to an important degree in the mechanisms leading to elevated blood pressure after chronic NO synthase inhibition with L-NAME in normal rats. In the chronic model of L-NAME-induced hypertension, blockade of the renin-angiotensin system does not unmask an endothelin-dependent vasopressor tone. In addition, either NO does not regulate vascular endothelin-1 gene expression or L-NAME exerts an inhibitory effect on endothelin expression in blood vessels.
Sventek
P
P
Clinical Research Institute of Montréal, University of Montréal, Québec, Canada.
Turgeon
A
A
Schiffrin
E L
EL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics*; D015870:Gene Expression; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester