Vascular Endothelin-1 Gene Expression and Effect on Blood Pressure of Chronic ET A Endothelin Receptor Antagonism After Nitric Oxide Synthase Inhibition With L- NAME in Normal Rats

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Abstract
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 ω -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. Methods and 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 ET A -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 ET A 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.