Enhanced or repressed pressor responses to endothelin-1 or IRL-1620, respectively, in eNOS knockout mice.
Nitric oxide (NO) has been shown to be a physiological antagonist of the potent pressor agent endothelin-1, a transcriptional and post-transcriptional repressor of the production of this particular peptide as well as an endogenous modulator of vascular resistance in several animal species as well as in man. The aim of the present study was to assess the hemodynamic properties of endothelin-1 in endothelial NO synthase knockout mice (eNOS (-/-) KO). Ketamine- xylazine anesthetized eNOS (-/-) KO mice show a significantly higher mean arterial pressure (+25.7 +/- 4.3 mmHg, n = 10) than their wild-type congeners (C57BL/6 background). eNOS (-/-) KO mice, when subjected to systemically administered endothelin-1 or the selective endothelin-B agonist IRL-1620 (1 nmol/kg, each), responded by markedly enhanced and reduced pressor responses (systolic, diastolic and mean arterial pressure), respectively, when compared with wild-type mice. Surprisingly, plasma levels of immunoreactive endothelin are not significantly different in endothelial nitric oxide synthase knockout mice and wild-type mice. Our results suggest that chronic repression of endothelial nitric oxide synthase affects in opposite fashion the functionality of endothelin-A and endothelin-B receptor-dependent responses. The increase in mean arterial pressure afforded in endothelial nitric oxide synthase knockout mice does not appear to involve an increase in production of endogenous endothelin in vivo.
Labonté
Julie
J
Department of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke, Québec, Canada.
D'Orléans-Juste
Pedro
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments / Q000494:pharmacology*; D044023:Receptor, Endothelin B / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D044023:Receptor, Endothelin B; C074308:sovateltide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse