ETA and ETB receptors mediate contraction to endothelin-1 in renal artery of aging SHR. Effects of FR139317 and bosentan.
We characterized vascular endothelin receptors of the renal artery from adult (12 to 16 weeks of age) and old (72 to 76 weeks) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Vessels were suspended in organ chambers (37 degrees C, aerated with 95% O2/5% CO2), and isometric tension was recorded. The endothelin-A (ETA) receptor antagonist FR139317, the combined ETA/ETB receptor antagonist bosentan, and the ETB-selective agonist sarafotoxin S6c were used. In old (and less so in adult) SHR, cumulative concentration-contraction curves to endothelin-1 showed a small contraction resistant to FR139317 (10(-5) mol/L) at 3 x 10(-9) to 10(-8) mol/L endothelin-1, which was completely inhibited by bosentan (10(-5) mol/L). This FR139317-resistant contraction to endothelin-1 was not present in WKY. Furthermore, in the presence of FR139317 (10(-5) mol/L), sarafotoxin S6c induced a stronger contraction in old SHR than in WKY (P < .05). In rings contracted with norepinephrine, sarafotoxin S6c caused endothelium-dependent relaxations in both strains; these relaxations were blocked by N omega-nitro-L-arginine methyl ester, indicating that nitric oxide is the mediator. In WKY but not SHR, release of nitric oxide by sarafotoxin S6c increased with age (P < .05). Thus, both ETA and ETB receptors mediate contraction to endothelin-1 in the renal artery from SHR but not WKY. ETB receptors on vascular smooth muscle seem to be unmasked with age in SHR, whereas those on endothelium (mediating nitric oxide release) exhibit more efficient responses with age in WKY.
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Department of Research, University Hospital, Basel, Switzerland.
Lüscher
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D000375:Aging / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D000077300:Bosentan; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C079574:FR 139317; D000077300:Bosentan