Mechanisms of endothelin-1-induced potentiation of noradrenaline response in rat mesenteric artery.
1. Subthreshold concentrations of endothelin (ET)-1 enhance the contractile responses to noradrenaline (NA). We investigated possible mechanisms underlying the ET-1-induced enhancement of vasoconstrictor responses to NA in rat perfused mesenteric arteries. 2. Perfusion of arteries with subpressor dose of ET-1 (3 x 10-10 mol/L) significantly potentiated the pressor responses to NA (10-6, 3 x 10-6 and 10-5 mol/L) and this action of ET-1 was endothelium independent. 3. The protein kinase C (PKC) inhibitors staurosporine (10-8 mol/L) and calphostin C (10-7 mol/L) markedly attenuated the ET-1-induced enhancement of NA responses. Vasoconstrictor responses to NA were potentiated when vessels were perfused with phorbol 12-myristate 13-acetate (10-8 mol/L). 4. The potentiating effect of ET-1 was efficiently suppressed by Y-27632 (10-6 mol/L), a selective Rho-kinase inhibitor. In the presence of both staurosporine and Y-27632, contractile responses to NA alone were decreased markedly and ET-1-induced potentiation was abolished. 5. Both staurosporine and Y-27632 decreased contractile responses to NA in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats to levels observed in normotensive control animals. 6. These findings suggest that ET-1-mediated potentiation of responses to NA occurs through activation of either PKC or Rho-kinase. This mechanism seems to contribute to the enhanced vasoconstrictor responces to NA observed in DOCA-salt hypertensive rats, in which the responses to NA are enhanced tonically by endogenous vascular ET-1.
Matsumura
Y
Y
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-11, Japan. matumrh@oysun01.oups.ac.jp
Kita
S
S
Okui
T
T
D000818:Animals; D003900:Desoxycorticosterone; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D014662:Vasoconstrictor Agents; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D009638:Norepinephrine