IngentaConnect Mechanisms Of Endothelin-1-Induced Potentiation Of Noradrenaline ...

Abstract:

SUMMARY

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 × 10^-10 mol/L) significantly potentiated the pressor responses to NA (10^-6, 3 × 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.

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Mechanisms Of Endothelin-1-Induced Potentiation Of Noradrenaline Response In Rat Mesenteric Artery