Molecular mechanism of action of the vasoconstrictor peptide endothelin

doi:10.1016/S0006-291X(88)80970-7

Biochemical and Biophysical Research Communications

Volume 157, Issue 3, 30 December 1988, Pages 977-985

https://doi.org/10.1016/S0006-291X(88)80970-7 Get rights and content

Summary

Endothelin, one of the most potent vasoconstrictor known, has been suggested to act as an endogenous agonist of L-type Ca²⁺ channels. In this paper we show that endothelin stimulates the metabolism of inositol phosphates and induces the mobilization of intracellular Ca²⁺ stores. The transient activation of Ca²⁺-sensitive K⁺ channel provokes an hyperpolarization of the membrane. It is followed by a sustained depolarization which is due to the opening of a non-specific cation channel which is permeable to Ca²⁺ and Mg²⁺. The depolarization then activates L-type Ca²⁺ channels. This mechanism of action explains why part of the endothelin-induced vasoconstriction is eliminated by L-type Ca²⁺ channel blockers.

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Raised tone reveals purinergic-mediated responses to sympathetic nerve stimulation in the rat perfused mesenteric vascular bed
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Noradrenaline and ATP are sympathetic co-transmitters. In rat isolated mesenteric small arteries, activation of sympathetic nerves can produce a vasoconstrictor response mediated by ATP. In contrast, the rat perfused mesenteric bed displays vasoconstrictor responses that are blocked solely by α₁-adrenoceptor antagonists. This study assessed the effect of raising tone with a vasoconstrictor on purinergic and noradrenergic responses to sympathetic nerve stimulation in the rat perfused mesentery. Rat mesenteric vascular beds were perfused with physiological salt solution and responses to nerve stimulation, or P2X-receptor agonists, were determined under basal conditions and after raising tone with endothelin-1. The contribution of noradrenaline and ATP to sympathetic nerve-mediated responses was assessed using the α₁-adrenoceptor antagonist, prazosin and the P2X-receptor desensitizing agent, α,β-methyleneATP. The effect of endothelin-1 on excitatory junction potentials generated in response to nerve stimulation in isolated mesenteric arteries was also assessed. Under baseline conditions, responses to nerve stimulation were mediated solely by activation of α₁-adrenoceptors. After raising perfusion pressure with endothelin-1 or the thromboxane mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F_2α (U44619), sympathetic nerve-mediated responses were larger than under basal conditions and the response was partly sensitive to P2X-receptor desensitization. Responses to exogenous P2X-receptor agonists were enhanced after treatment with endothelin-1, while endothelin-1 decreased the amplitude of excitatory junction potentials. These results indicate that ATP acts as an important, functional, sympathetic neurotransmitter in the perfused mesentery under raised tone conditions, where the perfusion pressure is closer to that found in vivo. This effect is due to a postjunctional enhancement of purinergic function.
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Molecular mechanism of action of the vasoconstrictor peptide endothelin

Summary

FEBS Lett.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Nature