Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ETA-Receptor Complexes

Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism.-receptor complexes.-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1

G-protein mediated inhibitory effect of a nitric oxide donor on the L-type Ca 2+ current in rat ventricular myocytes

International audienceThe role of the cGMP pathway in the modulation of the cardiac L-type Ca2+ current (ICa,L) by nitric oxide (NO) was examined in rat ventricular myocytes.The NO donors DEANO, SIN-1, SNP, SNAP and GSNO had no significant effects on basal ICa,L. However, DEANO (100 μM) inhibited ICa,L after the current had been previously stimulated by either isoprenaline (Iso, 1-10 nM), a β-adrenergic agonist, or isobutylmethyl-xanthine (IBMX, 10-80 μM), a wide spectrum phosphodiesterase (PDE) inhibitor.The anti-adrenergic effect of DEANO on ICa,L was not mimicked by other NO donors (SIN-1, SNAP and SPNO).The NO-sensitive guanylyl cyclase inhibitor ODQ (10 μM), antagonized the inhibitory effect of DEANO on ICa,L. Likewise, inhibitors of the cGMP-dependent protein kinase (cG-PK), Rp-8-chloro-phenylthio-cGMP (10 μM) and KT5823 (0.1 and 0.3 μM), also abolished the inhibitory effect of DEANO on Iso (1-10 nM)-stimulated ICa,L.Intracellular dialysis with exogenous cAMP (10-100 μM) blunted the inhibitory effect of DEANO (10 and 100 μM) on ICa,L. SNAP and SNP also had no effect on the cAMP-stimulated ICa,L.Pre-treatment of the myocytes with pertussis toxin (0.5 μg ml−1, 4-6 h at 37 °C) eliminated the inhibitory effect of DEANO (100 μM) on ICa,L, in the presence of either Iso (0.01 and 1 nM) or IBMX (10-80 μM).These results demonstrate that DEANO produces anti-adrenergic effects in rat ventricular myocytes. This effect of DEANO occurs in a cGMP-dependent manner, and involves activation of cG-PK and regulation of a pertussis toxin-sensitive G protein