G-PROTEINS AND ENDOTHELIUM-DEPENDENT RELAXATIONS

Endothelial cells control the tone of the underlying smooth muscle by releasing relaxing factors (nitric oxide, NO, prostacyclin and endothe lium-derived hyperpolarizing factor). G proteins couple a number of en dothelial cell receptors to the activation of NO synthase. Pertussis t oxin selectively ADP-ribosylates certain G proteins (mainly G(i)). In the porcine coronary artery, pertussis toxin inhibits the release of N O evoked by certain (serotonin, alpha(2)-adrenergic agonists, leukotri enes, thrombin), but not all, (bradykinin, adenosine diphosphate) endo thelium-dependent vasodilators. This suggests that both G(i) and G(q) proteins can couple receptor activation to the increase in endothelial Ca2+ concentration required to stimulate NO synthase. In arteries wit h regenerated endothelium and in cultured endothelial cells, the relea se of NO evoked by pertussis-toxin-sensitive mechanisms is severely re duced or absent, while the response to other endothelium-dependent ago nists is normal. To judge from experiments with cultured endothelial c ells, the curtailment in pertussis-toxin-sensitive release of NO is du e to an abnormal function rather than a reduced presence of G(i) prote ins, or a reduced sensitivity of the cell membrane receptor. The selec tive impairment of G(i) proteins in regenerated endothelial cells pred isposes the blood vessel wall to vasospasm and to the initiation of th e atherosclerotic process.