Endothelial cells control the tone of the underlying smooth muscle by releasing relaxing factors (nitric oxide, NO, prostacyclin and endothelium-derived hyperpolarizing factor). G proteins couple a number of endothelial cell receptors to the activation of NO synthase. Pertussis toxin selectively ADP-ribosy-lates certain G proteins (mainly G<sub>i</sub>). In the porcine coronary artery, pertussis toxin inhibits the release of NO evoked by certain (serotonin, α<sub>2</sub>-adrenergic agonists, leukotrienes, thrombin), but not all, (bradykinin, adenosine diphosphate) endothelium-dependent vasodilators. This suggests that both G<sub>i</sub> and G<sub>q </sub>proteins can couple receptor activation to the increase in endothelial Ca<sup>2+</sup> concentration required to stimulate NO synthase. In arteries with regenerated endothelium and in cultured endothelial cells, the release of NO evoked by pertussis-toxin-sensitive mechanisms is severely reduced or absent, while the response to other endothelium-dependent agonists is normal. To judge from experiments with cultured endothelial cells, the curtailment in pertussis-toxin-sensitive release of NO is due to an abnormal function rather than a reduced presence of G<sub>i</sub> proteins, or a reduced sensitivity of the cell membrane receptor. The selective impairment of G<sub>i</sub> proteins in regenerated endothelial cells predisposes the blood vessel wall to vasospasm and to the initiation of the atherosclerotic process.