Mechanisms of pinacidil-induced vasodilatation

The mechanism of the vasodilator effect of pinacidil was examined. Pinacidil (0.1-100 microM) inhibited the increases in cytosolic Ca2+ ([Ca2+]i) and muscle tension due to norepinephrine in rat aorta. In contrast, a Ca2+ channel blocker, verapamil, inhibited the norepinephrine-stimulated [Ca2+]i more strongly than the contraction. Higher concentrations of pinacidil (3-100 microM) inhibited the verapamil-insensitive portion of the contraction and [Ca2+]i. An inhibitor of ATP-sensitive K+ channels, glibenclamide, antagonized the inhibitory effect of low concentrations (less than or equal to 10 microM) of pinacidol. Pinacidil did not change the contraction induced by Ca2+ in vascular smooth muscle permeabilized with Staphylococcus aureus alpha-toxin. Norepinephrine (in the presence of GTP), 12-deoxyphorbol 13-isobutyrate (in the absence of GTP), and treatment with GTP gamma S potentiated the contraction of permeabilized smooth muscle induced by the addition of Ca2+. Pinacidil (100 microM) inhibited the potentiation due to GTP gamma S or norepinephrine but not to phorbol ester. These results suggest that pinacidil has dual effects on vascular smooth muscle contraction. At lower concentrations (greater than 0.1 microM), it decreases [Ca2+]i, possibly by activating ATP-sensitive K+ channels. At higher concentrations (greater than 3 microM), it may additionally inhibit the receptor-mediated, GTP-binding protein-coupled phosphatidyl inositol turnover.