The mechanism of the vasodilator effect of pinacidil was examined. Pinacidil (0.1–100 μM) inhibited the increases in cytosolic Ca
2+ ([Ca
2+]
i) and muscle tension due to norepinephrine in rat aorta. In contrast, a Ca
2+ channel blocker, verapamil, inhibited the norepinephrine-stimulated [Ca
2+]
i more strongly than the contraction. Higher concentrations of pinacidil (3–100 μM) inhibited the verapamil-insensitive portion of the contraction and [Ca
2+]
i. An inhibitor of ATP-sensitive K
+ channels, glibenclamide, antagonized the inhibitory effect of low concentrations ( 10 pM) of pinacidol. Pinacidil did not change the contraction induced by Ca
2+ in vascular smooth muscle permeabilized with
Staphylococcus aureus -toxin. Norepinephrine (in the presence of GTP), 12-deoxyphorbol 13-isobutyrate (in the absence of GTP), and treatment with GTP
γS potentiated the contraction of permeabilized smooth muscle induced by the addition of Ca
2+. Pinacidil (100 μM) inhibited the potentiation due to GTP
γS or noepinephrine but not to phorbol ester. These results suggest that pinacidil has dual effects on vascular smooth muscle contraction. At lower concentrations (>0.1 μM), it decreases [Ca
2+]
i, possibly by activating ATP-sensitive K+ channels. At higher concentrations (> 3 μM), it may additionally inhibit the receptor-mediated, GTP-binding protein-coupled phosphatidyl inositol turnover.
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