The K+ channel opener pinacidil, in clinical use as an antihypertensive agent, acts by opening ATP-sensitive K+ channels in striated and smooth muscle cells. In vitro and in vivo studies have suggested that it also diminishes insulin secretion. Insulin secretion can be influenced directly--by acting on the ATP-sensitive K+ channels of the pancreas--or indirectly--by activation of the sympathetic nervous system, caused by vasodilation. Therefore we studied the effect of pinacidil on insulin release after intravenous glucose challenge during alpha-adrenergic blockade with phentolamine. We found, that phentolamine precludes the effect of pinacidil on glucose induced insulin release in healthy man. This finding suggests that the inhibitory effect of pinacidil on insulin release is indirect and due to activation of the sympathetic nervous system. The latter effect is caused by the antihypertensive action of pinacidil. However, the suggestion of others, that pinacidil inhibits insulin secretion secretion via a direct action on ATP-sensitive K+ channels can not be excluded.