Imidazolines and the pancreatic B-cell -: Actions and binding sites

Stimulation of insulin secretion by imidazoline compounds displays variable characteristics. Phentolamine (10-100 mu M) increased secretion of perifused mouse islets at nonstimulatory glucose concentrations (5 mM) and even in the absence of glucose. Idazoxan (20-100 mu M) elicited a moderate increase in insulin secretion, which required the presence of a stimulatory glucose concentration (10 mM). Phentolamine is therefore a stimulator of secretion in its own right, whereas idazoxan may be termed an enhancer of secretion, Both compounds inhibited the activity of ATP-dependent K(+)channels in inside-out patches from B-eells; however, idazoxan achieved only an incomplete block. Both compounds depolarized the B-cell plasma membrane to an extent that permitted the opening of voltage-dependent Ca2+ channels (-40 to -30 mV), An increase in cytoplasmic Ca2+ concentration was induced by phentolamine and much less so by idazoxan, Activation of protein kinase C, a possible mechanism to amplify Ca2+-induced secretion, could not be verified for phentolamine. It thus appears that stimulation of insulin secretion by phentolamine is due to its blocking effect on K-ATP channels, which may be the correlate of non-adrenergic imidazoline bindilng sites which were characterized in insulin-secreting HIT cells. Whether incomplete closure of K-ATP channels by idazoxan or additional effects are responsible for the requirement of high glucose to stimulate secretion remains to be clarified.