EFFECTS OF CALCIUM-CHANNEL ANTAGONISTS ON THE INDUCTION OF NITRIC-OXIDE SYNTHASE IN CULTURED-CELLS BY IMMUNOSTIMULANTS

We investigated whether calcium channel antagonists would alter the in duction of nitric oxide (NO) synthesis by bacterial lipopolysaccharide (LPS) alone or in combination with interferon-gamma (IFN gamma) in cu ltured J774 macrophages, rat vascular smooth muscle cells, rat renal m esangial cells, and rat cardiac myocytes. The induction of NO synthesi s was determined by measuring nitrite, the stable end-product. The dih ydropyridine calcium channel antagonists, nifedipine, manidipine, nitr endipine, benidipine, barnidipine, perdipine, and nilvadipine all redu ced the LPS-induced nitrite production in a dose-dependent manner, eac h with a differing half-maximal inhibitory concentration, in cultured J774 macrophages. Nifedipine also inhibited nitrite production in vasc ular smooth muscle cells, mesangial cells, and cardiac myocytes. The h alf-maximal inhibitory concentrations of nifedipine were ranked as fol lows: smooth muscle cells < mesangial cells < cardiac myocytes. Diltia zem, at nontoxic concentrations, had no effect on the nitrite formatio n in the three cell types. Verapamil markedly increased the formation of nitrite in cardiac myocytes in response to LPS and IFN gamma, but n ot in vascular smooth muscle or mesangial cells. Exposure of cardiac m yocytes to LPS and IFN gamma caused the expression of NO synthase mRNA that was significantly increased by verapamil. Thus, certain calcium channel antagonists modulate NO synthesis by altering the induction of NO synthase.