INHIBITION OF PROLIFERATION, BUT NOT OF CA-2+ MOBILIZATION, BY CYCLIC-AMP AND GMP IN RABBIT AORTIC SMOOTH-MUSCLE CELLS

The effects on cellular proliferation and Ca2+ mobilization of analogues of cyclic AMP (cAMP) and cyclic GMP (cGMP) and of agents that elevate the intracellular concentrations of cyclic nucleotides were compared in closely similar preparations of first-passage rabbit aortic vascular smooth-muscle cells. Proliferation induced by foetal-bovine serum was inhibited by 78 % by 1 mm-8-bromo cAMP and by 42 % by 1 mm-8-bromo cGMP. In the presence of 100 muM-isobutylmethylxanthine, 100 muM-forskolin increased intracellular cAMP concentration 5-fold and inhibited proliferation by 87 % but did not affect cGMP concentration or cell viability (ATP concentration). Similarly in the presence of 100 muM-isobutylmethylxanthine, 1 mm-SIN-1 (3-morpholinosydnonimine) elevated cGMP concentration 4-fold and inhibited proliferation by 48 %, but did not affect cAMP or ATP concentration. Isobutylmethylxanthine (1 mM) elevated cAMP concentration by 3-fold and cGMP concentration by 20-fold and inhibited proliferation by 81 %. Concentrations of 8-bromo cAMP, 8-bromo cGMP, forskolin or SIN-I that inhibited proliferation did not affect the elevation of intracellular free Ca2+ concentration caused by 2 % (v/v) foetal-bovine serum, 100 nm-5-hydroxytryptamine or 10 nm-angiotensin II. The results demonstrate that elevation of intracellular cAMP and cGMP concentrations both independently inhibit vascular smooth-muscle cell proliferation, but these effects on proliferation are not mediated by inhibition of Ca2+ mobilization.