Synergistic action of vasodilators that increase cGMP and cAMP in the hamster cremaster microcirculation

Objective: Compounds such as endothelium derived nitric oxide (NO) and prostacyclin (prostaglandin I₂) which increase cGMP and cAMP inhibit platelet activation in a synergistic manner. The aim of this study was to examine whether these compounds also interact synergistically in the control of smooth muscle tone. Methods: Vascular diameters in the cremaster of 49 anaesthetised hamsters (465 arterioles) were studied during superfusion with compounds raising cAMP (isoprenaline and prostacyclin) and cGMP (sodium nitroprusside) alone or in combination. Results: (1) The isoprenaline induced maximum dilator response was significantly attenuated, from 86.1(SEM 0.7)% to 37.1(0.2)%, after inhibition of NO-synthase with N^G-nitro-L-arginine (L-NNA, 30μM). Superfusion with sodium nitroprusside (30 nM, dilatation alone: 6.7%), which was used to substitute for endothelium derived NO, restored the attenuated isoprenaline response. The combined effects of isoprenaline and sodium nitroprusside were supra-additive. Virtually identical results were obtained when prostacyclin, another cAMP raising compound, was used instead of isoprenaline. The K⁺ channel opener cromakalim (100 nM) which acts cGMP independently was without effect on the prostacyclin induced dilator response. (2) The sodium nitroprusside induced maximum dilator response was attenuated from 80.9(0.25)% to 70.1(0.4)%, after indomethacin (3 μM) and restored by simultaneous application of prostacyclin (1 nM, dilatation alone: 1.4%) but not of cromakalim. Again, the combined effects were supra-additive, suggesting a synergistic action of these compounds. (3) Although indomethacin or L-NNA alone decreased the resting diameter by approximately 9.5%, the simultaneous application of both inhibitors failed to decrease the resting diameter further (10.0%, p = 0.97). Conclusions: Vasodilators increasing cGMP and cAMP act synergistically in vivo. Continuous release of NO and prostaglandins by the endothelium may therefore not only modulate the efficacy of such cyclic nucleotide increasing vasodilators but also interact synergistically in controlling basal vascular tone.Cardiovascular Research 1994;28:1513-1518.