Development of Tolerance to Glyceryl Trinitrate in an Isolated Human Peripheral Vein and Its Relation to Cyclic GMP Metabolism

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Abstract
Human peripheral vein (v. saphena magna) was exposed in vitro to glyceryl trinitrate (GTN) 0.1 mM for 1 h. The subsequent relaxant effect of GTN (10 nM - 0.1 mM) on vessels contracted by serotonin (0.25 .mu.M) was significantly reduced on vessels preexposed to GTN as compared to control vessels, indicating a development of partial tolerance as far as the vascular smooth muscle relaxant effect is concerned. The impaired relaxant effect was paralleled by a reduced increment of intracellular cyclic GMP. This is, in turn, probably a consequence of both a diminished guanylate cyclase activity and an elevated phosphodiesterase activity in the GTN-tolerant vessels. The relaxant activity as well as the level of intracellular cyclic GMP were restored in GTN-tolerant vessels by dipyridamole (5 .mu.M), an agent with phosphodiesterase inhibiting properties.