Absence of desensitization to the relaxant activity of streptozotocin in isosorbide dinitrate-tolerant rat aorta.

The effect of in-vitro isosorbide dinitrate (ISDN)-induced tolerance on the vasodilatory actions of streptozotocin, a nitric oxide containing compound, and papaverine was studied in rat aortic strips precontracted by phenylephrine. Aortas made tolerant to ISDN remained fully responsive to streptozotocin but exhibited a greater response to low concentrations of papaverine compared with control strips. Methylene blue produced parallel displacement to the right of the relaxant concentration-effect curves of both ISDN and streptozotocin, whereas responses to only low concentrations of papaverine were significantly antagonized. These results indicate that the relaxant activity of streptozotocin is due to the stimulation of guanylate cyclase and impaired activity of this enzyme is not likely to be the operating mechanism for nitrate tolerance. It is also suggested that the vasodilating action of papaverine is partly dependent on the tissue cGMP level.