Vascular responses to endothelin-1 following inhibition of nitric oxide synthesis in the conscious rat.

1. The objectives of the present experiments were to assess the role of endogenous nitric oxide (NO) in mediating and/or modulating the effects of endothelin-1 (ET-1) on blood pressure and microvascular permeability in conscious rats. 2. Intravenous administration of the NO synthesis inhibitors, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) at a dose (25 mg kg-1 or 2 mg kg-1, respectively) which evoked maximum increase in mean arterial blood pressure (MABP) significantly attenuated (by about 40%) the vasodepressor response and potentiated (by 100-180%) the pressor response to ET-1 (1 nmol kg-1, i.v.) compared to the effects of ET-1 in animals where the peripheral vasoconstrictor effects of L-arginine analogues were mimicked by an infusion of noradrenaline (620-820 ng kg-1 min-1). Similar inhibition of the depressor and potentiation of the pressor actions of ET-1 were observed when the MABP which had been elevated by L-NMMA or L-NAME was titrated to normotensive levels with hydralazine or diazoxide before injection of ET-1. 3. L-NAME (2 mg kg-1) increased the vascular permeability of the large airways, stomach, duodenum, pancreas, liver, kidney and spleen (up to 280%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, skeletal muscle and skin was not affected significantly by L-NAME treatment. Elevation of MABP by noradrenaline infusion did not evoke protein extravasation in the vascular beds studied with the exception of the lung. In the large airways, tissue Evans blue content was similar following noradrenaline infusion and L-NAME.4. Both the pressor and permeability effects of L-NAME (2 mg kg-1) were effectively reversed by L-arginine (300 mg kg- 1) but not by D-arginine (300 mg kg-1 ). The D-enantiomer of L-NAME, D-NAME(2 mg kg-1) had no effect on the parameters studied.5. Protein extravasation was significantly enhanced by ET-1 (1 nmol kg-1) in the upper and lower bronchi, stomach, duodenum, kidney and spleen (up to 285%). This was potentiated by L-NAME(2 mg kg-1), resulting in marked increases in tissue Evans blue accumulation (up to 550%) in these tissues. The effects of L-NAME and ET-1 were additive in the trachea, duodenum, pancreas and liver.Combined administration of L-NAME plus ET-1 significantly increased protein extravasation in the pulmonary parenchyma, where neither L-NAME nor ET-1 alone caused significant increases.6. Noradrenaline infusion (620-820 ng kg-1 min-1) potentiated the permeability action of ET-1(1 nmol kg-1) in the pulmonary circulation, whereas it did not modify ET-1-induced protein extravasation in the other vascular beds.7. These results indicate that endogenous NO mediates, in part, the vasodepressor effect and attenuates the vasopressor action of ET-1 and modulates the effects of ET-1 on vascular permeability. These findings confirm the role of NO in the maintenance of blood pressure and suggest an important role for NO in the regulation of microvascular permeability.