REGIONAL AND CARDIAC HEMODYNAMIC-EFFECTS OF N(G), N(G), DIMETHYL-L-ARGININE AND THEIR REVERSIBILITY BY VASODILATORS IN CONSCIOUS RATS

1 A series of experiments was carried out on 3 separate groups of male Long Evans rats, chronically instrumented for the measurement of regi onal haemodynamics, to compare the effects of N(G),N(G), dimethyl-L-ar ginine (ADMA) and N(G)-monomethyl-L-arginine (L-NMMA), and their rever sibility by the nitric oxide donors, S-nitroso-N-acetyl-penicillamine (SNAP), S-nitroso-glutathione (SNOG), sodium nitroprusside (SNP), and the vasodilator, hydralazine. 2 As previously reported for L-NM MA, AD MA (1 - 100 mg kg-1) caused dose-dependent pressor and bradycardic eff ects, accompanied by renal, mesenteric and hindquarters vasoconstricti ons. The magnitude and duration of these effects were similar for ADMA and L-NMMA, consistent with their being equipotent inhibitors of nitr ic oxide synthase. 3 Infusion of SNAP or SNOG (300 mug kg-1 h-1) after injection of ADMA or L-NMMA (100 mg kg-1) reversed the pressor but di d not abolish the vasoconstrictor, effects of ADMA or L-NMMA. However, a higher dose of SNAP (3 mg kg-1 h-1) caused complete reversal of the pressor and mesenteric haemodynamic effects of ADMA (100 mg kg-1), al though its renal and hindquarters vasoconstrictor effects were not abo lished. 4 Infusion of SNP (300 mug kg-1 h-1) after administration of L -NMMA (100 mg kg-1), caused complete reversal of its pressor and mesen teric and hindquarters haemodynamic effects, and reduced substantially its renal vasoconstrictor action; hydralazine (7.5 mg kg-1 h-1) was a lmost as effective as SNP in reversing all these variables. 5 In anima ls chronically instrumented for the measurement of cardiac haemodynami cs, ADMA (100 mg kg-1) caused a pressor effect accompanied by a rise i n central venous pressure, and reductions in heart rate, cardiac index , stroke index, peak aortic flow, maximum rate of rise of aortic flow and total peripheral conductance. The reversal of the pressor effect o f ADMA by SNAP (300 mug kg-1 h-1) was accompanied by a reduction of ce ntral venous pressure below resting levels and a further diminution of stroke index; all other variables showed an increase, but they still remained below resting levels (with the exception of heart rate). 6 Th us, following inhibition of NO synthesis, pharmacological intervention with NO donors, or other vasodilators, may cause normalisation of the mean arterial pressure without necessarily returning all associated c ardiovascular variables to normal.