EVIDENCE OF AN ADENOSINE-DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF L-ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the h aemodynamic response to L-arginine is investigated. 2. The study has b een divided into two parts. The first part was a single blind, randomi zed, placebo-controlled study in which L-arginine i.v. infusion (0.07 mmol/kg per min) in five healthy volunteers caused a significant fall in systolic (-14.2%, from 129.0 +/- 8.2 to 110.6 +/- 8.5 mmHg; F = 62. 89, P < 0.01), diastolic (-16%, from 80.0 +/- 7.9 to 67.2 +/- 7.0 mmHg ; F = 18.97, P < 0.01) and mean (-15.5%, from 96.4 +/- 6.7 to 81.4 +/- 6.5 mmHg; F = 28.78, P < 0.01) arterial blood pressure, with a concom itant increase of plasma adenosine concentration (from 244.0 +/- 32.2 to 637.0 +/- 43.4 nmol/L; F = 79.3 P < 0.01). Maximal effects were obt ained at the end of L-arginine infusion: haemodynamic parameters retur ned to basal values in about 30 min while adenosine concentrations nor malized in about 15 min. Saline infusion had no effect on these parame ters. 3. In the second study the effect of L-arginine i.v. infusion on arterial blood pressure, lower limb blood flow and plasma adenosine, before and after theophylline treatment (1000 mg/day for 3 days, p.o.) was examined. In 10 healthy volunteers the i.v. infusion of L-arginin e (0.07 mmol/kg per min) was followed by the same haemodynamic changes as reported above and by a significant increase in lower limb blood f low (+36.7%, from 2.18 +/- 0.40 to 2.98 +/- 0.71 mL/min/100 mL; t = 4. 61, P < 0.01). Pretreatment with theophylline, an adenosine-receptor a ntagonist, did not affect basal values of arterial pressure, lower lim b blood flow and adenosine concentration. The pretreatment with theoph ylline reduced maximal decrease in systolic pressure (-8.2 vs -15%), i n mean pressure (-9.9 vs -13.7%) and maximal increase in lower limb bl ood now (+19 vs +37%) caused by i.v. infusion of L-arginine (0.07 mmol /kg per min). Such a treatment allowed a progressive restoration of ba sal blood pressure values and of blood now, during the second half of L-arginine infusion. This observation was confirmed by the analysis of the area under the curves (AUC). A significant difference in AUC valu es before and after treatment was obtained for systolic pressure (t = 8.25, P < 0.01), mean pressure (t = 6.67, P < 0.01) and blood flow (t = 2.31, P < 0.05). 4. Theophylline study suggested that the endogenous adenosine increase is sufficient to participate at least in part in t he haemodynamic changes caused by L-arginine and that it is involved i n a secondary response to L-arginine.