Acute administration of L -arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L -arginine in hypercholesterolaemic subjects during long-term administration. Plasma L -arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L -arginine administration (14–21 g/day). The average plasma L -arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μ g/ml respectively ( P < 0.05). Plasma concentrations of L -arginine remained above baseline throughout weeks 2–12. The L -arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC 0–8 ) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L -arginine concentrations or in the AUC 0–8 after oral and intravenous doses during subsequent visits ( P > 0.05). The mean non-renal clearance of L -arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L -arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.
1. Diabetic autonomic neuropathy causes loss of sympathetic cardiovascular control and is associated with increased vascular sensitivity to catecholamines. Supersensitivity to catecholamines could be due to either a postsynaptic increase in vascular sensitivity or to decreased catecholamine uptake into peripheral sympathetic nerve endings. 2. To differentiate between these possible mechanisms we have measured the responsiveness in vivo to noradrenaline and phenylephrine with local infusions into peripheral veins of diabetic patients with and without symptomatic autonomic neuropathy and of healthy control subjects. The dorsal hand vein compliance technique was used. 3. Symptomatic diabetic patients required significantly lower doses of noradrenaline for half-maximal venoconstriction (ED 50 ) (geometric mean 2.14 ng/min) than control subjects (geometric mean 6.61 ng/min, P = 0.032), but there was no difference in the results from the phenylephrine dose-response curves between the groups. Thesre were no differences in venous responsiveness to noradrenaline or phenylephrine between the asymptomatic diabetic group and the control group. However, in the asymptomatic diabetic group, postural blood pressure change (an index of loss of sympathetic control) was correlated with the ED 50 for noradrenaline ( r = 0.74, P = 0.014), but not with the ED 50 for phenylephrine. In the control group the ED 50 values for noradrenaline and phenylephrine were correlated with each other ( r = 0.81, P = 0.0005). 4. Both vasopressor drugs act on vascular α-adrenoceptors, but only noradrenaline is taken up into peripheral sympathetic nerve endings. Our results suggest that, in diabetic patients, vascular supersensitivity to catecholamines is primarily determined by decreased neuronal catecholamine uptake. A postsynaptic increase in vascular a-adrenoceptor stimulation does not appear to be prominent in diabetic autonomic neuropathy.
1. The basic biochemical defect of cystic fibrosis (CF) remains undetermined, but impaired function of the β-adrenoceptor-mediated adenosine 3′:5′-cyclic monophosphate (cyclic AMP)-dependent regulatory pathway in secretory cells is likely to be involved in the pathophysiology of the disease. 2. We have compared responsiveness to β-adrenergic stimulation in vivo by infusing isoprenaline locally into peripheral veins of CF patients and control subjects; the dorsal hand vein technique was used to measure the vascular response to isoprenaline. 3. CF patients required significantly higher doses of isoprenaline for half-maximal dilatation of the preconstricted veins (ED 50 ) than controls (geometric mean: 44.5 ng/min in CF patients compared with 14.8 ng/min in controls; P < 0.05). Maximal venodilatation was 74 ± 30% of baseline in CF patients compared with 94 ± 50% in controls (NS between groups). 4. The clinical score of CF patients was uncorrelated with the ED 50 of isoprenaline. Thus the decreased β-adrenergic responsiveness does not seem to be related to the severity of the disease. 5. Our results indicate a defect in the cyclic-AMP-dependent pathway in vascular smooth muscle cells of CF patients. Whether this is associated with the CF gene defect itself requires further study.