Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor.In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an EDs5 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects ofacetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANFlike immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.

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The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4-8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40-50% higher than of the d-isomers and there was a comparable in the half-life.

The effect of smoking on forearm haemodynamics was studied in four groups of healthy subjects, who had all smoked cigarettes (10-15 cigarettes/day) on average for 10 years. Changes in heart rate, blood pressure, forearm blood flow, forearm vascular resistance and pulse wave velocity were determined before and every 15 min for 75 min after smoking two cigarettes within 10 min. The inhaled nicotine was about 2.2 mg. There was no significant difference between the four groups in any haemodynamic variable before or after smoking, which indicated adequate reproducibility of the parameters studied and so made it possible to pool the results from all 30 subjects. Smoking significantly increased blood pressure, heart rate and pulse wave velocity and decreased forearm blood flow. Forearm vascular resistance remained unchanged. The rises in systolic blood pressure and pulse wave velocity were transient and both peaked (7% and 28%, respectively) 15 min after smoking. In contrast, heart rate and diastolic blood pressure remained significantly elevated and forearm blood flow was significantly decreased throughout the 75 min follow-up. The maximal changes were: heart rate +34%, diastolic blood pressure +17%, and forearm blood flow -24%. It is concluded that smoking produces statistically significant changes in forearm haemodynamics affecting both small and large arteries. The reproducibility of the study design means that it can be used to evaluate substances which may antagonize the haemodynamic effects of tobacco smoking.