Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(l-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r=0.81, n=28, p<0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60±0.43 hours. (Hypertension 1989;13:941-947) O ver the last decade, inhibition of the reninangiotensin system by converting enzyme inhibition has proved very effective for the treatment of hypertension and congestive heart failure.12 Converting enzyme inhibitors block the generation of angiotensin II, a potent pressor hormone. Because converting enzyme is identical to kininase II, it also contributes to the inactivation of the vasodilator hormone bradykinin.3 Accordingly, converting enzyme inhibition does not provide a totally specific means of blocking the reninangiotensin system. Furthermore, the disappearance of angiotensin II from the plasma triggers counterregulatory mechanisms that tend to limit the efficacy of angiotensin converting enzyme (ACE) inhibition. Thus, renin secretion is stimulated and, as a consequence, plasma angiotensin I is elevated. Even in the presence of pronounced ACE inhibition, some angtiotensin II may still be generated. More specific tools for blocking of the reninangiotensin system would be useful. Renin inhibitors have the theoretical advantage of specificity since renin has no known substrate other than angiotensinogen.5 So far, at least experimentally, renin has been blocked by means of various approaches: specific renin antibodies, 6 phospholipids, 78 peptides related to the renin prosegment, 9 pepstatin and its derivatives, 1011 and analogues of the renin substrate. The latter are derived from the minimal sequence of angiotensinogen reacting with renin.12 Actual inhibitors of this class contain a reduced bond between two amino acids at the cleavage site of renin. 13 The inhibitors seem to act by mimicking the transition state of the substrate formed during hydrolysis. Such compounds hav...

Rats with ablated frontal sensorimotor cortex and one with ablated sensorimotor connections to forebrain showed more vacuous chewing movements following 6-week chronic administration of a neuroleptic than did occipitally damaged rats or normal controls who were treated in the same way. The effect was still present 1 month after withdrawal. It was not clearly enhanced by subsequent treatments. Other behaviors (e.g., walking, rearing, or grooming) were not similarly affected by drug withdrawal. Additional results of terminal probes with amphetamine, apormorphine, and haloperidol are described, including movements labeled 'sham eating', observed only in frontal rats given apomorphine (AP). The results are interpreted in terms of a Jacksonina model of levels of brain organization; such a model may be applicable to tardive dyskinesia, seen in many schizophrenic patients who are maintained on neuroleptics for long periods.