DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.
Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.
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...
SUMMARY Two doses of synthetic atrial natriuretic peptide (0.5 and 5.0 /xg/min) and its vehicle were infused intravenously for 4 hours in eight salt-loaded normal volunteers, arid the effect on blood pressure, heart rate, renal hemodynamics, solute excretion, and secretion of vasoactive hormones was studied. The 0.5 /oig/min infusion did not alter blood pressure or heart rate, whereas the 5.0 /xg/min infusion significantly reduced the mean pressure by 20/9 mm Hg after 2.5 to 3 hours and increased the heart rate slightly. Inulin clearance was not significantly changed, but the mean p-aminohippurate clearance fell by 13 and 32% with the lower and higher doses, respectively. Urinary excretion of sodium and chloride increased slightly with the lower dose. With the higher dose, a marked increase in urinary excretion of sodium, chloride, and calcium was observed, reaching a peak during the second hour of the infusion. Potassium and phosphate excretion did not change significantly. A brisk increase in urine flow rate and fractional water excretion was seen only during the first hour of the high-dose infusion. Signs and symptoms of hypotension were observed in two subjects. No change in plasma renin activity, angiotensih II, or aldosterone was observed during either infusion, but a marked increase occurred after discontinuation of the high-dose infusion. In conclusion, the 5 /xg/min infusion induced a transient diuretic effect, delayed maximal natriuretic activity, and a late fall in blood pressure, with no change in inulin clearance but a dose-related decrease in p-aminohippurate clearance. Despite large amounts of sodium excreted arid blood pressure reduction, no coiinterregulatory changes were observed in the renin-angiotensin-aldosterone system or plasma vasopressin levels during the infusion. injections followed by a short infusion. 4 In these studies, the blood pressure effects as well as solute excretion were monitored. The peptides elicited natriuresis and diuresis 4 -8 -9 and induced a transient increase in creatinine clearance, 9 while slightly decreasing blood pressure. 8Although the triggering mechanisms and the daily profile of ANP secretion in humans are not yet known, it seems likely that a continuous infusion would yield more information on its physiological role in blood pressure regulation and renal handling of solutes than a bolus injection. We have recently evaluated the dosereponse relationship for blood pressure, heart rate, and skin blood flow during an ANP infusion lasting several hours. 10 The aim of the present study was to assess the pharmacological effect of a 4-hour infusion of synthetic ANP, at two different doses, or its vehicle on renal hemodynamics, urinary solute excretion, and plasma levels of various hormones in healthy volunteers under sodium-loaded conditions. 11-96by guest on May 10, 2018 http://hyper.ahajournals.org/ Downloaded from
This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.
The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril (S9490-3) was evaluated in 18 normotensive men. In three subjects the pressor response to exogenous angiotensin I was tested. A 8 mg oral dose reduced the pressor response by greater than 80%. Single oral perindopril doses of 2, 4, 8, and 16 mg were given to groups of five subjects each. Eight and 16 mg decreased plasma ACE activity within 4 hours to less than 10% of control; 72 hours later, plasma ACE activity was still reduced by at least 40%. Doses of 4 and 8 mg po once a day were then given for 8 days to two groups of six subjects. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone, and plasma ACE activity fell significantly, whereas blood angiotensin I and plasma renin activity rose. There was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed. Thus in normotensive subjects, perindopril seems an effective, orally active, long-lasting ACE inhibitor.
Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single‐blind, placebo‐controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5‐hour urinary sodium excretion was 15.7 ± 7.3 mmol for the placebo and 22.9 ± 5, 26.7 ± 6 (p < 0.05), and 30.9 ± 6.8 mmol (p < 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 ± 0.4 mmol after placebo and by 1.5 ± 0.3 (p< 0.01), 1.95 ± 0.3 (p < 0.01), and 2.4 ± 0.4 mmol (p < 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose‐dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate. These results demonstrate that neutral metalloendopeptidase inhibition with SCH 34826 can produce natriure‐sis and phosphate excretion in volunteers receiving a high‐salt diet maybe by reducing the renal atrial natriuretic peptide metabolism. Clinical Pharmacology and Therapeutics (1991) 50, 181–191; doi:
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