ramiprilat and Hypertension

Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the 'escape' phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete 'upstream' inhibition of the renin-angiotensin-aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13-17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.

Topics: Aging; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Fumarates; Half-Life; Humans; Hypertension; Ramipril; Renin-Angiotensin System

We investigated the contribution of nitric oxide to the short-term blood pressure reduction caused by interruption of the renin-angiotensin system in angiotensin-dependent hypertension. The blood pressure of rats made hypertensive by coarctation of the aorta between the renal arteries at their origin fell after administration of the angiotensin-converting enzyme inhibitor ramiprilat (2 mg/kg IV; -75 +/- 5 mm Hg) or the angiotensin II antagonist losartan (30 mg/kg IV; -79 +/- 6 mm Hg). But the antihypertensive effect of these agents was attenuated in rats pretreated with NG-nitro-L-arginine methyl ester (10 mg/kg IV) to inhibit nitric oxide synthesis (ramiprilat, -23 +/- 7 mm Hg; losartan, -37 +/- 5 mm Hg). In rats made hypertensive by long-term infusion of angiotensin II (60 ng/min IV, 6 to 7 days), the vasodepressor response to discontinuation of the angiotensin II infusion also was attenuated by pretreatment with the nitric oxide synthesis inhibitor (-52 +/- 7 versus -31 +/- 7 mm Hg); this attenuation was not demonstrable in rats receiving sodium nitroprusside (1 microgram.kg-1.min-1 IV) to replace the loss of endogenous nitric oxide (-72 +/- 9 mm Hg). Pretreatment with NG-nitro-L-arginine methyl ester did not interfere with the vasodepressor effect of sodium nitroprusside or prazosin in rats with aortic coarctation-induced hypertension or with the blood pressure reduction caused by discontinuation of an infusion of phenylephrine in rats made hypertensive by long-term administration of this drug. These data suggest a contribution of nitric oxide to the blood pressure reduction caused by interruption of the renin-angiotensin system in models of established angiotensin-dependent hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Coarctation; Arginine; Biphenyl Compounds; Blood Pressure; Hypertension; Imidazoles; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ramipril; Rats; Rats, Sprague-Dawley; Renin; Tetrazoles; Vasoconstrictor Agents

We studied the efficacy and safety of ramipril and the kinetics of its active moiety ramiprilat in 12 hypertensive patients receiving regular hemodialysis, after a single dose and after long-term (28 days) administration. Patients received 2.5 mg ramipril after each hemodialysis. On days 1 and 29, ramipril was administered 4 h before the hemodialysis and serial blood samples were obtained for 9 h for determination of pharmacokinetic parameters. Tolerability was good, and all patients completed the study. There was a high degree of angiotensin-converting enzyme (ACE) inhibition throughout the study. Ramipril had a clear-cut antihypertensive effect. Long-term administration of ramipril did not modify the time to peak ramiprilat concentration, but increased the mean maximal concentration significantly: 20.2 +/- 12.7 vs. 10.4 +/- 7.1 ng center dot ml-1. The mean accumulation ratio was 2.2. Ramiprilat hemodialysis clearance was 31.7 ml/min (range 4.2-64.9 ml/min) on day 1 and 21.0 ml/min (range 7.9-56.5 ml/min) on day 29. Ramipril 2.5 mg, administered after hemodialysis, appears to be safe and effective in hypertensive patients receiving periodic hemodialysis. Despite an increase in ramiprilat concentration from day 1 to day 29, the steady state was reached. We describe the role of nonrenal clearance of ramiprilat.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Prodrugs; Ramipril; Renal Dialysis

We investigated the role of kinins in the acute depressor effect of captopril and ramiprilat in spontaneously hypertensive rats. Since the vasodepressor action of kinins may be linked to the generation of prostaglandins and endothelium-derived relaxing factors, we also investigated the role of prostaglandins and nitric oxide in the blood pressure reduction caused by angiotensin converting enzyme inhibitors. To this end, we contrasted the hypotensive effects of captopril (10 mg/kg i.v.), ramiprilat (2 mg/kg i.v.), and the angiotensin II antagonist DuP 753 (30 mg/kg i.v.) in spontaneously hypertensive rats with and without pretreatment with a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) (200 micrograms/kg/min i.v.), an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine) (15 mg/kg + 10 mg/kg/hr i.v.), or an inhibitor of prostaglandin synthesis (indomethacin) (10 mg/kg i.v.). The kinin antagonist did not affect blood pressure in spontaneously hypertensive rats but did attenuate the hypotensive effect of captopril and ramiprilat; the kinin antagonist did not minimize the depressor action of DuP 753. The nitric oxide synthesis inhibitor increased blood pressure in spontaneously hypertensive rats and attenuated the hypotensive effect of captopril, ramiprilat, and DuP 753, but it did not impede the hypotensive effect of sodium nitroprusside. Pretreatment of hypertensive rats with indomethacin did not modify the acute hypotensive effect of ramiprilat or captopril. These data suggest a contribution of endogenous kinins and nitric oxide to the acute antihypertensive effect of captopril and ramiprilat in spontaneously hypertensive rats and of nitric oxide to the hypotensive effect of DuP 753.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arginine; Biphenyl Compounds; Blood Pressure; Captopril; Hypertension; Imidazoles; Kinins; Losartan; Male; Nitric Oxide; omega-N-Methylarginine; Pyrroles; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles

This open, general practice study looked at the pharmacokinetics of ramipril over a period of 1 year in elderly (greater than 65 years) hypertensive patients. Ten patients with a diastolic blood pressure between 95 and 125 mm Hg were treated with 5 mg of ramipril daily for 4 weeks, followed by an additional 11 months of treatment in which the dose was titrated against the blood pressure. Pharmacokinetic data were collected at baseline, 4 weeks, and 1 year. Mean peak concentrations of ramiprilat (the active diacid) were 11.5 ng/ml acutely, 18.5 ng/ml at 1 month, and 31.3 ng/ml at 1 year, and these were all statistically significantly different. Mean half-lives of ramiprilat were 5.5 h acutely, 5.2 h at 1 month, and 4.6 h at 1 year, and these were not statistically significantly different. Mean areas under the curve excluding the component for saturable binding were 106.8 ng/h/ml acutely, 115.7 ng/h/ml at 1 month, and 248 ng/h/ml at 1 year; the latter was statistically significantly different from the earlier readings. There is no evidence from this study that the pharmacokinetics change in any clinically relevant way.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Half-Life; Humans; Hypertension; Pyrroles; Ramipril

Angiotensin converting enzyme (ACE) activity was measured by fluorimetry in the plasma, lung, heart, aorta and kidney (cortex and medulla) of 3-, 5-, 8- and 11-week-old spontaneously hypertensive rats (SHR) and compared with that of age-matched Wistar-Kyoto rats (WKY). In the plasma, lung and kidney (cortex and medulla), ACE activity was lower in SHR than in WKY. This was evident as early as the age of 3 weeks. In contrast, there were no differences between SHR and WKY in the aorta and the heart. Age-related variations in ACE activities differed in each tissue and in both groups of rats, but no major modifications were correlated with the development of hypertension. A binding assay was performed with [3H]ramiprilat; affinity (KD) and the maximum number of binding sites (Bmax) were determined in plasma and tissues of 3-week-old SHR and WKY. The KD values were identical in the two groups but Bmax was lower in all SHR tissues except in the heart; these results might be related to the decrease in ACE activity. Our results probably reflect genetic differences in ACE activity between SHR and WKY, and suggest that ACE regulatory mechanisms act differently in each tissue.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Fluorometry; Hypertension; Peptidyl-Dipeptidase A; Pyrroles; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System

Studies were performed in normotensive volunteers and hypertensive subjects to examine the effect on forearm blood flow (FBF) of brachial artery infusions of angiotensin I (ANG I), angiotensin II (ANG II), and ramiprilat [the active metabolite of the angiotensin converting enzyme (ACE) inhibitor, ramipril]. Ramiprilat (10 mcg/min for 10 min) produced a 71% mean increase in FBF (n = 8; range, 26-130%; p less than 0.001) in vessels preconstricted with ANG I (64-128 pmol/min), with the effect maximal at the end of ramiprilat infusion and subsiding over 30 min. Doses of ANG I required to produce equivalent reductions of FBF were 2 to 4 times those of ANG II before ramiprilat, but after ramiprilat the dose of ANG I required to produce equivalent constriction was increased 20-fold (n = 6; p = 0.01) while that of ANG II was unaltered. Ramiprilat given alone produced only a small nonsignificant increase in FBF of 7 +/- 4% (n = 12; p = 0.29), though this increase did correlate significantly with plasma renin (r = 0.60; p = 0.04). These results confirm the presence of ACE within human resistance vessels and suggest the possibility that inhibition of ACE at sites other than the pulmonary bed might contribute to the hypotensive action of ACE inhibitors.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Forearm; Humans; Hypertension; Kinetics; Peptidyl-Dipeptidase A; Pyrroles; Ramipril; Reference Values; Regional Blood Flow; Renin

Previous studies have indicated that brain angiotensin II (ANG II) in the spontaneously hypertensive rat (SHR) may play an important role in the maintenance of hypertension. Preventing the synthesis of ANG II leads to a reduction in blood pressure and, therefore, brain ANG II levels in the SHR should be higher or have increased turnover than in the Wistar-Kyoto (WKY) rat. To investigate this issue we have dissected discrete areas of the brain from SHR and WKY and extracted, purified and quantified brain ANG II. Significantly higher levels were found in the hypothalamus, striatum, cortex and cerebellum in SHR compared to WKY. The new converting enzyme inhibitor, ramiprilat, injected centrally lowered blood pressure by synthesis inhibition but measurements of brain ANG II after ramiprilat did not indicate increased turnover. Further analysis of the peptide fragments needs to be done before turnover rates can be fully understood.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Brain; Hypertension; Pyrroles; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spinal Cord