enalaprilat-anhydrous and Hypertension--Renovascular

Angiotensin-converting enzyme inhibition (ACEI) renography is the only imaging examination that tests directly for the presence of renovascular hypertension (RVH); other imaging examinations test only for the presence of renal artery stenosis (RAS). Consensus panels have recommended that ACEI renograms be interpreted as low, intermediate, or high probability for RVH. ACEI renography is highly accurate in patients with normal renal function and suspected RVH. In this patient population, the sensitivity and specificity of ACEI renography for RAS are approximately 90%; as an initial approach, angiography is not cost effective. Data from 10 studies evaluating cure or improvement in blood pressure in 291 patients undergoing revascularization showed the mean positive predictive value of ACEI renography to be 92%. When azotemic patients present with suspected RVH, as many as 50% of patients may have an intermediate probability ACEI renogram and the sensitivity of detecting RVH falls to approximately 80% even when intermediate and high probability tests are combined.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Costs and Cost Analysis; Enalaprilat; Humans; Hypertension, Renovascular; Radioisotope Renography; Radiopharmaceuticals; Renal Artery Obstruction; Sensitivity and Specificity

We investigated the usefulness of phase-contrast MR imaging to measure renal artery velocity waveforms as an adjunct to renal MR angiography. We also examined whether an angiotensin-converting enzyme (ACE) inhibitor improves the diagnostic accuracy of waveform analysis.. Thirty-five patients referred for MR angiography of renal arteries underwent non-breath-hold oblique sagittal velocity-encoded phase-contrast MR imaging through both renal hila (TR/TE, 24/5; flip angle, 30 degrees; signal averages, two; encoding velocity, 75 cm/sec) before and after i.v. administration of an ACE inhibitor (enalaprilat). We analyzed velocity waveforms using established Doppler sonographic criteria. A timing examination with a test bolus of gadolinium contrast material was performed to ensure optimal arterial enhancement during breath-hold gadolinium-enhanced three-dimensional gradient-echo MR angiography.. MR phase-contrast waveform pattern analysis was 50% (9/18) sensitive and 78% (40/51) specific for the detection of renal artery stenosis equal to or greater than 60% as shown on MR angiography. Sensitivity (67%, 12/18) and specificity (84%, 42/50) increased slightly, but not significantly, after i.v. administration of an ACE inhibitor. Also, the accuracy of quantitative criteria such as acceleration time and acceleration index did not improve after the administration of ACE inhibitor.. Renal hilar velocity waveforms, measured using non-breath-hold MR phase-contrast techniques with or without an ACE inhibitor, are insufficiently accurate to use in predicting renal artery stenosis.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Contrast Media; Enalaprilat; False Positive Reactions; Female; Humans; Hypertension, Renovascular; Magnetic Resonance Angiography; Male; Middle Aged; Renal Artery; Sensitivity and Specificity

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P<0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P<0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dihydralazine; Electrophysiology; Enalaprilat; Female; Heart Rate; Humans; Hypertension, Renovascular; Male; Middle Aged; Muscle, Skeletal; Norepinephrine; Peroneal Nerve; Renal Artery Obstruction; Sympathetic Nervous System

1. Twenty-two patients with renovascular hypertension and significant lateralization of renin secretion were investigated with respect to arterial and renal venous plasma noradrenaline and dopamine concentrations before and 30 min after two different blood pressure-lowering procedures (enalaprilat or dihydralazine intravenously). 2. In one group of patients (n = 10) blood pressure reduction by 7.5 mg of dihydralazine caused stimulation of the renin-angiotensin system and increased heart rate (P < 0.01) as well as arterial and renal venous plasma noradrenaline and dopamine concentrations (P < 0.01 for both). The elevation of the plasma dopamine concentration was more pronounced than that of noradrenaline, yielding increased dopamine/noradrenaline ratios both peripherally (P < 0.05) and in the renal veins (P < 0.05). 3. In the second group of patients (n = 12) a comparable reduction in blood pressure elicited by 1.25 mg of enalaprilat was not accompanied by alterations in heart rate or in noradrenaline or dopamine levels in arterial plasma or renal venous plasma from either kidney. 4. Thus, inhibition of angiotensin-converting enzyme does not elicit the expected sympathetic counter-regulatory response to blood pressure reduction; the mechanism(s) involved remains to be clarified.

Topics: Adolescent; Adult; Aged; Dihydralazine; Dopamine; Enalaprilat; Female; Heart Rate; Humans; Hypertension, Renovascular; Male; Middle Aged; Norepinephrine; Renin-Angiotensin System; Stimulation, Chemical; Sympathetic Nervous System; Vasodilator Agents

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cyclic N-Oxides; Disease Models, Animal; Enalaprilat; Glomerular Filtration Rate; Hypertension, Renovascular; Male; Organ Size; Oxygen Consumption; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Renal Circulation; Spin Labels; Tetrazoles; Vascular Resistance

Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O(2)) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (Po(2)) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (N(G)-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical Po(2) of clipped kidneys was significantly lower than contralateral kidneys (35+/-1 versus 51+/-1 mm Hg; n=40 each). ACEI lowered renal venous Po(2), cortical Po(2), renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and N(G)-nitro-L-arginine methyl ester, but not candesartan, reduced the Po(2) of clipped kidneys and blocked the fall in Po(2) with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Enalaprilat; Enzyme Inhibitors; Glomerular Filtration Rate; Hypertension, Renovascular; Imidazoles; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxygen; Partial Pressure; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Circulation; Surgical Instruments; Tetrazoles; Vascular Resistance

Assessment of intrarenal doppler signals is of particular importance in screening for renal artery stenosis. We studied the effect of acute ACE-inhibition (1,25 mg enalaprilate i.v.) on intrarenal resistive indices in 10 hypertensive patients with unilateral renal artery stenosis versus 10 patients with essential hypertension. Any changes limited to poststenotic vessels could possibly improve the diagnostic value of duplex sonography. After ACE-inhibition a significant fall of the intrarenal Resistive Index occurred in both patient groups. In cases of unilateral renal artery stenosis we saw a tendency to an increased side difference of the Resistive Index due to a greater fall on the poststenotic side. Therefore a clear advantage of duplex scanning after acute ACE-inhibition due to a limited effect of enalaprilate on poststenotic vessels was not found. The results suggest that the vascular resistance and not only the degree of renal artery stenosis is of significance for the characteristics of the doppler signal.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalaprilat; Female; Humans; Hypertension, Renovascular; Injections, Intravenous; Male; Middle Aged; Renal Artery Obstruction; Renal Circulation; Ultrasonography, Doppler, Duplex; Vascular Resistance

The influence of the renin-angiotensin system (RAS) on the aortic wall mechanical properties under angiotensin I converting enzyme inhibition (enalaprilat, 0.3 mg/kg iv) or angiotensin II receptor (AT1) blockade (E-3174, 1 mg/kg iv) was examined in eight normotensive and eight renovascular hypertensive conscious dogs. Aortic diameter (D; sonomicrometry)-pressure (P; microtransducer) hysteresis loops during steady state and during rapid distal aortic occlusion allowed (after hysteresis elimination) calculation of the aortic wall viscosity index, the purely elastic P-D relationship, and derivation into compliance-pressure curves. At the early stage ofrenovascular hypertension when activation of RAS is more pronounced, aortic wall stiffness and wall viscosity were increased as compared with normotensive states. Blood pressure remained unchanged in normotensive animals and was reduced during hypertension after antihypertensive treatments. In hypertensive animals, enalaprilat and E-3174 decreased viscosity index and shifted the compliance-pressure curve upward with respect to pretreatment conditions. In normotensive dogs, whereas E-3174 did not change the compliance-pressure curve and viscosity index, enalaprilat increased compliance and reduced viscosity index. We concluded that in normotensive dogs converting enzyme inhibition modifies arterial viscoelastic parameters by angiotensin-independent mechanisms that contribute to the modulation of the buffering function of large arteries.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Dogs; Elasticity; Enalaprilat; Hypertension, Renovascular; Imidazoles; Losartan; Male; Reference Values; Tetrazoles; Viscosity

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalaprilat; Humans; Hypertension, Renovascular; Radioisotope Renography

This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 micrograms.kg-1.min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg.kg-1.h-1 increased renal blood flow (P < .01) and decreased renal vascular resistance (P < .01). The superimposition of the kinin antagonist at 1 micrograms.kg.min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist--the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P < .025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Enalaprilat; Hypertension, Renovascular; Kidney; Kinins; Male; Rats; Rats, Wistar; Receptor, Bradykinin B2; Reference Values; Regional Blood Flow; Renal Circulation; Vascular Resistance

We studied the mechanism of angiotensin-converting enzyme (ACE) inhibition-induced changes in hippurate renography of the poststenotic kidney.. Ten male mongrel dogs, six with unilateral and four with bilateral renal artery stenosis, were equipped with renal artery blood flow probes and catheters in the aorta, atrium and both renal veins.. Enalaprilat (10 mg intravenously) in conscious dogs with renal artery stenoses produced changes in all stenotic (n = 11) but not in nonstenotic kidney 123I-hippurate renograms (n = 6). Renographic changes correlated significantly with initiation of intrarenal 131I-hippurate retention, a decrease in mean arterial pressure (MAP), renal extraction of 131I-hippurate and 125I-iothalamate (r = 0.68, r = 0.62, r = 0.84, r = 0.83, respectively) but not with renal blood flow changes (r = 0.34). Furthermore, renal uptake of 131I-hippurate and 125I-iothalamate decreased in stenotic kidneys with a grade II renogram (-52 +/- 11% and -79 +/- 6%, respectively). Iodine-125-hippurate autoradiograms of stenotic kidneys during ACE inhibition showed tracer retention mainly in the proximal tubular cells. Results during osmotic diuresis supported our findings.. Angiotensin-converting enzyme inhibition-induced hippurate retention curves of poststenotic kidneys appear to result from a sequence of events. A decrease in MAP combined with efferent vasodilation leads to a decrease in intraglomerular capillary pressure. This decrease in pressure causes a decrease in glomerular filtration rate and proximal tubular urine flow. This decrease in turn hampers tubular hippurate transit and transport across the luminal membrane, leading to intrarenal hippurate retention and, in more severe cases, decreased renal hippurate uptake.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Blood Pressure; Contrast Media; Dogs; Enalaprilat; Glomerular Filtration Rate; Hypertension, Renovascular; Iodine Radioisotopes; Iodohippuric Acid; Iothalamic Acid; Kidney; Male; Radioisotope Renography; Renal Circulation; Time Factors

Angiotensin I-converting enzyme (ACE) is known to be present at the surface of endothelial cells and also in the adventitia in large vessels. The presence of ACE in the vascular smooth muscle remains controversial. We microdissected segments of adventitia and media with or without endothelium from a region devoid of collateral arteries. The membrane-bound ACE activity in the media averaged 41% (pmol [glycine-1-14C]hippuryl-L-histidyl-L-leucine hydrolyzed.g tissue-1.min-1) of the values found in the whole aorta, whereas the adventitia contained only 6%. Immunoreactive ACE in media was characterized by Western blotting. ACE mRNAs were detected and characterized after polymerase chain amplification in isolated media. Angiotensin I and angiotensin II were equally able to contract medial rings, and the response to angiotensin I was blocked by enalaprilat. In aortas of two-kidney, one-clip hypertensive rats, there was an increase in ACE mRNA estimated by ribonuclease protection assay (P = 0.02) and in ACE activity at 15 days and 1 and 3 mo after clipping. This corresponded to a 1.5- to 2-fold increase in the ACE activity of both the media and the adventitia compared with sham-operated rats (P < or = 0.02). Thus ACE gene expression occurs in smooth muscle of rat aorta, which contains roughly the same amount of enzyme as the endothelium and readily converts angiotensin I to angiotensin II. ACE in the medial layer and the adventitia is upregulated in renovascular hypertension.

Topics: Animals; Aorta, Thoracic; Base Sequence; Blood Pressure; Blotting, Western; Carbon Radioisotopes; DNA Primers; Enalaprilat; Gene Expression; Hypertension, Renovascular; Male; Molecular Sequence Data; Muscle Contraction; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Reference Values; RNA, Messenger

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalaprilat; Female; Humans; Hypertension, Renovascular; Male; Radioisotope Renography; Technetium Tc 99m Mertiatide; Technetium Tc 99m Pentetate

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as angiotensins, atrial natriuretic factor (ANF), bradykinin and endothelin. The effects of a highly selective NEP inhibitor (NEPI), retrothiorphan, of a converting enzyme inhibitor (CEI), enalaprilat, and of the combination, CEI + NEPI, were assessed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs) and renovascular hypertensive rats. NEPI increased diuresis, natriuresis and urinary cyclic GMP (cGMP), ANF and bradykinin in the three models. NEPI decreased blood pressure in DOCA-salt hypertensive rats only, whereas CEI decreased blood pressure in SHRs and renovascular hypertensive rats only and increased plasma renin. CEI had no effect on urinary aldosterone or bradykinin in any of the three models. CEI + NEPI increased diuresis and natriuresis in DOCA-salt hypertensive rats and SHRs, and increased urinary cGMP, ANF and bradykinin and plasma renin levels. CEI and NEPI interacted significantly to decrease blood pressure and to increase urinary cGMP in SHRs only. Hence, NEPI increases diuresis, natriuresis and urinary cGMP, ANF and bradykinin in experimental hypertension, whereas CEI acts on blood pressure and increases in plasma renin in SHRs and renovascular hypertensive rats. The significant interaction between CEI and NEPI to decrease blood pressure in SHRs indicates that simultaneous blockade of the two metallopeptidases results in potentiation of the hypotensive effect and that the SHRs appear to be a good model for studying NEP and ACE coinhibition. Finally, NEP rather than ACE appears to be involved in bradykinin renal catabolism in experimental hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone; Diuresis; Enalaprilat; Hypertension, Renovascular; Kidney; Male; Natriuresis; Neprilysin; Protease Inhibitors; Rats; Rats, Inbred SHR; Rats, Wistar; Sodium Chloride; Sulfhydryl Compounds; Thiorphan

The relationship between the renin-angiotensin system and erythropoietin was studied in twenty patients with renal artery stenosis and hypertension. Ten of the patients had a unilaterally activated renin-angiotensin system (group 1), while ten patients had not (group 2). Plasma erythropoietin was simultaneously measured in a brachial artery and both renal veins before and 5 and 30 min after an intravenous injection of 1.25 mg enalaprilat. The mean (+/- SD) arterial erythropoietin concentration was 27.3 +/- 16.8 mU/ml in group 1 and 14.1 +/- 11.3 mU/ml in group 2 patients (P less than 0.05). There was no significant change after enalaprilat i.v. in either group. The venous erythropoietin concentration in plasma from the stenotic kidney did not differ from that of the contralateral kidney. The higher erythropoietin concentration in group 1 patients may be explained by a systemic stimulatory effect of the renin-angiotensin system on erythropoietin production. As no side-differences were found, renal vein as well as peripheral erythropoietin measurements cannot be used as a tool in the diagnosis of the functional significance of a renal artery stenosis.

Topics: Adult; Aged; Enalaprilat; Erythropoietin; Female; Humans; Hypertension, Renovascular; Male; Middle Aged; Renal Artery Obstruction; Renal Veins; Renin-Angiotensin System

The effect of rapid converting enzyme inhibition (CEI) with intravenous enalaprilat on technetium-99m-(99mTc) diethylenetriaminepentaacetic acid (DTPA) and 99mTc-dimercaptosuccinic acid (DMSA) renograms was evaluated in rats with two-kidney, one-clip renovascular hypertension. Rapid sequential DTPA renograms, performed immediately before and five minutes after enalaprilat injection (30 micrograms/kg), demonstrated a selective decrease in clipped kidney DTPA plasma clearance following CEI and no significant effect on unclipped kidney function. Pre- and post-CEI data were obtained with a single injection of DMSA by administering enalaprilat five minutes after the radiopharmaceutical. Enalaprilat slowed the rate of DMSA accumulation in clipped relative to unclipped kidneys, and reduced the clipped/unclipped kidney ratio of absolute DMSA uptake at 10 and 30 min. DTPA and DMSA were equally effective in demonstrating the CEI effect. Enalaprilat was also compared with captopril (3 mg/kg, intraperitoneally), using sequential DTPA renograms. Clipped kidney DTPA plasma clearance was reduced to an identical degree (40%) by both converting enzyme inhibitors. Clinical renographic protocols can probably be devised to take advantage of the rapid, reliable CEI of enalaprilat, thereby shortening total procedure time.

Topics: Animals; Enalaprilat; Furosemide; Hypertension, Renovascular; Kidney; Male; Organotechnetium Compounds; Pentetic Acid; Radioisotope Renography; Rats; Rats, Inbred Strains; Succimer; Technetium Tc 99m Dimercaptosuccinic Acid; Technetium Tc 99m Pentetate; Time Factors

The effectiveness of 2 angiotensin converting enzyme inhibitors, intravenous enalaprilat and oral captopril, in stimulating renin secretion was compared in 47 hypertensive patients with suspected renovascular hypertension. Both inhibitors were more effective stimuli to renin secretion than head-up tilting of the patient. In patients with unilateral renovascular hypertension single doses of angiotensin converting enzyme inhibitors increased the renal venous renin ratio compared to the recumbent ratio. This therapy reduced the number of false negative studies more effectively than head-up tilting and was tolerated better. Contralateral suppression of renin in the unaffected kidney, an important ancillary diagnostic marker of unilateral renovascular hypertension, was preserved. No false positive studies owing to the use of angiotensin converting enzyme inhibitors acutely were apparent. Mean arterial pressure decreased by 5 minutes with intravenous enalaprilat and by 20 minutes with oral captopril, and it continued to decrease gradually for at least 2 hours. No significant syncopal symptoms were observed with either inhibitor. Plasma renin activity increased by 5 and 15 minutes with enalaprilat and captopril, respectively. Plasma aldosterone levels decreased by 10 minutes with enalaprilat and by 30 minutes with captopril, and these changes increased in magnitude during the 2 hours of observation. To achieve the maximum diagnostic effectiveness from the renal venous renin ratio, single dose angiotensin converting enzyme inhibitors warrant consideration for routine use. Intravenous enalaprilat may be preferable because of certain achievement of an effective blood level.

Topics: Administration, Oral; Aldosterone; Blood Pressure; Captopril; Enalapril; Enalaprilat; False Negative Reactions; Humans; Hypertension, Renovascular; Infusions, Intravenous; Renin

The tubuloglomerular feedback (TGF) mechanism was evaluated in the nonclipped kidney of Goldblatt hypertensive rats from both stop flow pressure (SFP) and single nephron glomerular filtration rate (SNGFR) responses to step increases in late proximal perfusion rate from 0 to 40 nl/min. During control conditions, increases in late proximal perfusion rate produced flow dependent decreases in SFP and SNGFR with maximal values of 10.2 +/- 1.0 mm Hg and 12.9 +/- 2.5 nl/min, values similar to those obtained in normal rats. During ACE inhibition (MK 422; 0.6 mg/kg/hr), arterial pressure decreased from 168 +/- 8 to 137 +/- 7 mm Hg and there was a marked attenuation in the magnitude of SFP feedback responses (delta = 2.5 +/- 0.3 mm Hg). SNGFR feedback responses, however, were not significantly impaired. Direct decreases in renal arterial pressure reduced control SFP but SFP feedback responses were maintained, indicating that the attenuated SFP feedback responses during ACE inhibition were not due to decreased arterial pressure. Superimposed infusion of angiotensin II during ACE inhibition partially restored SFP feedback responses. In contrast, norepinephrine infusion did not result in a similar restoration of SFP feedback sensitivity. These results indicate that the nonclipped kidney of Goldblatt hypertensive rats has an intact TGF mechanism as assessed from SFP and SNGFR feedback responses. Furthermore, ACE inhibition attenuates SFP but not SNGFR feedback responses, and systemic angiotensin II infusions can restore SFP feedback responsiveness towards normal.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Enalaprilat; Feedback; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney Glomerulus; Kidney Tubules; Male; Rats; Renal Circulation

Hypertension was induced in marmosets by ligating the minor branch of one renal artery. The blood pressure (BP), measured by a tail-cuff method, increased to hypertensive levels within 4-5 weeks and the maximum increases occurred after 4-15 weeks (BP, mean +/- s.e.m. was 120 +/- 3 and 152 +/- 6 mmHg before and 10 weeks after ligation, respectively; n = 9). There was a small increase in plasma renin activity (PRA) after 2 weeks, but PRA decreased thereafter and there was no correlation between PRA and BP. The renin inhibitor CGP 29,287 (Ciba-Geigy Ltd., Basle, Switzerland, synthesized by D.B. Rinker and P. Bühlmayer; 1 mg/kg i.p.) and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat (Merck Sharp and Dohme, USA.; 2 mg/kg i.p.), lowered the BP of the hypertensive marmosets to normotensive levels. These results indicate that although PRA is not elevated in this primate model of hypertension, BP is dependent on the activity of the renin-angiotensin system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Callitrichinae; Enalapril; Enalaprilat; Female; Heart Rate; Hypertension, Renovascular; Infarction; Kidney; Male; Oligopeptides; Renin

The hypotensive efficacy of a potent new renin inhibitor (N alpha-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA+ ++-L- phenylalanyl amide) containing (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy pentanoic acid (ACHPA) was compared with the converting enzyme inhibitor (enalaprilat) (MK-422) in conscious one-kidney dogs before and after tightening a renal artery clamp. Dose-response curves to 0.003 to 0.1 mg/kg/min i.v. infusions of the ACHPA-containing renin inhibitory peptide or enalaprilat (0.003-0.1 mg/kg i.v. bolus) were obtained in one-kidney dogs before and 3 days and 14 days after renal artery constriction. The ACHPA-containing renin inhibitory peptide and enalaprilat maximally decreased blood pressure by 10 +/- 2 and 9 +/- 2 mm Hg before constriction and by 12 +/- 2 and 12 +/- 4 mm Hg in dogs treated 14 days after renal artery constriction, respectively. Glomerular filtration rate and effective renal plasma flow were unaltered or slightly improved. In sharp contrast, both compounds elicited significant, dose-related decreases in blood pressure (-26 +/- 4 and -20 +/- 4 mm Hg, respectively), glomerular filtration rate (-21 +/- 3 and -23 +/- 3 ml/min), and renal plasma flow (-45 +/- 14 and -48 +/- 13 ml/min) in dogs examined 3 days after renal artery constriction. These data demonstrate that ACHPA-containing renin inhibitory peptide and enalaprilat are equally effective antihypertensive agents in dogs with renin-dependent renovascular hypertension and lend credence to the contention that the renin-angiotensin system supports renal function in hypertensive states in which renin levels are elevated.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dogs; Enalapril; Enalaprilat; Female; Glomerular Filtration Rate; Hypertension, Renovascular; Oligopeptides; Renal Circulation; Renin

The authors recently reported the development of a new method for measuring angiotensin converting enzyme (ACE) by means of a highly sensitive angiotensin II RIA technique. We have carried out a comparative study of the pharmacological properties of captopril and MK-422, two ACE inhibitors recently developed as new antihypertensive agents. In this study, in vivo and in vitro animal experiments were performed using the Göttingen Mini-pig (Mini-pig G) animal model of the human disease. In the in vivo experimental system, each drug was administered by intravenous injection at a dose of 1 mg/kg, and a slight difference was found in the time-course of the per cent inhibition of ACE in the blood. In the in vitro system (cultured aortic endothelial cells), the ACE inhibitory activities of the two drugs were compared in terms of the 50%-inhibition point on the dose response curve, and it was found that MK-422 was about 100 times more potent than captopril. These results indicate that our newly-developed experimental system can be useful in the establishment of the clinical dose of vasoactive drugs that act on the renin-angiotensin system.

Topics: Animals; Antihypertensive Agents; Captopril; Enalapril; Enalaprilat; Enzyme Inhibitors; Hypertension, Renovascular; Peptidyl-Dipeptidase A; Radioimmunoassay; Renin-Angiotensin System; Swine; Swine, Miniature

The angiotensin I converting enzyme (ACE) inhibitor enalapril (MK-421), at a dose of 1 mg/kg or more by gavage twice daily, effectively inhibited the pressor response to angiotensin I for more than 12 h and less than 24 h. Plasma renin activity (PRA) did not change after 2 or 4 days of treatment at 1 mg/kg twice daily despite effective ACE inhibition, whereas it rose significantly at 10 mg/kg twice daily. Blood pressure fell significantly and heart rate increased in rats treated with 10 mg/kg of enalapril twice daily, a response which was abolished by concomitant angiotensin II infusion. However, infusion of angiotensin II did not prevent the rise in plasma renin. Enalapril treatment did not change urinary immunoreactive prostaglandin E2 (PGE2) excretion and indomethacin did not modify plasma renin activity of enalapril-treated rats. Propranolol significantly reduced the rise in plasma renin in rats receiving enalapril. None of these findings could be explained by changes in the ratio of active and inactive renin. Water diuresis, without natriuresis and with a decrease in potassium urinary excretion, occurred with the higher dose of enalapril. Enalapril did not potentiate the elevation of PRA in two-kidney one-clip Goldblatt hypertensive rats. In conclusion, enalapril produced renin secretion, which was in part beta-adrenergically mediated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dinoprostone; Dipeptides; Electrolytes; Enalapril; Enalaprilat; Heart Rate; Hypertension, Renovascular; Indomethacin; Kallikreins; Male; Prostaglandins E; Rats; Rats, Inbred Strains; Renin