enalaprilat-anhydrous and Hypertension--Renal

Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.. Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.. Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.. Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cross-Sectional Studies; Enalapril; Enalaprilat; Female; Genotype; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

This study examined the proposition that kinins are involved in the renal hemodynamic effect of an ACE inhibitor in Goldblatt (GB) hypertension. The effects of the ACE inhibitor enalaprilat were compared in two groups of anesthetized two-kidney one-clip GB rabbits. One group (n = 11) was given enalaprilat (10 mg/kg, i.v.) while a second group (n = 10) received the kinin B2 receptor antagonist, icatibant (2.5-5 microg/kg/min, i.v.) prior to enalaprilat. Enalaprilat caused a 40% rise in renal blood flow and 11 mm Hg decrease in blood pressure in the untreated, but no significant renal effect in the icatibant-treated group. Blood pressure was reduced to the same degree in both groups. The results indicate that kinins play a major role in the renal hemodynamic, but not the blood pressure effect of ACE inhibition in the GB rabbit.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Drug Interactions; Enalaprilat; Hypertension, Renal; Kallikreins; Kidney; Organ Size; Rabbits; Receptor, Bradykinin B2; Renal Circulation

We studied effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on left ventricular (LV) diastolic relaxation in 11 normal control dogs and 16 LV hypertrophied (LVH) dogs with perinephritic hypertension. At baseline, LV systolic and end-diastolic pressures and end-systolic elastance were increased in the LVH group (all P < 0.01 vs. the control group). LV relaxation time constant was also prolonged (P < 0.01), suggesting impaired LV diastolic relaxation in this model of LVH. Before and after the administration of enalaprilat (0.25 mg/kg) and L-158,809 (0.30 mg/kg), LV relaxation was assessed over a wide range of LV loading conditions during vena caval occlusion. LV relaxation time constant was insensitive to load reduction in the control group, which was not affected by enalaprilat or L-158,809. In contrast, LV unloading caused a significant prolongation of the relaxation time constant in the LVH group. This load-sensitive LV relaxation abnormality was significantly improved by enalaprilat or L-158,809. These results support the concept that angiotensin II is involved in the pathogenesis of diastolic dysfunction in pressure-overloaded LVH and also suggest that angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor antagonists are potentially beneficial in the treatment of the hypertrophied heart.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Diastole; Dogs; Enalaprilat; Hemodynamics; Hypertension, Renal; Hypertrophy, Left Ventricular; Imidazoles; Tetrazoles

Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension.. LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels.. At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressure in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Diastole; Disease Models, Animal; Dogs; Enalaprilat; Hypertension, Renal; Hypertrophy, Left Ventricular; Imidazoles; Receptors, Angiotensin; Tetrazoles; Ventricular Function, Left

The current study was performed to determine whether baroreflex resetting after acute administration of converting enzyme inhibitors (CEIs) was dependent on the concomitant decrease in mean arterial pressure (MAP). Reflex changes in lumbar sympathetic nerve activity (LSNA) due to increases and decreases in MAP [i.v. phenylephrine (PE) and nitroprusside infusions] were determined in normotensive and renal hypertensive (1-kidney, 1-clip) anesthetized WKY rats 1) before (control), 2) 15 min after intravenous captopril (2 mg/kg) or enalaprilat (300 micrograms), and 3) 15 min after MAP was returned to pre-CEI levels with intravenous PE. CEIs decreased MAP and caused a leftward shift of the MAP-LSNA curve toward a lower operating pressure range in all hypertensive and in one group of normotensive rats. The baroreflex curve remained shifted to the left even after MAP was restored to pre-CEI levels by infusion of PE. Thus CEIs cause a pressure-independent resetting of baroreflex control of sympathetic outflow within 15 min. This effect of CEIs is most likely due to elimination of a central nervous system effect of circulating angiotensin II and could contribute to the antihypertensive actions of this class of compounds.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Blood Pressure; Captopril; Enalaprilat; Hypertension, Renal; Male; Phenylephrine; Rats; Rats, Inbred WKY; Reference Values; Sympathetic Nervous System; Time Factors

In autosomal dominant polycystic kidney disease (ADPKD) the pathophysiology of hypertension, which is frequently observed before loss of renal function, is not well understood. We investigated intrarenal dopamine, the renin-angiotensin-aldosterone system (RAAS), and plasma endothelin in relation to sodium homeostasis as potential hypertensive factors in this disease.. Eight borderline hypertensive ADPKD patients with (near) normal renal function and seven matched healthy control subjects were investigated at three levels of daily dietary sodium intake: 150, 50 and 450 mmol. In the 450-mmol sodium intake period we studied the effects of renally formed dopamine by infusing its precursor DOPA (DOPAi.v., 7 micrograms kg-1 min-1). In the 50-mmol sodium intake period we studied the influence of the RAAS by administering enalaprilate (42 micrograms kg-1), followed by angiotensin II (12 ng kg-1 min-1) intravenously. GFR and ERPF were measured by continuous infusion of inulin and PAH.. At all levels of sodium intake sodium balances were equal, but daily urinary excretions of dopamine and DOPA were higher (P < 0.01) in the ADPKD patients than in the controls. Renal vascular resistance, filtration fraction and blood pressure were higher in the ADPKD patients (all P < 0.05) while plasma renin activity was similar. DOPAi.v. normalized renal haemodynamics and increased plasma endothelin in ADPKD patients (all P < 0.05), while stimulation of natriuresis was equal in both groups. Enalaprilate increased plasma endothelin in the ADPKD patients and only partially normalized renal haemodynamics.. In borderline hypertensive ADPKD patients: (1) urinary dopamine excretion is increased at all levels of sodium intake, suggesting that this may be needed to maintain sodium balance; (2) stimulation of renal dopamine production is able to normalize renal haemodynamics, making dopamine receptor agonism a potential therapeutic option; (3) the activity of the RAAS is not clearly enhanced; (4) renal vasodilatation increases plasma endothelin levels.

Topics: Adult; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Dihydroxyphenylalanine; Dopamine; Dopamine Agents; Enalaprilat; Endothelins; Female; Hemodynamics; Humans; Hypertension, Renal; Infusions, Intravenous; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Sodium; Sodium, Dietary

The purpose of this study was to compare the acute hypotensive efficacy of different types of inhibitor of the renin-angiotensin system. A renin inhibitor (RI), CGP 44,099 A, a converting enzyme inhibitor (CEI), enalaprilat, a peptidic angiotensin II (Ang II) antagonist, [Sar1, Ile8]Ang II (P-Ang IIA), and a nonpeptidic Ang II antagonist devoid of agonistic properties, 2-butyl-4-chloro-1- ([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl)-5- (hydroxymethyl)imidazol (NP-Ang IIA), were administered intravenously to sodium-depleted rats (SDRs), renal hypertensive rats (two-kidney, one-clip) (RHRs), and spontaneously hypertensive rats (SHRs). The four compounds were all effective in lowering blood pressure (BP) in SDRs and RHRs. The maximum hypotensive response observed within 30 min of administration was similar for all four compounds (approximately 30 mm Hg in SDRs and 60 mm Hg in RHRs). In SHRs, the P-Ang IIA induced a pressor response whereas the RI, CEI, and NP-Ang IIA lowered BP to a similar extent (approximately 15 mm Hg). Pretreatment with the CEI completely prevented the hypotensive response to RI in SHRs, and vice versa. These observations indicate that the principal mechanism by which converting enzyme inhibitors lower BP after acute administration in these rat models is by inhibition of the formation of Ang II. The pressor response to the P-Ang IIA in SHRs is probably a consequence of its partial agonistic properties. Renin inhibitors and nonpeptidic Ang II antagonists, devoid of agonistic properties, promise to be effective antihypertensive agents similar to the CEIs.

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Enalaprilat; Hypertension; Hypertension, Renal; Imidazoles; Losartan; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin; Time Factors

A series of non-sulfhydryl modified dipeptides related to CI-906, CI-907, and enalapril was prepared in which various isosteric moieties (O, S, SO, SO2) have been substituted for the amino group and in which the proline residue has been replaced with various hydrophobic amino acids. The compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme and in vivo for antihypertensive activity. Compound 7c, the most potent member of this series, had an in vitro IC50 of 1.4 X 10(-8) M and showed modest oral antihypertensive activity at 30 mg/kg in conscious, two kidney, one clip Goldblatt hypertensive rats. Structure-activity relationships are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chemical Phenomena; Chemistry; Dipeptides; Enalapril; Guinea Pigs; Hypertension, Renal; Indoles; Isoquinolines; Quinapril; Rats; Structure-Activity Relationship; Tetrahydroisoquinolines