enalapril and Hypertrophy

The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electrolytes; Enalapril; Feces; Healthy Volunteers; Humans; Hypertrophy; Intestinal Mucosa; Intestines; Isoquinolines; Kidney; Male; Myocardium; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sodium; Sodium Chloride, Dietary; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sulfonamides

To determine whether the angiotensin converting enzyme inhibitor enalapril would lower systemic arterial and glomerular capillary pressure and reduce the magnitude of renal injury in a canine model of renal insufficiency.. 18 adult dogs that had renal mass reduced by partial nephrectomy.. After surgical reduction of renal mass and baseline measurements, dogs in 2 equal groups received either placebo (group 1) or enalapril (0.5 mg/kg, PO, q 12 h; group 2) for 6 months.. Values for systemic mean arterial blood pressure determined by indirect and direct measurement after 3 and 6 months of treatment, respectively, were significantly lower in group 2 than in group 1. During treatment, monthly urine protein-to-creatinine ratios were consistently lower in group 2 than in group 1, although values were significantly different only at 3 months. At 6 months, significant reduction in glomerular capillary pressure in group 2 was detected, compared with group 1, but glomerular filtration rate in group 2 was not compromised. Glomerular hypertrophy, assessed by measurement of planar surface area of glomeruli, was similar in both groups. Glomerular and tubulointerstitial lesions were significantly less in group 2, compared with group 1.. Data suggest that inhibition of angiotensin converting enzyme was effective in modulating progressive renal injury, which was associated with reduction of glomerular and systemic hypertension and proteinuria but not glomerular hypertrophy. Inhibition of angiotensin converting enzyme may be effective for modulating progression of renal disease in dogs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dogs; Enalapril; Female; Hypertrophy; Kidney Failure, Chronic; Kidney Glomerulus; Male; Peptidyl-Dipeptidase A; Time Factors

Local pulse pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean blood pressure (BP). The present study was designed to assess whether a beta-adrenoceptor antagonist-based or an ACE inhibitor-based treatment was able to reduce carotid artery wall hypertrophy through a reduction in carotid PP rather than by lowering mean BP and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery.. Ninety-eight essential hypertensive patients were randomized to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high-resolution echo-tracking systems. PP was measured locally with applanation tonometry and independently of mean BP. After 9 months of treatment, mean BP, carotid PP, and intimal-medial thickness (IMT) decreased significantly, with no difference between the 2 groups. The reduction in carotid PP but not in mean BP was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP.. The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Carotid Arteries; Celiprolol; Elasticity; Enalapril; Female; Heart Rate; Humans; Hypertension; Hypertrophy; Male; Middle Aged; Regression Analysis; Single-Blind Method

Local Pulse Pressure (PP) is an independent determinant of carotid artery wall thickness, stronger than mean BP. The present study was designed to assess whether a beta-adrenoceptor antagonist or an ACE inhibitor-based treatment was able to reduce carotid artery wall hypertrophy through the reduction in carotid PP rather than by lowering mean BP, and whether the influence of local PP reduction could also be detected at the site of a muscular artery, the radial artery.. Ninety-eight essential hypertensive patients were randomised to 9 months of double-blind treatment with either celiprolol or enalapril. Arterial parameters were determined with high resolution echotracking systems. PP was measured locally with PP applanation tonometry, and independently of mean BP. After 9 month's treatment, mean BP, carotid PP and intima-media thickness (IMT) decreased significantly, with no difference between the tow groups. The reduction in carotid pression pulsée, but not in mean BP, was a major independent determinant of the reduction in carotid IMT. Radial artery IMT and PP decreased significantly with both treatments. However, the reduction in radial artery IMT was not related to the changes in radial artery PP.. The regression of carotid artery wall hypertrophy during long-term antihypertensive treatment was dependent on the reduction in local PP rather than on the lowering of mean BP. The effect of PP lowering on IMT reduction was observed at the site of an elastic artery but not at the site of a muscular artery.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Carotid Arteries; Celiprolol; Chi-Square Distribution; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Hypertrophy; Male; Pulse; Radial Artery; Regional Blood Flow; Regression Analysis; Tunica Intima; Tunica Media; Ultrasonography; Vascular Resistance

The aim of the study was to determine whether enalapril monotherapy can improve left ventricular diastolic dysfunction (LVDD) in young and mild hypertensive patients without concomitant left ventricular hypertrophy (LVH). Fifty patients with hypertension < or = 160/100 mm Hg, aged < or = 50 years, normal two-dimensional echocardiographic (2-D echo) measurements, and LVDD were enrolled in this study. The LVDD was defined as a transmitral early (E) to atrial (A) peak velocity ratio of < or = 1. The mean documented hypertension was 6.3 years. The mean daily dose of enalapril was 13 mg. Baseline and 24-month follow-up echocardiograms were evaluated. Thirty-eight age- and sex-matched healthy subjects served to establish the normal reference values of 2-D echo measurements. After treatment, peak early diastolic velocity (E) (49 +/- 6 cm/sec v 48 +/- 10 cm/sec; P = not significant), peak atrial velocity (A) (62 +/- 9 cm/sec v 62 +/- 10 cm/sec; P = not significant), and E/A ratio (0.80 +/- 0.10 v 0.78 +/- 0.13; P = not significant) remained unchanged. Moreover, early to atrial velocity-time integral ratio (1.24 +/- 0.08 v 1.23 +/- 0.11; P = not significant) did not change. The left ventricular mass index, relative wall thickness, left ventricular end-systolic diameter, left atrial diameter, fractional shortening, heart rate, and body mass index did not show significant changes in all hypertensive patients. In conclusion, long-term antihypertensive therapy with enalapril did not lead to an improvement of LVDD in young and mild hypertension patients without concomitant LVH.

Topics: Adult; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Echocardiography, Doppler, Color; Echocardiography, Doppler, Pulsed; Enalapril; Female; Heart Rate; Humans; Hypertension; Hypertrophy; Male; Middle Aged; Observer Variation; Ventricular Function, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cell Enlargement; Cell Line; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enalapril; Enzyme Activation; Glycation End Products, Advanced; Humans; Hypertrophy; Kidney Tubules, Proximal; MAP Kinase Signaling System; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type II; S-Nitroso-N-Acetylpenicillamine; Signal Transduction; Thionucleotides

To investigate the protective effect of angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats (SHRs).. A cohort of male SHRs were randomly divided into three groups (n = 10 for each group): pseudo-experimental group, enalapril-treated group as a positive control group, ACE-inhibitory peptide LAP-treated group. After the experiment, the left common carotid artery from each rat was removed for morphological evaluation.. It was observed that the vascular medial thickness, media thickness/lumen diameter, medial cross-sectional area and mean nuclear area of smooth muscle cells of the left common carotid artery in the LAP group or enalapril group were significantly lower than those in the pseudo-experimental group, while there was no significant difference in these parameters observed between the LAP group and enalapril group. Additionally, the vascular area percentage of collagen fibers of the left common carotid artery in the LAP group and enalapril group was significantly lower than that of the pseudo-experimental group.. The protective vessel remodeling effect in SHRs was observed with ACE-inhibitory peptide LAP in SHRs by decreasing blood pressure, inhibiting smooth muscle cell hypertrophy and reducing the proliferation of collagen fibers.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Carotid Artery, Common; Carotid Intima-Media Thickness; Cell Proliferation; Disease Models, Animal; Enalapril; Fibrillar Collagens; Heart Rate; Hypertension; Hypertrophy; Male; Muscle, Smooth, Vascular; Peptides; Rats; Rats, Inbred SHR

One ultimate goal of hypertension therapy is to cause permanent reversal ("regression") of already established hypertension. Our aim was to examine whether high-dose "pulse" treatment with a renin-angiotensin system inhibitor could cause regression of established hypertension and to link this action to reversal of arteriolar hypertrophy and changes in vascular matrix metalloproteinase activities. First, 16-week-old male spontaneously hypertensive rats (n=60) were pulse treated for 2 weeks with high-dose angiotensin-converting enzyme inhibitor (enalapril), angiotensin receptor blocker (candesartan), calcium channel blocker (nifedipine), or vasodilator (hydralazine) with or without salt restriction, and the long-term effects on blood pressure were examined. Second, spontaneously hypertensive rats were treated with angiotensin receptor blocker or calcium channel blocker, and the effects on renal gene expressions, arteriolar structure, and vascular matrix metalloproteinase were compared. Treatment of spontaneously hypertensive rats with different antihypertensive agents caused apparently similar reductions in blood pressure during the course of the pulse treatment, within the limitations of the tail-cuff method. After cessation of medications, blood pressure in the rats treated with renin-angiotensin system inhibitor remained reduced by >30 to 40 mm Hg for 4 months. No such effect was seen with calcium channel blocker or vasodilator. The 2-week angiotensin receptor blocker treatment induced a marked reversal of the arteriolar hypertrophy specifically in the small (30 to 100 microm) renal arterioles, together with increased expression and activity of matrix metalloproteinase-13. In conclusion, transient high-dose pulse treatment with angiotensin receptor blocker caused changes in vascular matrix metalloproteinase activity, specific reversal of renal arteriolar hypertrophy, and regression of hypertension in spontaneously hypertensive rats.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterioles; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hydralazine; Hypertension; Hypertrophy; Kidney; Male; Matrix Metalloproteinase 13; Nifedipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Tetrazoles; Vasodilator Agents

Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Cytochrome P-450 Enzyme System; Enalapril; Enzyme Activation; Enzyme Inhibitors; Fasting; Glucose; Glycogen; Glycogen Synthase Kinase 3; Hypertension; Hypertrophy; Liver; Liver Cirrhosis; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptidyl-Dipeptidase A; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Renin-Angiotensin System

The renoprotection achieved by angiotensin II blockade in the treatment of diabetic nephropathy is well established in both the clinical and the experimental settings. In contrast, the therapeutic efficacy of calcium channel blockers (CCBs) in the treatment of diabetic nephropathy still remains controversial.. In the present study, we compared the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a dihydropyridine CCB, nilvadipine, on nephropathy in the db/db mouse, a rodent model of type 2 diabetes. Male db/db mice were divided into the following three groups at the age of 11 weeks, when treatment was started: vehicle, enalapril (10 mg/kg per day), and nilvadipine (10 mg/kg per day). Blood pressure, urine, and blood chemistry were monitored at the age of 17 and 27 weeks, and kidney samples were obtained at 29 weeks. Morphological changes were analyzed on periodic acid-Schiff-stained sections. Lipid peroxidation in kidney homogenates was measured.. Blood pressure remained normal and was similar in the three groups until 27 weeks. Blood glucose exceeded 300 mg/dl throughout the study in all groups. Reduction of microalbuminuria at 27 weeks, compared to the vehicle group, was 37% and 52% in the enalapril- and nilvadipine-treated groups, respectively. Increased lipid peroxidation was suppressed by 15% and 83% in the enalapril- and nilvadipine-treated groups, respectively. Glomerular hypertrophy, assessed by cross-sectional glomerular area, was significantly suppressed in the nilvadipine group, but not in the enalapril group, compared to the vehicle group.. Nilvadipine shows a stronger renoprotective effect than enalapril in the db/db mouse, independent of the blood-pressure-lowering effect. An antioxidative effect, indicated by the reduction in lipid peroxidation, may partly contribute to the renoprotection conferred by nilvadipine.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glomerular Mesangium; Hypertrophy; Kidney Function Tests; Lipid Peroxidation; Male; Malondialdehyde; Mice; Nifedipine; Organ Size

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats.. Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.. Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).. Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Drug Synergism; Enalapril; Hypertrophy; Kidney; Losartan; Male; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Transforming Growth Factor beta; Transforming Growth Factor beta1

PGE(2) and PGI(2) reduce extracellular matrix deposition and their production is altered after ACE inhibitor (ACEi) treatment. We therefore hypothesized that cyclooxygenase (COX)-2 inhibition would exacerbate renal injury and antagonize the effects of ACEi. To test these hypotheses, WKY and SHR were uninephrectomized (UNX) and treated with either vehicle, enalapril, NS398 or enalapril+NS398. NS398 did not affect systolic blood pressure nor antagonize the antihypertensive effect of enalapril. Urinary protein excretion in UNX WKY was significantly decreased after treatment with either enalapril or NS398. In UNX SHR, enalapril reduced proteinuria, but NS398 alone had no effect. Administration of both drugs, however, further reduced proteinuria. In UNX WKY, treatment with either NS398 alone or both drugs reduced glomerular volume and similar results were observed in SHR. Surprisingly, these results disprove our original hypothesis and suggest that inhibition of COX-2 provides additional renoprotection to that of enalapril alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Collagen Type II; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enalapril; Hypertrophy; Isoenzymes; Kidney Diseases; Male; Nephrectomy; Nitrobenzenes; Organ Size; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sulfonamides

It is still a controversial issue whether different classes of antihypertensive drugs are equally effective in the regression of cardiac hypertrophy and associated complications. The present study compared the effects of prolonged treatment with the Ca2+-channel blocker amlodipine and the ACE inhibitor enalapril, respectively, in TGR(mREN2)27 rats (TGR), an animal model of renin-dependent hypertension. TGR were divided into three groups and received either amlodipine, enalapril or drinking water without addition, Sprague-Dawley rats (SPRD) served as normotensive control group. Cardiovascular parameters were monitored by radiotelemetry, and drug doses were titrated until 24-h blood pressure was reduced to approximately 140/90 mmHg in both active treatment groups. After 8 weeks of treatment left ventricular (LV) hypertrophy was completely reversed in both treatment groups despite a tenfold increase in plasma angiotensin II in amlodipine-treated TGR. In untreated TGR LV catecholamines were depleted, and beta1-adrenergic stimulation of adenylyl cyclase was blunted. Treatment of TGR with enalapril prevented both the depletion of tissue catecholamines and the desensitisation of LV beta1-adrenoceptors. Amlodipine had no effect on cardiac adrenergic signal transduction. Basal activity of LV soluble guanylyl cyclase was not different between TGR and SPRD, but its sensitivity to stimulation by nitric oxide was slightly reduced in TGR. Treatment had no effect on basal and stimulated guanylyl cyclase activity. The present study in an animal model of renin-dependent hypertension suggests that blood pressure reduction per se is sufficient for a regression of cardiac hypertrophy. However, beta-adrenergic desensitisation was prevented only in the enalapril-treated group, supporting a blood pressure-independent contribution of the renin-angiotensin system to the regulation of beta-adrenergic signal transduction.

Topics: Adenylyl Cyclases; Amlodipine; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Blood Pressure; Calcium Channel Blockers; Diastole; Enalapril; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Hypertrophy; Male; Mice; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin; Signal Transduction; Solubility; Systole

Activation of the renal transforming growth factor beta (TGF-beta) axis has been suggested to play a part in the development of diabetic nephropathy by a direct stimulatory effect of hyperglycaemia or through the activation of the renin-angiotensin system. Our aim was to evaluate the involvement of the renin-angiotensin system by examining the effects of ACE-inhibition on intrarenal changes in all three TGF-beta isoforms and receptors in experimental diabetes in vivo.. Immunocytochemistry, western blotting and ribonuclease protection assays were carried out for each TGF-beta isoform and receptor on kidney from non-diabetic and streptozotocin-diabetic rats after treatment with the ACE inhibitor, enalapril, for 30 days.. Enalapril partially prevented the renal hypertrophy and fully prevented the increase in urinary albumin excretion rate in diabetic animals. The glomerular TGF-beta Type II Receptor mRNA and protein concentrations increased over 30 days in untreated diabetic animals compared with non-diabetic controls, while enalapril-treated diabetic animals showed a normalisation of TGF-beta Type II Receptor mRNA and protein.. The ACE-inhibition had pronounced inhibitory effects on the increased expression of the glomerular TGF-beta Type II Receptor in the diabetic kidney required for intracellular signalling through this growth factor axis. This suggests a new mechanism of action of the ACE-inhibition in regulating the development of diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Female; Gene Expression; Hypertrophy; Kidney; Kidney Glomerulus; Organ Size; Peptide Fragments; Procollagen; Rats; Rats, Wistar; Receptors, Transforming Growth Factor beta; RNA, Messenger

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl) propionic acid, prevents deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related organ damage, such as cardiovascular hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with candoxatril and enalapril, which are a selective NEP and ACE inhibitor, respectively. During DOCA-salt treatment for 4 weeks, the rats were given SA7060, candoxatril, enalapril or vehicle, once daily by gavage. The 4-weeks treatment with DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and increases in urinary excretion of protein and blood urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of atrial natriuretic peptide and cyclic GMP in SA7060- or candoxatril-treated animals. Histopathological examination of the kidney in DOCA-salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or candoxatril. When the vascular hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with the sham rats. The development of vascular hypertrophy was suppressed by the treatment with SA7060, candoxatril or enalapril. Our findings indicate that SA7060 efficiently prevents DOCA-salt-induced hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both renin-dependent and renin-independent hypertensive subjects, although further studies examining efficiency in a renin-dependent hypertensive model are needed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Body Weight; Cardiomegaly; Desoxycorticosterone; Enalapril; Heart; Hypertension; Hypertrophy; Indans; Kidney; Kidney Function Tests; Male; Naphthalenes; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Propionates; Rats; Rats, Sprague-Dawley; Urea

We investigated whether angiotensin II (Ang II) and endothelin-1(ET-1) are involved in submandibular hypertrophy in response to repeated treatment with isoproterenol (ISO) in rats. The immunoreactive Ang II (IRAng II) and immunoreactive ET-1 (IRET-1) contents of ISO-induced hypertrophy were significantly higher than those of control glands. Treatment of isolated gland tissues with ISO (1 microM) or dobutamine (1 microM) caused significant increases in the IRAng II and IRET- 1 contents of the glands compared with controls. These increases were suppressed by pretreatment with enalapril (3 microM) or captopril (3 microM). Treatment with Ang II (10 microM) also caused an increase in IRET-1 content. Our findings suggest that Ang II and ET-1 are involved in the submandibular gland hypertrophy that develops in rats repeatedly treated with ISO, and that these biologically active peptides may act as growth factors. They also imply that the tissue renin-angiotensin system and Ang II specific receptors are present in the submandibular glands.

Topics: Adrenergic beta-Agonists; Angiotensin II; Animals; Dobutamine; Enalapril; Endothelin-1; Hypertrophy; Isoproterenol; Male; Rats; Rats, Wistar; Submandibular Gland

Glomerular hyperfiltration and renal hypertrophy are both considered important in the progression of diabetic nephropathy. The aim of this study was to compare the effects of an equivalent reduction in blood pressure produced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPI) and an antihypertensive triple drug combination of hydralazine, reserpine and hydrochlorothiazide (HRH) on kidney function, proteinuria and renal structure in hypertensive diabetic rats.. Four groups of animals were evaluated in short-term and long-term studies. In both studies one group served as a non-diabetic hypertensive control (H). The other three groups were rendered diabetic and were allocated to one of the following groups: the first diabetic group received no specific therapy (HD), the second diabetic group was treated with SPI (HD-SPI) and the third diabetic group was treated with HRH (HD-HRH). In each of the two studies the systolic blood pressure (SBP), 24 h urinary total protein, glomerular filtration rate (GFR), glomerular area, proximal tubular area and glomerular sclerosis were evaluated.. The blood pressure reduction was equal in rats receiving either SPI or HRH. The GFR, proteinuria, glomerular area and tubular area were significantly increased in the HD group, both in the short-term and the long-term study. In the HD-SPI group the diabetic hyperfiltration and renal hypertrophy responses were prevented. In the HD-HRH group the GFR and proteinuria were slightly reduced in the later phases of diabetes, while the glomerular area and tubular area were not affected. Semiquantitative analysis of renal lesions showed that SPI was more effective than HRH in the prevention of the development of glomerulosclerosis.. The results of this study suggest that the control of early adaptive hyperfiltration and renal hypertrophy by SPI may be relevant in the prevention of glomerulosclerosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Diuretics; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Hydralazine; Hydrochlorothiazide; Hypertension; Hypertrophy; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Reserpine; Sodium Chloride Symporter Inhibitors

Most studies on the antiproliferative action of angiotensin converting enzyme inhibitors (ACEI) were performed in a rat hypertensive remnant kidney model with 5/6 kidney ablation which raised objections about the antihypertensive effect of ACEI and the influence of other antihypertensive drugs administered to remnant kidney control rats. To prevent these objections, a normotensive 4/6 remnant kidney model was elaborated and a subantihypertensive dosage of enalapril was used to evaluate its antiproliferative action. Subtotally nephrectomized rats (Nx) markedly increased the remnant kidney weight during a 4-week period and this rise was prevented by the treatment with enalapril (NxE) (Nx +297+/-35 mg vs. sham-operated +145+/-32 mg, p<0.001; NxE +154+/-35 mg vs. Nx p<0.001). While collagen concentration in the kidney cortex was not increased in sham-operated rats (Sham) in comparison with the control group (Ctrl) at the beginning of the study, the subsequent increase was significant in the Nx group and enalapril did not attenuate this increase (Sham 148+/-5 mg/100 g w.w. vs. Nx 164+/-2 mg/100 g w.w., p<0.01; NxE 161+/-4 mg/100 g w.w. vs. Sham p<0.05). The tubular protein/DNA ratio increase, which was significant in the Nx group, was inhibited by enalapril (Nx 26.2+/-10.5 vs. NxE 15.3+/-2.6, p<0.05). The protein/DNA ratio was much lower in glomeruli, with no significant changes in either the Nx or NxE groups. Serum urea concentrations were slightly higher in the Nx group than in the sham-operated group, but markedly elevated in the NxE group (Nx 10.71+/-0.76 mmol/l vs. Sham 6.10+/-0.33 mmol/l, p<0.001; NxE 28.9+/-2.6 mmol/l vs. Sham p<0.001). Creatinine concentrations in the Nx group were increased in comparison with the sham-operated group and markedly increased in the NxE group (Nx 63.7+/-3.56 micromol/l vs. Sham 37.2+/-2.84 micromol/l, p<0.001; NxE 107.0+/-5.2 micromol/l vs. Sham p<0.001). The clearance of creatinine was lower in the Nx group than in the sham-operated group and was markedly reduced in the NxE group (Nx 0.89+/-0.06 ml/min.g kidney wt. vs. Sham 1.05+/-0.16 ml/min x g kidney wt., p<0.01; NxE 0.58+/-0.029 ml/min x g kidney wt. vs. Sham, p<0.001). Enalapril improved proteinuria in comparison with the Nx group (NxE 5.6+/-0.6 mg/24 h vs. Nx 16.1+/-3.4 mg/24 h, p<0.05). Thus remnant kidney proliferation is substantial even in normotensive rats. It includes both proliferation and collagen accumulation with partial recovery of kidney weight and func

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Urea Nitrogen; Cell Division; Collagen; Creatinine; Dose-Response Relationship, Drug; Enalapril; Hyperplasia; Hypertension, Renal; Hypertrophy; Kidney; Male; Nephrectomy; Organ Size; Proteinuria; Rats; Rats, Wistar

Tubular overwork is thought to be a promoter of the tubular hypertrophy and renal failure that occur in response to renal mass reduction. Because Na-K-adenosinetriphosphatase (Na-K-ATPase) is an index of tubular work, we evaluated the effects of subtotal nephrectomy and of enalapril therapy, which delays the evolution of renal lesions, on tubular hypertrophy and Na-K-ATPase activity along the rat nephron. Within 6 wk, 70% reduction of renal mass engendered hypertrophy of the proximal convoluted tubule (PCT), thick ascending limb (TAL), and collecting duct (CD), as well as parallel increments in Na-K-ATPase activity per millimeter tubule length (Na-K-ATPase activity per unit surface area was not modified by subtotal nephrectomy). Chronic enalapril therapy prevented part of the hypertrophy (but not Na-K-ATPase stimulation) of the PCT and the whole stimulation of Na-K-ATPase (but not hypertrophy) in the CD, whereas it had no effect on the TAL. Enalapril effect on Na-K-ATPase in CD might result from reduced bradykinin metabolism, as the reduction in urinary excretion of bradykinin observed in subtotally nephrectomized rats was prevented by enalapril therapy.

Topics: Aldosterone; Animals; Bradykinin; Enalapril; Hypertrophy; Kidney Tubules; Male; Nephrectomy; Nephrons; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

Angiotensin-converting enzyme inhibitors prevent the development of vessel wall hypertrophy in some vascular beds in spontaneously hypertensive rats (SHR), but their effects on hypertrophy of renal arterial vessels have not been studied. We therefore used stereological techniques to study wall and lumen dimensions of the interlobular (cortical radial) and arcuate arteries in the kidneys of SHR (n = 7), SHR treated from 4 to 10 weeks of age with enalapril (25 to 30 mg/kg per day; SHR-E, n = 7), and Wistar-Kyoto rats (WKY, n = 7). All kidneys were perfusion-fixed at 10 weeks. Systolic blood pressure was 199 +/- 9, 139 +/- 11, and 156 +/- 8 mm Hg in the SHR, SHR-E, and WKY groups, respectively. For the interlobular arteries, the volume density of artery wall, wall-to-lumen ratio, and wall thickness in the untreated SHR were significantly greater than in the WKY (0.84 +/- 0.09 versus 0.69 +/- 0.07 x 10(-3), 0.75 +/- 0.20 versus 0.53 +/- 0.08, and 13.6 +/- 3.3 versus 10.6 +/- 0.8 microns, respectively), but values in the SHR-E were similar to those in the untreated SHR (1.10 +/- 0.20 x 10(-3), 0.88 +/- 0.22, and 14.0 +/- 2.6 microns, respectively). For the arcuate arteries, wall thickness and volume density were significantly greater in SHR than WKY (17.3 +/- 3.0 versus 13.9 +/- 1.7 microns and 1.63 +/- 0.51 versus 1.14 +/- 0.27 x 10(-3), respectively), and values in the SHR-E (15.7 +/- 1.7 microns and 1.69 +/- 0.50 x 10(-3), respectively) were not significantly different from those in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Enalapril; Hypertrophy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery

Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide-type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration. In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide.

Topics: Administration, Oral; Animals; Blood Pressure; Calcium; Cardiomegaly; Dose-Response Relationship, Drug; Electrolytes; Enalapril; Food; Hydrochlorothiazide; Hypertrophy; Kidney; Male; Rats; Rats, Inbred WKY; Rats, Wistar; Sodium Chloride, Dietary; Species Specificity

Juxtaglomerular (JG) cell hypertrophy and hyperplasia were investigated in rhesus monkeys given angiotensin II (AII) AT1 receptor antagonists L-158,338 and DUP 753 (MK-0954, losartan).. In 2 initial studies, L-158,338 was given orally at 10, 30, and 90 mg/kg/day for 3 or 14 weeks. To investigate the observed JG hypertrophy and hyperplasia, in a third 5-week experiment L-158,338 was given alone at 90 mg/kg/day, or with physiologic saline supplementation at 25 ml/kg/day, or coadministered with the angiotensin converting enzyme inhibitor enalapril at 10 mg/kg/day. Physiologic saline was given to attempt to suppress renin release through volume expansion and/or sodium retention. Enalapril was given to lower plasma AII levels and observe whether JG cell hypertrophy and hyperplasia were increased or decreased. For comparison, DUP 753 was given at 90 and 300 mg/kg/day. Plasma renin activity and AII concentration were measured in this study.. Dose- and time-dependent increases in JG cell hypertrophy and hyperplasia were seen in the 2 initial experiment. In the third experiment, plasma renin activity and AII concentration were increased 3-fold and 6-fold over pretest values by L-158,338 at 90 mg/kg/day for 5 weeks. Saline supplementation had no effect on these parameters but diminished the group mean severity grade for JG hypertrophy and hyperplasia from 1.5 to 1.0. Enalapril coadministration had no effect on plasma renin activity, whereas it blunted the plasma AII increase caused by L-158,338 and increased the group mean grade to 2.5. DUP 753 at 300 mg/kg/day produced similar increases in plasma renin activity and AII concentration but only resulted in grade 1 JG cell hypertrophy and hyperplasia.. L-158,338-induced JG cell hypertrophy and hyperplasia is an exaggerated pharmacologic response that can be modulated by saline supplementation and angiotensin converting enzyme inhibition. These results suggest that decreased renal perfusion or altered sodium homeostasis and plasma AII concentration are important variables that contribute to AT1 receptor blockade to induce JG cell hypertrophy and hyperplasia.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Dose-Response Relationship, Drug; Enalapril; Hyperplasia; Hypertrophy; Imidazoles; Immunosuppressive Agents; Juxtaglomerular Apparatus; Losartan; Macaca mulatta; Pyridines; Renin; Tetrazoles; Time Factors

Mesangial kinetics were studied in six groups of rats. Rats were either sham operated or were subjected to 1 1/3 nephrectomy (4/6 Nx). Each group was either untreated or was treated with enalapril (EN) or the drug regimen of hydralazine, hydrochlorothiazide, and reserpine (HHR). Four weeks after surgery rats were injected with iodinated aggregated bovine serum albumin (I-aggBSA) and mesangial localization quantified 2, 4, or 8 h later. Mesangial kinetics in untreated 4/6 Nx rats were characterized by accumulation of I-aggBSA to 4 h after injection with rapid clearance over the 4-8-h period; i.e. mesangial trafficking was increased following 4/6 Nx. Mesangial trafficking in 4/6 Nx rats treated with EN was reduced by virtue of lesser uptake of I-aggBSA at 4 h and retarded clearance over 4-8 h when compared with untreated 4/6 Nx animals. Treatment of 4/6 Nx rats with HHR maintained the increased trafficking observed in untreated 4/6 Nx rats. At 30 weeks untreated 4/6 Nx rats had severe albuminuria and glomerulosclerosis. Both indices of renal damage were significantly less in 4/6 Nx rats treated with enalapril. Treatment with HHR did not prevent albuminuria and had only limited effectiveness in preventing glomerulosclerosis. The different effects of EN and HHR on mesangial trafficking and glomerulosclerosis provide further evidence for a relationship between mesangial trafficking following partial renal ablation and subsequent development of glomerulosclerosis.

Topics: Albuminuria; Animals; Antihypertensive Agents; Biological Transport, Active; Enalapril; Glomerular Mesangium; Hydralazine; Hydrochlorothiazide; Hypertrophy; Kidney Glomerulus; Kinetics; Male; Nephrectomy; Rats; Rats, Wistar; Reserpine; Serum Albumin, Bovine; Tissue Distribution

Dietary protein provokes renal growth and synthesis of renin. Because angiotensin II (AII) has growth-promoting properties, we tested the possibility that protein-induced renal growth depends on angiotensin II. Normal adult male rats placed on a high-protein diet (50%) developed significant renal and glomerular growth over 6 days compared with rats on a low-protein diet (6%). However, neither angiotensin converting enzyme inhibition with enalapril nor angiotensin receptor antagonism with losartan influenced the degree of whole-kidney, cortical tubular, or glomerular growth. Thus, angiotensin II is not a necessary factor in dietary protein-induced renal growth in normal adult rats.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Dietary Proteins; Enalapril; Hypertrophy; Imidazoles; Kidney; Losartan; Male; Organ Size; Rats; Rats, Sprague-Dawley; Tetrazoles

Both glomerular hypertension and hypertrophy have been associated with the development of glomerular injury in models of hypertension and reduced renal mass. The purpose of this study was to examine the effects of antihypertensive therapy on these parameters in the remnant kidney model of progressive glomerular sclerosis. Rats underwent 5/6 nephrectomy and were randomly assigned to receive either no therapy, the calcium entry blocker (CEB), nifedipine, or the angiotensin converting enzyme inhibitor (CEI), enalapril. Administration of either drug was associated with a reduction in systemic blood pressure and in the severity of glomerular injury assessed eight weeks after renal ablation. Micropuncture studies four weeks after ablation revealed that systemic and glomerular capillary pressure were high in untreated remnant kidney rats and reduced by enalapril. Administration of nifedipine was associated with a decline in systemic pressure, however, plasma renin levels increased, causing efferent arteriolar vasoconstriction and persistence of glomerular hypertension. Morphometric analysis showed that kidney weight, glomerular volume and glomerular capillary radius were lower in nifedipine treated rats than in the other two groups, indicating that the CEB, but not enalapril, inhibited the hypertrophic response to ablation of renal mass. Therefore, both CEIs and CEBs reduce glomerular injury in rats with remnant kidneys but they may act by different mechanisms. CEI reduce glomerular capillary pressure while CEBs inhibit compensatory kidney growth.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Enalapril; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Hypertrophy; Kidney; Kidney Failure, Chronic; Male; Nifedipine; Proteinuria; Rats; Rats, Wistar

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.

Topics: Animals; Atrial Natriuretic Factor; Binding Sites; Clonidine; Cyclic GMP; Enalapril; Hypertension; Hypertrophy; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Renal growth often precedes scarring in experimental models of chronic renal failure in rats. Its control may therefore influence the subsequent development of renal scarring and failure in these animals. In this study we have attempted to manipulate, by pharmacological interventions, compensatory renal growth in rats who have undergone uninephrectomy. The effects of three drugs--enalapril, verapamil and indomethacin--were investigated. Compensatory renal growth was found to be 15.33 +/- 13.76% (mean +/- SD) 1 week after uninephrectomy in control adult male Wistar rats. Compensatory renal growth was significantly inhibited by pretreatment with enalapril 7.38 +/- 8.88% (P less than 0.05) but was unaffected by indomethacin; the effect of verapamil was inconclusive. In controls, both the protein and DNA content of the remaining kidney increased, indicating a mixed hypertrophic and hyperplastic response. Enalapril inhibited the hyperplastic component of compensatory renal growth. We conclude that following uninephrectomy in rats, compensatory hypertrophy can be manipulated by pharmacological interventions, in particular angiotensin-converting-enzyme inhibition by enalapril.

Topics: Animals; Body Weight; Enalapril; Hypertrophy; Indomethacin; Kidney; Male; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains; Verapamil

We quantitated the glomerular size and the degree of sclerosis simultaneously in individual glomeruli with the use of three-dimensional histological analysis on serial sections obtained from remnant kidneys with highly heterogeneous glomerular lesions after subtotal nephrectomy (sNPX). Four to six weeks after sNPX (Group I, N = 7), 90% of glomeruli had mild sclerosis (sclerosis index, SI; less than 1.5 on a 0 to 4 scale) with a strong positive correlation between the maximum planar area of glomerulus (PAmax) versus SI. Twelve weeks after sNPX (Group II, N = 6) more than 50% of glomeruli had advanced sclerosis (average SI:1.88), and a significant positive correlation was again found between PAmax and SI in glomeruli with mild to modest sclerosis (SI less than 1.5), whereas these two variables were correlated inversely in glomeruli with advanced sclerosis. Administration of enalapril (50 mg/liter drinking water) or hydralazine (200 mg/liter) + hydrochlorothiazide (50 mg/liter) for 12 weeks (Group III, N = 12) markedly attenuated the sclerosis to comparable degrees (average SI: 0.15 vs. 0.22). The former antihypertensive therapy decreased glomerular capillary hydraulic pressure (PGC) to normal range, whereas the latter triple drug therapy was largely without effect on PGC. Of note, the positive correlation between SI and PAmax remained unaffected by these anti-hypertensive drugs. SI of the glomeruli from both treated groups was expressed as a first-order function of PAmax. The correlation coefficient is identical to that found in non-treated Group II remnant glomeruli, so that the degree of sclerosis is mathematically uniquely correlated with the glomerular size, regardless of drug treatment. Thus, within a given remnant kidney, the magnitude of glomerular hypertrophy has a direct correlation with the degree of sclerosis, while the altered glomerular hemodynamic pattern has little modulatory role in determining the magnitude of this hypertrophy. Enalapril and triple drug therapy, at equi-depressor doses in regard to systemic blood pressure, had identical potency in sparing glomerular structure. The primary determinant for this antisclerotic potency appears to be related to the drugs' potency to inhibit glomerular growth rather than an effect on the abnormal hemodynamics which develop in the glomerulus.

Topics: Animals; Antihypertensive Agents; Enalapril; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hydralazine; Hydrochlorothiazide; Hypertrophy; Kidney Glomerulus; Male; Rats; Renal Circulation; Reserpine

The effect of long-term treatment with either enalapril or high dose verapamil on survival, proteinuria, blood pressure and renal morphology was studied in female Wistar rats with markedly reduced renal mass. Four weeks were allowed for remnant kidney hypertrophy before determining the response to renal ablation of individual animals regarding proteinuria and hypertension. At this time, five groups of 18 rats were formed with equal levels of proteinuria and hypertension. Groups E1 and E2 were treated with enalapril, groups V1 and V2 with verapamil, and one group served as control. The daily food allowance was 14 g/rat of a standard rat diet, containing 30% protein and 100 mmol NaCl/kg food in groups E1 and V1. NaCl content was reduced to 20 mmol/kg food in groups E2, V2 and control. The drugs were added to the drinking water, enalapril at a dose of 0.1 g/liter, verapamil at 0.5 to 0.7 g/liter. Drug intake thus amounted to 10 to 25 mg/kg for enalapril and 50 to 140 mg/kg for verapamil. Treatment was continued for 15 weeks. Three of the 18 control rats did not survive up to 15 weeks. Mortality was lower in the enalapril treated groups with a single nonsurvivor in group E1. In contrast, mortality was higher in the verapamil treated animals with seven nonsurvivors in group V1 and eight in group V2. Blood pressure control was excellent in both enalapril treated groups. and proteinuria decreased in most animals of group E1 and all of group 22. Glomerulosclerosis did not develop in the majority of the enalapril treated animals. Despite the high dose, verapamil barely lowered blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Enalapril; Female; Glomerulonephritis; Hypertension, Renal; Hypertrophy; Kidney; Nephrectomy; Proteinuria; Rats; Rats, Inbred Strains; Time Factors; Verapamil