lisinopril and Hypertension--Renal

To investigate the antihypertensive efficacy, dosing, tolerability and effects on growth of lisinopril (off label-use) in paediatric patients during long-term treatment.. We conducted a retrospective analysis of data from 123 patients treated with lisinopril in a paediatric nephrology clinic over a 9.3-year period. Patients were categorised by age group and predominant clinical diagnosis: hypertension (n=59), renal parenchymal disease (n=27), diabetes mellitus (n=33) and miscellaneous (n=4).. The vast majority were Caucasian (93%) and boys (66%). Mean duration of treatment was 2.0 years. Age at start of treatment ranged from two months to 17.7 years. Mean lisinopril starting and final doses were 0.105 mg/kg/day for hypertensive patients and 0.108 mg/kg/day for patients with renal disease, respectively. The most common adverse event was hypotension (8.6% of the patients). Haematology and serum biochemistry profiles were unaffected by lisinopril. Growth was not different from data recorded by Belgian population studies. In 29 of the 47 hypertensive patients who received lisinopril monotherapy, comparing blood pressure (BP) at baseline and after six months treatment, mean reductions in systolic/diastolic BP were 19/18 mmHg.. Lisinopril was well tolerated in paediatric patients. Doses of 0.1 mg/kg/day produced clinically significant BP reduction in hypertensive patients.

Topics: Antihypertensive Agents; Child; Growth; Humans; Hypertension, Renal; Lisinopril; Medical Records; Retrospective Studies; Treatment Outcome

Renal glycosuria associated with the use of angiotensin-converting enzyme inhibitors has been previously reported in two patients. A third patient was studied who developed isolated glycosuria associated with lisinopril therapy. As in the two previously described patients, this patient had a normal serum glucose level, underlying hypertension, and onset of glycosuria between 2 and 16 weeks after initiation of therapy with an angiotensin-converting enzyme inhibitor. The patient had renal artery stenosis with elevated renin levels. Age, time until resolution of glycosuria, and a rise in serum creatinine level did not have a consistent relationship with glycosuria associated with angiotensin-converting enzyme inhibitor therapy. Since glycosuria was the only defect noted, without evidence of any other urinary solutes, angiotensin-converting enzyme inhibitors may exert an effect on the glucose-specific proximal tubule transport system.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glycosuria, Renal; Humans; Hypertension, Renal; Lisinopril; Male

Microalbuminuria is known as an independent predictor for stroke, myocardial infarction, and death. The purpose of the VALERIA trial was a comparison of the efficacy and safety of combination therapy of valsartan and lisinopril with valsartan and lisinopril high-dose monotherapy in patients with hypertension and microalbuminuria.. This was a randomized, double-blind, interventional, parallel-group study. After a washout/placebo-run-in phase of 3 weeks, 133 patients were randomized to treatment (1: 1:1) with either lisinopril 40 mg, valsartan 320 mg, or a combination of valsartan/lisinopril 320/20 mg for 30 weeks.. At baseline, the urine albumin creatinine ratio was similar for the three treatment groups (geometric means, lisinopril 9.6 mg/mmol, valsartan 9.1 mg/mmol, and valsartan/lisinopril 9.5 mg/mmol). After 30 weeks of treatment, the geometric mean urine albumin creatinine ratio had decreased in all three groups by 41, 51, and 62% to 5.7 mg/mmol (lisinopril), 4.5 mg/mmol (valsartan), and 3.6 mg/mmol (valsartan/lisinopril). The decrease for valsartan/lisinopril was statistically significantly greater compared with lisinopril [adjusted ratio 60%, confidence interval (38-94%), P = 0.029]. Normalization of microalbuminuria was greatest with valsartan and valsartan/lisinopril (lisinopril 17%, valsartan 31%, and valsartan/lisinopril 38% of patients) and was statistically significant for lisinopril in contrast with valsartan/lisinopril (P = 0.034). Differences in blood pressure reduction between the groups were not statistically significant. All treatments were safe and well tolerated.. The combination of valsartan and lisinopril provided a significantly better reduction of urine albumin creatinine ratio and more than doubled the rate of patients with normalized urine albumin creatinine ratio compared with lisinopril alone. All treatments were safe and well tolerated.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Lisinopril; Male; Middle Aged; Tetrazoles; Treatment Outcome; Valine; Valsartan

Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. We examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine MCP-1 and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor.. In 22 patients with type 2 diabetes and diabetic nephropathy in stages 3-5, treatment with the ACEI lisinopril was initiated. Before treatment and after 12 months of continuous therapy, proteinuria, creatinine clearance, uMCP-1 levels, BMI, HbA(1c), and serum cholesterol were assessed.. Lisinopril treatment improved renal function. Proteinuria decreased from 410 +/- 662 mg per 24 h to 270 +/- 389 mg per 24 h. Creatinine clearance rose from 61 +/- 26 to 77 +/- 41 ml/min. Urinary MCP-1 levels decreased from 0.456 +/- 0.22 ng/mg creatinine to 0.08 +/- 0.096 ng/mg creatinine. The change in uMCP-1 correlated significantly (r = 0.61, P < 0.001) with the change in proteinuria. No other parameter correlated with the improvement in renal function.. Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension, Renal; Kidney; Lisinopril; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Treatment Outcome

Increased renal vascular resistance and microalbuminuria are associated with hypertensive target organ damage and may be predictors of hypertensive nephrosclerosis.. We investigated changes in renal resistive index (RI) and urinary albumin excretion (UAE) in a group of patients with primary hypertension before and during long-term antihypertensive treatment.. Thirty-two patients were randomized to receive antihypertensive treatment with either a calcium channel blocker (nifedipine GITS, up to 90 mg/day, n = 16) or an ACE inhibitor (lisinopril, up to 20 mg/day, n = 16), alone or in association with a diuretic (chlortalidone, 25 mg/day). Blood pressure, renal resistive index (by US Doppler) and UAE (mean of three nonconsecutive timed urinary collections, microg/min) were evaluated at baseline and over the course of 24 months of treatment.. Both regimens effectively lowered blood pressure (mean blood pressure from 123 +/- 1.8 at baseline to 103 +/- 1.5 mm Hg at 24 months in the lisinopril group and from 122 +/- 1.9 at baseline to 104 +/- 0.8 at 24 months in the nifedipine group, p < 0.001 for both groups). Overall, blood pressure decrease was associated with a reduction in UAE and no change in RI throughout the study. However, despite similar blood pressure reduction, the two regimens showed different specific effects. Lisinopril was associated with a significant decrease in both UAE (33.8 +/- 16.2 at baseline and 9.1 +/- 2.1 at 24 months, p < 0.01) and renal RI (0.61 +/- 0.02 at baseline and 0.56 +/- 0.04 at 24 months, p < 0.05) while nifedipine GITS did not significantly influence UAE (35.7 +/- 12.2 at baseline and 31.2 +/- 12.1 at 24 months, n.s.) or RI (0.61 +/- 0.01 at baseline and 0.59 +/- 0.02 at 24 months, n.s.).. Effective blood pressure control over a long period of time reduces the severity of organ damage, namely UAE while maintaining renovascular resistance in patients with essential hypertension. Different classes of antihypertensive agents might convey additional specific renal protection beyond blood pressure control. These data could be useful in devising individualized therapeutic strategies in hypertensive patients at increased renal risk.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Female; Humans; Hypertension, Renal; Lisinopril; Male; Middle Aged; Nifedipine; Renal Circulation; Vascular Resistance

Cardiac complications are the main cause of death in renal transplantation (RT), and left ventricular hypertrophy (LVH) may play an important role in these patients. The unfavorable genotype of the angiotensin-converting enzyme (ACE) gene has been associated with cardiovascular disease, including LVH. ACE inhibitors (ACEIs) reduce LVH, but little is known about the effects of ACEIs on LVH in RT patients with different insertion/deletion (I/D) genotypes of the ACE gene.. We prospectively studied 57 stable nondiabetic RT patients with hypertension and echocardiographic LVH as well as a functional graft for 69.5 +/- 5.6 months. Patients randomly received either lisinopril 10 mg/day (group A, N = 29; 5 were excluded due to reversible acute renal failure) or placebo (group B, N = 28) for 12 months. Echocardiography (M-mode, 2-B, and color flow Doppler) was performed at baseline and 6 and 12 months later by the same examiner without previous knowledge of the genetic typing. The ACE genotype (I or D alleles) was ascertained by polymerase chain reaction (PCR; group A, DD = 10 and ID/II = 14; group B, DD = 15 and ID/II = 13).. All patients maintained a good renal function (serum creatinine <2.5 mg/dL) during the follow-up and both groups received a similar proportion of antihypertensive drugs (beta-blockers 83 vs. 79%; Ca antagonists 66 vs. 68%; alpha1-adrenoreceptor antagonists 50 vs. 67%) during the study. As expected, mean arterial blood pressure and hemoglobin levels showed a higher percentage reduction in group A versus group B (-4 +/- 2.8 vs. 2.1 +/- 2.6%, P = 0.07, and -11.5 +/- 1.5 vs. -0.5 +/- 2.3%, P < 0.01, respectively). Group A patients showed a significantly higher decrement in LV mass index (LVMI) than group B at the end of follow-up, after adjusting for age, baseline LVMI, time after grafting and changes in systolic blood pressure, renal function, and hemoglobin levels (group A, -9.5 +/- 3.5% vs. group B, 3 +/- 3.2%, P < 0.05). As a result, 46% of group A and only 7% of group B patients showed a reduction of LVMI >/=15% (P < 0.01). The beneficial effect of lisinopril on LVMI reduction was more evident in DD patients (placebo DD, 8.4 +/- 4.1% vs. lisinopril DD, -7.2 +/- 5.3, P < 0.05), and a trend was observed in patients with other genotypes (placebo ID/II, 2.8 +/- 5.4% vs. lisinopril ID/II, -11.4 +/- 5%, P = 0.33).. Lisinopril decreases LVM in renal transplant patients with hypertension and LVH, and the ACE gene polymorphism may predict the beneficial effect of this therapy. This finding may be important in targeting prophylactic interventions in this population.

Topics: Acute Kidney Injury; Adult; Aged; Cardiotonic Agents; Echocardiography; Female; Humans; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney Transplantation; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prospective Studies; Single-Blind Method; Uremia

The aim of our study was to evaluate whether inhibition of ACE (lisinopril 10-20 mg/day) can reduce the rate of decline in kidney function more than reducing blood pressure with conventional antihypertensive treatment (atenolol 50-100 mg/day), usually in combination with a diuretic. We performed a prospective, randomized, parallel study for 42 months, double blind for the first 12 months and single blind thereafter. Forty-three (21 lisinopril and 22 atenolol) hypertensive NIDDM patients with diabetic nephropathy were enrolled. Data from 36 patients (17 lisinopril and 19 atenolol, 60 +/- 7 years of age, 27 men) who completed at least 12 months of the study period are presented. At baseline, the two groups were comparable: glomerular filtration rate (51Cr-EDTA plasma clearance) was 75 +/- 6 and 74 +/- 8 ml x min(-1) x 1.73 m(-2), mean 24-h ambulatory blood pressure (A&D TM2420) was 110 +/- 3 and 114 +/- 2 mmHg, and 24-h urinary albumin excretion rate was 961 (range 331-5,727) and 1,578 (476-5,806) mg/24 h in the lisinopril and atenolol groups, respectively. The mean follow-up time was similar, 37 and 35 months in the lisinopril and atenolol groups, respectively. Mean ambulatory blood pressure was equally reduced in the two groups, 12 +/- 2 and 10 +/- 2 mmHg in the lisinopril and atenolol groups, respectively. Glomerular filtration rate declined in a biphasic manner with a faster initial (0 to 6 months) change of 1.25 +/- 0.49 and 0.81 +/- 0.29 ml x min(-1) x month(-1) followed by a slower sustained decline (6 to 42 months) of 0.59 +/- 0.10 and 0.54 +/- 0.13 ml x min(-1) x month(-1) in the lisinopril and atenolol groups, respectively. No significant differences were observed in either initial or sustained decline in glomerular filtration rate between the two groups. Urinary albumin excretion was reduced (% reduction of baseline) more in the lisinopril than in the atenolol group, at 55 (95% CI 29-72) and 15% (-13 to 34), respectively (P = 0.01). In conclusion, the relentless decline in kidney function characteristically found in hypertensive NIDDM patients with diabetic nephropathy can be reduced equally effectively by two antihypertensive treatments, the beta-blocker atenolol and the ACE inhibitor lisinopril.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atenolol; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney; Lisinopril; Male; Middle Aged; Prospective Studies; Rabbits; Single-Blind Method; Time Factors

Topics: Adult; Basement Membrane; Captopril; Double-Blind Method; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Circulation

Renal transplantation is frequently accompanied by systemic hypertension. In the present study we evaluated the effect of 2.5 mg lisinopril in 12 hypertensive and proteinuric renal graft recipients with stable graft function over 3 months. Only patients with absence of renal artery stenosis, at least as judged by technetium-scan imaging, were included. Lisinopril was effective in lowering systemic blood pressure. Mean arterial pressure was unchanged despite reduction of concomitant antihypertensive medication. Mean serum creatinine was unchanged during the study (1.95 +/- 0.8 mg/dl in the pretreatment period vs. 1.77 +/- 0.76 mg/dl in the intervention period, n.s.). Glomerular filtration rate remained stable (62.75 +/- 21.96 vs. 60.17 +/- 18.27 ml/min/1.73 m2, n.s.) whereas renal plasma flow increased (224.75 +/- 91.66 vs. 244.92 +/- 94.13 ml/min/1.73m2, P < 0.01), leading to a drop in filtration fraction (31.4 +/- 12.4 vs. 26.8 +/- 8.6, n.s.). Renal vascular resistance was significantly reduced following angiotensin-converting enzyme (ACE) inhibitor therapy (26,447 +/- 14,574 vs. 23,425 +/- 12,430 dyne sec cm-5/1.73 m2, P < 0.01). Mean daily proteinuric decreased significantly (2.98 +/- 2.06 vs. 2.06 +/- 2.29 g, P < 0.01) whereas in a group of patients with comparable blood pressure but without ACE inhibitor therapy and similar degree of proteinuria, 24-hr proteinuria remained stable. No severe side effects were observed--in particular, mean serum potassium showed only a slight increase and no clinically significant hyperkalemic condition was observed. When lisinopril therapy was withdrawn after 3 months, blood pressure increased in all patients, requiring reinstitution of additional antihypertensive medication. Renal hemodynamic parameters and daily proteinuria returned to baseline values. We conclude that 2.5 mg lisinopril daily was safe and effective in this group of renal transplant recipients and showed a good antihypertensive as well as antiproteinuric effect.

Topics: Adult; Dipeptides; Female; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Function Tests; Kidney Transplantation; Lisinopril; Male; Middle Aged; Proteinuria

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Cardiotonic Agents; ErbB Receptors; Hypertension, Renal; Immunohistochemistry; Kidney; Lisinopril; Male; Mesenteric Arteries; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nephrectomy; Proteinuria; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, alpha-1

Topics: Albuminuria; Antihypertensive Agents; Drug Therapy, Combination; Humans; Hypertension, Renal; Lisinopril; Randomized Controlled Trials as Topic; Tetrazoles; Valine; Valsartan

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antimanic Agents; Bipolar Disorder; Diuretics; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydrochlorothiazide; Hypertension, Renal; Kidney Failure, Chronic; Lisinopril; Lithium; Middle Aged; Renal Dialysis; Risk Factors

The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a backcross of the hypertensive (mRen2)27 transgenic rat with normotensive Lewis rats, provides a new model by which primary hypertension can be studied without the genetic variability found in the original strain. The purpose of this study was to characterize the Lew.Tg(mRen2) rats by dually investigating the effects of type 1 angiotensin II (ANG II) receptor (AT(1)) blockade and angiotensin-converting enzyme (ACE) activity inhibition on the ANG-(1-7)/ACE2 axis of the renin-angiotensin system in this new hypertensive model. The control of blood pressure elicited by 12-day administration of either lisinopril (mean difference change = 92 +/- 2, P < 0.05) or losartan (mean difference change = 69 +/- 2, P < 0.05) was associated with 54% and 33% increases in cardiac ACE2 mRNA and 54% and 43% increases in cardiac ACE mRNA, respectively. Lisinopril induced a 3.1-fold (P < 0.05) increase in renal cortical expression of ACE2, whereas losartan increased ACE2 mRNA 3.5-fold (P < 0.05). Both treatment regimens increased renal ACE mRNA 2.6-fold (P < 0.05). The two therapies augmented ACE2 protein activity, as well as increased cardiac and renal AT(1) receptor mRNAs. ACE inhibition reduced plasma ANG II levels (81%, P < 0.05) and increased plasma ANG-(1-7) (265%, P < 0.05), whereas losartan had no effect on the peptides. In contrast with what had been shown in normotensive rats, ACE inhibition decreased renal ANG II excretion and transiently decreased ANG-(1-7) excretion, whereas losartan treatment was associated with a consistent decrease in ANG-(1-7) urinary excretion rates. In response to the treatments, the expression of both renal cortical renin and angiotensinogen mRNAs was significantly augmented. The paradoxical effects of blockade of ANG II synthesis and activity on urinary excretion rates of the peptides and plasma angiotensins levels suggest that, in Lew.Tg(mRen2) congenic rats, a failure of compensatory ACE2 and ANG-(1-7)-dependent vasodepressor mechanisms may contribute both to the development and progression of hypertension driven by increased formation of endogenous ANG II.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Congenic; Animals, Genetically Modified; Crosses, Genetic; Hypertension, Renal; Kinetics; Lisinopril; Losartan; Male; Models, Genetic; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Renin; Renin-Angiotensin System; RNA, Messenger; Time Factors

Angiotensin-converting enzyme (ACE)2, a homologue of ACE, which is insensitive to ACE inhibitors and forms angiotensin-(1-7) [Ang-(1-7)] from angiotensin II (Ang II) with high efficiency was investigated in response to chronic blockade with lisinopril, losartan, and both drugs combined.. Thirty-six adult Lewis rats were assigned to receive these medications in their drinking water for 2 weeks while their arterial pressure, water intake, and urine volume were recorded throughout the study. Measures of renal excretory variables included assessing excretion rates of angiotensin I (Ang I), Ang II and Ang-(1-7) while blood collected at the completion of the study was used for measures of plasma angiotensin concentrations. Samples from renal cortex were assayed for renin, angiotensinogen (Aogen), neprilysin, angiotensin types 1 and 2 (AT(1) and AT(2)) and mas receptor mRNAs by semiquantitative reverse transcriptase (RT) real-time polymerase chain reaction (PCR). ACE2 activity was determined as the rate of Ang II conversion into Ang-(1-7).. Comparable blood pressure reductions were obtained in rats medicated with either lisinopril or losartan, whereas both drugs produced a greater decrease in arterial pressure. Polyuria was recorded in all three forms of treatment associated with reduced osmolality but no changes in creatinine excretion. Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1-7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1-7) but increased plasma Ang II without changing urinary Ang II excretion. Combination therapy mimicked the effects obtained with lisinopril on plasma and urinary Ang I and Ang-(1-7) levels. Renal cortex Aogen mRNA increased in rats medicated with either lisinopril or the combination, whereas all three treatments produced a robust increase in renal renin mRNA. In contrast, ACE, ACE2, neprilysin, AT(1), and mas receptor mRNAs remained unchanged with all three treatments. Renal cortex ACE2 activity was significantly augmented in rats medicated with lisinopril or losartan but not changed in those given the combination.. Our data revealed a role for ACE2 in Ang-(1-7) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. The data further indicate that increased levels of Ang-(1-7) in the urine of animals after ACE inhibition or AT(1) receptor blockade reflect an intrarenal formation of the heptapeptide.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Carboxypeptidases; Gene Expression Regulation, Enzymologic; Hypertension, Renal; Kidney; Lisinopril; Losartan; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Lew; Receptors, Angiotensin; Renin-Angiotensin System

Topics: Antihypertensive Agents; Calcium Channel Blockers; Humans; Hypertension, Renal; Kidney Transplantation; Lisinopril; Nifedipine

The efficacy of an early and late treatment with the angiotensin converting enzyme inhibitor lisinopril or the angiotensin II receptor blocker ICI D8731 was investigated in uninephrectomized spontaneously hypertensive rats (SHR). Rats that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment, lisinopril shortly after UNX, lisinopril starting 16 weeks after UNX, ICI D8731 shortly after UNX, and ICI D8731 starting 16 weeks after UNX. Blood pressure was normalized with both treatments. After six months inulin clearance was not significant different, while proteinuria and prevalence of interstitial fibrosis were significantly reduced in all treatment groups. Immunohistochemical studies revealed an interstitial, periglomerular and perivascular increase of extracellular matrix proteins in all rats, but a markedly reduced expression of collagen I, IV and fibronectin after early and late treatment compared to untreated controls. We found a significant reduction of infiltrating macrophages and T-lymphocytes in all treated animals compared to untreated controls after 2, 4 and 6 months. Especially early treatment was associated with lower numbers of infiltrating cells. Both treatments reduced proliferation of tubular and interstitial cells. There were no striking differences with regard to nephroprotection between the ACE inhibitor and angiotensin II receptor blocker. These findings show that both treatments have beneficial effects on kidney structure and function. They suggest that both ACE inhibition and angiotensin II blockade decrease renal cell proliferation and suppress the infiltration of mononuclear cells that may trigger expression of extracellular matrix proteins and progressive nephrosclerosis.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Cell Division; Extracellular Matrix Proteins; Hypertension, Renal; Kidney; Lisinopril; Nephrectomy; Proliferating Cell Nuclear Antigen; Quinolines; Rats; Rats, Inbred SHR; Time Factors

To assess in conscious two-kidney, one clip renal hypertensive rats whether angiotensin converting enzyme (ACE) inhibition with lisinopril, angiotensin II receptor blockade with losartan or vasodilation with sodium nitroprusside have similar effects on intra-arterial mean blood pressure, heart rate and splanchnic nerve activity.. A bolus dose of lisinopril or losartan (both 10 mg/kg, intravenously) induced within 2 h an equal reduction in mean blood pressure, whereas sodium nitroprusside infused during the same period (at 10 micrograms/min) lowered mean blood pressure, but less strongly. The heart rate was accelerated significantly more during sodium nitroprusside infusion than during lisinopril or losartan treatment. Splanchnic nerve activity increased significantly only in those rats given sodium nitroprusside. No change in the parameters studied was observed in vehicle-treated rats. The doses of lisinopril and losartan were repeated after 12 and 24 h. Before administration of the last dose, the mean blood pressure was still low. Administration of lisinopril or losartan again 24 h after the initial dose had no further effect on the mean blood pressure, heart rate or splanchnic nerve activity.. These results obtained in rats with a renin-dependent form of hypertension show that blockade of the renin-angiotensin system for 24 h produces an equivalent blood pressure reduction irrespective of whether it is due to ACE inhibition or angiotensin II antagonism. The results also indicate that there is less reflex activation of sympathetic nerve activity when blood pressure is lowered with a blocker of the renin-angiotensin system rather than with a direct vasodilator such as sodium nitroprusside.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Heart Rate; Hypertension, Renal; Imidazoles; Lisinopril; Losartan; Male; Nitroprusside; Rats; Rats, Wistar; Renin-Angiotensin System; Splanchnic Nerves; Sympathetic Nervous System; Tetrazoles

Topics: Animals; Blood Pressure; Collagen; Creatinine; Disease Models, Animal; Heart; Heart Ventricles; Hypertension, Renal; Kidney; Lisinopril; Male; Nephrectomy; Rats; Rats, Wistar; Uremia

1. The population pharmacokinetics of lisinopril were investigated using data collected from two multicentre trials of lisinopril in the treatment of hypertension in elderly patients (n = 40) and patients with renal disease (n = 20). 2. Lisinopril was started at doses of 2.5-5 mg daily and increased at 2-4 weekly intervals as required for control of blood pressure. Steady-state concentration-time profiles were measured after at least 2 weeks at a constant dose. 3. All concentration-time data were analysed simultaneously using the program NONMEM and the influence of clinical factors on clearance/F and volume of distribution/F was tested. 4. Clearance was significantly influenced by creatinine concentration, age, weight and cardiac failure. No clinical features tested were found to influence volume of distribution. 5. The influence of renal function and cardiac failure on lisinopril clearance has been confirmed using a population pharmacokinetic analysis technique.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Weight; Creatinine; Enalapril; Half-Life; Heart Failure; Humans; Hypertension; Hypertension, Renal; Lisinopril

We studied the effects of lisinopril on mean arterial blood pressure (MAP), plasma renin activity (PRA), and renal hemodynamics in nine patients with chronic renal disease and hypertension, before, and after three months of therapy. Lisinopril normalized blood pressure in five of nine patients (responders) and did not in the remaining four (nonresponders). PRA rose after lisinopril (4.8 +/- 2.6 ng/mL/h to 25 +/- 15 ng/mL/h, P less than 0.05) in responders, but not in nonresponders (2.0 +/- 1.4 ng/mL/h to 3.4 +/- 2.9 ng/mL/h). Glomerular filtration rate remained stable in both groups (responders: 43 +/- 11 mL/min to 43 +/- 22 mL/min; nonresponders: 39 +/- 25 mL/min to 32 +/- 21 mL/min). In the responders renal hemodynamics remained stable after lisinopril (renal plasma flow: 223 +/- 80 mL/min to 216 +/- 91 mL/min; filtration fraction: .20 +/- .04 to .20 +/- .05; renal vascular resistance: 386 +/- 179 to 326 +/- 209 units). In the nonresponders, renal plasma flow decreased (228 +/- 141 mL/min to 162 +/- 117 mL/min, P less than 0.005), filtration fraction increased (.19 +/- .08 to .24 +/- .12, P less than 0.05), and renal vascular resistance increased (695 +/- 747 to 1265 +/- 1574 units, P less than 0.05) after chronic lisinopril therapy. We conclude (1) there is a heterogeneous response to lisinopril in patients with chronic renal disease and hypertension, (2) lisinopril monotherapy may result in effective blood pressure control without renal hemodynamic compromise, and (3) an increase in PRA following converting enzyme inhibition may identify those in whom the circulating renin angiotensin system is participating in systemic hypertension and intrarenal hemodynamic changes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Drug Evaluation; Enalapril; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Lisinopril; Middle Aged; Potassium; Proteinuria; Renin

The antihypertensive efficacy and safety of lisinopril, a long-acting angiotensin-converting enzyme inhibitor, were assessed in 23 patients with hypertension associated with impaired renal function (glomerular filtration rate 60 ml/min or less) in an open study of 12 weeks' duration. Lisinopril was given orally in single daily doses. The starting dose was 2.5 mg in patients with glomerular filtration rate (GFR) of less than 30 ml/min and 5 mg in all other patients. This was titrated to a maximum of 40 mg daily according to blood pressure response. A diuretic was then added if blood pressure was not controlled. Mean sitting and standing blood pressures were significantly reduced by lisinopril treatment. The median dose of lisinopril taken was 10 mg daily (range 2.5-40 mg), and only three patients required the addition of a diuretic. The mean glomerular filtration rate was unchanged during the study (38 +/- 16.4 ml/min at baseline, 41 +/- 21.0 ml/min after 12 weeks of treatment). Twenty-two patients completed the study. One patient was withdrawn because of nausea and vomiting due to reflux oesophagitis which was probably not drug related. Another patient had transient mild angioneurotic oedema and continued on lisinopril. No clinically significant haematological or biochemical changes were observed. In conclusion, lisinopril provided effective blood pressure control and was well tolerated in this group of hypertensives who are typically difficult to treat.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Furosemide; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension, Renal; Kidney Diseases; Lisinopril; Male; Middle Aged

Lisinopril is a new, long-acting, nonsulfhydryl angiotension-converting enzyme (ACE) inhibitor that is excreted unchanged by the kidney. The antihypertensive efficacy and safety profiles of lisinopril were assessed in 24 patients (15 men, 9 women; mean age 52.3 years; range 21-75 years) with hypertension associated with impaired renal function (glomerular filtration rate GFR 60 ml/min or less), in an open study of 12 weeks' duration. Previous antihypertensive drugs were discontinued at entry into the study. Lisinopril was given orally once daily; the starting dose was 2.5 mg in patients with a GFR of less than 30 ml/min, and 5 mg in all other patients. The dosage of lisinopril was titrated upward to 40 mg daily according to BP response. A diuretic could then be added if hypertension was inadequately controlled. Twenty-three patients completed the study. Mean sitting BP was reduced from 177 +/- 21.2/106 +/- 9.1 mm Hg (mean +/- SD) at entry to the study to 145 +/- 21.4/88 +/- 8.3 mm Hg after 12 weeks of treatment (p less than 0.001). The median dose of lisinopril used was 10 mg (range 2.5-40 mg) and only 4 patients had a diuretic added to the lisinopril. Overall GFR was unchanged during the study: mean baseline value was 37 +/- 16.4 ml/min (range 10-60 ml/min) at the beginning of the study and 40 +/- 21.0 ml/min at the end. As in a previous pharmacokinetic study in similar patients, a tendency toward drug accumulation was noted only in those patients with the most severe renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Drug Administration Schedule; Drug Evaluation; Enalapril; Female; Hemodynamics; Humans; Hypertension, Renal; Kidney Function Tests; Lisinopril; Male; Middle Aged