Effects of angiotensin I converting enzyme inhibitors on the renal excretory function, hemodynamics and renin release in isolated perfused rat kidney

Direct renal effects of angiotensin I converting enzyme inhibitors (CEIs), captopril, SA446 and MK421, were examined in isolated rat kidneys perfused with a renin-substrate-free medium. Among three CEIs, only captopril induced a significant natriuresis, whereas SA446 and MK421 did not. UKV, renal vascular resistance and creatinine clearance were not affected by any of these CEIs. Renin release from perfused rat kidneys were not influenced by CEIs under the present experimental conditions. These results suggest that among three different types of CEIs, only captopril possesses natriuretic action in the isolated perfused rat kidney and that this action may be independent of its inhibitory action on angiotensin converting enzyme. It is also suggested that these three CEIs themselves do not have a direct effect on the renal vascular bed.     

Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function

In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L, respectively, during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg), heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast, in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L, respectively (P less than .05), whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C, respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of converting enzyme inhibition on split renal function in renovascular hypertension

The effects of captopril on effective renal plasma flow and glomerular filtration rate were studied using a noninvasive radioisotopic method on individual kidneys in eight patients with renovascular hypertension and 12 patients with essential hypertension with various renin levels. Four patients with renovascular hypertension had unilateral while three had bilateral renal artery stenosis. The effective renal plasma flow and glomerular filtration rate were determined by using 131I-iodohippurate sodium and 99mTc-diethylenetriamine pentaacetic acid, respectively. Glomerular filtration rate and effective renal plasma flow were significantly reduced in the stenotic kidneys of patients with renovascular hypertension compared with values in nonstenotic kidneys (p less than 0.01). Treatment with captopril, 37.5 to 75 mg/day for 1 to 48 weeks, further reduced the glomerular filtration rate only in stenotic kidneys, and effective renal plasma flow increased in both kidney types. In two of the three renal hypertensive patients with bilateral renal artery stenosis, captopril produced a reversible azotemia that was unrelated to the fall in blood pressure, as evidenced by the lack of azotemia seen after a moderate blood pressure reduction induced by other antihypertensive medications. These results indicate that endogenous angiotensin II is essential in maintaining the glomerular filtration rate in stenotic kidneys and suggest that a reduction in glomerular filtration rate during captopril administration could indicate the presence of renal artery stenosis.     

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.     

Does blood pressure reduction necessarily compromise cardiac function or renal hemodynamics? Effects of the angiotensin-converting enzyme inhibitor quinapril.

Clinical studies indicate that the angiotensin-converting enzyme inhibitor quinapril is an effective antihypertensive agent when administered once daily. At the end of a 4-week, double-blind crossover trial comparing quinapril and placebo, patients were admitted for a hemodynamic profile study 12 hours after taking the previous dose. A final 20 mg dose of quinapril had no additional effect on blood pressure. This is interesting inasmuch as the plasma half-life of the active metabolite quinaprilat is approximately 2 hours and the effective accumulation half-life is approximately 3 hours. The blood pressure reduction in patients with mild hypertension receiving long-term quinapril therapy may be more closely related to prolonged angiotensin-converting enzyme inhibition or to an effect on tissue angiotensin II concentration than to the plasma half-life. This may be the case particularly for cardiac output and renal circulation, because quinapril lowers total vascular resistance without increasing cardiac output or disturbing autoregulation of renal blood flow. Reduced ventricular wall stress, improved diastolic function, and lower renal perfusion pressure may spare cardiac function and glomeruli from hypertensive vascular damage.     

Systemic and renal effects of a new angiotensin converting enzyme inhibitor, benazepril, in essential hypertension

Seventeen essential hypertensive patients with normal renal function were treated with a new non-sulphydryl orally active angiotensin converting enzyme (ACE) inhibitor, benazepril, 10 mg given once or twice daily, according to diastolic blood pressure levels, for 6 weeks. In all patients, changes in blood pressure, systemic and renal hemodynamics, plasma renin activity and urinary aldosterone and albumin excretions were assessed at the end of a 2-week placebo run-in period and at the end of the study. Benazepril monotherapy controlled blood pressure well. No changes in cardiac output, heart rate or stroke volume were observed, while peripheral vascular resistance was significantly decreased (-11%, P less than 0.05). Plasma volume was unaltered. The glomerular filtration rate was stable, but effective renal plasma flow was increased because of the marked reduction in renal vascular resistance (-35%) and, therefore, the filtration fraction was decreased. Urinary albumin excretion remained unchanged. A significant increase in plasma renin activity (P less than 0.001) and a decrease in urinary aldosterone excretion were seen. No side effects were observed during the treatment period. In conclusion, our results suggest that benazepril alone is an effective antihypertensive agent in patients with essential hypertension. The blood pressure lowering effect is due mainly to systemic vasodilation and is observed up to 24 h after administration of the drug. The vasodilation appears to be more consistent in the renal than in the systemic circulation.     

Use of the converting enzyme inhibitor enalapril in renovascular hypertension. Effect on blood pressure, renal function, and the renin-angiotensin-aldosterone system

Thirteen patients were entered into a protocol to assess the safety and efficacy of enalapril (MK 421), 5 to 20 mg b.i.d., and hydrochlorothiazide, 50 to 100 mg daily, for the treatment of renovascular hypertension. Specifically monitored were the effects of therapy on blood pressure and pulse, renal function, and the renin-angiotensin-aldosterone axis. Enalapril and hydrochlorothiazide therapy produced excellent control of blood pressure with no adverse side effects. After approximately 8 weeks of therapy, renal vascular resistance was decreased and no adverse effects on glomerular filtration rate or renal blood flow were noted, except in one patient with a functional unilateral stenotic kidney. Patients receiving enalapril and hydrochlorothiazide showed stimulation of plasma renin activity and suppression of plasma angiotensin II, although the initial degree of suppression was not sustained in all patients during prolonged therapy. Although plasma aldosterone concentration was initially suppressed, the degree of suppression was not sustained. Nine patients have been followed for an additional 6 months; none have experienced further progression of renal disease, as assessed by repeated measurements of glomerular filtration and effective renal plasma flow. These results suggest that combined enalapril and hydrochlorothiazide therapy is safe and effective in the medical management of renovascular hypertension and that blood pressure control may be achieved in the absence of sustained interruption of the renin-angiotensin-aldosterone system.     

Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.     

Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=-0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691±0.01 at baseline to 0.674±0.01 and 0.670±0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.     

Different cation transport inhibitor in benign and malignant experimental renal hypertension

The role of circulating humoral agents in the pathogenesis of abnormal vascular wall cation composition in benign and malignant renal hypertension was investigated. Male F344 rats with chronic benign (n = 38) and malignant (n = 44) one-kidney, one clip (1K1C) hypertension and normotensive control rats (n = 63) were studied. Malignant hypertension developed spontaneously and was characterized by failure to thrive, weight loss, oedema, renal insufficiency, anaemia or haemoconcentration and hyperkalaemia. For bio-assay, monolayers of quiescent vascular smooth muscle cells from F344 rats were incubated in plasma or plasma extracts of normotensive and hypertensive rats for measurement of labelled rubidium (86Rb) uptake in the presence and absence of 2 mmol/l ouabain and/or 1 mmol/l furosemide. Compared with controls, ouabain-sensitive Rb uptake of cells was reduced in plasma extracts but not in whole plasma of rats with benign hypertension. Ouabain-sensitive Rb uptake was unchanged and ouabain-insensitive Rb uptake was reduced in both plasma and plasma extracts of rats with malignant hypertension. The latter was due to a reduction in furosemide-sensitive Rb uptake. In malignant hypertension, the increased sodium (Na) content of the aorta which characterizes benign hypertension was reversed and bladder wall Na content was reduced. The findings suggest that in malignant hypertension a circulating, furosemide-like inhibitor of ouabain-insensitive cation transport is the cause of vascular wall Na depletion and of diuresis and natriuresis that trigger the syndrome.     

Effects of angiotensin converting enzyme inhibitor and calcium antagonist on endothelial function in patients with essential hypertension.

The endothelium plays an important role in maintaining vascular tone and function. Essential hypertension is associated with alterations in endothelial function. The effects of antihypertensive agents on endothelial function have not been fully evaluated in human hypertension and data on the forearm circulation of humans are controversial. The aim of this study was to determine whether treatment with an angiotensin converting enzyme (ACE) inhibitor or a calcium antagonist improves endothelial dysfunction in hypertensive patients and whether the mechanism involved could be related to antioxidant activity. Endothelial function was estimated using venous occlusion plethysmography in 18 hypertensive patients and 11 healthy volunteers. The patients in the hypertension group were treated with enalapril or amlodipine. The change of forearm blood flow (FBF) was measured during acetylcholine infusion through the brachial artery and also during intra-arterial vitamin C infusion to explore the effects of vitamin C on responses to acetylcholine. FBF response to acetylcholine was significantly enhanced by intra-arterial infusion of vitamin C in the hypertensive group before antihypertensive treatment. Co-infusion of L-NMMA(N(G)-monomethyl-L-arginine), an inhibitor of nitric oxide synthase, blunted forearm blood flow response to acetylcholine. After antihypertensive treatment with enalapril or amlodipine for 2 months in the hypertensive group, endothelium-dependent vasorelaxation (vasodilatory response to acetylcholine) was significantly improved. Even though the mechanisms leading to depressed endothelial function in essential hypertension remain to be elucidated, our study shows that treatment with an ACE inhibitor or a calcium antagonist resulted in demonstrable improvement by a mechanism that is probably related to antioxidant activity.     

Effects of angiotensin-converting enzyme inhibitors and sclerotherapy on portal hemodynamics in patients with portal hypertension

BACKGROUND/AIMS: Since pharmacotherapy of portal hypertension has always been a subject of wide interest, we decided to study the effects of different angiotensin-converting enzyme inhibitors and endoscopic sclerotherapy on portal hemodynamics in patients with portal hypertension and bleeding esophageal varices. METHODOLOGY: The study included 72 patients with portal hypertension divided into 6 equal groups. Endoscopic sclerotherapy was done to all patients every 2 weeks for 3 months. In addition, the first 5 groups of patients were maintained on angiotensin-converting enzyme inhibitors for 3 months as follows: group I on perindopril, II on ramipril, III on fosinopril, IV on lisinopril and V on captopril. Portal hemodynamics were determined before and after therapy (using an ultrasonic duplex system). New Doppler portal indices were derived and portal vein kinetic pressure was estimated for the first time by using data derived from the ultrasonic duplex system. RESULTS: 1) Short-term endoscopic sclerotherapy alone resulted in significant elevation of portal vein kinetic pressure, wall stress index and flow volume (P < 0.01) and non-significant increase in the total portal circulation resistance index (P > 0.05) and significantly decreased portal vein compliance and distensibility indices (P < 0.05); 2) Angiotensin-converting enzyme inhibitors reduced the maximum and average portal velocities, the portal flow volume, total portal circulation resistance index and increased portal vein compliance and distensibility indices, hence they reduced the portal vein kinetic pressure significantly in group IV (P < 0.05 for the flow volume and P < 0.01 for other indices); 3) The only side effect encountered was allergic cough (in 8.33% of patients). No effects were noticed on the pulse, systolic, diastolic or mean blood pressures or Child-Pugh Score of liver disease. CONCLUSIONS: 1) Angiotensin-converting enzyme inhibitors when added to endoscopic sclerotherapy can ameliorate the effects of the latter on portal hemodynamics in patients with portal hypertension; 2) Portal vein kinetic pressure, total portal circulation resistance index, portal vein wall stress index, compliance and distensibility indices are new Doppler portal indices that proved to be of value in the follow-up of patients with portal hypertension under sclerotherapy alone or in conjunction with pharmacotherapy; 3) Angiotensin-converting enzyme inhibitors are safe drugs that can be used for portal decompression with endoscopic sclerotherapy. Their use as sole portal anti-hypertensive agents still awaits further studies.     

Effect of clonidine therapy on renal hemodynamics in renal transplant hypertension

Antihypertensive medications have a variable effect on renal hemodynamics and may contribute to renal insufficiency in some patients. Since clonidine has actually been found to improve renal hemodynamics in patients with essential hypertension, we studied the effects of clonidine therapy in patients with renal transplant hypertension. Baseline measurements of BP and renal hemodynamics were made in six patients after two weeks of therapy with furosemide. Clonidine was then added and titrated until BP was controlled. Repeated measurements of renal hemodynamics were made four and 16 weeks after clonidine therapy was begun. Glomerular filtration and effective renal plasma flow as assessed by inulin and aminohippurate sodium clearances were preserved during prolonged clonidine therapy.     

Assessment of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker on the split renal function in the patients with primary hypertension

Bilateral kidney damage in hypertensive patients is not parallel. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), as a commonly used antihypertensive drug, could protect kidney function and delay its deterioration. Most studies focused on overall renal function, but the researches on split renal function (SRF) are rare. We investigated the effects of ACEI/ARB on the SRF in patients with primary hypertension.Patients with primary hypertension (n = 429; male: 213; female: 216) admitted to our department between January 2014 and December 2016 were included in this study. The glomerular filtration rate (GFR) of split and total renal function were determined using diethylenetriaminepentaacetic acid tagged with 99mTc renal dynamic imaging method. For the same patient, the side with high GFR was considered as higher GFR kidney, whereas that with a low GFR was considered as lower GFR kidney. The split function score (Q value) was utilized to evaluate the differences of bilateral renal function. The patients were divided into 3 groups based on the Q values (Group 1, Q value <5%; Group 2, Q value of 5%–10%; Group 3, Q value ≥10%). All the patients received antihypertensive therapy based on ACEI/ARB. The renal dynamic imaging was performed in the 1-year follow-up to investigate the changes of the SRF.Compared with the baseline level, significant decline was noticed in the serum creatinine (Scr) in Group 2 and Group 3 (P < .05). The cystatin C in Group 3 showed significant decline (P < .05). Compared with the baseline, there was significant decline in the Q value in Group 2, whereas the GFR of lower GFR kidney showed significant increase (P < .05). No statistical differences were noticed in the Q value and split GFR in Group 1 and Group 3 (P > .05).In primary hypertension patients, ACEI/ARB therapy could improve the SRF of lower GFR kidney in the presence of certain differences between the SRF. As a result, the SRF difference was reduced. In case of Q value in a range of 5% to 10%, ACEI/ARB could improve the renal function effectively. It may be significant for the design of antihypertensive drugs.     

Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension.

OBJECTIVE: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. DESIGN: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. SETTING: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). PATIENTS: Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. INTERVENTIONS: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. MAIN OUTCOME MEASURES: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. RESULTS: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. CONCLUSIONS: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.