Effects Of Captopril In Patients Research Articles

P1839GLOMERULAR HYPERFILTRATION: THEORY AND APPLICATIONS

Abstract Background and Aims The role of glomerular hyperfiltration in the development and progression of diabetic and non-diabetic chronic kidney disease (CKD) was established during the 80’s of the last century and represented a paradigm shift in current nephrology practice. Method A web-based review of relevant bibliography: articles and textbooks, reporting the development of hyperfiltration theory and its clinical applications was conducted. Results In 1982, after a series of animal studies, Brenner and colleagues proposed that glomerular hyperfiltration, in diabetic and other glomerulopathies, contributes to intrarenal hypertension and predispose to progressive glomerular sclerosis and deterioration of renal function. Clinical trials during late 80’s and early 90’s then focused on inhibition of Renin Angiotensin Aldosteron system (RAAS) to reverse glomerular hyperfiltration, and suggested that ACE inhibitors can be anti-proteinuric independent of their blood pressure-lowering effect in non-diabetic and diabetic nephropathies. In 1993, a randomized controlled trial (RCT) by Lewis and colleagues proved a beneficial effect of captopril in patients with nephropathy caused by type 1 diabetes. Few years later, the results of Ramipril Efficacy in Nephropathy (REIN) study proved the renoprotective role of ACE inhibition in patients with non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria in 2 Lancet articles in 1997 and 1999 respectively. The renoprotective role of RAAS inhibition with ARBs in patients with type 2 diabetes was proven in 3 RCTs published in the New England Journal of Medicine in 2001: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) Study, Irbesartan Diabetic Nephropathy Trial (IDNT), and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Dual blockade with an ACE inhibitor and an ARB was then attempted to further ameliorate glomerular hyperfiltration. Yet this approach was faced by an increased risk of hyperkalemia and acute kidney injury in 2 RCTs: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) in 2008 and The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study in 2013. It was until 2014 when evidence appeared for a potential role of SGLT2 inhibition in attenuating glomerular hyperfiltration. The 1st clinical evidence of renoprotective effect of SGLT2i appeared in 2016 when the results of the EMPA-REG OUTCOME study found that empagliflozin was associated with lower rates of renal events. Subsequently, the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program trials and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial found similar reductions in composite renal endpoints. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial published in 2019 was the first study designed to assess the effects of a SGLT2i, canagliflozin, on renal outcomes in patients with type 2 diabetes and albuminuric CKD, and proved significant reduction in the composite renal outcome with canagliflozin. The potentiality for renoprotective role of SGLT2i in patients with non-diabetic CKD has stimulated a number of ongoing clinical trials: DIAMOND and Dapa-CKD using Dapagliflozin and EMPATHY and EMPA-KIDNEY using Empagliflozin. Conclusion The hyperfiltration theory represents the basis for current therapeutic interventions in diabetic and non-diabetic CKD. Current guidelines recommend using RAAS blockers in diabetic and non-diabetic proteinuric CKD and SGLT2i in patients with type 2 diabetes and CKD. Whether SGLT2i could be considered in patients with CKD independent of the diabetic state awaits the results of ongoing studies which might change the management practice of CKD.

Evaluation of Placebo Effect in Treatment of Asthma Based Onmetaanalysis of Trials on Selected Antiasthmatic Drugs

Introduction: Apart from the well-studied mechanisms of disease course modification, many therapeutic interventions, at leastin part, exert non-specific effects on patients. These effects can be measured by patient self-assessment or by technicalanalyses. The aim of the study was to assess the extent of placebo effect in the treatment of asthma based on revaluation ofresults of high-quality trials on inhaled antiasthmatic drugs and in the context of various applied investigative methods. Material and methods: A systematic search of the Medline database (using the Entrez Pubmed browser) was performedusing international drug names and English terms: inhaled, randomised, placebo-controlled. The aim of the search was toidentify trials on the efficacy of inhaled antiasthmatic drugs. Of the returned 454 studies, 41 were further included inmetaanalysis and assessed for correlations between drug effects and respective applied investigative methods. For com-parison, analogical analysis was performed for captopril, with 232 identified published studies of which 10 were included inthe metaanalysis. Results: The placebo effect in the treatment of asthma was significantly stronger (29%) as compared to the placebo effect ofcaptopril in patients treated for arterial hypertension (17%). The placebo effect was more prominent in studies applyingclinical (subjective) indicators of drug efficacy as compared to trials using objective (device-based) methods of drug effectmeasurement. Conclusions: The placebo effect is more prominent in treatment of asthma as compared to pharmacotherapy of arterialhypertension. Its extent depends on the applied methods of drug efficacy measurement and is often greater if only clinicalindicators are used. This phenomenon can lead to different interpretations of treatment goals in asthma as perceived by thephysician and the patient. This also points out the necessity of patient activation in taking control over his/her disease so asto achieve a better and more satisfying treatment result.

Aspirin Inhibits the Acute Arterial and Venous Vasodilator Response to Captopril in Patients with Chronic Heart Failure

The potentially beneficial hemodynamic effects of angiotensin-converting enzyme (ACE) inhibitors in heart failure may relate, in part, to their ability to increase the production of vasodilator prostanoids. Low dose aspirin is commonly prescribed in CHF and may attenuate the vasodilator effects of ACE inhibitors. We sought to determine the effects of low dose aspirin on the peripheral hemodynamic effects of captopril in patients with chronic heart failure (CHF). Nine patients with chronic heart failure were randomized in a placebo controlled, cross over study, to 75 mg of aspirin daily or placebo. After 7 days treatment the response to 25 mg of captopril was evaluated over 180 min using venous occlusion plethysmography. Forearm blood flow (FBF) and forearm venous capacitance (FVC) were measured. Mean arterial pressure and heart rate did not change. After placebo, FBF increased in response to captopril (+18%, 95%CI 24.2, 11.8), a response inhibited by aspirin (-1.4%, 2.9, -5.7), p < 0.005. After placebo, FVC increased in response to captopril (+7.6%, 9.8, 5.4), which was also inhibited by aspirin (+2.0%, 4.6, -0.6), aspirin vs. placebo, p = 0.02). In patients with chronic heart failure even low dose aspirin inhibits both the acute arterial and venous dilator responses to captopril. This action of aspirin may reduce the long-term clinical benefits of ACE inhibitors.

About the role of antibodies formation in the decrease of therapeutic effect of captopril in patients with arterial hypertension

Captopril being hapten is connected with blood serum albumin and is capable to induce antibodies elaboration. Captopril conjugate with bull serum albumin can be used as a specific diagnosticum for the hardphase immunofermental analysis. Specific immunoglobulins are one of the factors of the escaping effect development of the captopril hypotensive action.

Short- and Long-term Hemodynamic Effects of Captopril in Patients with Pulmonary Hypertension and Selected Connective Tissue Disease

To assess the pulmonary and systemic hemodynamic effects of oral captopril in patients with connective tissue disease and pulmonary hypertension, we performed right heart catheterization in eight patients with diffuse systemic sclerosis, the CREST syndrome, or mixed connective tissue diseases prior to and immediately following administration of captopril (dose range 12.5 to 50.0 mg, short-term study). Four of these patients underwent repeat right heart catheterization after three to six months of oral captopril therapy (long-term study). In the short-term study, oral captopril produced a significant decrease in mean pulmonary vascular resistance from 6.2 +/- 3.6 to 4.6 +/- 3.8 units (p < 0.01). This was accompanied by a significant decrease in mean pulmonary artery pressure, mean blood pressure, mean systemic vascular resistance and a significant increase in cardiac output. Similar changes in pulmonary hemodynamics were noted in the long-term study. Thus, oral captopril is capable of producing an acute and sustained reduction in pulmonary vascular resistance in patients with pulmonary hypertension associated with the aforementioned connective tissue diseases.

The relationship between diuretic dose, and the haemodynamic response to captopril in patients with cardiac failure.

The effect of diuretic dose on the haemodynamic response to captopril was assessed in nine patients with chronic cardiac failure. Each patient was given an intravenous dose of captopril while maintained on (a) a low dose diuretic regime, and (b) a high dose diuretic regime. Activity of the renin angiotensin aldosterone system, as assessed by plasma concentrations of these hormones, was greater when patients were receiving the higher dose diuretic regime. The magnitude of haemodynamic response produced by intravenous captopril was greater when the patients were maintained on the high dose diuretic regime, although no significant correlation was found between resting plasma renin activity and resting plasma angiotensin II concentration and the change produced by captopril in any haemodynamic response on either diuretic regime. An increased dosage of loop diuretic potentiates the haemodynamic effects of captopril in patients with cardiac failure. Reduction of diuretic dose prior to introduction of captopril may protect against severe first dose hypotension.

Short-term vasodilator effect of captopril in patients with severe mitral regurgitation is parasympathetically mediated.

Few data exist regarding the effects of angiotensin converting enzyme inhibitors in patients with regurgitant valvular lesions. We postulated an immediate improvement in cardiac performance with captopril in mitral regurgitation, which, in a hemodynamically compensated group of patients, might be mediated through parasympathetic vasodilation rather than through blockade of angiotension converting enzyme. Hemodynamics were examined before and 90 minutes after oral captopril (25-50 mg) in 18 patients (mean age, 31 years) with chronic, severe mitral regurgitation in New York Heart Association functional class II and III. One group of patients was given captopril alone (group 1, n = 9) and a second group was given captopril plus atropine 0.04 mg/kg i.v. (group 2, n = 9). Captopril alone (group 1) produced decreases in heart rate (90-81 beats/min, p less than 0.001), mean arterial pressure (90-73 mm Hg, p less than 0.001), systemic resistance (28-23 Wood units, p = 0.068), and pulmonary wedge pressure (19-14 mm Hg, p less than 0.001). There was no improvement in either arteriovenous oxygen difference or thermodilution cardiac output; in fact, the latter slightly declined (3.45-3.35 l/min, p = 0.002). Pretreatment with atropine (group 2) diminished the effects of captopril on heart rate (107-103 beats/min, p = 0.065 for atropine effect by two-way ANOVA), mean arterial pressure (88-82 mm Hg, p = 0.01 for atropine effect), and systemic resistance (26-27 Wood units, p = 0.04 for atropine effect). In patients with chronic, severe mitral regurgitation, captopril reduced systemic arterial and left ventricular filling pressures but did not immediately augment cardiac output as expected. Furthermore, the modest systemic vasodilator effect of captopril was parasympathetically mediated.

Peripheral hemodynamic effects of captopril in patients with congestive heart failure

In 14 patients with severe congestive heart failure, the effects of captopril on the forearm circulation were evaluated with strain gauge plethysmography. Changes in plasma renin activity, angiotensin II, norepinephrine, epinephrine, bradykinin, prostaglandin E 2, and 6-keto-prostaglandin F 1α concentrations were also measured. To determine whether the prostaglandins contribute to the peripheral hemodynamic response to captopril, the hemodynamic and hormonal measurements were repeated after pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Ninety minutes after administering a single dose of captopril (25 mg), mean blood pressure and venous pressure decreased ( p < 0.01 and p < 0.05, respectively), forearm blood flow and maximum venous volume increased ( p < 0.05 for both), and forearm vascular resistance and forearm venous tone decreased ( p < 0.05 for both). Captopril also improved forearm venous distensibility ( p < 0.05). Pretreatment with oral indomethacin (50 mg) significantly blunted all of these captopril-induced hemodynamic changes. The blockage of the renin-angiotensin system by captopril was unaltered by indomethacin pretreatment. Captopril significantly increased plasma bradykinin, prostagiandin E 2, and 6-keto-prostaglandin F 1α ( p < 0.05 for each). Indomethacin pretreatment did not affect the captopril-induced increase in bradykinin, but it did completely eliminate the increase in the prostaglandins. Plasma catecholamines did not change with captopril. These data suggest that the vasodilator prostaglandins play a significant role in captopril's peripheral vasodilative effects in congestive heart failure.

Effects of captopril in patients with chronic obstructive pulmonary disease and secondary pulmonary hypertension.

Ten patients with chronic obstructive pulmonary disease (COPD) with normal left ventricular function were given a single dose of captopril (0.25 mg/kg). Mean systemic arterial pressure, heart rate and coronary flow to the right ventricle were reduced significantly after captopril. In contrast captopril did not cause a significant fall in pulmonary arterial pressure or pulmonary vascular resistance. We conclude that captopril fails to produce haemodynamic benefits in such hypoxic patients and that angiotensin II is not playing a significant role in maintaining pulmonary vasoconstriction.

Mechanism of the acute antihypertensive effect of captopril in patients on hemodialysis

Mechanism of the acute antihypertensive effect of captopril in patients on hemodialysis

Hemodynamic patterns of response during long-term captopril therapy for severe chronic heart failure.

To determine the relationship between the early and late hemodynamic effects of captopril in patients with severe heart failure, we performed serial right heart catheterizations in 51 such patients who were treated with the drug for 2 to 8 weeks. Four hemodynamic patterns of response were observed. Nine patients had minimal responses initially (type I); six failed to improve during long-term treatment, but three showed delayed hemodynamic benefits. Twenty-eight patients had initial beneficial drug effects that were sustained after 48 hr and after 2 to 8 weeks (type II). In seven patients, first doses of captopril produced marked beneficial responses, but these became rapidly attenuated after 48 hr; nevertheless, continued therapy for 2 to 8 weeks was accompanied by spontaneous restoration of the hemodynamic effects of first doses of the drug, i.e., triphasic response (type III). In the remaining seven patients, attenuation of initial response was not reversed by prolonged captopril therapy; hemodynamic variables after 2 to 8 weeks had returned to their pretreatment values, i.e., drug tolerance (type IV). Plasma renin activity was lower in patients with minimal responses (0.6 +/- 0.2 ng/ml/hr) and was higher in patients with triphasic responses (9.4 +/- 2.5 ng/ml/hr) than in patients with types II and IV response patterns (4.4 +/- 0.7 and 2.8 +/- 0.5 ng/ml/hr, respectively; both p less than .05). Although first-dose effects of captopril are frequently sustained, the occurrence of delayed, attenuated, and triphasic responses indicates that a complex and variable relationship may exist between the early and late hemodynamic effects of vasodilator drugs in patients with severe heart failure.

Hemodynamic effects of captopril in patients with severe chronic heart failure

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 ± 0.14 to 2.28 ± 0.30 liters/min/m 2 (p < 0.05) while pulmonary capillary wedge pressure decreased from 22.7 ± 2.0 to 14.7 ± 4.7 mm Hg (p < 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 ± 6.7 to 71.2 ± 12.0 mm Hg (p < 0.001) and from 1,909 ± 246 to 1,362 ± 347 dynes-s-cm 5 (p < 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = −0.82, p < 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).

Long-term captopril therapy in severe refractory congestive heart failure.

1 The favourable haemodynamic effects of captopril in patients with congestive heart failure have been reported. 2 We have treated 25 patients with severe chronic congestive heart failure with captopril in doses of 75-450 mg daily. Before entering the study all patients remained in New York Heart Association functional class IV despite high-dose diuretic and vasodilator therapy. 3 Mean cardiothoracic ratio was 60%, and all patients had a shortening fraction of 18% or less on echocardiography (normal 25 to 40%). 4 Five patients died within one month of captopril and five between four and seven months, three of whom had improved to class IIM and one to IIS before death. 5 Of the 15 survivors one was referred for a heart transplant when he had improved to class IIM. The remaining 14 patients were followed for 8-16 months. Ten improved to New York Heart Association class I or IIS and four to class IIM or III. Diuretic requirements were decreased considerably in all 14. Side effects were common but captopril did not have to be withdrawn. Captopril is a highly effective drug in the treatment of patients with congestive heart failure refractory to currently accepted therapy.

Captopril in congestive heart failure.

British Journal of Clinical PharmacologyVolume 14, Issue S2 p. 193S-199S Free Access Captopril in congestive heart failure. G Liebau, G LiebauSearch for more papers by this authorAJ Riegger, AJ RieggerSearch for more papers by this authorP Schanzenbacher, P SchanzenbacherSearch for more papers by this authorH Steilner, H SteilnerSearch for more papers by this authorS Oehrlein, S OehrleinSearch for more papers by this author G Liebau, G LiebauSearch for more papers by this authorAJ Riegger, AJ RieggerSearch for more papers by this authorP Schanzenbacher, P SchanzenbacherSearch for more papers by this authorH Steilner, H SteilnerSearch for more papers by this authorS Oehrlein, S OehrleinSearch for more papers by this author First published: April 1982 https://doi.org/10.1111/j.1365-2125.1982.tb02077.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References COHN, J.N. (1981). Physiological basis of vasodilator therapy for heart failure. Am. J. Med., 71, 135– 139. COLUCCI, W.S., WILLIAMS, G.H., ALEXANDER, R.W. & BRAUNWALD, E. (1981). Mechanisms and implications of vasodilator tolerance in the treatment of congestive heart failure. Am. J. Med., 71, 89– 99. GREENBERG, B.H., DeMOTS, H., MURPHY, E. & RAHIMTOOLA, S.H. (1982). Arterial dilators in mitral regurgitation: Effects on rest and exercise haemodynamics and long-term clinical follow up. Circulation, 65, 181– 187. FORD, L.E. (1980). Effect of afterload reduction on myocardial energetics. Circ. Res., 46, 161– 166. HOCKINGS, B.E., COPE, G.D., CLARKE, G.M. & TAYLOR, R.R. (1980). Comparison of vasodilator drug prazosin with digoxin in aortic regurgitation. Br. Heart J., 43, 550– 555. IKRAM, H., MASLOWSKI, A.H. & NICHOLLS, G.M. (1981). Haemodynamic effects of dobutamine in patients with congestive heart failure receiving captopril. Br. Heart J., 46, 528– 530. LIEBAU, G. (1982). Captopril in congestive heart failure. Klin. Wschr., 60, 107– 113. LIEBAU, G., RIEGGER, A.J.G. & STEILNER, H. (1981). Haemodynamic effects of captopril in patients with congestive heart failure and hypertension. In: Recent advances in hypertension therapy: captopril. pp. 76– 86, Amsterdam, Excerpta Medica. Citing Literature Volume14, IssueS2April 1982Pages 193S-199S ReferencesRelatedInformation