enalapril and Hypertension--Pulmonary

The renin-angiotensin system is an important regulator of vascular resistance in many patients with hypertension and congestive heart failure. To quantitatively evaluate this contribution requires correlation of markers of the renin-angiotensin system with haemodynamic parameters, notably blood pressure, cardiac output, and calculated systemic vascular resistance. In addition, to determine ventricular loading properties, assessment of cardiac filling pressures is also required. The availability of specific pharmacological inhibitors of the renin-angiotensin system greatly enhances such correlation, as the haemodynamic consequence of blocking the renin-angiotensin system can then more fully identify its contribution. In the last decade, highly specific pharmacological inhibitors have become available to serve such a purpose. Renin inhibitory peptides, and renin-specific antibodies can block the rate-limiting step of the renin-angiotensin cascade: namely, the cleavage of 4 amino acids from the angiotensinogen substrate by renin. However, this method of blockade is still at the early stages of investigation. More readily available are converting enzyme inhibitors which block the formation of angiotensin II, the potent vasoconstrictor which mediates increased systemic vascular resistance, and angiotensin II analogues which compete with endogenous angiotensin II for vascular and adrenal receptors. Although hypertension and chronic congestive heart failure are clinically distinct entities in many respects, their common bond is the fact that both pathological mechanisms are mediated by an increase of systemic vascular resistance. The implications of blocking the resulting vasoconstriction in both entities are therefore quite similar. This review summarises our present knowledge of the contribution of the renin-angiotensin system to the vasoconstriction of hypertension and congestive heart failure, and also summarises the haemodynamic consequences of such inhibition. The implications of the response to these specific pharmacological probes, as well as their limitations, are discussed. Their importance rests not only in their therapeutic application, but also in their contribution as probes for pathophysiological mechanisms of vasoconstriction in cardiovascular disease.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Dipeptides; Enalapril; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Kinetics; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin; Renin-Angiotensin System; Teprotide

The aim of this study was to compare the efficacy of intravenous cyclophosphamide (IVCYC) versus oral enalapril in mild or moderate pulmonary hypertension (PH) in systemic lupus erythematosus (SLE). Thirty-four patients with SLE who had systolic pulmonary artery pressure (SPAP) > 30 mmHg by Doppler echocardiography were randomized to receive IVCYC (0.5 g/mt2 body surface area, monthly), or oral enalapril (10 mg/day) for six months. The primary outcome was the significant decrease in SPAP. An additional outcome measure included the improvement in the heart functional class (NYHA). Sixteen patients received cyclophosphamide and 18 enalapril. IVCYC decreased the median values of SPAP from 41 to 28 mmHg (P < 0.001), and enalapril from 35 to 27 mmHg (P = 0.02). IVCYC reduced more than twice as much SPAP than enalapril (P = 0.04). In those patients with SPAP > or = 35 mmHg, cyclophosphamide decreased from 43 to 27 mmHg (P = 0.003), but enalapril was not effective (P = 0.14). The NYHA functional class improved only in those with cyclophosphamide (P = 0.021). Also IVCYC had a higher frequency of side effects including infections (RR = 1.6; 95% CI, 1.001-2.47), and gastrointestinal side effects (RR = 14.6; 95% CI, 2.15-99.68). We concluded that IVCYC was effective in mild and moderate PH associated with SLE. Further research is needed to evaluate its long-term efficacy.

Topics: Administration, Oral; Adolescent; Adult; Cyclophosphamide; Enalapril; Humans; Hypertension, Pulmonary; Injections, Intravenous; Lupus Erythematosus, Systemic; Middle Aged; Pulse Therapy, Drug; Treatment Outcome; Ultrasonography

A pilot trial of efficiency of enalapril maleate in the treatment of residual pulmonary hypertension was made in 22 patients operated for rheumatic mitral valve defects. Degree I, II and III of pulmonary hypertension was registered in 5, 13 and 4 patients, respectively. Thus, the patients had NYHA functional classes III and IV (22.7 and 77.3%, respectively. Enalapril given for 6 months in a mean daily dose 12.3 +/- 1.57 mg/m2 (5-30 mg a day) normalized pressure in the pulmonary artery in 18.2% of patients. 50% of patients showed hypertension degree I, only one female retained hypertension degree III. To the end of the treatment the functional classes were the following: II--in 68.2%, III--in 27.3% and IV--in 4.5%.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mitral Valve; Pulmonary Wedge Pressure; Rheumatic Heart Disease; Treatment Outcome

The ESS-1 study was designed to evaluate the long-term effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril (10 mg per day) on the cardio-pulmonary system in patients with scleroderma (SSc). We estimated changes in heart diameters, systolic and diastolic left ventricle function and mean values of pulmonary artery pressure after 3 months treatment. The study group comprise 41 patients with SSc. 18 patients received placebo and 23 ones were given enalapril. After 3 months of treatment we did not observe statistically significant differences in heart diameters and left ventricle systolic function parameters between treated group and placebo. Enalapril therapy did not affect left ventricle diastolic function, nevertheless differences in MVA were almost of statistical significance. Echocardiographic signs of pulmonary hypertension were found in 4 patients.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Double-Blind Method; Echocardiography; Enalapril; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Scleroderma, Systemic; Ventricular Function, Left

This report describes the diagnosis and treatment of pulmonary arterial hypertension (PAH) in an adult male captive chimpanzee. Although cardiovascular disease in general is common in human and great apes, diagnosis and treatment of PAH in nonhuman primates are uncommon. In the case we present, the adult chimpanzee was diagnosed with an arrhythmia during an annual physical examination and later with PAH during a scheduled cardiovascular evaluation. PAH can either be primary or secondary and can lead to right ventricular overload and heart failure. This description is the first case study of pulmonary arterial hypertension in a great ape species.

Topics: Animals; Antihypertensive Agents; Aspirin; Atrial Fibrillation; Cardiotonic Agents; Digoxin; Diuretics; Enalapril; Furosemide; Hypertension, Pulmonary; Liver; Lung; Male; Myocardium; Pan troglodytes; Platelet Aggregation Inhibitors; Primate Diseases

A 61-year-old male patient complained about diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical relevance were signs of congestive heart failure and a distinct kyphoscoliosis.. A cardiac catheter examination proved a pulmonary hypertension without cardiac genesis. Both, pulmonary function test and computed tomography of the thorax rule out obstructive bronchial asthma and embolism of the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was diagnosed. Since the patient refused noninvasive positive pressure ventilation, a medication with calcium entry blocker and ACE blocker was induced, followed by oxygen breathing. This successfully helped to reduce pulmonary resistance (746 vs. 332 dyn*s*cm(-5)).. Kyphoscoliosis can create a considerable increase of pulmonary resistance. Medical treatment and oxygen breathing have proven to be an efficient method to lower that significantly.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Enalapril; Humans; Hypertension, Pulmonary; Kyphosis; Male; Middle Aged; Oxygen Inhalation Therapy; Radiography, Thoracic; Respiratory Function Tests; Scoliosis; Time Factors; Tomography, X-Ray Computed

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-alpha (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 +/- 2.5 mmHg (P < 0.05) vs. 15.2 +/- 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-kappaB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 +/- 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-kappaB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Bleomycin; Body Weight; Cardiac Output; Collagen Type I; Disease Models, Animal; Enalapril; Female; Gene Expression; Hemodynamics; Hypertension, Pulmonary; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Pneumonia; Pulmonary Circulation; Receptors, Tumor Necrosis Factor; RNA, Messenger; Specific Pathogen-Free Organisms; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Pulmonary arterial hypertension (PAH) is associated with structural changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have beneficial effects in treating PAH, but its precise mechanism of action in the remodeling process is unclear. p21 is a cyclin-dependent kinase inhibitor that may have a protective role in this process by inhibiting cellular proliferation. Endothelial nitric oxide synthase (eNOS) has also been shown to be protective by its vasodilatory effect. Therefore, we investigated whether expression of p21 and eNOS was modulated by ACEI treatment in a rat model.. Monocrotaline (MCT) was administered to 2 groups of Sprague-Dawley rats fed a high-cholesterol diet, ie, one group received MCT concomitantly with enalapril treatment (MCT(+)/ACEI(+) rats), and the other group did not receive enalapril (MCT(+)/ACEI(-) rats). After 5 weeks, MRI showed right ventricular hypertrophy in MCT(+)/ACEI(-) rats. MCT(+)/ACEI(+) rats showed a preserved right ventricular morphology. Isolated pulmonary perfusion studies showed that ACEI significantly upregulated NO production, as measured by nitrite levels. Addition of N-methyl-D-glucamine dithiocarbamate-Fe solution, an NO-trapping agent, reversed the basal vasodilatory effect of ACEI in the pulmonary vasculature. Immunoblot analysis showed decreased p21 and eNOS expression in the lung in MCT(+)/ACEI(-) rats, whereas their expression was preserved with enalapril treatment.. ACEI suppresses the development of MCT-induced PAH in rats. The mechanism of action might involve the preservation of p21 and eNOS expression. Both p21 and endothelium-derived NO appear to have protective roles in the development of PAH.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dietary Fats; Disease Models, Animal; Enalapril; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Magnetic Resonance Imaging; Male; Monocrotaline; Nitrates; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Perfusion; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Signal Transduction

Angiotensin-converting enzyme (ACE) inhibition attenuates pulmonary hypertension and delays the development of pulmonary vascular remodeling in animal models. Thus, ACE inhibition might be a useful treatment for primary pulmonary hypertension (PPH). To determine the dose of ACE inhibitor required to specifically block pulmonary ACE in humans, we measured the combined forward rate constant (CFRC) for [(18)F]-fluorocaptopril, which is proportional to the mass of ACE in the lung, using positron emission tomography (PET). In five normal subjects, CFRC was measured twice, 1 wk apart, to assess measurement reproducibility. The CFRC was 0.151 +/- 0.067 for the first measurement and 0.140 +/- 0.060 for the second measurement (p = not significant [NS]). In five normals, CFRC decreased on average 84%, from 0.177 +/- 0.053/s to 0.028 +/- 0.017/s (p < 0.05), after 1 wk ingestion of 5 mg enalapril orally once a day (the scans were performed 24 h after the last medication). Similarly, in five patients with PPH, CFRC decreased on average 76%, from 0.052 +/- 0. 020/s to 0.012 +/- 0.003 (p < 0.01), after 1 wk enalapril, despite much lower baseline values. We conclude that the total mass of pulmonary ACE appears to be significantly reduced in PPH and that only low doses of ACE inhibitors may be needed to block the effects of ACE on vascular remodeling in PPH.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Enalapril; Female; Humans; Hypertension, Pulmonary; Image Processing, Computer-Assisted; Male; Middle Aged; Peptidyl-Dipeptidase A; Pulmonary Circulation; Tomography, Emission-Computed

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Chronic Disease; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenyl Ethers; Treatment Outcome

Chronic hypoxia induces pulmonary hypertension and right ventricular hypertrophy. These changes are completely reversible, except for persistent myocardial fibrosis. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can reduce the ventricular collagen content in animals recovering from chronic hypoxia. Adult male Wistar rats were exposed to intermittent high-altitude hypoxia simulated in a barochamber (7000 m, 8 hr/day, 5 days a week, 24 exposures), then transferred to normoxia and divided into two groups: (a) treated with enalapril (0.1 g/kg/day for 60 days) and (b) without treatment. The corresponding control groups were kept under normoxic conditions. Enalapril significantly decreased the heart rate, systemic arterial pressure, and absolute left and right ventricular weights in both hypoxic and control rats; on the other hand, the pulmonary blood pressure was unchanged. The content and concentration of collagen was reduced in both ventricles of enalapril-treated hypoxic and control animals by 10-26% compared with the corresponding untreated groups. These data suggest that the partial regression of cardiac fibrosis due to enalapril may be independent of the pressure load.

Topics: Altitude Sickness; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Enalapril; Hemodynamics; Hydroxyproline; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Myocardium; Organ Size; Pulmonary Fibrosis; Rats; Rats, Wistar

Cardiac transplantation is a proven, effective therapy for selected patients with end-stage congestive heart failure. Recipient selection is performed by a multidisciplinary team consisting of transplant physicians and surgeons. Clinicians responsible for patient assessment must establish the severity of cardiac dysfunction, formulate a prognosis, and stratify patients according to risk for mortality. Patients whose survival and quality of life are most limited without cardiac transplantation are candidates for therapy. The scarcity of organ donors makes careful screening of potential recipients necessary to identify those individuals most likely to obtain a long-term benefit. Recipient selection criteria and management strategies are evolving because of extended waiting times and high mortality caused by the lack of sufficient numbers of donors. Alternative therapies should be applied wherever possible.

Topics: Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Case Management; Cause of Death; Communicable Diseases; Enalapril; Heart Failure; Heart Transplantation; Heart-Assist Devices; Hemodynamics; Humans; Hypertension, Pulmonary; Life Expectancy; Patient Selection; Prognosis; Risk Factors; Waiting Lists

We investigated the redistribution of myocardial isoenzymes of creatine kinase (CK) and lactate dehydrogenase (LD) in rats with right heart failure induced by monocrotaline and assessed the effect of enalapril, an angiotensin converting enzyme inhibitor. Wistar rats were divided into four groups: (1) control (n = 20), (2) control + enalapril (25 mg/kg/day) (n = 22), (3) monocrotaline (50 mg/kg) (n = 45), (4) monocrotaline (50 mg/kg) + enalapril (25 mg/kg/day) (n = 32). After 4 weeks, the monocrotaline group developed severe pulmonary hypertension and right ventricular hypertrophy with marked decrease in myocardial norepinephrine and increase in both plasma atrial natriuretic peptide and mortality rate (33.3%). The marked decrease in both MM and mitochondrial CK ('creatine shuttle') and the relatively constant BB and MB CK caused the net depression of total CK. The depression of LD1 (aerobic LD) was remarkable compared with the relatively constant total LD. In the monocrotaline+enalapril group, mortality rate (9.4%), cardiac hypertrophy and plasma atrial natriuretic peptide were all significantly reduced and myocardial norepinephrine recovered although pulmonary hypertension was not improved at all. However, myocardial total, MM and mitochondrial CK and LD1 activities were all recovered completely or partially in this group. Thus, enalapril reduced cardiac hypertrophy and failure and improved the prognosis in this model of pulmonary hypertension. This beneficial effect of enalapril was not associated with pulmonary vasodepression but with the inhibition of myocardial isoenzyme redistribution of CK and LD, i.e. the preservation of 'creatine shuttle' and aerobic LD.

Topics: Animals; Atrial Natriuretic Factor; Cardiomyopathy, Hypertrophic; Creatine Kinase; Enalapril; Heart; Hypertension, Pulmonary; Isoenzymes; L-Lactate Dehydrogenase; Male; Monocrotaline; Myocardium; Norepinephrine; Rats; Rats, Wistar

Losartan is a potent, nonpeptide, angiotensin II type 1 receptor antagonist. We investigated the possibility that losartan may interact with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors. We measured changes in mean systemic (MS) and pulmonary (MP) arterial pressures (AP) as well as in hematocrit induced by the TxA2 analog, U-46619 (9, 11-dideoxy-9 alpha, 11 alpha-methanoepoxy PGF2 alpha, during pharmacological blockade of either TxA2/PGH2 receptors or the renin-angiotensin system. In anesthetized, open chest rats, U-46619 dose dependently increased MPAP whereas MSAP presented a biphasic evolution. The U-446619 (1.25 micrograms/kg)-increased MPAP (52.4 +/- 12.1%; P < .005) was dose dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha (5z),3 alpha, 4 alpha]]-7- [3-[[2-[(phenylamino)-carbonyl)hydrazino]methyl]-7-oxabiacyclo [2.2.1]hept-2-yl]-5-heptenoic acid) (10.6 +/- 2 and 2.1 +/- 1.4% at 0.63 and 2.5 mg/kg, respectively; both P < .05 vs. U-46619 in control rats). Losartan dose dependently reduced this increase (45.5 +/- 5.8 and 11.9 +/- 1.8% at 2.5 and 10 mg/kg, respectively; P = N.S. and P < .05 vs. U-46619 in control rats) whereas chronic suppression of angiotensin II generation by the converting-enzyme inhibitor enalapril (10 mg/kg/day per os for 4-5 days) did not affect this response. None of these treatments significantly reduced the U-46619-associated increase in MSAP. Moreover, the angiotensin II-evoked increases in MSAP and MPAP were suppressed by pretreatment with losartan but not with SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Enalapril; Fatty Acids, Unsaturated; Hematocrit; Hydrazines; Hypertension, Pulmonary; Imidazoles; Losartan; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Tetrazoles; Thromboxane A2

Ten patients with severe pulmonary hypertension due to Toxic Oil Syndrome underwent cardiac catheterization to analyse the acute effect of intrapulmonary injection of 1.25 mg of enalaprilat. Haemodynamic parameters were obtained at basal state, 15, 30, 45 and 60 minutes after administration of the drug. Enalaprillat did not produce any statistically significant changes in pulmonary pressures and resistances or cardiac output. This lack of response is unknown but may be related to the presence of endothelial damage and fixed pulmonary vascular lesions observed at autopsy in three patients.

Topics: Enalapril; Fatty Acids, Monounsaturated; Humans; Hypertension, Pulmonary; Injections, Intra-Arterial; Plant Oils; Pulmonary Circulation; Pulmonary Wedge Pressure; Rapeseed Oil; Respiratory Distress Syndrome; Syndrome; Vascular Resistance

Enalapril was used to treat five patients with pulmonary arterial hypertension secondary to congenital cardiopathy, three with ventricular septal defect, one with arterial septal defect, and one with patent ductus arteriosus. The dose of enalapril was 20 mg/day. All patients underwent pretreatment and posttreatment cardiac catheterization. It was concluded that enalapril may be a useful drug in the treatment of pulmonary arterial hypertension secondary to congenital cardiopathy.

Topics: Adult; Enalapril; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged