Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifteen patients presented between January 1986 and January 1991 with deterioration in renal function coincident with the introduction of angiotensin converting enzyme inhibitors. There was evidence of extrarenal vascular disease in 12 patients and preexisting renal impairment in 13. Four patients remained dialysis-dependent and died within 4 weeks of presentation. Five patients required short-term dialysis. Serum creatinine remained above pre-treatment values in seven patients. Conventional explanations of the decline in renal function with ACE inhibition do not account for irreversible decrements in renal function. Possible mechanisms for this observation and clinical guidelines to identify patients at risk are suggested. We conclude that these agents should be used with great care in patients in whom atherosclerotic vascular disease is likely.
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PMID:Deterioration in renal function associated with angiotensin converting enzyme inhibitor therapy is not always reversible. 147 49

Administration of the pyrrolizidine alkaloid monocrotaline (MCT) to rats results in hypertensive pulmonary vascular disease characterized by a structurally based increase in pulmonary vascular resistance and right ventricular hypertrophy. Alterations in lung angiotensin converting enzyme activity in MCT-treated rats have suggested a role for angiotensin II (AII) in the pathogenesis of this model of hypertensive pulmonary vascular disease. To determine if increases in AII contribute to the development of pulmonary hypertension in MCT-treated rats, we examined the effect of chronic administration of the nonpeptide AII receptor antagonist Losartan on indices of pulmonary hypertension, Losartan (DuP 753; 10 mg/kg s.c.) administration for 21 days did not prevent the development of hypertensive pulmonary vascular disease in MCT-treated rats. However, 18 hr after the last dose of Losartan, AII (0.1 micrograms/kg i.v.)-induced pressor responses were inhibited by 63% in Losartan-treated rats. Losartan administration in MCT-treated rats did not prevent increases in pulmonary artery pressure or development of right ventricular hypertrophy. Additionally, increases in medial arterial thickness in pulmonary artery vessels (less than 50 microns and 50-100 microns external diameter) from MCT-treated rats were still evident in Losartan-treated rats. However, Losartan administration decreased medial pulmonary artery thickness of 50 to 100 microns external diameter vessels in control rats. These results demonstrate that AII. acting at the AT1 receptor subtype, does not contribute to pulmonary hypertension in this animal model.
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PMID:Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist. 152 21

The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update. 153 95

In 1985, an assessment of arterial hypertension treatment in insulin-treated diabetic patient gave disappointing results. In 1988, we carried out another study in order to assess the impact of new antihypertensive drugs (angiotensin converting enzyme inhibitors and calcium antagonists) on the management of arterial hypertension and to identify patients in whom strict normal blood pressure control is mandatory. Seven hundred and fifty four patients were selected. The prevalence of arterial hypertension was 38.4 p. 100 (n = 290). Two hundred and thirty five patients (31.2 p. 100) were on antihypertensive treatment: monotherapy: 60.4 p. 100 (n = 142), bitherapy: 30.6 p. 100 (n = 72), tritherapy: 9 p. 100 (n = 21). In descending order of frequency, the following drugs were used: angiotensin converting enzyme inhibitors, calcium antagonists, diuretics, cardio-selective beta-blockers, central acting agents. Blood pressure values significantly decreased (148/83 mmHg, in 1988, vs 157/85 mmHg, in 1985, p less than 0.05). However, 20 p. 100 of the patients still had blood pressure values greater than or equal to 160 and/or 95 mmHg with or without antihypertensive treatment, and on average, blood pressure values remained higher in patients with antihypertensive treatment than in those without (148/83 mmHg vs 131/77 mmHg, p less than 0.001). Patients with urinary albumin excretion above or equal 30 mg/24 h compared to those with normal albuminuria had significant higher values of blood pressure, glycosylated haemoglobin and blood lipids (p less than 0.01). Only 51 p. 100 of these patients, received an antihypertensive treatment. This study emphasizes the difficulty of antihypertensive treatment in insulin-treated diabetic patients and the necessity to improve education in patients with high risk for widespread angiopathy, and particularly those with increased urinary albumin excretion.
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PMID:[Treatment of arterial hypertension in insulin-treated diabetic patients. Change over 3 years (1985-1988)]. 167 85

Lipid peroxides and fluorescent serum proteins, possible markers of free radical activity, are increased in diabetic patients, particularly those with angiopathy. Captopril, an angiotensin converting enzyme (ACE) inhibitor, scavenges free radicals in vitro independently of ACE inhibition. This is probably due to the presence of a sulphydryl group which is not present in other ACE inhibitor drugs. We have compared the effects of captopril and enalapril on free radical activity in thirty-two diabetic subjects with hypertension (BP greater than 160/95 mmHg). After a three week run-in period on no antihypertensive therapy, patients were randomly allocated to receive captopril or enalapril, the dose titrated according to BP response. After three months, BP was well controlled in both groups and glycaemic control unchanged. Both drugs were associated with a reduction of fluorescent IgG (captopril:Baseline [BL] 0.564 vs. 12 weeks [w] 0.428, P less than 0.05, enalapril:BL 0.603 vs. 12w 0.422 P less than 0.05) and thiobarbituric acid reactive material (captopril:BL 2.35 nmol MDA vs. 12w 1.46 nmol, P less than 0.05, enalapril:BL 2.44 nmol vs. 12w 1.72 nmol, P less than 0.01). In contrast to in vitro studies, there was no significant difference between the drugs when used in therapeutic doses, questioning a hypothesised advantage of captopril over enalapril.
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PMID:Comparison of the free radical scavenging activity of captopril versus enalapril: a three month in vivo study in hypertensive diabetic patients. 179 11

The heart is one of the major target organs that becomes secondarily involved with the unrelenting and progressive vascular disease of essential hypertension. As a result of this increasing afterload that is imposed upon the left ventricle, the ventricular chamber adapts structurally and functionally. Structural changes involve an increase in muscle mass that is achieved through left ventricular hypertrophy (in a manner similar to the arteriolar changes demonstrated by increased thickening). Unless antihypertensive therapy is interdicted in this disease process, left ventricular failure will ensue as the major cardiac hemodynamic consequence. Left ventricular hypertrophy is also associated with a risk that is independent of the pressure overload and hemodynamic risk. Although antihypertensive therapy will reduce from the hemodynamic alterations, only recently have epidemiological findings suggested that the independent risk of LVH may be reduced with pharmacological therapy. There are no data available to indicate just which agents may reduce the risk from LVH; but relatively recent studies seem to indicate that while all agents may reduce LVH with prolonged therapy only certain classes of agents will do so independent of their hemodynamic factors. Some of these agents, however, may impair cardiac function if arterial pressure is increased abruptly following therapeutic reduction of cardiac mass. Other agents may preserve normal function--or even may improve function. Among those classes of antihypertensive agents that reduce cardiac mass at least in part due to nonhemodynamic factors, are the angiotensin converting enzyme inhibitors, the calcium antagonists, and most adrenergic inhibitors. Evidence will be presented demonstrating the hemodynamic/structural dissociation of those pharmacological agents that reduce cardiac mass with short-term treatment in spontaneously hypertensive rats with left ventricular hypertrophy. Although centrally active adrenolytic, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists all reduce cardiac mass, their structural and cardiac functional effects differ greatly. Even within the ACE inhibitor group their effects vary--improving, impairing, or not changing the Frank-Starling relationships following reduction in left ventricular mass. We postulate great variability of cardiac intramyocytic penetrance of the pharmacological agents and their local intracellular effects on mitogenesis of the ventricular myocyte. The implications on cardiac function and therapy have vast potential. Therefore, current investigative areas involving new concepts of molecular biology of the cardiac myocyte may provide great promise to the quest of unraveling some of the newly postulated questions: What is the role of ionized intracellular calcium? Do the local renin-angiotensin systems in the cardiac and vascular myocyte participate in the development and regression of hypertrophy?(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Left ventricular hypertrophy: dissociation of structural and functional effects by therapy. 183 47

The role of the heart in hypertension has finally emerged as a major issue of cardiovascular concern by the clinician, physiologist, pharmacologist, biochemist, and molecular biologist. This discussion provides an overview of the present state of knowledge and current areas of investigation in this active area of broad interest. Generally, these relate to: the active participation of the heart (e.g. hemodynamic, humoral, autocrine/paracrine); the adaptive response of the heart (i.e. hemodynamic); non-hemodynamic relationships (vis-a-vis, age, race, gender, humoral, coexistent disease); and current thoughts on mechanisms of so-called regression of left ventricular hypertrophy. Several antihypertensive classes of compounds are characterized by decreasing cardiac mass and left ventricular wall thicknesses. The angiotensin converting enzyme inhibitors are included among these agents; their physiological effects in producing "regression" are under active study as are the mechanisms responsible for these changes. These concerns are no longer of incidental or theoretical interest but have major impact on selection of antihypertensive therapy and the management of the patient with hypertension. Thus, the heart may participate actively in the pathogenesis and maintenance of the disease; it adapts to the vascular disease hemodynamically; but in this regard the response has both positive beneficial concerns as well as negative implications as an independent risk factor. These latter concerns should be explored in great depth before conclusions are made with respect to the long-term implications of antihypertensive therapy on the heart.
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PMID:Overview of hemodynamic and non-hemodynamic factors associated with left ventricular hypertrophy. 253 39

During late gestation, intimal cushions form in the ductus arteriosus (DA) and these cause the vessel to close when it constricts in the postnatal period. The formation of intimal cushions suggests highly specialized functions of DA endothelial and smooth muscle cells. To investigate these properties, we established, from fetal lambs on Day 138 of a 148-day term gestation, primary cell cultures of DA endothelium and smooth muscle and compared them to cells derived from the adjacent pulmonary artery and aorta. Purity of the endothelial cell cultures from each vascular site was assessed by the contact inhibited "cobblestone" monolayer phenotype, by positive immunofluorescence for factor VIII and by angiotensin converting enzyme activity. Purity of smooth muscle cell cultures at each vascular site was assessed by the "hills and valleys" phenotype and by positive immunofluorescence with a smooth muscle actin specific monoclonal antibody. Endothelial and smooth muscle cells had different growth curves, ultrastructural features, and protein profiles on single and two-dimensional SDS-polyacrylamide gel electrophoresis (PAGE), but vascular sites were similar. To further determine whether differences related to DA origin were indeed present, endothelial and smooth muscle cells from all three vascular sites were incubated with the radiolabeled amino acids [14C]leucine, [14C]proline, and [14C]valine and the proteins in both the cells and the conditioned medium were analyzed by autoradiography after SDS-PAGE. A dense band corresponding to a 42-kDa protein was observed in valine-labeled DA endothelial cells and conditioned medium and a 52-kDa protein was observed in the conditioned medium of leucine-labeled DA smooth muscle cells only. Further isolation and characterization of these endothelial and smooth muscle proteins will be necessary to determine whether they are related to the mechanism of intimal cushion formation in the late gestation DA or are present abnormally in association with the intimal proliferation observed in pulmonary and systemic vascular disease.
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PMID:Qualitative and quantitative differences in protein synthesis comparing fetal lamb ductus arteriosus endothelium and smooth muscle with cells from adjacent vascular sites. 284 87

Teprotide, a nonapeptide isolated from the venom of a Brazilian pit viper, Bothrops jararaca, was the first angiotensin converting enzyme (ACE) inhibitor to be discovered and tested. It was found to be an effective, non-toxic antihypertensive agent as well as an afterload-reducing agent for patients with congestive heart failure (CHF). The primary activity of teprotide resulted from blockade of the angiotensin I converting enzyme--the pivotal step in the renin-angiotensin-aldosterone system (RAAS), and consequent reductions in angiotensin II levels. There was limited clinical testing for teprotide because of: its scarcity; the need for parenteral administration; and the subsequent discovery and synthesis of captopril, the first orally active angiotensin converting enzyme inhibitor. Captopril is the prototype oral angiotensin converting enzyme inhibitor and has been extensively studied since the initiation of formal studies in 1976. Perhaps one of the most closely researched drugs in modern times, the experience with captopril now includes more than 12,000 patients studied in formalized trials and over 4,000,000 patients treated world-wide by physicians for hypertension and congestive heart failure. Enalapril (MK421) is the first of what appears to be a growing number of analogues which are structurally and pharmacodynamically different from captopril; yet, they possess the same capacity for inhibiting the activity of angiotensin converting enzyme. The side effect profile of enalapril (and presumably future) angiotensin converting enzyme inhibitors appears to be similar to captopril, though clearly more experience is needed with newer agents. The initial use of captopril was troubled by a relatively high incidence of side effects which will form the focus of this discussion. Partially the result of incomplete pharmacokinetic information, captopril was administered in early studies at dosages now recognised to be far in excess of those necessary for drug action. In addition, dosages were given without regard for deficiencies of renal function, now known to be the main excretory route of captopril. The population of those patients studied frequently had chronic, treatment-resistant hypertension, often associated with concomitant end-organ disease (especially renal disease); and many additional factors further complicating the clinical setting, e.g. a relatively high incidence of collagen vascular disease and immunosuppressive treatments.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. 302 83

When captopril was first introduced, it was used in high doses for severe hypertension, often in the presence of renal insufficiency, and side effects such as proteinuria, rash, neutropenia, and altered taste sensation were noted. Upon analysis, these effects were most commonly seen in patients with renal disease, autoimmune disease, or collagen vascular disease. These complications usually reversed rapidly upon discontinuation of treatment. In contrast, the growing use of the angiotensin converting enzyme inhibitors, captopril and enalapril, for treating mild to moderate hypertension and the trend toward the use of lower doses has shown these agents to be well tolerated with a low frequency of troublesome adverse effects. In fact, the original spectrum of adverse effects has virtually disappeared with the use of lower doses in patients with uncomplicated hypertension. In low doses, the converting enzyme inhibitors produce remarkably few incidences of symptomatic discomfort; the most common is skin rash, which often responds to dosage reduction. Cough and rare occurrences of angioedema have also been reported. Moreover, evidence is evolving that indicates that the converting enzyme inhibitors may sometimes decrease proteinuria and improve renal function; these effects may be especially important in diabetic hypertensive patients. Of note, these drugs can also attenuate the unwanted metabolic side effects of concurrent diuretic treatment.
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PMID:Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitors. 306 5


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