ACE Inhibitors In Hypertension Research Articles

Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors in hypertension or heart failure?

There is a wealth of data that suggests an important interaction between aspirin and angiotensin-converting enzyme inhibitors in patients with chronic stable cardiovascular disease. The interaction is less obvious in the postinfarction setting, possibly reflecting the fact that many patients stop their aspirin therapy within a few months of such an event. An interaction is biologically plausible, because there is considerable evidence that angiotensin-converting enzyme inhibitors exert important effects through increasing the production of vasodilator prostaglandins, whereas aspirin blocks their production through inhibition of cyclooxygenase, even at low doses. There is some evidence that low-dose aspirin may raise systolic and diastolic blood pressure. There is also considerable evidence that aspirin may entirely neutralize the clinical benefits of angiotensin-converting enzyme inhibitors in patients with heart failure. In addition, aspirin may have an adverse effect on outcome in patients with heart failure that is independent of any interaction with angiotensin-converting enzyme inhibitors, possibly by blocking endogenous vasodilator prostaglandin production and enhancing the vasoconstrictor potential of endothelin. The evidence is not sufficient to justify advising long-term aspirin therapy for patients with cardiovascular disease in general, and for those with heart failure in particular. Thus, the lack of evidence of benefit with aspirin in patients with heart failure and coronary disease, along with growing evidence that aspirin is directly harmful in patients with heart failure and that aspirin may negate the benefits of angiotensin-converting enzyme inhibitors suggest that, unless there is an opportunity to randomize the patient into a study of antithrombotic strategies, then aspirin should be withdrawn or possibly substituted with an anticoagulant or an antiplatelet agent that does not block cyclooxygenase. In contrast, there is fairly robust evidence for a benefit of both aspirin and angiotensin-converting enzyme inhibitors during the first 5 weeks after a myocardial infarction, with little evidence of an interaction. The combination of aspirin and angiotensin-converting enzyme inhibitors is warranted during this period, after which discontinuation or substitution of aspirin with another agent should be considered.

Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events.

Endothelial cells are a rich source of a variety of vasoactive substances, which either cause vasodilation or vasoconstriction. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin. nitric oxide exerts potent anti-atherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. Endothelium-derived contracting factors include the 21 amino acid peptide endothelin (ET). vasoconstrictor prostanoids such as thromboxane A2 and prostaglandin H2, as well as free radicals and components of the renin angiotensin system. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modem therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Angiotensin converting enzyme (ACE) inhibitors are a primary candidate for that concept as they inhibit the circulating and local renin angiotensin system. Angiotensin converting enzyme is an endothelial enzyme which converts angiotensin-I (A-I) into angiotensin-II (A-II). This effect of the ACE inhibitor prevents direct effects of angiotensin-II such as vasoconstriction and proliferation in the vessel wall but also prevents activation of the ET system and of plasminogen activator inhibitor. Furthermore, inhibition of ACE prolongs the half-life of bradykinin and stabilizes bradykinin receptors linked to the formation of nitric oxide and prostacyclin. In isolated arteries ACE inhibitors prevent the contractions induced by angiotensin II and enhance relaxation induced by bradykinin. Chronic treatment of experimental hypertension with ACE inhibitors normalizes endothelium-dependent relaxation to acetylcholine and other agonists. In addition, the dilator effects of exogenous nitric oxide donors are enhanced, at least in certain models of hypertension. In humans with essential hypertension ACE inhibitors augment endothelium-dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3-6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.

ACE inhibitors for all--'Hope' for the heart and failure for the kidneys?

The body of evidence that supports the use of angiotensin-converting enzyme (ACE) inhibitors in an ever-wider spectrum of clinical conditions grows steadily greater. These drugs are now widely employed by general physicians, cardiologists, gerentologists, diabetologists and of course by nephrologists. Indeed, for the treatment of hypertension ACE inhibitors are now prescribed more frequently than beta-blockers in the United States. 1 Therapy with an ACE inhibitor is established for reducing excessive blood pressure, reducing mortality in patients with congestive heart failure (CHF), preventing the development of CHF in patients with asymptomatic left ventricular (LV) dysfunction, and preventing death and CHF when initiated early after the onset of acute myocardial infarction (MI). Although these benefits have been attributed largely to haemodynamic mechanisms, recent preclinical and clinical evidence reveal ACE inhibition as potent in preventing ischaemic events and in blocking an array of ischaemic processes, including atherogenesis. 2 Yet further benefits from ACE inhibition are seen in diabetic retinopathy 3 and are suggested in neoplasia. 4 Renal indications for the preferential use of ACE inhibitors now include not only ‘nephro-protection’ in type I diabetics with micro-albuminuria with or without raised blood pressure, 5,6 non-diabetic proteinuria, 7‐10 chronic allograft nephropathy 11,12 but also control of hypertension, reversal or amelioration of LV hypertrophy (LVH) 13,14 amelioration of increased large artery stiffness, 13 and post-transplant erythrocytosis. 15 ACE inhibitors are now widely used in patients with all types of renal disease— tempered only by hyperkalaemia and rare anaphyl

Interaction between angiotensin-converting enzyme inhibitors and aspirin: a review.

Aspirin and angiotensin-converting enzyme inhibitors (ACEIs) are often associated for the treatment of coronary disease and/or chronic heart failure, but conclusions of some prospective and retrospective studies show a possible negative interaction between aspirin and ACEIs. ACEIs inhibit the conversion of angiotensin I to angiotensin II and also the catabolism of bradykinin, which results in increased synthesis of vasodilatory agents [prostaglandins and nitric oxide (NO)], whereas aspirin inhibits prostaglandin synthesis. Thus, a potential interaction from the opposing effects of aspirin and ACEIs could affect the metabolism of bradykinin. We conducted an extensive Medline search, as well as a manual search, of published literature including pharmacodynamic studies and clinical trials concerning the impact of aspirin on the effect of ACEIs in hypertension, coronary disease and chronic heart failure. A review of this literature shows five studies in hypertension (all prospective and using blood pressure as the main criterion of assessment), five in coronary disease (three retrospective and two prospective trials, four of which use mortality as the criterion of assessment) and 13 in chronic heart failure (eight using haemodynamic measurements of which seven are prospective--one prospective study using pulmonary tests, four using clinical events including mortality as criterion of assessment of which two are prospective). The counteraction of ACEI efficacy by aspirin is demonstrated in one out of five studies in hypertension, one out of four of studies in coronary disease and nine out of thirteen in chronic heart failure. This counteraction is more often observed with high dosages of aspirin (greater than 250 mg/day, four out of six studies) and less often with lower dosages (less than or equal to 250 mg/day, three out of 11 studies). These studies are retrospective analyses or use haemodynamic end-points, so there is as yet no methodological argument strong enough to contraindicate the aspirin-ACEI association or to prove the clinical relevance of this interaction. In conclusion, prospective studies using mortality as a criterion of assessment are needed to offer the practitioner the answer to the question of ACEI-aspirin association.

Isolated Visceral Angioedema: An Underdiagnosed Complication of ACE Inhibitors?

Angiotensin-converting enzyme (ACE) inhibitors are known to cause potentially fatal peripheral angioedema in some patients. ACE inhibitors may also cause isolated visceral angioedema, a rarely reported complication. This article describes 2 patients who experienced this complication. Both patients came to medical attention with episodes of recurrent abdominal symptoms that had occurred while taking ACE inhibitors for hypertension. Each patient had undergone surgical procedures for symptoms that persisted after surgery and were ultimately relieved with cessation of their ACE inhibitors. These cases call attention to what may be an underappreciated cause of abdominal pain in patients presenting to emergency departments.

Role of angiotensin-converting-enzyme inhibitors in the treatment of hypertension.

Therapeutic goals for the treatment of hypertension and the ability of various angiotensin-converting-enzyme (ACE) inhibitors to meet these goals are presented. The 1997 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) does not recommend ACE inhibitors for first-line therapy in the treatment of hypertension; however, these guidelines do identify compelling indications for ACE inhibitor therapy, including diabetes mellitus (type 1) with proteinuria, heart failure, or previous myocardial infarction with systolic dysfunction. Since the JNC-VI guidelines were developed, the results of a prospective randomized clinical trial in patients with uncomplicated hypertension have demonstrated that ACE inhibitor therapy is as effective as conventional treatment in the prevention of cardiovascular morbidity and mortality. In hypertensive patients with diabetes, therapy with captopril, enalapril, fosinopril, or ramipril has resulted in significant reductions in cardiovascular events. In addition, tight blood pressure control with an ACE inhibitor has resulted in a greater reduction in the risk of macrovascular and microvascular complications of diabetes than was seen with less tight control. Recent study results support broader use of ACE inhibitors for hypertension than was recommended in the JNC-VI guidelines.

ACE inhibitors in hypertension: still a shortage of evidence.

The extensively cited pooled analysis of the unconfounded randomised control trials of the treatment of hypertension 1 showed that a reduction in diastolic blood pressure of 5‐6 mmHg maintained for a period of five years, was associated with a 38% reduction in the incidence of stroke and a 16% reduction in the incidence of coronary heart disease (CHD) events. From prospective observational studies, similar differences in diastolic blood pressure maintained over a more prolonged observation period would account for a 35‐40% difference in stroke incidence and a 20‐25% difference in coronary heart disease incidence. Thus it was concluded that there was a shortfall in coronary heart disease prevention observed in the intervention trials and several hypotheses were put forward to explain this lack of benefit. One such hypothesis propounded that the old drugs used in the trials, namely the diuretics and β-adrenoreceptor blocking drugs, although effective antihypertensive agents, were associated with long-term adverse metabolic side effects, the consequences of which could mitigate the beneficial effects of blood pressure lowering. Following on from this hypothesis was the suggestion that the more recently developed classes of drugs such as the angiotensin-converting-enzyme (ACE) inhibitors and the calcium channel blockers, by virtue of their absence of metabolic sequelae, might confer additional benefit in terms of coronary heart disease prevention when compared with older agents. Over recent years there has also been growing recognition of the importance of other peptidergic systems which are closely related to the activity of the renin-angiotensin-aldosterone system. The role of atrial natriuretic peptides and kinins particularly bradykinin, for example, remain controversial and only recently has insight been gained on the potential importance of the endothelins, some of the most potent naturally occurring vasoconstrictor substances yet identified. Moreover, observations with these newer drugs in experimental models and selected subgroups of patients indicated the possibility of additional reductions in cardiovascular morbidity and mortality as a consequence of what has been termed ‘tissue protection’. 2,3

Effect of ACE inhibitor on DOCA-salt- and aortic coarctation-induced hypertension in mice: do kinin B2 receptors play a role?

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.

Treating Anesthesia-Induced Hypotension by Angiotensin II in Patients Chronically Treated with Angiotensin-Converting Enzyme Inhibitors

Although angiotensin II bolus administration may be used to increase blood pressure in patients chronically treated with angiotensin-converting enzyme inhibitors (ACEI) who have severe hypotension on anesthetic induction, no data are available describing its time course and its effects on the left ventricular function. Fourteen patients chronically treated with ACEI for hypertension and scheduled for vascular surgery were prospectively studied. Patients with cardiac insufficiency were excluded. A transesophageal echocardiography probe was inserted to assess systolic left ventricular function. When hypotension was observed (systolic arterial pressure [SAP] <85 mm Hg), an I.V. bolus of 2.5 microg of angiotensin II (AII) was given, and hemodynamic variables were recorded each 30 s over 5.5 min. Results are expressed as mean +/- SEM. Sixty seconds after the AII bolus injection, the SAP increased from 78 +/- 3 to 152 +/- 6 mm Hg. SAP remained higher than control until the 5th min. This was associated with significant increases in end-diastolic area (from 15.1 +/- 0.6 to 19.3 +/- 1.0 cm2, P < or = 0.001), end-systolic area (from 6.6 +/- 0.4 to 10.7 +/- 0.7 cm2, P < or = 0.001), end-systolic wall stress (from 32 +/- 0.05 to 82 +/- 7 kdynes/cm2, P < or = 0.001). In addition, a decrease in fiber-shortening velocity (from 1.1 +/- 0.05 to 0.76 +/- 0.04 circ/s, P < or = 0.05) and in fractional area change (from 0.57 +/- 0.02 to 0.44 +/- 0.02, P < or = 0.05) was observed. Heart rate did not significantly change during the study. Increases in preload and afterload were observed. However, the administration of AII causes a transient impairment in left ventricular function. We conclude that AII, given as an I.V. bolus of 2.5 microg, is effective in restoring arterial blood pressure within 60 s in patients chronically treated with ACEI. Severe hypotension on anesthetic induction in patients chronically treated with angiotensin-converting enzyme inhibitors for hypertension could be treated with an I.V. bolus of 2.5 microg of angiotensin II.

Total costs of older vs newer ACE inhibitors in hypertension

Total costs of older vs newer ACE inhibitors in hypertension

Trends in Pharmacologic Management of Hypertension in the United States

Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension. Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States. Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of beta-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992. Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and beta-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.

Role of ACE inhibitors in hypertension with left ventricular hypertrophy

Role of ACE inhibitors in hypertension with left ventricular hypertrophy

Role of ACE inhibitors in hypertension complicated by vascular disease.

Role of ACE inhibitors in hypertension complicated by vascular disease.

Angiotensin-converting enzyme inhibitors in hypertension. A dozen years of experience

Angiotensin-converting enzyme inhibitors in hypertension. A dozen years of experience

Cardioprotection with angiotensin‐converting enzyme inhibitors: Redefined for the 1990s

The concept of "cardioprotection" with ACE inhibitors has evolved over the last decade. In the 1980s, protective benefits of ACE inhibitors in hypertension were established, regression of left ventricular hypertrophy was demonstrated, and improved ventricular function and survival in mild-to-moderate and severe congestive heart failure was documented. A further "protective" role of ACE inhibitors in coronary artery disease is emerging as more attention is focused on the concept of local tissue renin-angiotensin systems. Recent contributions to the literature describe significant benefits of ACE-inhibitor therapy in acute myocardial infarction, including suppression of ventricular arrhythmias and reduction of both early and late ventricular dilation, preservation of left ventricular function, and improved survival. All of the above effects can be considered "cardioprotective." However, as new benefits are reported in the 1990s, a broadened view of "cardiovascular protection" emerges from investigative studies in the literature. ACE inhibitors may reduce tolerance to nitrates, reduce angina in some but not all studies, and limit smooth muscle cell proliferation (and perhaps restenosis) induced by experimental balloon angioplasty. Local vascular effects may attenuate atherosclerotic changes in the arterial wall in experimental animals and may decrease the incidence of aneurysm formation in hypertensive animals. The effectiveness of ACE inhibitors in acute myocarditis, suggested by reports that captopril may reduce lesions of murine myocarditis when administered early after infection with coxsackievirus B3, requires clinical confirmation. Despite these apparently diverse "cardiovascular protective" consequences of ACE inhibitor therapy, the mechanism(s) of action of these agents remain to be elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

ACE inhibitors for hypertension in IDDM

ACE inhibitors for hypertension in IDDM

Blood pressure, angiotensin-converting enzyme (ACE) inhibitors, and the kidney

Angiotensin II plays an important role in the kidney by regulating renal flow, glomerular filtration rate, mesangial cell function, and sodium reabsorption. Blockade of the renin-angiotensin system has powerful effects on kidney function. Studies in animal models of renal failure suggest that converting enzyme inhibitors slow down the inevitable progression of the renal failure. This could be in part due to their effect on reducing glomerular pressure or by reducing glomerular hypertrophy. In patients with malignant hypertension, diabetic nephropathy, and other causes of renal failure, preliminary evidence suggests that lowering the blood pressure with angiotensin-converting enzyme (ACE) inhibitors may possibly carry some other benefits compared with other blood pressure lowering regimens. However, single drug therapy is rarely sufficient to control blood pressure in these patients. Further properly controlled randomized trials should give a clear indication of whether any particular class of drug has any advantage in slowing down the progressive renal impairment for a given lowering of blood pressure. In patients with renovascular hypertension ACE inhibitors are effective drugs in lowering blood pressure. However, in certain settings they may cause a reversible decline in renal function.

Modulation of coronary circulation and the cardiac matrix by the renin-angiotensin system

There are short-term and long-term modulations of cardiac function and cardiac composition by the endocrine and paracrine renin-angiotensin system. First, there is an enhancement of coronary vasoconstrictor tone in severe congestive heart failure due to stimulation of this system. Therapeutic interventions that block the RA-system are able to reduce the increased resistance to coronary flow. Second, there is a relationship between the occurrence of arrhythmias and the degree of sympathetic stimulation in congestive heart failure. The renin-angiotensin system may be involved in arrhythmogenesis because of presynaptic modulation of sympathetic neurotransmitter release. However, in the isolated perfused rat heart no class-specific antiarrhythmic properties could be found for ACE inhibitors during progressive myocardial ischaemia. Third, proliferation of the neointima following injury of a coronary artery is at least in part mediated by angiotensin II. Although ACE inhibition was an effective tool in animal experiments to prevent excessive proliferation of the neointima following ballooning, it was less effective in preventing restenosis in man following a repeat coronary angioplasty. Fourth, preferential proliferation of the cardiac interstitium in experimental hypertension has been associated with activation of the renin-angiotensin system. In patients with essential hypertension ACE inhibitors were not only capable of controlling blood pressure but also of normalizing the previously pathological pattern of diastolic left ventricular filling. In summary, by therapeutic intervention that cause a blockade of this system, cardioprotective and cardioreparative processes can be supported.

Angiotensin-Converting Enzyme Inhibitors in the Treatment of Hypertension

This article examines the evidence justifying the use of angiotensin-converting enzyme (ACE) inhibitors as first-line antihypertensive drugs. ACE inhibitors are as effective as traditional antihypertensive agents and, in addition, exert their blood-pressure-lowering effect with near optimal hemodynamic alterations. These drugs have a good tolerance and safety profile although they induce cough in an appreciable number of patients. They can be safely associated with other antihypertensive agents to provide therapeutic benefit in a large proportion of the hypertensive population. ACE inhibitors are contraindicated only in bilateral renal artery stenosis or stenosis of a single kidney. Although to date no prospective study has examined the ability of ACE inhibitors to reduce cardiovascular morbidity and mortality in hypertension, several features of these drugs suggest that this may be the case as several effects of ACE inhibitors in hypertension are potentially nephroprotective and cardioprotective.

Angiotensin-Converting Enzyme Inhibition and Vascular Structure in Hypertension

The pathogenesis of hypertension is associated with a remodeling of vascular structure. Folkow has postulated that the decreased luminal area and thickened medial layer in hypertensive vessels enhance the vasoconstrictive response to vasoactive agents. It is hypothesized that this increase in vascular reactivity may serve to perpetuate hypertension. These same structural changes also predispose to the end-organ damage associated with hypertension. A growing body of evidence suggests that autocrine-paracrine vasoactive substances and growth factors modulate vascular structure in hypertension. It is speculated that therapeutic interventions that normalize blood pressure as well as reverse the vascular remodeling process may have special clinical value. The roles of the paracrine renin-angiotensin system and angiotensin-converting enzyme inhibitors in hypertension are discussed in this context.