Beneficial Effects Of Angiotensin-converting Enzyme Inhibitors Research Articles

Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension

Abnormalities in fibrinolysis have been reported in hypertension. Angiotensin converting enzyme (ACE) inhibitors have been shown to improve altered fibrinolytic balance in hypertensive patients. It has not been documented, however, whether this is due to a decrease in angiotensin II (Ang-II) generation or is a consequence of elevated local levels of bradykinin. Accordingly, the aim of this study was to determine the effects of an ACE inhibitor (perindopril) and an Ang-II receptor antagonist (losartan) on fibrinolytic kinetics. We have examined the serum levels of the plasminogen activator inhibitor type-1 (PAI-1) antigen and activity, tissue plasminogen activator (t-PA) antigen and activity, soluble thrombomodulin (sTM), and tissue factor pathway inhibitor (TFPI) before and after reaching the target blood pressure (< 140/90 mm Hg) in 13 hypertensive patients receiving perindopril (mean age 40 ± 11 years, 6 women, 7 men) and in 12 patients receiving losartan (mean age 38 ± 9 years, 6 women, 6 men). We also compared the baseline fibrinolytic activity of hypertensive patients with that of 12 normotensive control persons (mean age 40 ± 9 years, 6 women, 6 men). The mean basal plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were significantly higher in the hypertensive patients than in normal controls ( P < .005). The values of other analytes were similar in both groups. Increased plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were reduced in patients after they were given perindopril and losartan ( P < .005); the reductions in losartan-receiving group were more pronounced ( P < .05). There were no significant effects on the plasma levels of t-PA antigen, t-PA activity, and TFPI in patients receiving the two therapeutic regimens ( P > .05). In conclusion, chronic hypertension is associated with hypofibrinolysis. The beneficial effect of ACE inhibitors on fibrinolysis seems to be related to the blockade of Ang-II, and increased kinin activity does not appear to play a major role.

Modulation of the renin-angiotensin-aldosterone system - pivotal in heart failure treatment.

The therapy of heart failure has evolved considerably over the last few decades. Whereas in the early years the focus was on improvement of cardiac pump function and symptomatic therapy by reducing overload through diuretic therapy, attention has now shifted toward prevention of (worsening of) the syndrome. This conceptual shift has been brought about by our recent understanding of the pathophysiological mechanisms underlying the progression of heart failure, in particular neurohormonal activation and cardiac remodeling, and the potential of neurohormonal antagonists such as ACE inhibitors, bblocking agents and aldosterone receptor antagonists, to modulate these processes and thereby significantly reduce or retard heart failure-related morbidity and mortality. The reninangiotensin system and aldosterone are two of the major, closely related neurohormonal systems involved in the pathogenesis of left ventricular dysfunction. Initially, ACE inhibitor therapy for heart failure was based on the concept that as, at least in more severe heart failure, circulating renin and angiotensin II levels are increased, the ACE inhibitor was considered to be a vasodilator of potential importance. Parallel to subsequent observations that ACE inhibitors beneficially affected morbidity and mortality in heart failure, this concept changed toward one in which it was realized that, in addition to the the circulating, endocrine-acting RAS, many tissues produce components of a local tissue renin-angiotensin system, and the concept that angiotensin II, in addition to being a potent vasoconstrictor, also had growth-promoting properties and was able to stimulate other neurohormonal systems, such as the sympathetic nervous system. The beneficial effects of ACE inhibitors on morbidity and mortality become apparent after a relatively long-term treatment period and are not necessarily accompanied by clear-cut hemodynamic improvement or an increase in exercise capacity. Hence, one may correctly assume that the long-term beneficial effects of these agents relate to their chronic structural effects on the heart and the vascular wall, effects which combine inhibition of cardiac and vascular remodeling, an improvement in endothelial function and a reduction in myocardial ischemia, and which all result from modulation of the local tissue renin-angiotensin system, and which relate not or significantly less to their modulating effect on the circulating renin-angiotensin levels.

Does the addition of losartan improve the beneficial effects of ACE inhibitors in patients with anterior myocardial infarction? A pilot study

OBJECTIVETo verify the efficacy of the combination of captopril (75 mg day) and losartan (25 mg/day) in early postinfarction phases of reperfused anterior acute myocardial infarction.DESIGN AND PATIENTS99 patients, hospitalised...

Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: A cohort study of 11,575 patients with coronary artery disease

OBJECTIVESThe purpose of this study was to investigate the significance of the possible negative interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors.BACKGROUNDSeveral provocative reports have recently suggested that aspirin is unsafe in patients with heart failure and has negative interaction with ACE inhibitors that might attenuate their beneficial effects upon survival.METHODSWe analyzed mortality data of 11,575 patients with coronary artery disease screened for the Bezafibrate Infarction Prevention trial. A total of 1,247 patients (11%) were treated with ACE inhibitors. Of them, 618 patients (50%) used aspirin.RESULTSFive-year mortality was lower among patients on ACE inhibitors and aspirin than patients on ACE inhibitors without aspirin (19% vs. 27%; p < 0.001). After adjusting for confounders, treatment with aspirin and ACE inhibitors remained associated with lower mortality risk than using ACE inhibitors only (relative risk [RR] = 0.71; 95% confidence interval [CI] = 0.56 to 0.91). Subgroup analysis of 464 patients with congestive heart failure treated with ACE inhibitors revealed 221 patients (48%) on aspirin and 243 patients not on aspirin. Although clinical characteristics and therapy were similar, patients taking aspirin experienced lower mortality than patients who did not (24% vs. 34%; p = 0.001). After adjustment, treatment with aspirin was still associated with lower mortality (RR = 0.70; 95% CI = 0.49 to 0.99).CONCLUSIONSAmong coronary artery disease patients with and without heart failure who are treated with ACE inhibitors, the use of aspirin was associated with lower mortality than treatment without aspirin. Our findings contradict the claim that aspirin attenuates the beneficial effect of ACE inhibitors and supports its use in patients with coronary artery disease treated with ACE inhibitors.

Interrupting the renin-angiotensin system: the role of angiotensin-converting enzyme inhibitors and angiotensin ii receptor antagonists in the treatment of hypertension

The renin-angiotensin system has two roles in clinical hypertension: its vasoconstrictor properties directly govern blood pressure, and its actions on arterial smooth muscle, connective tissue, and endothelial integrity affect cardiovascular prognosis. Additionally, the direct actions of angiotensin II on the function and structure of the heart and renal vasculature influence clinical events. Angiotensin-converting enzyme (ACE) inhibitors have produced functional and clinical outcome benefits in clinical trials of patients with congestive heart failure, systolic dysfunction after myocardial infarction, and diabetic nephropathy. Similar favorable trends have been noted in observational studies in hypertension. Because such enzymes as chymase can substitute for ACE, the ACE inhibitors may not completely block angiotensin II formation, although they enhance bradykinin accumulation and secondarily stimulate nitric oxide and vasodilatory prostaglandins. Angiotensin II receptor blockers (ARB) selectively block the angiotensin II type 1 (AT 1) receptor that not only mediates the known effects of angiotensin II but, according to recent reports, might be responsible for sequestering angiotensin II molecules in renal and cardiac cells. Moreover, by increasing plasma concentrations of angiotensin II, the ARB stimulate the unblocked angiotensin II type 2 (AT 2) receptors, which—if they exist in meaningful numbers in human hypertension—mediate additional vasodilatory and antiproliferative effects. The contrasting actions of these two classes of drugs might be clinically relevant. For example, they may have additive antihypertensive efficacy; they have differing effects on renal plasma flow; and in a small pilot study of patients with congestive heart failure, the ARB demonstrated an apparent advantage in survival. Ongoing clinical trials will try to determine whether the effects of ARB can equal or even exceed the beneficial effects of ACE inhibitors on cardiovascular prognosis.

Does Captopril Have a Direct Pro-Apoptotic Effect?

The beneficial effect of ACE inhibitors on cardiovascular remodelling from hypertension and ischemic disease may be due to the effect of these drugs on the proliferation/cell death balance. We therefore investigated the effect of the addition of captopril in vitro, on the onset of apoptosis in human vascular myocytes, by using a propidium iodide fluorescence analysis and a morphological analysis using the acridine orange technique. Captopril (0.23 mM) caused an increase in apoptotic phenomena that was more than 3.5-fold than in controls both at the 24th (7.7 vs. 2%) and the 48th h (10.1 vs. 3.8%). The addition of propranolol strengthened the effect on apoptosis. The induction of apoptotic phenomena may be a mechanism by which ACE inhibitors affect cardiovascular remodelling and it might also explain the favorable effect these drugs have on diseases such as IgA nephropathy and diabetic nephropathy.

Renal protection and antihypertensive drugs: current status.

The renal protective effect of antihypertensive drugs is linked to 2 mechanisms. First, reduction in blood pressure (BP) is a fundamental prerequisite common to all antihypertensive drugs. The exact definition of the level to which BP should be reduced remains to be established, although there is some evidence that BP should be reduced below 130/85 mm Hg in patients with diabetic and nondiabetic nephropathies and below 125/75 mm Hg in patients with nondiabetic nephropathies and proteinuria >1 g/day. However, available data suggest that tight BP control (BP<140/80 mm Hg) can reduce the risk of cardiovascular complications in hypertensive patients with type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus; NIDDM). Secondly, intrarenal actions on mechanisms such as glomerular hypertension and hypertrophy, proteinuria, mesangial cell proliferation, mesangial matrix production and probably endothelial dysfunction, which can cause and/or worsen renal failure, are relevant for the renal protective action of some drug classes. ACE inhibitors possess such properties and also seem to lower proteinuria more than other antihypertensive drugs, despite a similar BP lowering effect. Calcium antagonists likewise exert beneficial intrarenal effects, but with some differences among subclasses. It remains to be evaluated whether angiotensin II-receptor antagonists can exert intrarenal effects and antiproteinuric actions similar to those of ACE inhibitors. While primary prevention of diabetic nephropathy is still an unsolved problem. there is convincing evidence that in patients with type 1 (insulin-dependent diabetes mellitus; IDDM) or 2 diabetes mellitus and incipient nephropathy ACE inhibitors reduce urinary albumin excretion and slow the progression to overt nephropathy. Similar effects have been reported with some long-acting dihydropyridine calcium antagonists, although less consistently than with ACE inhibitors. In patients with diabetic overt nephropathy, ACE inhibitors and nondihydropyridine calcium antagonists are particularly effective in reducing proteinuria and both drugs can slow the decline in glomerular filtration rate more successfully than other antihypertensive treatment. Available data in patients with nondiabetic nephropathies indicate that ACE inhibitors can be beneficial, principally in patients with significant proteinuria, in slowing the progression of renal failure. However, it is still unclear whether this beneficial effect of ACE inhibitors is particularly evident in patients with mild and/or more advanced renal failure and whether calcium antagonists possess a similar nephroprotective effect. Overall, data from clinical trials thus seem to indicate that ACE inhibitors and possibly calcium antagonists should be preferred in the treatment of patients with diabetic and nondiabetic nephropathies. However, further information is needed to understand renal protection.

Angiotensin II Participates in Mononuclear Cell Recruitment in Experimental Immune Complex Nephritis Through Nuclear Factor-κB Activation and Monocyte Chemoattractant Protein-1 Synthesis

AbstractAngiotensin-converting enzyme (ACE) inhibitors reduce macrophage infiltration in several models of renal injury. We approached the hypothesis that angiotensin II (AngII) could be involved in inflammatory cell recruitment during renal damage through the synthesis of monocyte chemoattractant protein-1 (MCP-1). In a model of immune complex nephritis, we observed an up-regulation of renal MCP-1 (mRNA and protein) coincidentally with mononuclear cell infiltration that were markedly reduced by treatment with the ACE inhibitor quinapril. Exposure of cultured rat mesangial cells to AngII increased MCP-1 mRNA expression (2.7-fold) and synthesis (3-fold), similar to that observed with TNF-α. Since NF-κB is involved in the regulation of MCP-1 gene, we explored whether the effects of AngII were mediated through NF-κB activation. Untreated nephritic rats showed increased renal NF-κB activity (3.5-fold) that decreased in response to ACE inhibition. In mesangial cells, AngII activated NF-κB (4.3-fold), and the NF-κB inhibitor pyrrolidine dithiocarbamate abolished the AngII-induced NF-κB activation and MCP-1 gene expression. Our results suggest that AngII could participate in the recruitment of mononuclear cells through NF-κB activation and MCP-1 expression by renal cells. This could be a novel mechanism that might further explain the beneficial effects of ACE inhibitors in progressive renal diseases.

Neurohormonal markers of clinical outcome in cardiovascular disease: is endothelin the best one?

Endothelin-1 (ET-1) is the most potent vasoconstrictor yet described. The active 21-amino-acid peptide is derived from the conversion of the inactive precursor "Big ET-1" by an enzyme called endothelin-converting enzyme. In addition to its potent action as a vasoconstrictor, endothelin promotes growth and proliferation of smooth muscle and myocardial hypertrophy. ET-1 levels are elevated in acute myocardial infarction (MI), atherosclerosis, renal failure, diabetes, pulmonary hypertension, and congestive heart failure (CHF). ET-1 levels correlate extremely well with the seriousness of the pathophysiologic condition. ET-1 levels at 72 h post MI accurately predict long-term survival. In patients with heart failure, ET-1 levels also predict long-term outcome, with the prognosis being severely compromised in patients with elevated ET-1 levels. Levels of plasma big ET-1 have been demonstrated to predict 1-year mortality and have been shown to be a better predictor of 1-year outcome than plasma atrial natriuretic peptide and norepinephrine, NYHA class, age, and echocardiographic left ventricular parameters. Although a small number of studies have reported beneficial effects of ACE inhibitors on ET-1 levels in animal models, most reports in humans have not found an effect of ACE inhibitors on ET-1 levels. Only one ACE inhibitor, fosinopril, has been shown to be effective in normalizing ET-1 levels in clinically relevant situations, such as the long-term study of patients with CHF. This observation may point to a superior role of fosinopril compared with other ACE inhibitors in CHF patients and may indicate beneficial effects of fosinopril beyond blood pressure control.

Left Ventricular Dilatation After Myocardial Infarction

Left ventricular (LV) dilatation after myocardial infarction (MI) is a major predictor of prognosis and identifies which patients will develop heart failure. Left ventricular dilatation or remodeling starts immediately after MI and progresses in the chronic phase of heart failure. Factors influencing remodeling, such as infarct size and neurohumoral activation, including the sympathetic and renin-angiotensin system, are discussed. Remodeling can be affected by reduction of infarct size and inhibition of neurohumoral activation. The effect of thrombolysis, β-blockade, and angiotensin-converting enzyme (ACE) inhibition in the acute phase after MI and in the chronic phase of heart failure on remodeling are discussed. On the basis of beneficial effects of ACE inhibition and β-blockade in acute MI and in chronic heart failure, a treatment strategy is proposed in which both ACE inhibition and β-blockade are started early after MI. Depending on infarct size and ventricular function, continued treatment in the chronic phase of heart failure must be considered.

Left ventricular dilatation after myocardial infarction: ACE inhibitors, beta-blockers, or both?

Left ventricular (LV) dilatation after myocardial infarction (MI) is a major predictor of prognosis and identifies which patients will develop heart failure. Left ventricular dilatation or remodeling starts immediately after MI and progresses in the chronic phase of heart failure. Factors influencing remodeling, such as infarct size and neurohumoral activation, including the sympathetic and renin-angiotensin system, are discussed. Remodeling can be affected by reduction of infarct size and inhibition of neurohumoral activation. The effect of thrombolysis, beta-blockade, and angiotensin-converting enzyme (ACE) inhibition in the acute phase after MI and in the chronic phase of heart failure on remodeling are discussed. On the basis of beneficial effects of ACE inhibition and beta-blockade in acute MI and in chronic heart failure, a treatment strategy is proposed in which both ACE inhibition and beta-blockade are started early after MI. Depending on infarct size and ventricular function, continued treatment in the chronic phase of heart failure must be considered.

Current perspective on the use of angiotensin-converting enzyme inhibitors in the management of coronary (atherosclerotic) artery disease.

To review the pathophysiology of atherosclerosis, the role of the renin-angiotensin system in atherogenesis, and studies supporting the potential beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in reducing cardiovascular events with long-term use. Through its action in converting angiotensin I to angiotensin II and by degrading bradykinin, local tissue ACE exerts many effects that can contribute to the development of atherosclerosis. Therefore, the use of ACE inhibitors can possibly result in antiatherogenic effects. Possible mechanisms for antiatherogenic effects of ACE inhibitors include: (1) reduction of blood pressure; (2) antiproliferative and antimigratory effects on vascular smooth muscle cells, neutrophils, and monocytes; (3) restoration of endothelial function; (4) stabilization of fatty plaque by preventing vasoconstriction; (5) antiplatelet effects; and (6) enhancement of endogenous fibrinolysis. English-language clinical studies, abstracts, and review articles pertaining to the use of ACE inhibitors and atherosclerosis. Relevant human studies examining the role of ACE inhibitors and atherosclerosis. Studies evaluating the possible beneficial effects of ACE inhibitors in the development of atherosclerosis are reviewed and critiqued. Design of ongoing studies with clinical and surrogate end points are discussed. Based on current published studies, recommendations are made regarding the use of ACE inhibitors in atherosclerosis. Therapeutic monitoring parameters for efficacy and adverse effects are also reviewed.

ACE-inhibition prevents postischemic coronary leukocyte adhesion and leukocyte-dependent reperfusion injury.

Polymorphonuclear leukocytes (PMN), retained in the microvascular bed, can contribute to postischemic myocardial reperfusion injury. Since a beneficial effect of ACE-inhibition on reperfusion injury has been reported, we investigated the impact of cilazaprilat on PMN dependent reperfusion injury in isolated guinea pig hearts. Hearts (n = 5 per group) were subjected to 15 min of ischemia. Immediately thereafter, a bolus of PMN was injected into the coronary system. External heart work (EHW) and total cardiac nitric oxide release were measured. For microscopic evaluation, hearts received rhodamine 6G labelled PMN after ischemia, were arrested 5 min later and further perfused with FITC dextran (0.1%). Localization of retained PMN was assessed by fluorescence microscopy. Leukocyte activation was studied by FACS analysis of the adhesion molecule CD11b before and after coronary passage of the PMN. The ACE-inhibitor cilazaprilat (Cila, 2 microM) and the NO-synthase inhibitor nitro-L-arginine (NOLAG, 10 microM) were used to modulate nitric oxide formation of the heart. Postischemic EHW recovered to 67 +/- 5% (controls) and 64 +/- 6% (Cila) of the preischemic value. Addition of PMN severely depressed recovery of EHW (39 +/- 2%) and NO release (39 +/- 6% of the preischemic value). Simultaneously, ischemia led to a substantial increase in postcapillary PMN adhesion (from 21 +/- 5 to 172 +/- 27 PMN/mm2 surface) and CD11b-expression of the recovered PMN (3-fold). Cila attenuated postischemic PMN adhesion (83 +/- 52 PMN/mm2) and activation of PMN, whereas it improved recovery of work performance (64 +/- 4%) and NO release (65 +/- 4%) in the presence of PMN. Conversely, NOLAG increased PMN adhesion (284 +/- 40 PMN/mm2) and myocardial injury. We conclude that ACE-inhibition prevents leukocyte dependent reperfusion injury mainly by inhibition of postcapillary leukocyte adhesion. The effect may be mediated by NO, given the proadhesive effect of NOLAG.

Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts. Evidence for renin binding.

A local renin-angiotensin system in the heart is often invoked to explain the beneficial effects of ACE inhibitors in heart failure. The heart, however, produces little or no renin under normal conditions. We compared the cardiac tissue levels of renin-angiotensin system components in 10 potential heart donors who died of noncardiac disorders and 10 subjects with dilated cardiomyopathy (DCM) who underwent cardiac transplantation. Cardiac levels of renin and prorenin in DCM patients were higher than in the donors. The cardiac and plasma levels of renin in DCM were positively correlated, and extrapolation of the regression line to normal plasma levels yielded a tissue level close to that measured in the donor hearts. The cardiac tissue-to-plasma concentration (T/P) ratios for renin and prorenin were threefold the ratio for albumin, which indicates that the tissue levels were too high to be accounted for by admixture with blood and diffusion into the interstitial fluid. Cell membranes from porcine cardiac tissue bound porcine renin with high affinity. The T/P ratio for ACE, which is membrane bound, was fivefold the ratio for albumin. Cardiac angiotensinogen was lower in DCM patients than in the donors, and its T/P ratio was half that for albumin, which is compatible with substrate consumption by cardiac renin. These data in patients with heart failure support the concept of local angiotensin production in the heart by renin that is taken up from the circulation. Membrane binding may be part of the uptake process.

KININS AND CARDIOPROTECTION

During the past decade it was recognised that kinins are potent endogenous vasoactive peptides with important cardioprotective actions which are of therapeutic relevance in the acute and chronic beneficial effects of ACE inhibitors. The effect of kinins is mediated through the release of autocoids from the endothelium, particularly nitric oxide (NO). In this review article the cardioprotective effects of kinins and their importance for the therapeutic effects of ACE inhibitors are highlighted.

Quinapril decreases renal endothelin-1 expression and synthesis in a normotensive model of immune-complex nephritis.

Angiotensin-converting enzyme (ACE) inhibitors diminish proteinuria and the progression to renal failure in several experimental models of renal injury. Endothelin-1 (ET-1) possesses potent biological actions on renal vessels and has been considered as a potential mediator of renal damage. Because angiotensin II (Ang II) induces ET-1 synthesis in endothelial and mesangial cells, we hypothesized that some of the beneficial effects of the ACE inhibitors could result from the blockade of ET-1 synthesis. In a normotensive model of immune-complex nephritis, in which there exists an increase in renal ACE activity, the effect of the ACE inhibitor quinapril on preproET-1 and ETA receptor mRNA expression, as well as on ET-1 protein levels, was examined in this study. In relation to controls, nephritic rats showed an increase in preproET-1 and ETA receptor gene expression in renal cortex and medulla, coinciding with the maximal renal ACE activity. PreproET-1 mRNA (in situ hybridization) and ET-1 protein (immunohistochemistry) were localized in glomerular capillary walls, mesangial and glomerular epithelial cells, as well as in the brush border of some proximal tubules, and in small vessels. In nephritic rats, there was an increase in preproET-1 mRNA levels and ET-1 protein in all of these areas, without modification of their distribution. The administration of the ACE inhibitor quinapril decreased proteinuria and morphological lesions, preproET-1 gene transcription, and ET-1 protein levels, as well as the ETA receptor mRNA. The results from this study show that in a normotensive model of immune-complex nephritis, there was an overexpression of ET-1 in several structures of the kidney that was downregulated by quinapril administration. The beneficial effect of ACE inhibitors could be a result of the modulation of local production of Ang II and ET-1.

Endothelin-1 upregulation in the kidney of uninephrectomized spontaneously hypertensive rats and its modification by the angiotensin-converting enzyme inhibitor quinapril.

Endothelin (ET-1) is a potent vasoconstrictor that plays an important role in the control of renal circulation and tubular function. The contribution of this peptide to the pathogenesis of systemic hypertension and renal failure remains largely undefined. In spontaneously hypertensive rats (SHR) uninephrectomized at 20 weeks of age (UNX-SHR) and followed until 45 weeks of age, we determined ET-1 gene expression in renal tissue by reverse transcription-polymerase chain reaction and its localization by in situ hybridization in paraffin-embedded kidney sections. Age-matched SHR and normotensive Wistar-Kyoto (WKY) rats were chosen as controls. At the end of the follow-up, UNX-SHR had high systolic blood pressure, intense proteinuria, mesangial expansion, focal and segmental glomerular sclerosis, and tubulointerstitial lesions. In relation to WKY and SHR, UNX-SHR exhibited an increase in ET-1 gene expression in renal cortex and medulla. By in situ hybridization and immunoperoxidase staining, an overexpression of ET-1 gene and protein were seen in mesangial and glomerular epithelial cells and in some proximal tubules and vessels. Angiotensin-converting enzyme (ACE) activity was significantly increased in the renal brush border. Since in mesangial cells, angiotensin II induces ET-1 synthesis, a group of UNX-SHR received the ACE inhibitor quinapril from the time of UNX. These animals had a decrease in blood pressure, proteinuria, and serum and brush border ACE activity and in the expression and synthesis of ET-1 in all renal areas. On the whole, these data show that UNX-SHR have an upregulation of ET-1 gene and protein in several structures of the kidney compared with SHR and WKY rats. Quinapril diminished ACE activity and ET-1 expression and synthesis coincidentally with an improvement in proteinuria and morphological lesions. The beneficial effects of ACE inhibitors may be due to the diminution of both angiotensin II and ET-1 generation.

Impact of pharmacological treatment on mortality after myocardial infarction in diabetic patients

Several studies performed before and after the introduction of fibrinolysis as a routine treatment of patients with myocardial infarction (MI) consistently showed that diabetic patients have a higher mortality in-hospital and after discharge. Women with insulin-dependent diabetes (IDD) appear to have a particularly ominous prognosis. So far, very few randomized prospective studies evaluated the effect of pharmacological treatments on prognosis of diabetic patients during acute MI: most of the information on the effect of commonly used cardiovascular drugs in diabetic patients with acute MI (AMI) has been obtained only from retrospective subgroup analyses of some of the large trials or as nonrandomized comparisons. The overview of fibrinolytic trials in acute MI found that fibrinolytic treatment was associated with a 35 days mortality of 13.6% versus 17.3% in diabetics (−21.7%) and 8.7% versus 10.2% in nondiabetics (−14.3%). Data from trials with aspirin suggest that the beneficial effect of this drug is maintained in diabetic patients with acute MI, but the optimal dosage remains undefined. Based on available evidence, β blockers appear to be able to reduce mortality post-MI in diabetic patients, with an absolute and relative beneficial effect that is, in most cases, larger than that observed in nondiabetic patients. The pooled data from studies non β blockers indicate a 37% mortality reduction in diabetic patients, compared to 13% in nondiabetics during the acute phase, and a 48% reduction of mortality compared to 33% in nondiabetics post-discharge. Data on outcome of diabetic patients in trials evaluating calcium antagonists are lacking, and there is a strong need for a reevaluation of data from completed trials to obtain some hints on the possible effect of these agents in this population. The “long-term” studies on angiotensin-converting enzyme (ACE) inhibitors in patients with left ventricular dysfunction some time after AMI have shown that the beneficial effect documented in the overall population is present also when limiting the analysis to patients with a history of diabetes, whereas the “acute” studies enrolling patients within 24–36 h after the onset of symptoms have shown a marked beneficial effect of ACE inhibitors in diabetic patients. For example, in the GISSI 3 study, treatment with lisinopril was associated with a decreased 6-week mortality in both IDD (11.8% versus 21.1, p < 0.05) and non-IDD (8.0% versus 10.6%, p < 0.05) patients corresponding to a 44.1% and 24.5% reduction, respectively. All these results must be taken with great caution because in no studies the effect of treatment in diabetic patients was a predefined analysis. They strongly suggest, however, that ACE inhibitors and β blockers may be particularly beneficial during the acute phase of MI and also post-discharge, offering a strong rationale for their widespread use in diabetic patients with acute MI.

Endothelial function and bradykinin in humans.

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors (EDRFs) under basal conditions. In addition, the endothelium can increase the release of EDRFs in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions, the most important stimulus to the release of EDRFs is an increase in blood flow leading to increased shear stress on endothelial cells. Recent experimental studies raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or a hyperpolarising factor [endothelium-derived hyperpolarising factor (EDHF)]. This concept is also supported by recent studies in humans demonstrating that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has now been shown to be important in both human peripheral and coronary arteries. Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. This raises the possibility that beneficial vascular effects of ACE inhibitors may be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect of ACE inhibition is bradykinin dependent. These findings raise the possibility that the beneficial effects of ACE inhibition in heart failure and coronary artery disease might be partly due to improved endothelial function.

The Captopril Prevention Project (CAPPP) in Hypertension—Baseline Data and Current Status

Hansson L., Hedner T., Lindhoim L., Niklason A., Luomanmäki K., Niskanen L., Lanke J., Dahlöf B., de Faire U., Mörlin C., Karlberg B.E., Wester P.O., Björck J.-E. for the CAPPP Study Group. The Captopril Prevention Project (CAPPP) in hypertension—Baseline data arid current status.The Captopril Prevention Project (CAPPP) is an ongoing intervention study conducted in 11,019 hypertensive patients in Sweden and Finland. Patients have been randomized to receive either conventional antihypertensive therapy (diuretics and/or beta-blockers) or captopril-based treatment. A prospective, randomized, open, blinded-endpoint evaluation (PROBE) study design is used to compare these two therapeutic regimens as regards cardiovascular morbidity and mortality.The rationale for the CAPPP Study are the many observations of beneficial effects of ACE inhibition, as compared to diuretics and beta-blockers, on intermediary endpoints such as insulin sensitivity, serum lipoproteins, left ventricular hypertrophy and renal function. Captopril has also been shown to be markedly effective in the treatment of left ventricular dysfunction as well as congestive heart failure. The hypothesis is that these differences might result in improved risk reduction when ACE inhibitors are used in the treatment of hypertension.The present paper describes the baseline data and the changes in blood pressure during the first year in the total cohort. During the first year the average blood pressure was reduced by 11/8 mm Hg. A number of substudies have been conducted in the CAPPP Study. In one of these insulin sensitivity was compared in a subgroup of the patients using the euglycemic insulin clamp technique. In another substudy the ACE gene was sequenced and some new polymorphisms were discovered. Several other substudies are in progress or in the planning phase.The main results of the CAPPP Study should be available by mid-1998. Some of the intended anayses of the final results as well as other planned substudies are briefly described here.