Eprosartan in the primary prevention of cardiac allograft vascular disease: a double-blind prospectively randomized study using intravascular ultrasound.

The angiotensin blocker (ARB) eprosartan (600 mg once daily) and the calcium antagonist diltiazem (90 mg twice daily) were studied in a 24-month prospective, randomized, double-blind trial involving 53 heart transplant patients. The study compared their effects on the development of post-transplant cardiac allograft vasculopathy, a condition that frequently impairs long-term post-transplantation survival and where angiotensin blockers might be expected to play a preventive role. From baseline to month 12, the mean plaque volume increased by 7.7 mm(3) for eprosartan-treated patients and by 34.4 mm(3) for diltiazem-treated patients, but the eprosartan-related trend for reduced myointimal hyperplasia was not statistically significant. The trend in favour of eprosartan for secondary parameters (mean intimal index, vessel volume, lumen volume and coronary flow reserve) also failed to reach significance. The lack of effect might be due to a lower than planned sample size and observation periods due to recruitment difficulties. A larger study is required to confirm these preliminary findings.

Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.

BACKGROUND: Endothelial dysfunction of coronary and peripheral arteries has been demonstrated in patients with chronic heart failure (CHF) and appears to be associated with functional implications. However, it is unknown whether endothelial dysfunction in CHF is independently associated with impaired outcome or progression of the disease. METHODS AND RESULTS: We assessed the follow-up of 67 consecutive patients with CHF [New York Heart Association (NYHA) functional class II-III] in which flow-dependent, endothelium-mediated vasodilation (FDD) of the radial artery was assessed by high resolution ultrasound. The primary endpoint was defined by cardiac death, hospitalization due to worsening of heart failure (NYHA class IV, pulmonary oedema), or heart transplantation. Cox regression analysis was used to determine whether FDD was associated with these heart failure-related events. During a median follow-up of 45.7 months 24 patients had an event: 18 patients were hospitalized due to worsening of heart failure or heart transplantation, six patients died for cardiac reasons. Cox regression analysis demonstrated that FDD (P<0.01), diabetes mellitus (P<0.01), and ejection fraction (P<0.01) were independent predictive factors for the occurrence of the primary endpoint. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with FDD above the median (6.2%) compared with those with FDD below the median (P<0.013). CONCLUSION: These observations suggest that endothelium-mediated vasodilation represents an independent predictor of cardiac death and hospitalization in patients with CHF, consistent with the notion that endothelium-derived nitric oxide may play a protective role in heart failure.

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data.

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase.

BACKGROUND: Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT(1)-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. METHODS AND RESULTS: Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT(1)-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4+/-1.1 versus 3.8+/-0.9 and AT(1)-A, 13.5+/-1.0 versus 3.9+/-0.9 U. mL(-1). min(-1); each P<0.01). CONCLUSIONS-Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.

Endothelial dysfunction in hypercholesterolemia: mechanisms, pathophysiological importance, and therapeutic interventions.

Since the demonstration of the obligatory role of the endothelium in arterial relaxation by Furchgott and Zawadzki (1980), there has been great interest in the role of the endothelium in vascular disease. Apart from endothelium-dependent vasodilation, other important functions of the endothelium have now been studied, that is, the regulation of adhesion and infiltration of leukocytes and inhibition of platelet adhesion and aggregation. Many functions of the endothelium are influenced by nitric oxide (NO), which is synthesized by endothelial NO synthase. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Multiple factors contribute to this, including increased inactivation of NO by radicals and inhibition of NO formation by different mechanisms. The functional implications of endothelial dysfunction are not completely defined. However, recent studies suggest that endothelial dysfunction contributes to myocardial perfusion abnormalities. Furthermore, endothelial dysfunction may play an important role with respect to development and progression of atherosclerosis because the endothelium is involved in the regulation of key events of the atherosclerotic process. Endothelial dysfunction in hypercholesterolemia is reversible by cholesterol-lowering treatment, that is treatment with HMG-CoA-reductase inhibitors. First experimental data suggest that maneuvers that increase the bioavailability of NO in hypercholesterolemia may even result in regression of preexisting atherosclerotic lesions.

Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation.

BACKGROUND: Increased inactivation of nitric oxide by oxygen free radicals contributes to endothelial dysfunction in patients with coronary artery disease (CAD). We therefore determined the activity of extracellular superoxide dismutase (EC-SOD), the major antioxidant enzyme system of the vessel wall, and its relation to flow-dependent, endothelium-mediated dilation (FDD) in patients with CAD. METHODS AND RESULTS: SOD isoenzyme activity was determined in coronary arteries from 10 patients with CAD and 10 control subjects. In addition, endothelium-bound EC-SOD activity (eEC-SOD), released by heparin bolus injection, and FDD of the radial artery were measured in 35 patients with CAD and 15 control subjects. FDD, determined by high-resolution ultrasound, was assessed at baseline, after intra-arterial infusion of vitamin C, N-monomethyl-L-arginine, and combination of both. EC-SOD activity in coronary arteries (control subjects: 126+/-14; CAD: 63+/-11 U/mg protein; P<0.01) and eEC-SOD activity in vivo (control subjects: 14.5+/-1.1; CAD: 3.8+/-1.1 U. mL(-1). min(-1); P<0.01) were reduced in patients with CAD. Activity of eEC-SOD was positively correlated with FDD (r=0.47; P<0. 01) and negatively with the effect of the antioxidant vitamin C on FDD (r=-0.59; P<0.01). In young individuals with hypercholesterolemia, however, eEC-SOD activity was increased (21. 0+/-1.2 U. mL(-1). min(-1); n=10; P<0.05). CONCLUSIONS: In patients with CAD, vascular EC-SOD activity is substantially reduced. The close relation between endothelium-bound EC-SOD activity and FDD suggests that reduced EC-SOD activity contributes to endothelial dysfunction in patients with CAD. In young hypercholesterolemic individuals, however, endothelium-bound EC-SOD activity is increased and may, in part, counteract impairment of endothelial function as the result of increased formation of oxygen free radicals.

Endothelial dysfunction in human disease.

The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (i.e. endothelium-derived relaxing factor (EDRF = nitric oxide, NO) and prostacyclin) and vasoconstrictor substances (i.e. thromboxane A2, free radicals, or endothelin). Using either agents like acetylcholine or changes in flow to stimulate the release of EDRF (NO), clinical studies have revealed the importance of EDRF in both basal and stimulated control of vascular tone in large epicardial coronary arteries and in the coronary microcirculation. The regulatory function of the endothelium is altered by cardiovascular risk factors or disorders such as hypercholesterolemia, chronic smoking, hypertension or chronic heart failure. Endothelial dysfunction appears to have detrimental functional consequences as well as adverse longterm effects, including vascular remodelling. Endothelial dysfunction is associated with impaired tissue perfusion particularly during stress and paradoxical vasoconstriction of large conduit vessels including the coronary arteries. These effects may cause or contribute to myocardial ischemia. Several mechanisms may be involved in the development of endothelial dysfunction, such as reduced synthesis and release of EDRF or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized low-density lipoprotein (LDL). Increased plasma levels of oxidized LDL have been noted in chronic smokers and are related to the extent endothelial dysfunction, raising the possibility that chronic smoking potentiates endothelial dysfunction by increasing circulating and tissue levels of oxidized LDL. In heart failure, cytokines and/or reduced flow (reflecting reduced shear stress) may be involved in the development of endothelial dysfunction and can be reversed by physical training. Other mechanisms include an activated renin-angiotensin system (i.e. postmyocardial infarction) with increased breakdown of bradykinin by enhanced angiotensin converting enzyme (ACE) activity. There is evidence that endogenous bradykinin is involved in coronary vasomotor control both in coronary conduit and resistance vessels. ACE inhibitors enhance endothelial function by a bradykinin-dependent mechanism and probably also by blunting the generation of superoxide anion. Endothelial dysfunction appears to be reversible by administering L-arginine, the precursor of nitric oxide, lowering cholesterol levels, physical training, antioxidants such as vitamin C, or ACE inhibition.

Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with endothelial dysfunction, including impaired flow-dependent (endothelium-mediated) dilation (FDD). We have previously shown that ACE inhibition improves endothelium-mediated vasodilation in healthy volunteers. The present study was designed to determine whether ACE inhibition improves the impaired FDD in patients with CHF. Because their affinity to tissue ACE may influence the ability of ACE inhibitors to affect endothelial function, we compared the effects of quinaprilat (high affinity to tissue ACE) and enalaprilat (low affinity to tissue ACE) on FDD in patients with CHF. METHODS AND RESULTS: High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in patients with CHF. The effects of intra-arterial infusion of quinaprilat 1.6 microg/min (n=15) and enalaprilat 5 microg/min (n=15) were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after N-monomethyl-L-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Quinaprilat improved FDD by >40% (10.2+/-0.6% versus 6.9+/-0.6%; P<0.01), whereas enalaprilat had no effect. In particular, the part of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased by >100% with quinaprilat (5.6+/-0.5% versus 2.5+/-0.5%; P<0.01). Enalaprilat had no effect on FDD even when it was infused twice in the same dose (5 microg/min) and up to 30 microg/min. The effect of sodium nitroprusside on radial artery diameter and blood flow was similar in patients treated with quinaprilat, enalaprilat, and placebo. CONCLUSIONS: Quinaprilat improves FDD in patients with CHF as the result of increased availability of nitric oxide, whereas enalaprilat does not. This observation suggests that intrinsic differences exist between quinaprilat and enalaprilat that determine the ability to improve endothelium-mediated vasodilation, ie, their different affinity to tissue ACE.

Effect of ACE inhibition on endothelial dysfunction in patients with chronic heart failure.

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors(s) (EDRF) under basal conditions. In addition, the endothelium can increase the release of EDRF in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions the most important stimulus to the release of EDRF is an increase in blood flow, leading to increased shear stress on endothelial cells. Recent experimental studies have 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 endothelium-derived hyperpolarizing factor. Recent studies in humans have demonstrated that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has been shown to be important in humans in both peripheral and coronary arteries. Angiotensin-converting enzyme (ACE) inhibitors not only decrease angiotensin II but also increase bradykinin levels, since ACE is identical to kininase II, which degrades bradykinin. The beneficial vascular effects of ACE inhibitors may therefore 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 is bradykinin-dependent. Our preliminary data also indicate that ACE inhibition improves endothelium-mediated vasodilation in patients with heart failure and coronary artery disease due to an enhanced availability of nitric oxide. These findings suggest that the beneficial vascular effects of ACE inhibition in heart failure may be due in part to improved endothelial function.

Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). There is evidence for increased radical formation in CHF, raising the possibility that nitric oxide is inactivated by radicals, thereby impairing endothelial function. To test this hypothesis, we determined the effect of the antioxidant vitamin C on FDD in patients with CHF. METHODS AND RESULTS: High-resolution ultrasound and Doppler was used to measure radial artery diameter and blood flow in 15 patients with CHF and 8 healthy volunteers. Vascular effects of vitamin C (25 mg/min IA) and placebo were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after intra-arterial infusion of N-monomethyl-L-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Vitamin C restored FDD in patients with heart failure after acute intra-arterial administration (13.2+/-1.7% versus 8.2+/-1.0%; P<.01) and after 4 weeks of oral therapy (11.9+/-0.9% versus 8.2+/-1.0%; P<.05). In particular, the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased after acute as well as after chronic treatment (CHF baseline: 4.2+/-0.7%; acute: 9.1+/-1.3%; chronic: 7.3+/-1.2%; normal subjects: 8.9+/-0.8%; P<.01). CONCLUSIONS: Vitamin C improves FDD in patients with CHF as the result of increased availability of nitric oxide. This observation supports the concept that endothelial dysfunction in patients with CHF is, at least in part, due to accelerated degradation of nitric oxide by radicals.

Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.

BACKGROUND: There is evidence for increased formation of free radicals in patients with hypertension, raising the possibility that NO is inactivated by free radicals, which impairs coronary endothelial function. Therefore, we tested the hypothesis that the antioxidant vitamin C could improve abnormal endothelial function of coronary arteries in patients with hypertension. METHODS AND RESULTS: In 22 hypertensive patients without relevant coronary artery stenoses, endothelium-dependent vascular responses of the left anterior descending coronary artery (LAD) to acetylcholine (0.01, 0.1, and 1.0 micromol/L) were determined before and immediately after intravenous infusion of 3 g vitamin C (17 patients) or placebo (5 patients). In a subgroup of 10 patients, papaverine-induced flow-dependent vasodilation (FDD) was measured before and after vitamin C (5 patients) or placebo (5 patients) infusion. Segmental responses of the coronary artery luminal area were analyzed with quantitative coronary angiography. Before vitamin C infusion, the mean changes of LAD luminal areas at increasing doses of acetylcholine were -6.1+/-2.2%, -15.2+/-4.9%, and -33.9+/-8.1% (negative numbers symbolize vasoconstriction) and during FDD, 5.4+/-1.0%. The vasoconstrictor response during acetylcholine was reduced and FDD was augmented by vitamin C. After vitamin C infusion, LAD luminal areas changed by -3.2+/-2.3%, -5.8+/-3.6%, and -10.2+/-5.6% (P<.05, acetylcholine) and 17.8+/-2.8% (P<.05, FDD). Doppler flow velocity (during baseline, acetylcholine, and FDD) was not significantly affected by vitamin C. CONCLUSIONS: Vitamin C improves the endothelium-dependent vasomotor capacity of coronary arteries in patients with hypertension and patent coronary arteries. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in hypertensive patients.

Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans.

BACKGROUND: The angiotensin-converting enzyme (ACE) not only generates angiotensin II but is also the main enzyme that destroys bradykinin. It has been hypothesized, therefore, that bradykinin is involved in the vascular effects of ACE inhibitors. However, its contribution has never been demonstrated in humans because of the lack of specific bradykinin receptor antagonists. METHODS AND RESULTS: High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in 10 healthy volunteers. The vascular effects of the ACE inhibitor quinaprilat, the selective bradykinin B2-receptor antagonist icatibant, and their combination were determined at rest, during reactive hyperemia (with increased flow causing endothelium-mediated, flow-dependent dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Neither icatibant nor quinaprilat affected arterial diameter or blood flow at rest. However, icatibant reduced flow-dependent dilation by 33%, and quinaprilat increased flow-dependent dilation over baseline by 46%. After coinfusion of quinaprilat and icatibant, flow-dependent dilation was reduced to a similar extent as after infusion of icatibant alone. CONCLUSIONS: ACE inhibition enhances flow-dependent, endothelium-mediated dilation in humans by a bradykinin-dependent mechanism. This observation indicates that accumulation of endogenous bradykinin is involved in the vascular effects of ACE inhibitors in humans.

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.

Physical training improves endothelial function in patients with chronic heart failure.

BACKGROUND: Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative. METHODS AND RESULTS: To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, 7 mumol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baseline, after 4 weeks of daily handgrip training, and 6 weeks after cessation of the training program. FDD was impaired in heart failure patients compared with normal subjects. L-NMMA attenuated FDD, indicating that the endothelial release of nitric oxide is involved in FDD. Physical training restored FDD in patients with heart failure. In particular, the portion of FDD inhibited by L-NMMA (representing FDD mediated by nitric oxide) was significantly higher after physical training (8-minute occlusion: 8.0 +/- 1% versus 5.4 +/- 0.9%; P < .05; normal subjects: 9.2 +/- 1%). CONCLUSIONS: These results indicate that physical training restores FDD in patients with chronic heart failure, possibly by enhanced endothelial release of nitric oxide.

Importance of endothelial function in chronic heart failure.

Chronic heart failure (CHF) is associated with neurohumoral activation and alterations of the peripheral circulation. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone. Recent data suggest an important role of the endothelium for peripheral perfusion in CHF. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe CHF and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flow-dependent dilation is reduced in CHF, reflecting endothelial dysfunction of large conduit vessels. To investigate endothelial function in humans in vivo, agents such as acetylcholine are used to stimulate the release of endothelium-derived nitric oxide (NO). Conversely, N-mono-methyl-L-arginine (L-NMMA), a specific inhibitor of NO synthesis from L-arginine, decreases forearm blood flow by inhibiting the basal release of NO. Conversely to the impaired stimulated release of NO by acetylcholine, the decrease in blood flow induced by L-NMMA appears to be exaggerated in CHF. The blood flow response to nitroglycerin or sodium nitroprusside, both endothelium-independent vasodilators, is usually preserved in patients with nonedematous CHF, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous NO. Therefore, impaired endothelium-dependent dilation of peripheral resistance vessels emerges in CHF, suggesting a reduced release of NO on stimulation. Endothelial dysfunction may therefore be involved in the impaired vasodilator capacity in the peripheral circulation, e.g., during exercise. In contrast, the basal release of NO from endothelium of resistance vessels appears to be enhanced and may play an important compensatory role in CHF.

Development and prevention of skeletal muscle structural alterations after experimental myocardial infarction.

The present study was designed to assess whether structural alterations develop within skeletal muscle 1 yr after myocardial infarction (MI) and failure and, if so, whether these structural alterations can be prevented by angiotensin-converting enzyme (ACE) inhibition. Infarcted rats were randomized and treated for 1 yr with either placebo (MI-IP, n = 9), a low dose of lisinopril (MI-LL, 0.5 mg.kg-1.day-1, n = 12), or a high dose of lisinopril (MI-LH, 5 mg.kg-1.day-1, n = 9). Sham-operated animals served as controls (SH, n = 14). One year after MI, in situ fixation of rat hindlimb was performed to investigate interstitial collagen volume fraction (CVF), capillary density, and media thickness of resistance vessels (80-200 microns) of musculus quadriceps femoris muscle. Infarct size was similar in all infarct groups and averaged 26 +/- 4%. Right ventricular weight was increased in MI-IP compared with SH, MI-LL, and MI-LH. Both left ventricular (LV) CVF and skeletal muscle CVF were increased in MI-IP. LV CVF and skeletal muscle CVF were closely related to each other (n = 44, r = 0.5377, P < 0.002). In infarcted rats, high-dose ACE inhibition significantly reduced skeletal muscle and LV CVF. Skeletal muscle capillary density and capillary-to-muscle fiber ratio were significantly decreased in infarcted rats but were restored by low- and high-dose ACE inhibition. Media thickness of intramuscular resistance vessels was increased in the MI-IP group and significantly reduced by high-dose ACE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of long-term angiotensin-converting enzyme inhibition on vascular function in patients with chronic congestive heart failure.

The present study demonstrates that peripheral vasodilatory capacity is impaired in patients with chronic congestive heart failure not treated with aspirin, but preserved in patients taking aspirin. This decreased peripheral vasodilatory capacity can be restored by chronic angiotensin-converting enzyme inhibition, indicating that locally acting cyclooxygenase-dependent factors contribute to peripheral vasoconstriction in chronic congestive heart failure.

Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure.

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data suggest an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flow-dependent dilation and the nitroglycerin-induced dilator response is attenuated in congestive heart failure as compared to normal subjects, indicating both endothelial dysfunction and a defect of smooth muscle relaxation. Recent data suggest that angiotensin-converting enzyme (ACE) inhibitors can improve endothelial function of resistance vessels, reduce serum level of the soluble endothelial (vascular cell) adhesion molecule (VCAM-1) and, in addition, improve peripheral vascular function by reducing or limiting the influence of cyclo-oxygenase-dependent vasoconstricting factor(s). It is conceivable that these beneficial effects of chronic ACE inhibition are due, in part, to blockade of bradykinin degradation by the ACE and the increased endothelial synthesis of prostaglandins and/or the release of nitric oxide by enhanced tissue levels of bradykinin.

[Increased vascular sensitivity to nitroglycerin in patients with hypercholesterolemia and peripheral endothelial dysfunction]. / Gesteigerte vaskuläre Sensitivität auf Nitroglycerin bei Patienten mit Hypercholesterinämie und peripherer Endotheldysfunktion.

The effects of the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerin and a drug which inhibits basal nitric oxide (NO) release (L-NG-monomethyl-arginine [L-NMMA]) on the diameter of the radial artery and blood flow were studied in eight patients with hypercholesterolaemia (total cholesterol: 280 +/- 9 mg/dl, age 54 +/- 3 years) and eight healthy subjects of the same age (total cholesterol 197 +/- 12 mg/dl, age 51 +/- 4 years). Arterial diameter was measured by a recently developed high resolution ultrasound technique. Increasing concentrations of acetylcholine (10(-8) to 10(-6) mol/l) produced dose-dependent increases in flow rate in the healthy subjects (maximum +150% +/- 6% at 10(-6) mol/l), but much less in the patients with hypercholesterolaemia (+24% +/- 12%). L-NMMA caused comparable reductions in forearm blood flow in both groups. Nitroglycerin increased blood flow in the hypercholesterolaemia group to a significantly greater extent (+370% +/- 69%) than in the controls (+145 +/- 62%). The effects of acetylcholine, L-NMMA and nitroglycerin on radial artery diameter did not differ significantly between the two groups. The poor response (in terms of blood flow) to acetylcholine in the hypercholesterolaemia group points to an endothelial dysfunction in the arterial microcirculation. The fact that L-NMMA caused similar reductions in forearm blood flow in the controls and hypercholesterolaemia patients alike shows that basal NO synthase activity must be comparable in the two groups and therefore cannot be held responsible for the endothelial dysfunction. This endothelial dysfunction is linked with increased responsiveness to the endothelium-independent vasodilator nitroglycerin.