Differences in treatment and outcome of patients with acute myocardial infarction admitted to hospitals with compared to without departments of cardiology; results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA 1+2) Registries and the Myocardial Infarction Registry (MIR).

AIMS: The specialty of the admitting physician may influence treatment and outcome in patients with acute myocardial infarction. METHODS AND RESULTS: The pooled data of three German acute myocardial infarction registries: the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) 1+2 studies and the Myocardial Infarction Registry (MIR) were analysed. Patients admitted to hospitals with departments of cardiology were compared to hospitals without such departments. A total of 24 814 acute myocardial infarction patients were included, 9020 (36%) patients at 91 (29.8%) hospitals with departments of cardiology and 15 794 (64%) at 214 (70.2%) hospitals without cardiology departments. There were only minor differences in patient characteristics and prevalence of concomitant diseases between the two types of hospital. The first electrocardiogram was more often diagnostic at hospitals with cardiology departments (71.8% vs 66.5%, P<0.001). Reperfusion therapy and adjunctive medical therapy, such as aspirin, beta-blockers and ACE-inhibitors were used more often at cardiology departments (all P -values <0.001), even after adjustment for confounding parameters. Treatment improved at both types of hospital over time. Admission to a hospital with a department of cardiology was independently associated with a lower hospital mortality (14.2% vs 15.4%, adjusted OR=0.91; 95%CI: 0.83-0.99). Additional logistic regression models showed that the higher use of reperfusion therapy and recommended concomitant medical therapy was responsible for most of the survival benefit at such hospitals. CONCLUSION: Treatment of acute myocardial infarction patients at hospitals with departments of cardiology was independently associated with a higher use of recommended therapy and a lower hospital mortality compared to hospitals without such departments.

Primary angioplasty versus no reperfusion therapy in patients with acute myocardial infarction and a pre-hospital delay of > 12-24 hours: results from the pooled data of the maximal individual therapy in acute myocardial infarction (MITRA) registry and the myocardial infarction registry (MIR).

OBJECTIVE: In patients with acute myocardial infarction (AMI), treatment with thrombolysis is superior to no reperfusion therapy only up to 12 hours after the onset of symptoms. There are no data addressing whether this time limit is also justified for treatment with primary angioplasty. DESIGN: The pooled data of two German ST-segment elevation AMI registries, the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) study and the Myocardial Infarction Registry (MIR), were analyzed. PATIENTS: Out of 22,749 patients, eight hundred and forty-eight with a pre-hospital delay of > 12 hours and < or = 24 hours were treated with either primary angioplasty (94/848; 11.1%) or no reperfusion therapy (754/848; 88.9%). RESULTS: Patients treated with primary angioplasty were 10 years younger (59 years versus 69 years; p = 0.001), more often male [72.3% versus 59.9%; odds ratio (OR) = 0.57; 95% confidence interval (CI) = 0.36-0.92] and less likely to be diabetics (17% versus 27.2%; OR = 0.55; 95% CI = 0.31-0.97). Hospital mortality was 8.5% in patients treated with primary angioplasty compared to 17.1% in patients with no reperfusion therapy (OR = 0.45; 95% CI = 0.21-0.95; p = 0.033) and the combined endpoint (death, reinfarction or stroke) occurred significantly less often (11.7% versus 20.3%; OR = 0.52; 95% CI =0.27-1; p = 0.045). However, multiple logistic regression showed only a non-significant trend for lower mortality (OR = 0.54; 95% CI =0.20-1.23) and the combined endpoint (OR = 0.65; 95% CI = 0.29-1.31) in patients treated with primary angioplasty. CONCLUSIONS: These data show the possibility of a benefit of primary angioplasty over conservative treatment in patients with pre-hospital delays of > 12 up to 24 hours, although multiple logistic regression analysis failed to find significant differences between treatments. This might be due to inadequate study power or a selection bias. These findings encourage further investigation of this subject.

Effect of preinfarction angina pectoris on outcome in patients with acute myocardial infarction treated with primary angioplasty (results from the Myocardial Infarction Registry.

Preinfarction angina is associated with better clinical outcome in patients with acute myocardial infarction (AMI) who receive intravenous thrombolysis. This has not been proved in patients with AMI treated with primary angioplasty. We analyzed the data of the prospective multicenter Myocardial Infarction Registry (MIR). Of 14,440 patients with AMI, 774 with a prehospital delay of < or =12 hours were treated with primary angioplasty. Five hundred thirty-two patients (68.7%) had preinfarction angina. Patients with preinfarction angina were slightly older than patients without (63 vs 62 years, p = 0.042), prehospital delay was 1 hour longer (180 vs 120 minutes, p = 0.001), and arterial hypertension was more prevalent (47.6% vs 32.2%, odds ratio [OR] 1.91, 95% confidence intervals [CI] 1.39 to 2.62). There was no significant difference in hospital mortality (5.6% vs 3.3%, OR 1.75, 95% CI 0.79 to 3.87), reinfarction, stroke, or the combined end point of death, reinfarction, or stroke between the 2 groups. Logistic regression analysis showed no association of preinfarction angina with the occurrence of either death (OR 2.21, 95% CI 0.91 to 6.08) or the combined end points (OR 1.10, 95% CI 0.55 to 2.31). There was also no significant difference in mortality (6% vs 5.1%, OR 1.19, 95% CI 0.56 to 2.52), reinfarction, stroke, postinfarction angina, or the combined end points between patients with preinfarction angina within 48 hours compared with patients with preinfarction angina between 49 hours and 4 weeks before the AMI. Thus, the MIR data showed no protective effects of preinfarction angina in patients with AMI treated with primary angioplasty.

Decreasing hospital mortality between 1994 and 1998 in patients with acute myocardial infarction treated with primary angioplasty but not in patients treated with intravenous thrombolysis. Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Registry and the Myocardial Infarction Registry (MIR).

OBJECTIVES: We investigated changes in the clinical outcome of primary angioplasty and thrombolysis for the treatment of acute myocardial infarction (AMI) from 1994 to 1998. BACKGROUND: Primary angioplasty for the treatment of AMI is a sophisticated technical procedure that requires experienced personnel and optimized hospital logistics. Growing experience with primary angioplasty in clinical routine and new adjunctive therapies may have improved the outcome over the years. METHODS: The pooled data of two German AMI registries: the Maximal Individual Therapy in AMI (MITRA) study and the Myocardial Infarction Registry (MIR) were analyzed. RESULTS: Of 10,118 lytic eligible patients with AMI, 1,385 (13.7%) were treated with primary angioplasty, and 8,733 (86.3%) received intravenous thrombolysis. Patients characteristics were quite balanced between the two treatment groups, but there was a higher proportion of patients with a prehospital delay of >6 h in those treated with primary angioplasty. The proportion of an in-hospital delay of more than 90 min significantly decreased in patients treated with primary angioplasty over the years (p for trend = 0.015, multivariate odds ratio [OR] for each year of the observation period = 0.84, 95% confidence interval [CI]: 0.73-0.96) but did not change significantly in patients treated with thrombolysis. Hospital mortality decreased significantly in the primary angioplasty group (p = 0.003 for trend; multivariate OR for each year = 0.73, 95% CI: 0.58-0.93). However, for patients treated with thrombolysis, hospital mortality did not change significantly (p for trend 0.175, multivariate OR for each year: 1.02, 95% CI: 0.94- 1.11). CONCLUSIONS: Compared with thrombolysis the clinical results of primary angioplasty for the treatment of AMI improved from 1994 to 1998. This indicates a beneficial effect of the growing experience and optimized hospital logistics of this technique over the years.

Selective downregulation of rat cardiac beta 1-adrenoceptors by cyclosporine A: prevention by diltiazem or angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study attempted to determine whether long-term treatment with cyclosporine A in rats affects cardiac beta 1-adrenoceptors and whether this can be prevented by angiotensin-converting enzyme inhibitors or calcium-entry blocking agents. BACKGROUND: In the transplanted human heart the density of beta 1-adrenoceptors decreases with time after transplantation, whereas that of beta 2-adrenoceptors does not. Because heart transplant recipients are treated with cyclosporine A, we studied whether administration of cyclosporine A in rats might cause this beta 1-adrenoceptor downregulation. METHODS: We performed two studies. First, we treated groups of 10 male normotensive Wistar rats orally with 30 mg/kg body weight per day of cyclosporine A, 10 mg/kg per day of enalapril and 60 mg/kg per day of diltiazem, alone or in combination, for 6 weeks each. Second, we treated groups of 15 male normotensive Wistar rats orally with 15 mg/kg per day of cyclosporine A and 10 mg/kg per day of lisinopril, alone or in combination, for 6 weeks each. At the end of each treatment regimen, cardiac beta-adrenoceptor density and subtype distribution were assessed by (-)-[125I]iodocyanopindolol binding. RESULTS: Both doses of cyclosporine A caused a significant decrease in cardiac beta 1-adrenoceptor density without affecting beta 2-adrenoceptor density. Although diltiazem and the angiotensin-converting enzyme inhibitors alone did not affect cardiac beta-adrenoceptors, they prevented the cyclosporine A-induced downregulation of beta 1-adrenoceptors. CONCLUSIONS: In normotensive Wistar rats, cyclosporine A causes a significant decrease in cardiac beta 1-adrenoceptors without affecting beta 2-adrenoceptors. This can be prevented by diltiazem or angiotensin-converting enzyme inhibitors. In heart transplant recipients, who undergo long-term treatment with cyclosporine A, there is a very similar beta 1-adrenoceptor down-regulation with time after transplantation. Thus, administration of cyclosporine A may cause these beta-adrenoceptor subtype alterations.

Preventive effects of diltiazem on cyclosporin A-induced vascular smooth muscle dysfunction.

Cyclosporin A may cause vascular smooth muscle dysfunction due to calcium overload as a consequence of chronically augmented calcium influx. In the present study, the responsiveness to vasocontrictors was investigated in rats after chronic treatment for 6 weeks with placebo, cyclosporin A (30 mg/kg per day), diltiazem (60 mg/kg per day), or cyclosporin A plus diltiazem. Twenty-four hours after the last oral treatment the animals were sacrificed and rings of the thoracic aorta were suspended in organ chambers under isometric conditions in the absence of cyclosporin A or diltiazem. Chronic treatment with cyclosporin A significantly augmented contractions to angiotensin II (10(-9)-10(-5) M). This effect was prevented by cotreatment with diltiazem. Diltiazem did not affect the cyclosporin A-induced reduction in the response to potassium chloride (10-80 mM). The contractions to phenylephrine (10(-9)-10(-6) M) and endothelin-1 (10(-9)-10(-7) M) were not significantly different in the four groups. The preventive effect of diltiazem against the cyclosporin A-induced hypersensitivity to angiotensin II supports the hypothesis of increased calcium influx during cyclosporin A therapy. The results may provide an additional rationale for the use of calcium antagonists in the treatment of the vascular side effects of cyclosporin A.

Effect of cyclosporin on kidney proteolytic enzymes in men and rats.

Cyclosporin (CsA) induces autophagolysosomes in proximal tubules. A major lysosomal function is degradation of cell proteins. Cathepsin B and L are marker enzymes for the activity of lysosomal protein degradation. Therefore we measured cathepsin activities in microdissected proximal tubule segments and urine from rats treated with CsA, 30 mg/24 h by gavage for 42 days. Cathepsin activity was increased in proximal tubule by 117% and in 24-h urine by 37% compared to controls. Unchanged values of serum cathepsin activity and of proteinuria excluded increased glomerular filtration or decreased tubular absorption as major source of urine cathepsins. Therefore urine cathepsin excretion reflected tubular cathepsin activity. Urine cathepsin excretion was also measured in patients without renal disease treated with CsA for multiple sclerosis (MS). It was increased by 59% in patients with CsA serum values > 120 ng/ml compared to MS patients without CsA or with serum CsA < 120 ng/ml. Urine cathepsin excretion increased linearly with serum CsA (P < 0.001). The data suggest that cathepsin activity is increased in proximal tubules of CsA-treated patients. Hence CsA may stimulate protein degradation in proximal tubules of men and rats.

Calcium entry blockade may prevent cyclosporin A-induced hypersensitivity to angiotensin II and endothelial dysfunction in the rat aorta.

Vascular smooth muscle dysfunction after chronic treatment with cyclosporin A was in part explained by chronically augmented calcium influx leading to calcium overload. The potential protective effect of calcium antagonism with diltiazem as regards endothelial and vascular smooth muscle reactivity was investigated during chronic treatment with cyclosporin A. Male Wistar rats were orally treated for 6 weeks with either cyclosporin A (30 mg.kg-1 x day-1 in 1 ml, n = 8), with the vehicle alone (n = 10), with diltiazem (60 mg.kg-1 x day-1, n = 10) or with a combination of cyclosporin A and diltiazem (30 mg.kg-1 x day-1 and 60 mg.kg-1 x day-1, n = 8), respectively. Rings of the isolated thoracic aorta were mounted in organ chambers to measure isometric force. Chronic treatment with diltiazem alone did not affect the responsiveness to any of the drugs tested, but the augmentation of contractions to angiotensin II (10(-9) to 10(-6) M) after treatment with cyclosporin, was prevented by co-treatment with diltiazem. Co-treatment with diltiazem, however, did not affect the response to potassium chloride (20-80 mM), endothelin-1 (10(-9) to 10(-7) M) or phenylephrine (10(-9) to 10(-6) M). Endothelium-dependent relaxations to calcitonin gene-related peptide (CGRP, 10(-10) to 10(-7) M) and acetylcholine (10(-8) to 10(-5) M) were reduced in cyclosporin A treated rats. Co-treatment with diltiazem normalized the response to CGRP. The response to acetylcholine was not significantly affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Local regulation of vascular tone by bradykinin and angiotensin converting enzyme inhibitors.

Part of the vasodilator response to angiotensin converting enzyme (ACE) inhibitors depends on stimulation of bradykinin receptors, but in most studies the anticipated increase in plasma kinin concentration during ACE inhibition was not detected. We investigated the role of local ACE inhibition on endothelial control of vascular tone. Rings of bovine coronary, renal and tail arteries, as well as human coronary arteries, were mounted in organ chambers so that the isometric force could be recorded. The ACE inhibitors, captopril, fosinoprilat, enalaprilat, lisinopril, and ramiprilat alone had no affect on the vascular tone of bovine coronary arteries with endothelium. However, these ACE inhibitors did potentiate relaxations to bradykinin and the slowly degradable bradykinin derivative [Hyp3-Tyr(Me)8]-bradykinin (3 x 10(-11) M). A similar response was observed in human coronary arteries. The response was not observed in rings of any vessel without endothelium, or after incubation with nitro-L-arginine (10(-4) M), or the bradykinin2-receptor antagonists Hoe 140 (10(-8) M). The sensitivity to bradykinin was higher and the potentiating effect of ACE inhibition larger in the bovine coronary artery than in the renal and tail artery. Thus, ACE inhibition causes selective coronary vasodilation by potentiating the bradykinin-induced release of nitric oxide from the endothelium. The related mechanism underlying these effects must occur at the surface or within the arterial wall and seems to be independent of the degradation of the kinins.

Degradation of bradykinin by neutral endopeptidase (EC 3.4.24.11) in cultured human endothelial cells.

The presence of neutral endopeptidase 24.11 was demonstrated in human umbilical vein endothelial cells by immunostaining. Enzymatic activity of neutral endopeptidase was determined as 0.167 +/- 0.02 mU/mg protein in the membrane fraction of human umbilical vein endothelial cells, using the fluorogenic peptide substrate, dansyl-D-Ala-Gly-Phe(pNO2)-Gly. No activity was found in the cytosolic fraction of endothelial cells. The role of this peptidase in the degradation of the endogenous vasodilator bradykinin was investigated by incubating human umbilical vein endothelial cell monolayers with bradykinin (10(-8) mol/l). The inhibitor of neutral endopeptidase, phosphoramidon (10(-8) mol/l), decreased the degradation of bradykinin in the supernatant of endothelial cells; the half-life of bradykinin was then increased from 29 +/- 1 to 46 +/- 2 minutes. The angiotensin-converting enzyme inhibitor, lisinopril (10(-8) mol/l), increased the half-life of bradykinin to 244 +/- 20 minutes; the combination of both inhibitors increased the half-life of bradykinin to 381 +/- 51 minutes. Inhibitors of aminopeptidase (amastatin) and carboxypeptidase (2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid) caused no significant effect. The effect of phosphoramidon was small in comparison with that of lisinopril, but was pronounced in combination with lisinopril. Neutral endopeptidase activity is localized in the membranes of human endothelial cells and seems to be involved in the degradation of bradykinin by the vascular endothelium, particularly during angiotensin converting enzyme inhibition.

Effect of angiotensin-converting-enzyme inhibition on bradykinin metabolism by vascular endothelial cells.

The degradation of bradykinin by angiotensin-converting-enzyme (ACE) activity in cultured human endothelial cells was studied by direct measurement of bradykinin and by its effect on the release of endothelium-derived relaxing factors. The half-life of exogenous bradykinin (10,000 pg/ml) was calculated from the decay of the bradykinin concentration as 46 +/- 2 min in cell monolayers, 133 +/- 15 min in conditioned medium, and 24 +/- 2 min in homogenates. Most of the bradykinin-degrading activity in cell monolayers could be inhibited in a concentration-dependent manner by the ACE inhibitors lisinopril, ramiprilat, and captopril. Bradykinin-degrading activity was released into the culture medium containing one-fourth of the bradykinin-degrading activity found in the presence of cell monolayers. In cell homogenates higher unspecific bradykinin-degrading activities were present. The functional consequence of bradykinin degradation was demonstrated by the potentiating effect of ramiprilat on the generation of endothelium-derived relaxing factors nitric oxide and prostacyclin from endothelial cells. The study supports the concept of increased vasodilatory effects of bradykinin during ACE inhibition.

Endothelial and vascular smooth muscle function after chronic treatment with cyclosporin A.

We wished to characterize the altered reactivity of vascular smooth muscle and endothelial cells in rat aorta during chronic treatment with cyclosporin. Male adult rats were treated orally for 6 weeks with either cyclosporin A (30 mg/kg/day in 1 ml olive oil, n = 9) or with vehicle alone (n = 10). Rings of isolated thoracic aorta were mounted in organ chambers to measure the change in isometric force in response to smooth muscle-contracting drugs and endothelium-dependent and independent vasodilators. Contractions to potassium chloride (20-80 mM) were markedly reduced in cyclosporin-treated rats. Contractions to phenylephrine (10(-10)-10(-6) M) were reduced at high concentrations (> or = 10(-7) M); those to endothelin-1 (10(-10)-10(-7) M) were not significantly altered. In contrast, contractions to angiotensin II (AII 10(-9)-10(-6) M) were significantly augmented. Endothelium-dependent relaxations to acetylcholine (ACh 10(-8)-10(-5) M) or ADP (10(-7)-10(-5) M) were reduced in cyclosporin-treated rats; endothelium-independent relaxations to SIN-1 (10(-7)-10(-5) M) and atrial natriuretic peptide (ANP 10(-10)-10(-7) M) remained unaffected. Thus, chronic treatment with cyclosporin affects both endothelium-dependent vasodilation and vascular smooth muscle contraction in rat aorta depending on the stimulus applied. The enhanced response to AII and the reduced release of endothelium-derived relaxing factor (EDRF) may contribute to augmented vascular tone and further damage to the arterial wall.

ACE inhibitors are endothelium dependent vasodilators of coronary arteries during submaximal stimulation with bradykinin.

OBJECTIVE: The effect of angiotensin converting enzyme (ACE) inhibitors on vascular tone of isolated coronary arteries was determined in the presence of bradykinin and other vasodilators to elucidate the mechanisms leading to augmented bradykinin effects during ACE inhibition. METHODS: Rings of isolated bovine and human coronary arteries were mounted in organ chambers for measurement of isometric force. The effects of lisinopril, enalaprilat, and captopril were investigated in the presence of submaximal concentrations of bradykinin or other vasodilators. RESULTS: ACE inhibitors alone did not affect vascular tone. Threshold concentrations of bradykinin (10(-10) M), kallidin (10(-9.5) M), and the slowly degraded bradykinin agonists D-Arg(Hyp3)-bradykinin (10(-9.5) M) and [Hyp3-Tyr(Me)8]-bradykinin (10(-10.5) M) caused partial relaxation of bovine rings with endothelium. Subsequent addition of ACE inhibitors markedly potentiated the relaxations to the kinins. Bradykinin concentrations in the organ bath measured by a specific bradykinin radioimmunoassay remained stable during the addition of lisinopril. Variation of the exposure time to bradykinin (10 to 60 min) did not affect the relaxations to the ACE inhibitor. The relaxations to lisinopril were not observed after either removal of the endothelium or incubation with nitro-l-arginine or the bradykinin-2 receptor antagonist Hoe 140. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium dependent relaxation to lisinopril and captopril was also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M), but not in those treated with substance P (10(-8) M). CONCLUSIONS: ACE inhibitors selectively potentiate endothelium dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries by a local mechanism. This effect on endothelial cells might occur in addition to augmented bradykinin concentrations in the blood and reduced angiotensin II generation.

In vivo measurement of endothelium-dependent vasodilation with substance P in man.

Endothelial cells synthesize and metabolize vasoactive substances which are involved in the regulation of vascular tone. Among these factors, the endothelium-derived nitric oxide (NO) appears to be of major importance. Many studies observed an impairment of the generation, release, or the diffusion of endothelial NO across the vascular intima in laboratory animals with various experimental diseases such as hypercholesterolemia, atherosclerosis and hypertension. In human coronary arteries obtained from explanted hearts impaired endothelium-dependent relaxations were measured in atherosclerotic segments. The hypothesis of a decreased NO mediated vasodilation in patients with coronary artery disease was further underscored by in vivo studies in man using intracoronary infusions of the endothelium-dependent vasodilator acetylcholine and quantitative coronary angiographic measurements of the diameter changes. From these observations it was assumed that endothelial dysfunction, in particular a profound inability of the coronary endothelium to relax via NO dependent mechanisms may play an important role in the pathogenesis of abnormal coronary vasomotion. However, further investigations in man reveal that the ability of the coronary endothelium of patients with coronary artery disease or vasospastic angina to produce endothelial NO is less affected as judged from the effects of acetylcholine. In recent investigations a largely preserved endothelial function could be measured in these patients when the endothelium-dependent vasodilator substance P was used as a tool for the measurement of NO dependent relaxation. Thus, endothelial dysfunction does not appear to serve as a major cause of abnormal vasoconstriction in coronary artery disease or vasospastic angina in man.

Relaxation of human coronary artery and arteria mammaria by K(+)-channel openers.

Three agents with K(+)-channel-opening activity--nicorandil, bimakalim (EMD 52692), and EMD 56431--were tested for vasorelaxation abilities in human coronary artery and human arteria mammaria. The potency orders were bimakalim = EMD 56431 >> nicorandil for relaxation in human coronary artery and bimakalim = EMD 56431 >> nicorandil in human arteria mammaria. These data demonstrate that K(+)-channel openers are effective vasorelaxant agents in human coronary artery and human arteria mammaria. Bimakalim and EMD 56431 were more potent than nicorandil, a drug that also activates guanylate cyclase.

Bradykinin degrading activity in cultured human endothelial cells.

The role of angiotensin-converting enzyme (ACE), neutral endopeptidase 24.11 (NEP), and other peptidases in the endothelial degradation of bradykinin was investigated in cultured human umbilical vein endothelial cells (HUVEC). The major part of the kininase II activity on intact cells was attributed to ACE activity, the minor part to NEP activity. Amastatin, as aminopeptidase inhibitor, and DL-2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid (MGTA), an inhibitor of kininase I, did not affect endothelial kininase activity. The decline of the bradykinin concentrations in the supernatant of intact endothelial monolayer indicated a total kininase activity of 289 +/- 27 fmol/min/dish. The calculated activity of ACE was 223 fmol/min/dish and the neutral endopeptidase activity was 51 fmol/min/dish. Thus, ACE and neutral endopeptidase are the main kininases in the degradation of bradykinin by intact endothelial cells. In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA.

Local potentiation of bradykinin-induced vasodilation by converting-enzyme inhibition in isolated coronary arteries.

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Endothelium-dependent relaxations are augmented in rats chronically treated with the angiotensin-converting enzyme inhibitor enalapril.

The study was designed to evaluate the effects of chronic inhibition of angiotensin-converting enzyme (ACE) on the reactivity of the endothelium and the smooth muscle to vasoconstrictor and vasodilator stimuli in normal rats. Male rats were treated orally for 6 weeks with enalapril (10 mg/kg/day, n = 10) or with placebo (n = 10). Endothelium-dependent relaxations to acetylcholine and adenosine diphosphate were augmented in aortic rings from rats treated with enalapril compared with controls, whereas the response to the endothelium-independent vasodilator SIN-1 were similar. Contractions induced by phenylephrine and angiotensin II remained unchanged. Thus, the results suggest that chronic ACE inhibition enhances the release of relaxing factors from the endothelium in normotensive rats.

Effects of converting enzyme inhibition on endothelial bradykinin metabolism and endothelium-dependent vascular relaxation.

The effects of ACE-inhibitors on bradykinin metabolism and bradykinin-induced endothelium-dependent relaxation were studied in isolated coronary arteries and endothelial cells in culture. The results suggest that ACE-inhibitors affect coronary vascular tone by at least two endothelium-dependent and bradykinin-mediated mechanisms: First, ACE-inhibitors decrease endothelial bradykinin degredation which is accompanied by an augmented bradykinin mediated endothelium-dependent relaxation. Second, ACE-inhibitors evoke endothelium-dependent relaxations in coronary arteries stimulated with threshold concentrations of bradykinin, which cannot be attributed to an inhibition of bradykinin degradation. The effect appears to represent a new mechanism which may be based on an interaction of the bradykinin receptor and the angiotensin converting enzyme on the cellular level.

Myocardial catecholamine concentrations in dilated cardiomyopathy and heart failure of different origins.

Myocardial catecholamine concentrations were determined in endomyocardial biopsies from patients with heart failure to assess if tissue catecholamine levels relate to the severity of myocardial damage or the aetiology of the underlying disease. Methodological studies revealed a good reproducibility of catecholamine determinations in biopsies; the variance between paired biopsies was below 17% when myocardial catecholamines were related to non-collagen protein (NCP). Myocardial norepinephrine (in pg micrograms-1 NCP) levels were comparable in patients with dilated cardiomyopathy (DCM, 5.3 +/- 3.4, n = 22) and in patients with coronary or valvular heart disease (5.6 +/- 4.7, n = 14). In both groups, a significant reduction of myocardial norepinephrine was found (controls 12.0 +/- 3.4, P less than 0.0006). In a subgroup of patients with heart failure and a LVEF less than 30% (3.9 +/- 3.5, n = 17) myocardial norepinephrine content was lower than in patients with heart failure and LVEF of 31-55% (6.6 +/- 3.4, n = 19) (both P less than 0.05 against controls: 12.0 +/- 3.4, n = 16). A correlation between myocardial norepinephrine and LVEF was found in DCM (P less than 0.001, r = 0.70). The loss of myocardial norepinephrine is a characteristic feature of heart failure. It is independent of the origin of failure, but correlates with the impairment of LV function.