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Aims Platelets play a central role in the restenosis process by inducing neointimal proliferation after coronary interventions. Glycoprotein IIb/IIIa PlA2polymorphism has been associated with the occurrence of acute coronary syndromes and increased restenosis rates. Statins have been shown to exert potent antiproliferative, antiinflammatory and antithrombotic properties, thereby potentially interfering with the major processes of in-stent restenosis. Therefore, we sought to find out whether statin therapy interferes with restenosis and clinical outcome at 6 months following successful coronary stent implantation in the presence or absence of the PlA2allele.Methods and Results Six hundred and fifty consecutive patients were followed for 6 months after coronary stent insertion. Carriers of the PlA2allele demonstrated a significantly increased restenosis rate, which was abrogated by statin therapy (50·9% vs 28·6%, P=0·01). Moreover, statin therapy was associated with a significant reduction (28·2% vs 49·3%,P <0·01) in the occurrence of major adverse coronary events (myocardial infarction, cardiac death, target vessel revascularization) in the 6 months after the intervention in patients with the PlA2allele.Conclusion Statin therapy reduces increased stent restenosis rates and improves clinical outcome following coronary stent implantation in patients bearing the PlA2allele, suggesting that statins interfere with the functional consequence of a genetically determined platelet-mediated risk factor associated with PlA2polymorphism. [ABSTRACT FROM PUBLISHER]

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 (). 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. [ABSTRACT FROM PUBLISHER]

1. The primary action of the converting enzyme inhibitors to prevent the formation of angiotensin II can explain a decrease in peripheral vascular resistance in patients with elevated, but not in those with normal or reduced plasma renin levels. 2. The inhibition of the breakdown of bradykinin will potentiate the vasodilator properties of the endogenously produced peptide. These include direct relaxation of certain vascular smooth muscle, production of vasodilator prostanoids and release of endothelium-derived relaxing factor(s). The greater release of the latter in the kidney could exert a negative feedback on the release of renin. 3. In addition, converting enzyme inhibitors may directly (by a prejunctional effect) and indirectly (by curtailing the production of angiotensin II) reduce the release of noradrenaline in the blood vessel wall. 4. Converting enzyme inhibitors may also directly reduce the responsiveness of vascular smooth muscle to vasoconstrictor stimuli (e.g. alpha-adrenoceptor activation). 5. The different effects of these therapeutic agents may concur to induce peripheral vasodilatation. [ABSTRACT FROM AUTHOR]

The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation. [ABSTRACT FROM AUTHOR]

In a prospective observational study, 40 patients were treated with coronary stent grafts covered by a polytetrafluoroethylene membrane. These devices may be regarded as therapy of choice for acute coronary rupture; treatment of conventional in-stent restenosis was not associated with a favorable outcome, whereas the promising results in degenerated vein grafts warrant a randomized, controlled trial. [ABSTRACT FROM AUTHOR]

Objective: The following retrospective observational study assesses the long-term results of intracoronary beta-radiation therapy for patients with in-stent restenosis., Background: Beta-radiation has been used to treat patients with coronary in-stent restenosis. However, long-term clinical success using this technique has not at this time been established., Methods: Two-hundred and thirteen consecutive patients received intracoronary brachytherapy (noncentered beta-emitter, Novoste BetaCath) for in-stent restenosis and were followed up over a period of 39.1 +/- 18.4 months. The combined end-point was defined as a major adverse clinical event (MACE)and comprised mortality, acute myocardial infarction, or target vessel revascularization (TVR)., Results: MACE occurred in 110 patients (51.6%): death in 27 patients (12.7%), acute myocardial infarction in 8 patients (3.8%), TVR in 90 patients (42.3%). TVR comprised percutaneous coronary reinterventions in 76 patients (35.7%) and coronary bypass surgery in 24 patients (11.3%). Secondary end-point was determined as target vessel failure and occurred in 93 patients (43.7%). Of note, the frequency of at least two previous target lesion interventions as well as impairment of left ventricular function was associated with reduced success rate, whereas other clinical parameters did not indicate outcome after treatment with intracoronary radiation therapy., Conclusion: During the mean, a period of 3 years, more than half of the patients receiving intracoronary radiation therapy reached primary end-point, representing, in the main, TVR. During this period a mortality rate of nearly 13% was documented. These results signify a delayed, though continued, restenotic process after index procedure.

Aims: Restenosis in bare-metal stents is in part related to stent design and material. Optimized strut design of cobalt-chrome (CoCr) stents may yield nearly comparable results to drug-eluting stents (DES) in selected lesions. The prospective multicenter DaVinci registry investigates the clinical outcome of a CoCr coronary stent (MULTI-LINK VISION), particularly in terms of patients with diabetes and complex lesions (B1, B2, C)., Methods and Results: The prospective internet-based registry included 1,344 patients (76% males, aged 66 +/- 10 years) undergoing stent implantation (n = 1,642) in 32 centres from July 2003 to June 2004. Follow-up data (median 9 +/- 1 months) of this cohort were available for 1,289 patients (98.1%). Of these patients 327 (26.2%) were diabetics. In total, 1,429 de-novo lesions (A 11.9%, B1 47.7%, B2 31.6%, C 8.8%) were treated with the CoCr stent. The predefined primary endpoint was defined as a composite of death, Q-wave myocardial infarction (STEMI), non-STEMI (NSTEMI), target vessel revascularization (TVR) by coronary bypass graft (CABG) or PCI at 270 days (target vessel failure, TVF). Secondary endpoints include death, time to the first myocardial infarction, TVR and CABG. The cumulative incidence of major adverse cardiac events (MACE) was 12.4% with 0.8% deaths, 1.5% non-fatal MI, and 9.7% TVR. TVF in the overall cohort was documented in 137 (10.8%) patients. For diabetics and complex lesions TVF was 13.8% (95% CI 4.2-18) and 11.4% (95% CI 2.0-13.3), respectively., Conclusion: This large registry confirms good acute and long-term success of CoCr stents making this strategy valuable, particularly in a special cohort (diabetics and complex lesions) as long as late stent thrombosis with DES plays a role and short-term antiplatelet therapy is favoured.

Unlabelled: The number of elderly patients with coronary heart disease is rapidly growing. Morbidity, related with PTCA is increased in elderly patients, presumably because of the more complex adverse baseline characteristics. However, it has not been firmly elucidated whether routine use of coronary stents is associated with a more favourable outcome in this population. Therefore, we investigated the influence of age on acute procedural success, rate of restenosis (quantitative coronary angiography) and major cardiovascular events (death/myocardial infarction [MI]) 6 months after intra-coronary stent implantation in 1306 patients. Patients were categorised into < 65 years (n = 709),65-75 years (n = 443) and >75 years (n= 154)., Results: Older patients had a higher amount of multivessel disease (p < 0.001) and a lower left ventricular ejection fraction (p < 0.001). Nevertheless, the rate of acute success and restenosis were comparable between the different age groups. In contrast, older patients had significantly more adverse clinical events during long-term followup. (Death/MI < 65 years 3.0%, 65-75 years 3.9%, > 75 years 7.8%, p = 0.02). However, by multivariate analysis age was no longer an independent predictor of adverse clinical events (p = 0.26), which were predominantly determined by coexisting impaired left ventricular function (p < 0.001)., Conclusion: After proper judgement of the clinical situation, coronary stent implantation should be considered in selected elderly patients. Thus, advanced age as a solely factor should not be regarded as a contraindication for coronary stent implantation.

Background: The introduction of robotics into cardiosurgical practice in 1998 has enabled totally endoscopic closed chest procedures. Totally endoscopic grafting of the LAD (TECAB) is no longer an experimental procedure., Case Report: We report on a case with totally endoscopic bilateral internal thoracic artery bypass grafting to the left anterior descending and right coronary artery in a 36-year-old obese female diabetic patient using the daVinci surgical system. The patient, suffering from juvenile diabetes for 26 years, presented with stable angina (CCS class II). A coronary angiogram revealed 2-vessel disease with a long complex proximal lesion of the left anterior descending artery (LAD) (90%) and 80% stenosis of the proximal right coronary artery (RCA). Due to the condition of the proximal LAD (high risk PTCA with rather poor prognosis), the patient was referred for minimally invasive operative revascularisation of the LAD and the RCA. After informed consent was obtained the patient underwent totally endoscopic double internal thoracic artery bypass revascularisation on the arrested heart using computer-enhanced telemanipulation technology., Results: The feasibility and safety of successful closed chest, totally endoscopic double coronary bypass grafting with two internal thoracic arteries is demonstrated in this case. Preservation of a stable chest cavity and reduced risk for wound healing complications in diabetics with an excellent cosmetic result are the obvious advantages of the techniques described.

Statin therapy reduces clinical events in patients with stable coronary artery disease. Recent data indicate that the beneficial effects of statin therapy may also extend to patients experiencing an acute ischemic coronary event. However, the potential role of statins to further modify clinical outcome in patients undergoing coronary stent implantation has not been addressed. Therefore, we investigated whether the initiation of statin therapy immediately after successful coronary stent implantation improves short-term clinical outcome in 704 patients (335 patients with stable angina pectoris [AP], 224 patients with unstable AP, and 145 patients with Q-wave acute myocardial infarction [AMI]). Compared with the lowest risk group (patients with stable AP receiving statin therapy), patients with unstable AP (RR 6.9, 95% confidence interval [CI] 1.5 to 31, p = 0.004) and patients with Q-wave AMI (RR 7.6, 95% CI 1.5 to 37, p = 0.004) experienced an increased risk for the occurrence of the primary combined end point of cardiac death and AMI. Importantly, initiation of statin therapy abrogated the increased risk in patients with unstable AP to the level of patients with stable AP receiving statin therapy (RR 1.5, 95% CI 0.2 to 11, p = 0.7). In contrast, statin therapy did not affect the RR in patients with Q-wave AMI during 6-month follow-up (RR 7.9, 95% CI 1.6 to 39 vs RR 7.6, 95% CI 1.5 to 37, p = NS). The beneficial effects of statin therapy after successful coronary stent implantation in unstable AP were most prominent during the first 4 weeks after the ischemic episode. Statins appear to contribute to the rapid transformation of unstable coronary artery disease into a stable condition with a very low event rate over the forthcoming 6 months in patients with unstable AP undergoing successful coronary stent implantation.

Objectives: We sought to investigate whether statin therapy affects the association between preprocedural C-reactive protein (CRP) levels and the risk for recurrent coronary events in patients undergoing coronary stent implantation., Background: Low-grade inflammation as detected by elevated CRP levels predicts the risk of recurrent coronary events. The effect of inflammation on coronary risk may be attenuated by statin therapy., Methods: We investigated a potential interrelation among statin therapy, serum evidence of inflammation, and the risk for recurrent coronary events in 388 consecutive patients undergoing coronary stent implantation. Patients were grouped according to the median CRP level (0.6 mg/dl) and to the presence of statin therapy., Results: A primary combined end point event occurred significantly more frequently in patients with elevated CRP levels without statin therapy (RR [relative risk] 2.37, 95% CI [confidence interval] [1.3 to 4.2]). Importantly, in the presence of statin therapy, the RR for recurrent events was significantly reduced in the patients with elevated CRP levels (RR 1.27 [0.7 to 2.1]) to about the same degree as in patients with CRP levels below 0.6 mg/dl and who did not receive statin therapy (RR 1.1 [0.8 to 1.3])., Conclusions: Statin therapy significantly attenuates the increased risk for major adverse cardiac events in patients with elevated CRP levels undergoing coronary stent implantation, suggesting that statin therapy interferes with the detrimental effects of inflammation on accelerated atherosclerotic disease progression following coronary stenting.

Objectives: This study assessed the predictive value of preprocedural C-reactive protein (CRP) levels on six-month clinical and angiographic outcome in patients undergoing coronary stent implantation., Background: Recent data indicate that low-grade inflammation as detected by elevated CRP serum levels predicts the risk of recurrent coronary events., Methods: We prospectively investigated the predictive value of preprocedural CRP-levels on restenosis and six-month clinical outcome in 276 patients after coronary stent implantation. The primary combined end point was death due to cardiac causes, myocardial infarction related to the target vessel and repeat intervention of the stented vessel., Results: Grouping patients into tertiles according to preprocedural CRP-levels revealed that, despite identical angiographic and clinical characteristics at baseline and after stent implantation, a primary end point event occurred in 24 (26%) patients of the lowest tertile, in 42 (45.6%) of the middle tertile and in 38 (41.3%) of the highest CRP tertile, p = 0.01. On multivariate analysis, tertiles of CRP levels were independently associated with a higher risk of adverse coronary events (relative risk = 2.0 [1.1 to 3.5], tertile I vs. II and III, p = 0.01) in addition to the minimal lumen diameter after stent (p = 0.04). In addition, restenosis rates were significantly higher in the two upper tertiles compared with CRP levels in the lowest tertile (45.5% vs. 38.3% vs. 18.5%, respectively, p = 0.002)., Conclusions: Low-grade inflammation as evidenced by elevated preprocedural serum CRP-levels is an independent predictor of adverse outcome after coronary stent implantation, suggesting that a systemically detectable inflammatory activity is associated with proliferative responses within successfully implanted stents.

This study explored the modulatory effects of nitric oxide and thromboxane A2 on contractions to ergonovine and methylergonovine in human coronary arteries. To elucidate the different role of nitric oxide synthase in the response to the ergot alkaloids, the serotonin (5-HT) receptors involved in nitric oxide synthase in the response to the ergot alkaloids, the 5-HT receptors involved in nitric oxide release and the contraction of the vascular smooth muscle were characterized with more selective 5-HT-receptor agonists and antagonists. Rings of human coronary arteries from explanted hearts were suspended in organ chambers for isometric tension recording. After testing for contractile (potassium chloride, 60 mM) and endothelial function (substance P, 10(-8) M), respectively, they were exposed to ergot alkaloids or other agonists in the absence or presence of U 46619 (10(-9) M), or nitro-L-arginine (10(-4) M), or both. Ergonovine and methylergonovine were comparable, weak vasoconstrictors in untreated preparations. Contractions to ergonovine were augmented by U 46619, but not by nitro-L-arginine. Contractions to methylergonovine were augmented only by combining U 46619 and nitro-L-arginine. Serotonin and methylergonovine, but not ergonovine, elicited endothelium-dependent, nitric oxide-mediated relaxations. Nonselective 5-HT(1B/1D)-receptor stimulation caused both contractions and relaxations; selective 5-HT1B stimulation caused relaxations only. In the human coronary artery, contractions to ergonovine are not dependent on NO release but are synergistically augmented by thromboxane. Methylergonovine causes similar effects on the vascular smooth muscle, but contractions are inhibited by the release of NO from the endothelium. The 5-HT receptor on the endothelium appears to be different from the receptor on the vascular smooth muscle, which mediates the contractile response to the ergot alkaloids.

Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation of coagulatory and anticoagulatory factors by endothelial cells contributes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable conditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivalents and was 0.78+/-0.14 nM MDA/mg LDL for native LDL and 13.63+/-1.18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-1 activity were higher in macrovascular endothelial cells. Incubation of n-LDL in concentrations ranging from 3 to 100 microM/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in both cell types. Ox-LDL (3 to 100 microM/ml LDL protein) decreased t-PA secretion in a concentration dependent manner from 30.9+/-1.7 to 13.7+/-30 ng/ml per 24 h per 10(6) cells (P < 0.01), increased PAI-1 antigen from 2772+/-587 to 4441+/-766 ng/ml per 24 h per 10(6) cells (P < 0.05) as well as PAI-1 activity from 34+/-6 to 55+/-9 AU/ml per 24 h per 10(6) cells (P < 0.05) in macrovascular endothelial cells but had only minor effects on microvascular endothelial cells. Procoagulant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197+/-6 to 76+/-6 s/24 h per 10(6) cells (P < 0.05). The effect on PAI-1 secretion showed a dependency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE), which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macrovascular endothelial cells to ox-LDL may partially determine the localization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients.

Coronary spasms are defined as reversible coronary stenosis, which limits coronary blood flow under resting conditions. The demonstration of either spontaneous or provoked coronary spasm proves coronary hypercontractility and thus the diagnosis of variant angina. Several stimuli can provoke coronary vasospasm, but the highest sensitivity and specificity has been shown with ergonovine. Alternatively acetylcholine or with less sensitivity, but high specificity, hyperventilation may be employed. Typically coronary vasospasm presents with angina pectoris at rest; the manifestation with myocardial infarction or syncope are of great clinical importance. The prevalence of the disease is unknown due to the rarely performed provocation tests in Western countries. The incidence of positive test results strongly depends on the symptoms of the patients; from 0% in patients without any evidence for myocardial ischemia up to 54% in patients with typical angina at rest have been observed. Coronary vasospasm is closely related to atherosclerotic coronary artery disease, since intravascular ultrasound studies reveal atherosclerotic plaques in almost any spastic segment. Risk factors for coronary artery disease and coronary vasospasm, however, differ profoundly. For the latter cigarette smoking is the only established risk factor. Although several candidates and predisposing factors (serotonin, histamine, thromboxane, endothelin) have been described, the mediators and the pathogenesis of the disease remains unknown. Endothelial dysfunction alone is not sufficient to explain the features of variant angina. Some evidence supports the hypothesis of local inflammation. The mortality in variant angina depends on the extent of the coronary artery disease. Pure coronary vasospasm does not lead to increased mortality; patients with highly active disease presenting with syncope may have an increased risk. Medical treatment should include long-acting calcium antagonists or nitrates, beta-blockers may even favor the occurrence of ischemic attacks. Although the benefit has not been proven, the use of aspirin may considered in highly active disease.

The effects of long-term angiotensin-converting enzyme (ACE) inhibition, angiotensin II (AT1)-receptor blockade, calcium-entry blockade, or cyclosporin A treatment on rat aortic wall structure were investigated to determine the role of the renin-angiotensin system in the physiologic regulation of vascular structure in vivo. Groups of 15 Wistar rats were treated for 6 weeks either with the ACE inhibitors lisinopril or fosinopril or with the AT1-antagonists D 8731 or losartan (each 10 mg/kg/day) or with the calcium antagonist isradipine, 60 mg/kg/day, or cyclosporin A, 15 mg/kg/day, or a combination of cyclosporin with one of the vasodilators. Media thickness, vascular smooth-muscle cell density, and intima thickening were measured in histologic sections of the abdominal aorta. In addition, aortic contractility and heart weight were determined. Long-term ACE inhibition, AT1-receptor blockade, and calcium-entry blockade reduced aortic media thickness and increased media smooth-muscle cell density. Only ACE inhibition significantly reduced the extent of intima lesions. Media thickness correlated well with the maximal aortic contraction to phenylephrine and serotonin but not to angiotensin II. ACE inhibition and AT1-receptor blockade decreased heart weight, whereas calcium antagonism increased it. Cyclosporin treatment was without effect on any of these parameters. The data demonstrate a significant long-term influence of the renin-angiotensin system on aortic wall structure and function in Wistar rats.

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.

Nitroglycerin and its derivatives are among the most potent drugs to treat angina pectoris. The compounds relax all smooth muscle cells by stimulating the soluble guanylate cyclase. The clinical application takes advantage of the different sensitivities of the vascular smooth muscles (veins > arteries > arterioles) to nitrates. Selective vasodilation of capacity veins and coronary arteries leads to reduced myocardial oxygen consumption and improved myocardial perfusion. Hypotension due to effective dilation of resistance arteries limits the antianginal effects because of reduced coronary perfusion. Treatment of symptoms in stable angina is well established and unquestioned as long as the dose regimen avoids tolerance; however, there is no evidence of reducing mortality with nitrates in these patients. In acute coronary syndromes such as unstable angina pectoris and acute myocardial infarction nitrates, but not nitroprusside, can be applied safely to relief symptoms and to treat vasospasm, if the dose is titrated to avoid hypotension. Recent large multicenter trials (GISSI-3, ISIS-4) have not confirmed the postulate derived from previous studies, that nitrates reduce the mortality from acute myocardial infarction within the first month.

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.

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.