β-endorphin-sensitive opioid receptors in the rat tail artery

Summary Isolated tail arteries of rats were perfused and field-stimulated every 2 min with 2 pulses at 1 Hz. Different opioid peptides depressed the contractile responses to stimulation; their concentration-response curves showed a maximum at about 40% inhibition. The rank order of potency of the peptides was -endorphin (IC₅₀ = 97 nmol/1) BAM-22P > FK-33824 > DAGO > [d-Ala²,d-Leu⁵]-enkephalin metorphamide > dynorphin A-(1-13) [Met⁵]enkephalin. All these substances have in common a certain activity at opioid -receptors, although the enkephalins are preferential -, and the dynorphins preferential -agonists. However, the selective -agonist [d-Pen²,l-Pen⁵]enkephalin was ineffective at up to 10 mol/l, and the -agonists ethylketocyclazocine and U-50488 acted only at concentrations higher than 3 mol/l. Whereas the effects of -endorphin, DAGO and [d-Ala²,d-Leu⁵]enkephalin could be reduced by the -preferential antagonist naloxone, the effects of ethylketocyclazocine and U-50488 were not changed. The -selective antagonist ICI 174864 did not influence the action of [d-Ala²,d-Leu⁵]enkephalin. Naloxone in a concentration (1 mol/l) which nearly abolished the effect of DAGO 3 mol/l, slightly enhanced responses to stimulation. Neither -endorphin nor DAGO influenced vasoconstriction evoked by the application of noradrenaline or adenosine triphosphate; U-50488 reduced it. In arteries preincubated with [³H]noradrenaline DAGO depressed, whereas naloxone enhanced the tritium overflow and vasoconstriction evoked by field stimulation (0.4 Hz, 24 pulses every 14 min). In addition, naloxone antagonized the effect of DAGO. We suggest that the axon terminals of postganglionic sympathetic neurones in the rat tail artery possess -endorphin-sensitive opioid receptors of the -type. The activation of these receptors by exogenous or endogenous opioids inhibits the release of the neuroeffector transmitter.This work was supported by the Deutsche Forschungsgemeinschaft (SFB 325) Send offprint requests to P. Illes at the above address     

Allen’s test in patients with peripheral artery disease

Introduction

Transradial (TR) approach for coronary and peripheral angiography has become a popular technique. The Allen’s test (AT) could be used to determine the presence of collateral flow in the hand. Recently, angiographic background of modified AT was evaluated, but patients with peripherial arterial disease (PAD) were excluded in these studies. Therefore, the present study was designed to assess reliability of AT in patients with symptomatic PAD.

Methods

The present study comprised 92 symptomatic patients with PAD (Rutherford class 2–6). Perfusion of the hand was assessed with AT before outpatient peripheral angiography.

Results

Significant RA stenosis (n=6, 12.5%) and UA stenosis (n=26, 54.2%) were found in 30 patients with positive AT (62.5%). In patients with negative AT, only UA showed significant stenoses (n=6, 13.6%). Thirty-eight patients with positive AT had anatomic abnormality in the forearm arteries or in the palmar arch (79.2%). Anatomic abnormality in the forearm arteries or in the palmar arch could be detected in 15 cases with negative AT (34.1%, p<0.0001). Conclusions. In the presence of an abnormal AT and concommitant PAD, the use of RA for peripheral or coronary catheterization and angioplasty is not recommended.     

L-Arginine: a novel therapy for coronary artery disease?

Coronary artery disease (CAD) is a significant cause of morbidity and mortality today. The treatment of CAD is improving, but its prevalence is increasing: both primary and secondary prevention measures are of vital importance. Atherosclerosis starts at an early age; it is initiated at the vascular endothelium level, a single layer entity that modulates vascular function. Modulation of vascular function is carried out through the L-arginine/nitric oxide (NO) pathway. Normal endothelial function requires an intact L-arginine/NO pathway and endothelium. Endothelial dysfunction may be a precursor to overt CAD. CAD risk factors have been shown to influence endothelial function, and the treatment of these risk factors can restore endothelial function. L-Arginine is a safe, novel, semiessential amino acid that increases NO production, thereby improving endothelial function. L-Arginine/NO has numerous beneficial neurohormonal modulating properties. Numerous animal model and human studies have been carried out to assess L-arginine in CAD and other related disorders such as congestive heart failure (CHF), peripheral vascular disease (PVD) and acute myocardial infarction (AMI). Prospective clinical trials are required to assess the promising role of L-arginine in CAD and related disorders     

Functional α1-adrenergic receptor subtypes in human right gastroepiploic artery

AIM: To study the functional alpha1-adrenergic receptor (alpha1-AR) subtypes in human right gastroepiploic artery (RGA). METHODS: The effects of alpha2-AR, alpha1-AR, and alpha1-AR subtype selective antagonists on norepinephrine (NE)-induced vasoconstriction in isolated human RGA were observed by contractile function experiment. RESULTS: Cumulative concentration-response curves for NE were competitively antagonized in RGA by alpha2-AR selective antagonist yohimbine (pA2 6.82+/-0.28, slope 1.12+/-0.40),alpha1-AR selective antagonist prazosin (pA2 9.77+/-0.22, slope 0.90+/-0.22),alpha1A-AR selective antagonists RS17053 (pA2 8.42+/-0.20, slope 0.93+/-0.20) and 5-MU (pA2 8.42+/-0.22, slope 0.88+/-0.18),alpha1D-AR selective antagonist BMY7378 (pA2 6.84+/-0.32, slope 1.05+/-0.17), and alpha1A-,alpha1B-AR selective antagonist WB4101 (pA2 8.88+/-0.20, slope 1.15+/-0.16). The correlation coefficients between these pA2 values of alpha1-AR selective antagonists with pKi values of which obtained from alpha1A-, alpha1B- and alpha1D-AR cloned cells are 0.95, 0.82, and 0.42. After the vessels were pretreated by chlorethylclonidine (CEC), an alpha1B- and alpha1D-AR irreversible alkylating agent, the pD2 values were changed from 5.9+/-0.5 to 5.6+/-0.6 and the maximal contraction was changed from (8.9+/-3.2) g to (8.0+/-3.2) g, respectively. The difference was not significant. CONCLUSION: In human RGA, the contraction response is mainly mediated by alpha1-AR, of which alpha1A-AR plays an important role, whereas alpha1B- and alpha1D-AR are not involved in the contraction response.     

Carotid artery atherosclerosis: what is the evidence for drug action?

Carotid artery disease is a well-established cause of cerebrovascular events. This risk is predicted by the severity of stenosis and other plaque characteristics that can be documented using imaging techniques. Among these techniques, ultrasound is the most widely available. Increased carotid intima-media thickness (IMT) measured ultrasonically is associated with a higher risk for cerebrovascular as well as coronary heart disease. Furthermore, it is increasingly recognized that echolucent and heterogeneous carotid plaques in patients with high-grade carotid stenosis are associated with a greater risk for cerebrovascular events. Several local and systemic factors can influence plaque stability. Identifying the high-risk carotid plaque could improve selection for vascular intervention (surgery/angioplasty) and increase cost-effectiveness. Aggressive medical treatment should always be provided for these high-risk patients. For example, lipid-lowering, anthihypertensive and antiplatelet drugs decrease the carotid IMT, stabilize carotid plaques or reduce the risk of cerebrovascular and systemic events. Continuously evolving technology will lead to more accurate identification of high-risk carotid plaques. A combination of comprehensive non- or minimally-invasive imaging techniques together with measuring clinical and systemic biochemical markers of risk may facilitate the identification of the vulnerable plaque in the vulnerable patient, and help select the best treatment options.     

Contribution of thromboxane a₂ in rat common carotid artery response to serotonin

Serotonin is a vasoactive substance that in different blood vessels mostly induces vasoconstriction. Considering the important role of common carotid artery in brain blood supply, the aims of this study were to investigate the effect of serotonin on isolated rat common carotid artery and also to examine participation of intact endothelium, cyclooxygenase products, Ca(++) channels and 5-HT(2) receptors in serotonin-evoked action. Endothelium was mechanically removed from some vascular rings. Circular artery segments were placed in organ baths containing KrebsaRinger bicarbonate solution. Cumulative concentration-contraction curves for serotonin were obtained in rings previously equilibrated at basal tone. Serotonin produced concentration-dependent contraction, which was unaltered by endothelial denudation. Serotonin-induced effect was notably and comparably reduced by indomethacin (cyclooxygenase inhibitor) or OKYa046 (thromboxane A(2)-synthase inhibitor) on intact or denuded rings. Nifedipine (Ca(++) channel blocker) or ketanserin (5-HT(2) receptor antagonist) strongly reduced serotonin-evoked effect. Our results suggest that serotonin produced concentration-dependent and endothelium-independent contraction of carotid artery, which was initiated by activation of 5-HT(2) receptors located on smooth muscle cells and mediated via L-type Ca(++) channels. Thromboxane A(2) from smooth muscle cells notably contributed to the overall contraction of carotid artery induced by serotonin.     

Lipid-lowering treatment in coronary artery disease: how low should cholesterol go?

The randomised clinical trial data, which supports preventing coronary heart disease (CHD) events by lowering low density lipoprotein cholesterol (LDL-C) levels, is substantial, consistent and highly significant. HMG-CoA reductase inhibitors (statins), which are the preferred medications for lowering LDL-C levels, are well tolerated, with greater efficacy than other lipid-altering medications. In 1993, the National Cholesterol Education Program (NCEP) guidelines recommended LDL-C target levels to be achieved with therapy in high-risk individuals. In particular, the LDL-C goal of therapy in patients with CHD was < or = 100 mg/dl (2.6 mmol/L), with no specific guidance as to the lower limit or whether additional clinical benefit could be expected. Because little clinical trial data existed at that time to offer support, and because some epidemiological data raised concern about the potential detriments associated with very low total cholesterol and LDL-C levels, the NCEP Adult Treatment Panel remained appropriately vague on the 'how low should you go' question. In the last few years, several additional clinical trials have provided sufficient efficacy and safety data to re-examine that question. Analyses of on-treatment LDL-C levels and subsequent CHD events from three landmark trials with HMG-CoA reductase inhibitors suggest that progressively lower LDL-C levels are associated with lower CHD events in a curvilinear fashion. The Post Coronary Artery Bypass Graft (Post-CABG) trial and Atorvastatin Versus Revascularisation Trial (AVERT) examined a more intensive versus less intensive drug regimen for LDL-C reduction, and concluded that the more aggressively treated patients had better angiographic and end-point outcomes. Most importantly, there did not appear to be any change in noncardiovascular end-points associated with lower LDL-C levels. In several ongoing clinical trials, patients with CHD have been randomised to receive HMG-CoA reductase inhibitors with targets for LDL-C levels of 100 mg/dl versus 75 mg/dl (1.94 mmol/L). These trials have sufficient patient numbers and power to definitely determine if reducing LDL-C levels to approximately 75 mg/dl can provide an acceptable benefit-to-risk-ratio.     

β-Adrenergic responses are significantly enhanced in rat carotid artery with intimal hyperplasia

The objective of the present study was to investigate the influence of balloon injury and subsequent neointima formation in the rat carotid artery on the beta-adrenoceptor function. Rat left common carotid artery was subjected to balloon injury with an arterial embolectomy catheter; the contralateral artery was sham-operated. Immediately, and at 2, 8 and 16 weeks post-injury, both the injured and the sham-operated carotid arteries were isolated and mounted in an isometric wire-myograph set-up. Subsequently, concentration-response curves (CRCs) were constructed for the beta-adrenoceptor agonist isoprenaline after precontraction with the thromboxane A2 (TP)-receptor agonist U46619 (30 nM) of the injured and sham-operated artery preparations. To evaluate the involvement of the beta1- and the beta2-adrenoceptor subtypes, CRCs were constructed in the presence of CGP 20712A (0.1 nM, a beta1-adrenoceptor-selective antagonist) and ICI 118,551 (10 nM, a beta2-adrenoceptor-selective antagonist). L-NAME (100 microM) and indomethacine (10 microM) were used to evaluate the influence of nitric oxide (NO) or prostanoids, respectively. Immediately post-injury, isoprenaline-induced vasorelaxation was impaired in the injured carotid artery preparations: Emax=19.6 +/- 2.2% vs. 64.0 +/- 4.6%, injured vs. sham, n=8, P<0.05. However, from 2 weeks post-injury onwards, this response appeared enhanced in the injured preparations: Emax, 2 weeks= 86.4 +/- 2.2% vs. 49.7 +/- 5.7%, injured vs. sham, n=5, P<0.05. In addition, the sensitivity for isoprenaline was increased in these preparations: pD2, 2 weeks=7.48 +/- 0.08 vs. 6.88 +/- 0.10, injured vs. sham, n=5, P<0.05. The beta-adrenoceptor population in both types of preparations consisted mainly of the beta2-adrenoceptor subtype, although at 8 and 16 weeks post-injury, the beta1-adrenoceptor subtype appeared to be present as well in the injured artery preparations. Inhibition of NO synthesis led to significant decreases of beta-adrenoceptor-mediated vasorelaxation both in injured and in sham-operated artery preparations for all time points, except at 16 weeks. Cyclo-oxygenase inhibition had no influence on isoprenaline-induced vasorelaxation in injured and sham-operated preparations. From this, it is concluded that beta-adrenoceptor-mediated vasorelaxation in rat carotid artery is partially NO-dependent and occurs mainly via activation of the beta2-adrenoceptor subtype. Balloon injury and subsequent neointima formation in the rat carotid artery lead initially to an impairment, but subsequently to an enhancement of the beta-adrenoceptor-mediated vasorelaxation. The impairment is attributable to the removal of endothelium, whereas the enhanced beta-adrenoceptor-mediated function may be related to the occurrence of an NO system in the neointimal smooth muscle cells.     

Is tai chi exercise programme beneficial for patients with coronary artery disease?

Chang RY, Koo M, Kan CB, Yu ZR, Chu IT, Hsu CT, Chen CY. Effect of tai chi rehabilitation on heart rate responses in patients with coronary artery disease. Am J Chin Med 2010; 38: 461–72.     

Inhibition of the renin–angiotensin system for lowering coronary artery disease risk

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Simvastatin evokes an unpredicted inhibition of β-adrenoceptor-mediated vasodilatation in porcine coronary artery

HMG-CoA reductase inhibitors, or statins, are widely used as cholesterol-lowering agents in the treatment of dyslipidemias. Statins have also been reported to have pleiotropic effects, independent of their effects on cholesterol synthesis, possibly through inhibition of the monomeric G proteins Ras and Rho, which are able to signal through ERK and Rho kinase activities, respectively. We have previously demonstrated that inhibition of ERK activation enhances β-adrenoceptor-mediated vasodilatation in the porcine isolated coronary artery. As statins can also inhibit ERK activation, the initial aim of this study was to determine whether statins have a similar influence on β-adrenoceptor-evoked vasodilatation. Segments of porcine distal coronary artery were mounted in a Mulvany wire myograph and bathed in Krebs-Henseleit buffer gassed with 95% O(2)/5% CO(2) and maintained at 37°C. Tissues were pre-contracted with the thromboxane mimetic U46619 prior to cumulative concentration-response curves to the β-adrenoceptor agonist salbutamol in the absence or presence of simvastatin (1, 5 or 10μM), pravastatin (10μM), or lovastatin (10μM). Simvastatin inhibited the salbutamol-induced relaxation of the coronary artery. Similar effects were seen with lovastatin, but not pravastatin or the sodium salt of simvastatin. Simvastatin, but not pravastatin also inhibited the relaxations to the Ca(2+)-activated K(+) channel opener NS1619 and the K(ATP) channel opener pinacidil. Unexpectedly, these data indicate that, rather than enhancing β-adrenoceptor-mediated vasodilatation, lipophilic statins impair these responses. This is likely to be due to effects on K(+) channels.     

Is impaired flow-mediated dilatation of the brachial artery a cardiovascular risk factor?

Endothelial dysfunction is thought to be an important factor in the development of atherosclerosis. Over the past decade, a non-invasive technique has evolved to evaluate flow-mediated vasodilation ([FMD), an endothelium-dependent function, in the brachial artery. FMD decreases with increasing age and subjects with diabetes mellitus, hypercholesterolemia, smokers and hypertension have decreased FMD. There are a few concise studies reporting that FMD predicts cardiovascular events. However, the assumption that focal measurement of brachial artery FMD predicts coronary artery disease deserves further investigation.     

Inhibitors of cholesteryl ester transfer protein – a new approach to coronary artery disease

Despite the use of the statins to lower low-density lipoprotein-cholesterol, leading to major reductions in the mortality and morbidity that is associated with coronary artery disease, considerable mortality and morbidity remains. Increasing high-density lipoprotein (HDL)-cholesterol levels has been associated with reduced coronary artery disease mortality and morbidity in several studies. Inhibition of cholesteryl ester transfer protein (CETP) activity leads to increased HDL-cholesterol. In cholesterol-fed rabbits, antibodies against CETP increased HDL-cholesterol and decreased atherosclerotic lesions. In healthy subjects with mild dyslipidaemia, the CETP inhibitors JTT-705 and torcetrapib increased HDL-cholesterol and decreased low-density lipoprotein-cholesterol. Increasing HDL-cholesterol with CETP inhibitors is a new approach to dyslipidaemia that requires further investigation, especially in patients who have coronary artery disease.     

Long-term incubation with β-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery

Alzheimer's disease is associated to a cerebral amyloid angiopathy with dysregulation of cerebral blood flow (CBF). In vitro studies have shown that short-term application of β-amyloid (Aβ) peptides to isolated vessels affects vascular tone within 1 h, but no studies have examined the effect of long-term incubation with Aβ. Here we evaluate the effect of Aβ_(1–40) and Aβ_(25–35) in rat basilar artery for up to 24 h. Basilar artery segments were incubated with 25 μM Aβ_(1–40) or Aβ_(25–35), for 6 or 24 h. After treatment, arteries were mounted in a wire myograph, in physiological salt solution gassed with O₂/CO₂, in the absence of Aβ, and challenged with vasoconstrictors and vasodilators. Vasomotor responses were not significantly changed by 6 h treatment with Aβ peptides whereas 24 h treatment with either Aβ_(25–35) or Aβ_(1–40) increased vasoconstriction to 5-hydroxytryptamine (5-HT) and reduced endothelium-dependent vasodilatation to acetylcholine (ACh). Analysis of endothelial cells did not show apoptotic changes associated to endothelial dysfunction, as assessed by TUNEL immunostaining and examination of nuclear morphology, but basal phosphorylation of endothelial nitric oxide synthase (at serine 1177) appeared reduced.These data suggest that long incubation with Aβ peptides induces an alteration of endothelial function in isolated basilar artery, involving eNOS activity without changing cell morphology. This endothelial dysfunction may play a role in the pathogenesis of CBF dysregulation occurring in cerebral amyloid angiopathy and Alzheimer's disease.     

Acute potentiating effects of estrogens on endothe- lium-independent relaxation in porcine coronary artery rings

AIM: While the risk for coronary artery disease is reducedfollowing exposure to estrogens, the mechanisms of protectionhave yet to be fully elucidated. We recently found that short-term exposure to a physiological concentration (1 nmol·L~(-1)) of17β-estradiol potentiated endothelium-independent relaxation. Wetherefore sought to determine if estrone, another naturallyoccurring estrogen and diethylstilbestrol, a synthetic non-steroidalestrogen have similar enhancing effects. METHODS: Porcinecoronary artery rings were incubated with vehicle (ethanol), 17β-estradiol (1 nmol·L~(-1)), estrone (1 nmol·L~(-1)-1μmol·L~(-1)) or     

Dual effects of tetrandrine on calcium-activated potassium channels in pulmonary artery smooth muscle cells

目的：研究粉防己碱（Ｔｅｔ）对大鼠肺动脉平滑肌细胞钙激活钾（ＫＣａ）通道的影响．方法：内面朝外膜片箝单通道记录法．结果：Ｔｅｔ７５和１５μｍｏｌ·Ｌ－１使ＫＣａ的开放概率由０２５１±００１２增加到０３４０±００１３和０４１５±００１１（Ｐ＜００１）．关闭时间由（６１±１５）ｍｓ缩短到（３３±１０）和（２８±１１）ｍｓ（Ｐ＜００１）．Ｔｅｔ３０μｍｏｌ·Ｌ－１使开放概率和开放时间分别降低到（０１１４±０００８）和（１４７±００９）ｍｓ（Ｐ＜０．０１）．结论：Ｔｅｔ对大鼠肺动脉平滑肌细胞ＫＣａ通道有双重作用．     

（—）Epicatechin induces and modulates endotheliumdependent relaxation in isolated rat mesenteric artery rings

AIM:The present study was aimed to examine the role of endothelial nitric oxide in the relaxant response to green tea (-)epicatechin and its modulation of endothelium-mediated relaxation in the isolated rat mesenteric artery rings.METHODS:Changes in the isometric tension were measured with Grass force-displacement transducers.RESULTS:The (-)epicatechin-induced relaxation was largely dependent on the presence of intact endothelium and was reversed by N^G-nitro-L-arginine methyl ester 10μmol/L or methylene blue 10μmol/L,the inhibitors of nitric oxidemediated relaxation.L-Arginine at 1mmol/L antagonized the effect of L-NAME or methylene blue.Pretreatment of endothelium-intact rings with (-)epicatechin 10μmol/L enhanced the relaxation induced by endothelium-dependent vasodilator,acetylcholine,while this concentration did not influence the endothelium-independent relaxation induced by sodium nitroprusside in the endothelium-denuded artery rings.CONCLUSION:The results indicate that the endothelium-dependent vasodilation by (-)epicatechin is mainly mediated through nitric oxide and low concentration of (-)epicatechin augments endothelium-dependent vasorelaxation in the rat mesenteric arteries.