The current endothelin receptor classification: Time for reconsideration?

The possible involvement of endothelins in a variety of diseases has attracted the attention of many pharmacologists in search of a novel therapeutic approach. The rapid development of endothelin research has resulted in the molecular characterization and pharmacological recognition of ETA and ETB receptors, and in the development of compounds selective for these receptors. However, the characterization of receptors in various assays has shown that a number of effects are mediated by receptors that do not fit the present criteria for ETA or ETB receptors. In this article. Willem Bax and Pramod Saxena address endothelin receptors in general, and atypical receptors in particular

Pharmacology of the human isolated coronary artery : effects of 5-HT, platelets and peptides

Ischemia of the heat1 is characterized by a deprivation of oxygen combined with inadequate removal of metabolites. Myocardial ischemia may be due to an increased oxygen requirement, or to a decreased supply of oxygen to the myocardium. The myocardial consumption of oxygen is determined by myocardial wall tension, contractility, and heart rate. Processes in the myocardium, not directly related to contractile function, require only 20% of the total oxygen consumption, while the amount needed for electrical depolarization is only approximately 1% of total oxygen consumption. The myocardial oxygen demand is increased by physical exercise or by mental stress. In healthy individuals, an increased oxygen demand is likely to be compensated via an increase of coronary blood flow. An increased oxygen demand may result in cardiac ischemia only in patients with existing coronary artery impairment. Myocardial oxygen supply is dependent mainly on coronaty blood supply. The coronary at1ery diameter declines passively when the lumen is narrowed by intimal hyperplasia or atherosclerosis, or by the formation of a secondaty thrombus in a susceptible coronary at1ery segment. In addition to that, the mechanisms regulating coronaty at1ery diameter may be altered in such a way that contraction of the coronaty artery smooth muscle contributes actively to the already present luminal naHowing. In a small group of patients, vasoconstriction may be solely responsible for myocardial ischemia. The coronary at1elY mechanisms underlying disturbed coronary m1elY flow regulation are outlined in chapter 2. For now it must be emphasized that the present chapter on clinical aspects of ischemic heart disease is bound to be incomplete when considering the voluminous detailed text books on this topic. However, this chapter should be read as a prologue, setting the stage for hypotheses and experimental investigations, which are only a modest reflection of clinical reality described here

Endothelin receptors in the human coronary artery, ventricle and atrium - A quantitative autoradiographic analysis

In the present experiments we investigated endothelin (ET) receptors in the human coronary artery, and in ventricular and atrial muscle using quantitative receptor autoradiography. Displacement of [125I]Sf6b (Sarafotoxin S6b) (30 pM)- and [125I]ET-1 (30 pM)-labeled binding sites was studied using ET-1, the ETA receptor selective ligand BQ-123 (cyclo[D-Asp-L-Pro-D Val-L-Leu-D-Trp-]), and the ETB receptor selective ligand [Ala1,3,11,15]ET-1. Specific binding was more dense in atrium and coronary artery (relative optical density (r.o.d.): 0.14±0.01 and 0.16±0.01, respectively) than in ventricular muscle (r.o.d.: 0.10±0.01). In the coronary artery, binding was especially dense in the media. ET-1 displaced [125I]ET-1 and [125I]Sf6b monophasically in atrium, ventricle and coronary artery. [Ala1,3,11,15]ET 1 and BQ-123 displaced [125I]ET-1 and [125I]Sf6b-labeled sites biphasically in the ventricle and in the atrium. In the human coronary artery, [Ala1,3,11,15]ET-1 and BQ-123 displaced [125I]ET-1-labeled sites monophasically (pIC50): ET-1 (9.72±0.12) > BQ-123 (6.84±0.08) > [Ala1,3,11,15]ET-1 (6.40±0.12). In contrast, [Ala1,3,11,15]ET-1 and BQ-123 displaced [125I] Sf6b-labeled coronary artery sites biphasically (high affinity pIC50: BQ-123, 9.03±0.25;[Ala1,3,11,15]ET-1, 8.40±0.14; low affinity pIC50: BQ-123, 7.24±0.14; [Ala1,3,11,15]ET-1, 6.99±0.09). These data indicate that both [125I]ET-1 and [125I] Sf6b-labeled ETA and ETB binding sites in human ventricular and atrial muscle. In the human coronary artery, both radioligands labeled ETA binding sites, but [125I] Sf6b also labeled a non-ETA, non-ETB binding site with relatively high affinity for both BQ-123 and [Ala1,3,11,15] ET-1

Coronary side-effect potential of current and prospective antimigraine drugs

BACKGROUND: The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan). METHODS AND RESULTS: Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the recept

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 μg · kg−1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean ± S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 ± 0.3 μmol · kg−1 and the highest dose (1000 μg · kg−1) produced a 67 ± 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carbboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 μmol · kg−1, i.v.). Compared to sumatriptan (pD2: 6.12 ± 0.15; Emax: 31.3 ± 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 ± 0.2; Emax: 21.0 ± 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects

Effects of avitriptan, a new 5 HT(1B/1D) receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, f

Intraperitoneal irinotecan with concomitant FOLFOX and bevacizumab for patients with unresectable colorectal peritoneal metastases: Protocol of the multicentre, open-label, phase II, INTERACT-II trial

Introduction The peritoneum is the second most affected organ for the dissemination of colorectal cancer (CRC). Patients with colorectal peritoneal metastases (CPM) face a poor prognosis, despite the majority of patients being treated with palliative systemic therapy. The efficacy of palliative systemic therapy is limited due to the plasma-peritoneum barrier. The poor prognosis of unresectable CPM patients has resulted in the development of new treatment strategies where systemic therapy is combined with local, intraperitoneal chemotherapy. In the recently published phase I study, the maximum tolerated dose and thus the recommended phase II dose of intraperitoneal irinotecan was investigated and determined to be 75 mg. In the present study, the overall survival after treatment with 75 mg irinotecan with concomitant mFOLFOX4 and bevacizumab will be investigated. Materials and methods In this single-arm phase II study in two Dutch tertiary referral centres, 85 patients are enrolled. Eligibility criteria are an adequate performance status and organ function, histologically confirmed microsatellite stable and unresectable CPM, no previous palliative therapy for CRC, no systemic therapy20, too extensive small bowel involvement), a peritoneal access port and a port-a-cath are placed for administration of intraperitoneal and intravenous chemotherapy, respectively. Patients may undergo up to 12 cycles of study treatment. Each cycle consists of intravenous mFOLFOX4 with bevacizumab and concomitant intraperitoneal irinotecan (75 mg), which is repeated every 2 weeks, with a maximum of 12 cycles. Modified FOLFOX-4 regimen consists of 85 mg/m 2 oxaliplatin plus 200 mg/m 2 LV and 5-FU 400 mg/m 2 bolus on day 1 followed by 1600 mg/m 2 5-FU as a 46 hours infusion. Study treatment ends after the 12th cycle, or earlier in case of disease progression or unacceptable toxicity. The primary outcome is overall survival and key secondary outcomes are progression-free survival, safety (measured by the amount of grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0)), patient-reported outcomes and pharmacokinetics of irinotecan. It is hypothesised that the trial treatment will lead to a 4 month increase in overall survival; from a median of 12.2 to 16.2 months. Ethics and dissemination This study is approved by the Dutch Authority (CCMO, the Hague, the Netherlands), by a central medical ethics committee (MEC-U, Nieuwegein, the Netherlands) and by the institutional research boards of both research centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. Trial registration number NCT06003998

Multimodality Imaging: Bird's-Eye View from the 65th Annual Scientific Sessions of the American College of Cardiology, Chicago, Ill, April 2-4, 2016

Cardiolog

Lifestyle management to prevent atherosclerotic cardiovascular disease: evidence and challenges.

Lifestyle management is the cornerstone of both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and the importance of lifestyle management is emphasised by all major guidelines. Despite this, actual implementation of lifestyle management is poor. Lifestyle modification includes smoking cessation, weight loss, dietary change, increasing physical inactivity, and stress management. This review summarises evidence-based opportunities and challenges for healthcare professionals to promote healthy lifestyles at an individual level for the prevention of ASCVD