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Recent advances in pharmacological treatment of heart failure.
Iacoviello, M, Palazzuoli, A, Gronda, E
European journal of clinical investigation. 2021;(11):e13624
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BACKGROUND Over the last years, several trials offered new evidence on heart failure (HF) treatment. DESIGN AND RESULTS For HF with reduced left ventricular ejection fraction, type 2 sodium-glucose cotransporter inhibitors, aside from sacubitril-valsartan, demonstrated extraordinary efficacy in ameliorating patients' prognosis. Some new molecules (eg vericiguat, omecamtiv mecarbil and ferric carboxymaltose) correct iron deficiency and have shown to be capable of furthering reducing the burden of HF hospitalisation. Finally, there is new evidence on the possible therapeutic approaches of HF patients with mid-range or preserved left ventricular ejection fraction. CONCLUSIONS This review aimed to revise the main novelties in the field of HF therapy and focus on how the daily clinical approach to patient treatment is changing.
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Hypothesis: The potential therapeutic role of nicorandil in COVID-19.
Ashour, H, Elsayed, MH, Elmorsy, S, Harb, IA
Clinical and experimental pharmacology & physiology. 2020;(11):1791-1797
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At present, there is yet no specific antiviral treatment or immunization against the newly identified human severe acute respiratory syndrome virus (SARS-CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID-19). We believe in a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests that exaggerated patient's inflammatory response and oxidative stress are likely to aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy. These disturbances can generate severe acute respiratory distress syndrome (ARDS) that can progress into respiratory and circulatory failure. Nicorandil is an anti-anginal vasodilator drug acts by increasing nitric oxide bioavailability and opening of the KATP channel. Recently, nicorandil has been recognized to possess multiple protective effects against tissue injury. Here, we address a possible modulatory role of nicorandil against COVID-19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID-19.
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Effects of mitochondrial ATP-sensitive potassium channel activation (nicorandil) in patients with angina pectoris undergoing elective percutaneous coronary interventions: A meta-analysis of randomized controlled trials.
Zhu, H, Xu, X, Fang, X, Zheng, J, Chen, T, Huang, J
Medicine. 2019;(3):e14165
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AIMS: Nicorandil, which is a mitochondrial ATP-sensitive potassium channel opener, is believed to improve perioperative myocardial injury (PMI) in patients undergoing percutaneous coronary intervention (PCI), but recent studies have shown that nicorandil treatment did not improve functional and clinical outcomes in patients with angina pectoris who underwent elective PCI. We performed a meta-analysis to investigate the protective effect of nicorandil on perioperative injury in patients with angina pectoris who underwent elective PCI. METHODS The Medline, EMBASE, and Cochrane databases were searched for randomized clinical trials examining the effects of nicorandil. Two investigators independently selected suitable trials, extracted data, and assessed trial quality. RESULTS Seven studies of patients undergoing elective PCI, comprising a total of 979 patients, were included in this review. The results showed that nicorandil did not reduce the levels of markers of myocardial injury (standardized mean difference [SMD] 0.31 [95%CI -0.6, 1.22] for creatine kinase-MB [CK-MB] and 1.29 [95%CI -2.18, 4.76] for troponin I [TNI]), perioperative complications (relative risk [RR] 0.91 [95%CI 0.46-1.81]), target vessel revascularization (RR 0.79 [95%CI 0.50-1.25]) or major adverse cardiac events (MACE) (RR 0.83 [95%CI 0.49-1.43]). Nicorandil did reduce the corrected TIMI frame count (SMD-0.30 [95%CI -0.52, -0.09]). CONCLUSION Although nicorandil did not reduce the overall incidence of perioperative complications and the incidence of major adverse cardiac events (MACE) in patients with angina pectoris who underwent elective PCI, it could still improve no reflow and slow coronary flow.
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Clinical effect of trimetazidine on prevention of contrast-induced nephropathy in patients with renal insufficiency: An updated systematic review and meta-analysis.
Ye, Z, Lu, H, Su, Q, Guo, W, Dai, W, Li, H, Yang, H, Li, L
Medicine. 2017;(9):e6059
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BACKGROUND With the continuous development of cardiac interventional medicine, the incidence of contrast-induced nephropathy (CIN) is increasing every year, which is a serious threat to people's physical and mental health. Trimetazidine (TMZ) is a type of anti-ischemic drug developed in recent years, which can significantly reduce the incidence of CIN. At present, a systematic review and meta-analysis was conducted to evaluate the clinical effect of TMZ on prevention of CIN in patients with renal insufficiency. However, the study did not include patients from other countries and speaking different languages. So we conducted this study to update the previous meta-analysis that investigated the effects of TMZ on prevention of CIN in patients with renal insufficiency, and provided some theoretical reference for clinical. METHODS By searching PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, VIP database, and Wang Fang database for randomized controlled trial, which is comparing TMZ versus conventional hydration for prevention of CIN. Two researchers independently screened literature, and then evaluated the quality of literature and extracted the relevant data. Stata 11.0 software was used for statistical analysis. RESULTS Finally, this updated review showed that 3 studies that were not included in the previous meta-analysis were included in our study (3 articles were published in the Chinese Journal, 1 study for CIN, 1 study for CIN, serum creatinine (Scr), and superoxide dismutase, 1 study for CIN and Scr), and 1 outcome (Scr) reflecting the change of renal function was additionally included in our study. Of the 932 studies, 6 randomized controlled trials met the criteria, including 377 patients in TMZ group and 387 patients in control group. This meta-analysis for all studies showed that TMZ can significantly reduce the incidence of CIN (relative risk 0.27, 95% confidence interval [CI] 0.16, 0.46, P = 0.000), and can decrease the level of Scr after operation, including Scr of postoperative 24 hours (standardized mean difference [SMD] -0.30, 95% CI -0.51, -0.09, P = 0.005), Scr of postoperative 48 hours (SMD -0.66, 95% CI -1.23, -0.10, P = 0.022), and Scr of postoperative 7 days (SMD -0.74, 95% CI -1.36, -0.11, P = 0.021). However, the Scr of postoperative 72 hours between TMZ group and control group has no statistical significance (P = 0.362). CONCLUSION Our study showed that when comparing with conventional hydration, TMZ can significantly reduce the incidence of CIN and the level of postoperative Scr. Therefore, we could suggest that TMZ was superior to conventional hydration for the treatment of CIN in patients with renal insufficiency. However, due to the restriction of quality and number of included articles, it still needs to carry out multicenter, randomized, double-blind clinical trials to confirm this conclusion in the future.
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Nitrates for the prevention of cardiac morbidity and mortality in patients undergoing non-cardiac surgery.
Zhao, N, Xu, J, Singh, B, Yu, X, Wu, T, Huang, Y
The Cochrane database of systematic reviews. 2016;(8):CD010726
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BACKGROUND Cardiac complications are not uncommon in patients undergoing non-cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial. OBJECTIVES • To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.• To identify the influence of different routes and dosages of nitrates on patient outcomes. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.We reran the search in January 2016. We added three potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into our formal review findings for the review update. SELECTION CRITERIA We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia. DATA COLLECTION AND ANALYSIS We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis. MAIN RESULTS We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains.In summary, we found no difference in the primary outcome - all-cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia.Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons. AUTHORS' CONCLUSIONS This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence.However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery.Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non-cardiac surgery. This review underlines the need for well-designed trials in this field.
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The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: a systematic review and meta-analysis.
Zhang, N, Lei, J, Liu, Q, Huang, W, Xiao, H, Lei, H
Cardiology. 2015;(2):86-96
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BACKGROUND Coronary artery bypass grafting (CABG) is a key and effective surgical treatment modality for coronary artery disease. Unfortunately, ischemia-reperfusion injury during and after CABG can lead to reversible and irreversible myocardial damage. Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride] is a metabolic anti-ischemic agent with demonstrated cardioprotective effects; however, its effects with respect to myocardial preservation in CABG patients remain unclear. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to investigate the effectiveness of myocardial preservation of preoperative trimetazidine therapy in CABG patients by assessing the postoperative levels of several blood-based biochemical markers of myocardial injury, including creatine kinase (CK), creatine kinase-muscle and brain (CK-MB), creatine phosphokinase (CPK), troponin T (TnT) and troponin I (TnI). The RCTs were classified into two subgroup analyses by the timing of sample collection (either ≤12 or >12 h after CABG). RESULTS Six RCTs were finally included in the meta-analysis. The pooled effect sizes showed significantly lower postoperative levels of CK, CK-MB, TnT and TnI in the trimetazidine-treated CABG patients relative to control CABG patients. However, there were no significant differences in the postoperative CPK levels between trimetazidine-treated CABG patients relative to control CABG patients. In both the ≤12 and >12 h post-CABG subgroup analyses, significant differences in CK, CK-MB, TnT and TnI were detected between the trimetazidine-treated CABG patients relative to control CABG patients. CONCLUSIONS Preoperative trimetazidine therapy appears to have a positive effect on myocardial preservation in CABG patients.
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Nonantithrombotic medical options in acute coronary syndromes: old agents and new lines on the horizon.
Soukoulis, V, Boden, WE, Smith, SC, O'Gara, PT
Circulation research. 2014;(12):1944-58
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Acute coronary syndromes (ACS) constitute a spectrum of clinical presentations ranging from unstable angina and non-ST-segment elevation myocardial infarction to ST-segment myocardial infarction. Myocardial ischemia in this context occurs as a result of an abrupt decrease in coronary blood flow and resultant imbalance in the myocardial oxygen supply-demand relationship. Coronary blood flow is further compromised by other mechanisms that increase coronary vascular resistance or reduce coronary driving pressure. The goals of treatment are to decrease myocardial oxygen demand, increase coronary blood flow and oxygen supply, and limit myocardial injury. Treatments are generally divided into disease-modifying agents or interventions that improve hard clinical outcomes and other strategies that can reduce ischemia. In addition to traditional drugs such as β-blockers and inhibitors of the renin-angiotensin-aldosterone system, newer agents have expanded the number of molecular pathways targeted for treatment of ACS. Ranolazine, trimetazidine, nicorandil, and ivabradine are medications that have been shown to reduce myocardial ischemia through diverse mechanisms and have been tested in limited fashion in patients with ACS. Attenuating the no-reflow phenomenon and reducing the injury compounded by acute reperfusion after a period of coronary occlusion are active areas of research. Additionally, interventions aimed at ischemic pre- and postconditioning may be useful means by which to limit myocardial infarct size. Trials are also underway to examine altered metabolic and oxygen-related pathways in ACS. This review will discuss traditional and newer anti-ischemic therapies for patients with ACS, exclusive of revascularization, antithrombotic agents, and the use of high-intensity statins.
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Interventions for deliberately altering blood pressure in acute stroke.
Bath, PM, Krishnan, K
The Cochrane database of systematic reviews. 2014;(10):CD000039
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BACKGROUND It is unclear whether blood pressure should be altered actively during the acute phase of stroke. This is an update of a Cochrane review first published in 1997, and previously updated in 2001 and 2008. OBJECTIVES To assess the clinical effectiveness of altering blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. SEARCH METHODS We searched the Cochrane Stroke Group Trials Register (last searched in February 2014), the Cochrane Database of Systematic reviews (CDSR) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (Ovid) (1966 to May 2014), EMBASE (Ovid) (1974 to May 2014), Science Citation Index (ISI, Web of Science, 1981 to May 2014) and the Stroke Trials Registry (searched May 2014). SELECTION CRITERIA Randomised controlled trials of interventions that aimed to alter blood pressure compared with control in participants within one week of acute ischaemic or haemorrhagic stroke. DATA COLLECTION AND ANALYSIS Two review authors independently applied the inclusion criteria, assessed trial quality and extracted data. The review authors cross-checked data and resolved discrepancies by discussion to reach consensus. We obtained published and unpublished data where available. MAIN RESULTS We included 26 trials involving 17,011 participants (8497 participants were assigned active therapy and 8514 participants received placebo/control). Not all trials contributed to each outcome. Most data came from trials that had a wide time window for recruitment; four trials gave treatment within six hours and one trial within eight hours. The trials tested alpha-2 adrenergic agonists (A2AA), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARA), calcium channel blockers (CCBs), nitric oxide (NO) donors, thiazide-like diuretics, and target-driven blood pressure lowering. One trial tested phenylephrine.At 24 hours after randomisation oral ACEIs reduced systolic blood pressure (SBP, mean difference (MD) -8 mmHg, 95% confidence interval (CI) -17 to 1) and diastolic blood pressure (DBP, MD -3 mmHg, 95% CI -9 to 2), sublingual ACEIs reduced SBP (MD -12.00 mm Hg, 95% CI -26 to 2) and DBP (MD -2, 95%CI -10 to 6), oral ARA reduced SBP (MD -1 mm Hg, 95% CI -3 to 2) and DBP (MD -1 mm Hg, 95% CI -3 to 1), oral beta blockers reduced SBP (MD -14 mm Hg; 95% CI -27 to -1) and DBP (MD -1 mm Hg, 95% CI -9 to 7), intravenous (iv) beta blockers reduced SBP (MD -5 mm Hg, 95% CI -18 to 8) and DBP (-5 mm Hg, 95% CI -13 to 3), oral CCBs reduced SBP (MD -13 mmHg, 95% CI -43 to 17) and DBP (MD -6 mmHg, 95% CI -14 to 2), iv CCBs reduced SBP (MD -32 mmHg, 95% CI -65 to 1) and DBP (MD -13, 95% CI -31 to 6), NO donors reduced SBP (MD -12 mmHg, 95% CI -19 to -5) and DBP (MD -3, 95% CI -4 to -2) while phenylephrine, non-significantly increased SBP (MD 21 mmHg, 95% CI -13 to 55) and DBP (MD 1 mmHg, 95% CI -15 to 16).Blood pressure lowering did not reduce death or dependency either by drug class (OR 0.98, 95% CI 0.92 to 1.05), stroke type (OR 0.98, 95% CI 0.92 to 1.05) or time to treatment (OR 0.98, 95% CI 0.92 to 1.05). Treatment within six hours of stroke appeared effective in reducing death or dependency (OR 0.86, 95% CI 0.76 to 0.99) but not death (OR 0.70, 95% CI 0.38 to 1.26) at the end of the trial. Although death or dependency did not differ between people who continued pre-stroke antihypertensive treatment versus those who stopped it temporarily (worse outcome with continuing treatment, OR 1.06, 95% CI 0.91 to 1.24), disability scores at the end of the trial were worse in participants randomised to continue treatment (Barthel Index, MD -3.2, 95% CI -5.8, -0.6). AUTHORS' CONCLUSIONS There is insufficient evidence that lowering blood pressure during the acute phase of stroke improves functional outcome. It is reasonable to withhold blood pressure-lowering drugs until patients are medically and neurologically stable, and have suitable oral or enteral access, after which drugs can than be reintroduced. In people with acute stroke, CCBs, ACEI, ARA, beta blockers and NO donors each lower blood pressure while phenylephrine probably increases blood pressure. Further trials are needed to identify which people are most likely to benefit from early treatment, in particular whether treatment started very early is beneficial.
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Effect of intracoronary nitroprusside in preventing no reflow phenomenon during primary percutaneous coronary intervention: a meta-analysis.
Zhao, S, Qi, G, Tian, W, Chen, L, Sun, Y
Journal of interventional cardiology. 2014;(4):356-64
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BACKGROUND Adjunctive therapy with intracoronary nitroprusside (NTP) in primary percutaneous coronary intervention (PPCI) had controversial benefits in patients with ST segment elevation myocardial infarction (STEMI). OBJECTIVES To evaluate the effect of intracoronary NTP on no reflow phenomenon (NR) and clinical outcomes in STEMI patients undergoing PPCI. METHODS We searched the following databases without language or time limitation in January 2014: PubMed, EMBASE, CENTRAL, ISI Web of Science, and CNKI. Trials compared the effect of intracoronary NTP with control group (placebo or no NTP treatment) on NR in STEMI patients undergoing PPCI enrolled for analyzing. RESULTS A total of 7 trials involving 781 patients were included into this meta-analysis. Intracoronary NTP significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) flow grade (TFG) ≤2 (RR: 0.47, 95% CI: 0.30-0.73, P = 0.001); the corrected TIMI frame count (CTFC) (WMD: -5.28, 95% CI: -6.79 to 3.78, P = 0.000) increased the events of myocardial blush grade (MBG) ≥2 (RR: 1.12, 95% CI: 1.01-1.24, P = 0.038), and reduced the incidence of major adverse cardiac events (MACE) (RR: 0.43, 95% CI: 0.27-0.70, P = 0.001). Although the events of the complete ST segment resolution (STR) did not reach statistical significance, there was a trend indicating improvement in the intracoronary NTP group (RR: 1.143, 95% CI: 0.97-1.34, P = 0.101). CONCLUSIONS Intracoronary NTP can significantly reduce the incidence of angiographic NR during PPCI, as well as the incidence of MACE. It seems to be a promising adjunctive therapy for NR during PPCI.
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Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12.
Maguire, JJ, Davenport, AP
British journal of pharmacology. 2014;(24):5555-72
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Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ETA and ETB . Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-193-166 , has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research.