Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Simendan”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed1996

Levosimendan potentiates the inotropic actions of dopamine in conscious dogs.

We examined the hemodynamic and left ventricular (LV) functional actions of dopamine with and without levosimendan in dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dtmax, subendocardial segment length, and cardiac output (CO). On different experimental days, dogs were randomly assigned to receive dopamine (2.5, 5.0, and 10.0 micrograms kg-1 min-1) in the absence and presence of levosimendan (0.125, 0.25, and 0.5 microgram kg-1 min-1) or levosimendan alone. Dopamine increased heart rate (HR), CO, stroke volume (SV), and pressure-work index (PWI) and decreased systemic vascular resistance (SVR). Dopamine also increased LV systolic and end-diastolic pressures (LVSP and LVEDP) and mean arterial pressure (MAP). Dopamine caused dose-related positive inotropic [increases in preload recruitable stroke work (Mw) and + dP/ dtmax] and lusitropic effects [decreases in the time constant of isovolumic relaxation (tau) and increases in maximum segment-lengthening velocity (dL/dtmax)]. Dopamine also increased the regional chamber thickness constant (Kp) concomitant with increases in LVEDP. In the presence of levosimendan, dopamine-induced increases in HR, PWI, CO, and SV and decreases in SVR were enhanced. Increases in MAP, LVSP, and LVEDP observed with dopamine alone were attenuated by the addition of levosimendan. Dopamine-induced increases in Mw and +dP/dtmax were enhanced by levosimendan. Reductions in tau and increases in dL/dtmax produced by dopamine were similar with and without levosimendan. However, levosimendan abolished increases in Kp caused by dopamine alone. Levosimendan alone caused dose-related improvements in indices of LV systolic and diastolic function. The results indicate that levosimendan potentiates the positive inotropic effects of dopamine in conscious, unsedated dogs, while attenuating the deleterious action of dopamine on chamber compliance.

Animals↗
PubMed1997

Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy.

We examined the left ventricular (LV) mechanical actions of levosimendan (LSM) before and after the development of pacing-induced cardiomyopathy in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), the maximal rate of segment-lengthening velocity (dL/dt), and a regional chamber-stiffness constant (Kp). On different experimental days, dogs were assigned to receive LSM (12- or 24-microgram/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion) before rapid ventricular pacing was initiated. Dogs were then paced at 240 beats/min for 22 +/- 2 days, and the low and high doses of LSM were repeated on separate days. LSM increased Mw and +dP/dt in dogs before the initiation of pacing, consistent with enhanced myocardial contractility. LSM also improved indices of LV diastolic function (decreases in tau and Kp and increases in dL/dt) in dogs before pacing. Rapid ventricular pacing over a 3-week period increased LV end-diastolic pressure and produced systolic (decreases in Mw and +dP/dt) and diastolic (increases in tau and Kp and decreases in dL/dt) dysfunction. LSM significantly (p < 0.05) increased Mw (54 +/- 3 to 98 +/- 6 mm Hg) +dP/dt and dL/dt (57 +/- 13 to 72 +/- 13 mm/s) and decreased tau (66 +/- 4 to 52 +/- 3 ms) and Kp (1.14 +/- 0.14 to 0.71 +/- 0.03 mm-1) in the presence of LV dysfunction. In contrast to the findings in normal dogs, however, LSM did not alter heart rate and calculated indices of myocardial oxygen consumption in dogs after pacing. The findings indicate that LSM produces favorable alterations in hemodynamics and positive inotropic and lusitropic effects in conscious dogs with left ventricular dysfunction.

Animals↗
PubMed1998

Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties.

We examined the action of levosimendan, a new Ca2+-sensitizing inodilator, on isolated porcine coronary arteries. Vessel rings were studied in isometric myographs. Arterial cyclic adenosine monophosphate (cAMP) levels were determined by radioimmunoassay. Levosimendan (10(-7)-10(-3) M) completely relaxed arteries preconstricted by prostaglandin F2alpha (PGF2alpha) with a pD2 (-logEC50) value of 3.99 +/- 0.05 (n = 6-9 in all experiments). Pretreatment with levosimendan also prevented contraction induced by PGF2alpha. The vasorelaxation produced by levosimendan (10(-7)-10(-3) M) was not attenuated by removal of the endothelium. Levosimendan (10(-7)-10(-3) M) relaxed contractions induced by 30 mM K+ as well as 80 mM K+, whereas the K+ channel opener levcromakalim selectively relaxed contraction induced by 30 mM K+. Neither the cyclooxygenase inhibitor indomethacin nor the beta-adrenoceptor blocker propranolol influenced levosimendan-induced vasorelaxation. The Ca2+-entry blocker isradipine failed to relax arteries precontracted by endothelin-1 in Ca2+-free/EGTA medium. However, levosimendan (10(-7)-3 x 10(-3) M) completely relaxed endothelin-1-induced contractions in this medium. Levosimendan potentiated the relaxant effect of a cAMP-stimulating drug, isoprenaline, but also that of nitroglycerin and isradipine. At a maximal effective concentration, it increased arterial tissue contents of cAMP twofold. In conclusion, levosimendan produces coronary vasorelaxation by a mechanism that seems to be endothelium independent and not mediated by K+ channel opening, Ca2+-entry blockade, release of cyclooxygenase products, or beta-adrenoceptor stimulation. Accumulation of cAMP may possibly participate in vasorelaxation at high concentrations of levosimendan, but a cAMP-independent mechanism seems to be involved at lower concentrations.

Animals↗
PubMed1999

Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial.

Levosimendan is a new myofilament calcium (Ca2+) sensitizer that increases myocardial contractility by stabilizing the Ca2+-bound conformation of troponin C. We tested the hypothesis that levosimendan enhances cardiac performance after cardiopulmonary bypass (CPB). Anesthesia was induced and maintained with midazolam, sufentanil, and vecuronium in 18 patients randomly assigned to receive levosimendan (18 or 36 microg/kg loading dose and 0.2 or 0.3 microg/kg/min infusion, respectively) or placebo 15 min before and continued for 6 h after CPB. Significant (p < 0.05) increases in heart rate (HR) and decreases in systemic vascular resistance (SVR) occurred 15 min after CPB in patients receiving placebo. Later increases in mean arterial pressure (MAP) and cardiac output (CO) and decreases in stroke volume (SV) and pulmonary vascular resistance also were observed. HR was greater in patients receiving high- but not low-dose levosimendan versus placebo immediately after CPB. MAP also was lower in patients treated with either dose of levosimendan compared with placebo after CPB. Levosimendan increased CO and decreased SVR (4.2 +/- 0.4 to 7.9 +/- 0.4 L/min and 1,150 +/- 99 to 512 +/- 42 dyn/s/cm5, respectively, 15 min after CPB; mean +/- SEM). CO and SV were higher and SVR was lower in patients receiving levosimendan versus placebo after CPB. No differences in arterial oxygenation and perioperative arrhythmias (Holter analysis) were observed between groups. The results indicate that levosimendan enhances cardiac performance after CPB in humans.

Aged↗
PubMed2000

Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function.

Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.

Action Potentials↗
PubMed2000

Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium.

We performed experiments in rabbit ventricular papillary muscles loaded with aequorin to elucidate the mechanism of positive inotropic effect (PIE) of OR-1896, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic: PIE of OR-1896 reached a plateau at 10(-5) M (first phase), and the CRC became steeper at 10(-3) M and higher (second phase). Maximal response of the first phase was 11% of the maximal response to isoproterenol (ISOmax) and associated with an increase in Ca2+ transients of 5% of ISOmax. For a given degree of PIE, the increase in Ca2+ transients by OR-1896 was lower than that induced by elevation of [Ca2+]o. The PIE of OR-1896 was not associated with impairment of relaxation, and it was abolished by carbachol. In conclusion, OR-1896 has a PIE partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted through crosstalk with signal transduction mediated by cyclic adenosine monophosphate (cAMP).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels.

Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of levosimendan were unaltered. The effect of bisindolylmaleimide and levosimendan on DCFV was additive. The results indicate that levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.

Animals↗
PubMed2004

Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart.

Levosimendan is a novel calcium sensitizer that increases contraction force without change in intracellular calcium ([Ca2+]i); milrinone is a phosphodiesterase inhibitor that exerts a positive inotropic effect by increasing [Ca2+]i. The effects of levosimendan and milrinone on oxygen consumption in the isolated guinea-pig heart were studied. Isolated guinea-pig hearts were paced (280 beats/min) and perfused according to the Langendorff technique. Levosimendan (0.01-1 microM) or milrinone (0.1-10 microM) were added cumulatively and changes from baseline for diastolic and systolic pressure (LVEDP and LVSP), contractility and relaxation (+dP/dt and -dP/dt), and coronary flow and oxygen consumption (CF and VO2) were calculated. Levosimendan was found to be 10 to 30 times more potent than milrinone as an inotropic agent. The effect on VO2 was markedly lower in levosimendan-perfused hearts than in milrinone-perfused hearts (P = 0.031 between the concentration-dependent effects of the two drugs). The maximum increase in VO2 was 10 +/- 4% in the levosimendan group and 38 +/- 15% in the milrinone group. The economy of the contraction was more advantageous in levosimendan-perfused hearts (P </= 0.005 vs. milrinone group on both VO2/+dP/dt and VO2/LVSP). It was concluded that levosimendan exerts a positive inotropic effect without disturbing the energy balance of the heart.

Animals↗
PubMed2004

Comparision of the inotropic effects of levosimendan, rolipram, and dobutamine on human atrial trabeculae.

The aim of this study was to compare the positive inotropic effects of 3 different agents with 3 different mechanisms of actions-levosimendan, rolipram, and dobutamine-on human atrial trabecular muscles. Samples of right atrial appendage (1 cm, 500-1000 mg) were removed and immersed in preoxygenated and modified Tyrode solution. In oxygenated Tyrode solution, preparations were used to investigate the concentration-effect relationship of levosimendan, dobutamine, and rolipram on percentage developed tension (DT), from 10 to 10 M, each concentration for 15 minutes. All 3 agents produced concentration-dependent increments in DT. We found that levosimendan was the most efficacious positive inotropic agent on isolated human atrial trabeculae. Both the sensitivity (pD2) and maximum response (Emax) of human atrial trabeculae to levosimendan (6.711 +/- 0.26 and 23.2 +/- 2.2 mN, respectively) were significantly greater than those of dobutamine (6.663 +/- 0.19 and 17.6 +/- 2.8 mN) and rolipram (6.497 +/- 0.18 and 15.0 +/- 1.0 mN). pD2 and Emax values for dobutamine were significantly higher than those for rolipram. It was suggested that because of its potential to enhance cardiac performance without predisposition to calcium-induced arrhythmias, levosimendan might be more useful as a positive inotropic agent in clinical practice.

Adult↗
PubMed2004

Levosimendan in off-pump coronary artery bypass: a four-times masked controlled study.

We tested the hypothesis that levosimendan produced beneficial hemodynamic effects during and after off-pump coronary artery bypass grafting in patients with good preoperative left ventricular function. Levosimendan at low dose (12 microg/kg), high dose (24 microg/kg), or placebo were administered in thirty-one patients in a randomized and four-times masked controlled study. Heart rate was not significantly different between experimental groups. Significant increases in cardiac output and left ventricular ejection fraction occurred after high-dose (P < 0.001; P = 0.006) and low-dose levosimendan (P = 0.001; P = 0.002). Both doses of levosimendan produced significant increased stroke volume and decreased systemic vascular resistance. Mean arterial pressure, pulmonary capillary wedge pressure, and left ventricular end-systolic volume were not significantly different between groups. The low-dose levosimendan produced better hemodynamic response than high-dose and may be preferable in patients undergoing off-pump coronary artery bypass grafting.

Anesthesia↗
PubMed2003

The role of Ca++-sensitizers for the treatment of heart failure.

For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-III (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented.

Calcium↗
PubMedDate not supplied

Levosimendan: a unique approach to the treatment of heart failure.

Levosimendan is one of the first agents of a new class of drugs known as calcium sensitizers. These drugs are believed to increase cardiac contractility by sensitizing cardiac myofibrils to calcium, and may therefore be of clinical benefit in the treatment of low-cardiac output states, particularly congestive heart failure. In addition to sensitizing troponin to intracellular calcium, levosimendan has been shown to inhibit phosphodiesterase III, which may contribute to its positive inotropic effect, and open adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)), which may produce vasodilation. Unlike currently available intravenous inotropes, levosimendan does not increase myocardial oxygen utilization, has not been shown to be proarrhythmic, and has been used effectively in the presence of beta-blocking medications. Levosimendan also has not been shown to impair ventricular relaxation, which was an initial concern with this class of drugs. Clinical studies of levosimendan have demonstrated short-term hemodynamic benefits of levosimendan over both placebo and dobutamine. While large-scale, long-term morbidity and mortality data are scarce, the Levosimendan Infusion versus Dobutamine in severe low-output heart failure (LIDO) study suggested a mortality benefit of levosimendan over dobutamine up to 180 days after treatment. Clinical studies comparing levosimendan with other positive inotropes, namely milrinone, are lacking. Levosimendan treatment appears to be well-tolerated, with the primary adverse events being headache and hypotension. No clinically significant drug-drug interactions have been reported with levosimendan to date. The clinical future of levosimendan will depend on the results of larger, ongoing clinical trials.

Cardiotonic Agents↗
PubMed2006

Newer approaches to the pharmacological management of heart failure.

PURPOSE OF REVIEW: The treatment of acute heart failure is gaining importance, specifically in the perioperative setting. Increasing evidence shows that established forms of therapy using beta-adrenergic inotropic drugs have no effect on long-term survival; thus, anesthetists and intensive care specialists are focusing on new strategies. This review examines, with respect to the literature of the past year, whether these strategies will gain significance in the perioperative setting. RECENT FINDINGS: Owing to its unique efficacy profile, levosimendan, a calcium sensitizer, improves long-term survival in patients with acute heart failure and has been incorporated into the European Society of Cardiology guidelines. Improved heart function without increased oxygen consumption, anti-ischemic effects, no arrhythmogenic effect and positive effects on intestinal perfusion have been described. Despite the positive effects on hemodynamics and symptoms, tezosentan, an endothelin antagonist, did not improve outcome, perhaps due to too high dosages of the drug. Nesiritide, a recombinant brain natriuretic peptide, may represent an alternative to nitroglycerin and dobutamine and possibly have a benefit for survival. No final conclusions can yet be drawn, however. L-NAME, a nitric oxide synthase antagonist, represents a promising new approach for the treatment of cardiogenic shock. The results must be confirmed in large, randomized studies. SUMMARY: For perioperative treatment of acute heart failure, levosimendan, nesiritide and L-NAME constitute promising alternatives to conventional inotropic and vasodilatory drugs. The strongest evidence for improving outcome is given for levosimendan. According to the present literature, tezosentan does not currently have any significance for treatment of perioperative heart failure.

Calcium Signaling↗
PubMed2003

Effects of levosimendan on right ventricular function and ventriculovascular coupling in open chest pigs.

OBJECTIVE: Levosimendan is a promising calcium sensitizer that potentially could be useful in settings of pulmonary vasoconstriction and right ventricular dysfunction. There is a shortage of information concerning its effects on right ventricular function and ventriculovascular coupling. The aim of the present study was to characterize the effects of levosimendan on right ventricular and pulmonary vascular function by means of pressure-volume and pulsatile flow analysis. DESIGN: Prospective laboratory investigation. SETTING: University hospital laboratory. SUBJECTS: Eight landrace pigs (mean weight, 37 kg). INTERVENTIONS: Following instrumentation with biventricular conductance catheters, pulmonary and right coronary artery flow probes, a high-fidelity pulmonary pressure catheter, and a right coronary venous catheter, hemodynamic measurements were performed in baseline conditions and during levosimendan infusion at three increasing plasma concentrations (mean values, 27.5, 67.6, and 142.5 ng/mL). MEASUREMENTS AND MAIN RESULTS: Levosimendan increased heart rate and cardiac output, reduced systemic vascular resistance, and had a positive inotropic effect on the left ventricle and increased left ventricular mechanical efficiency. Moreover, levosimendan increased right ventricular contractility and hydraulic power. However, total pulmonary vascular resistance and characteristic impedance did not change throughout the protocol, and right ventricular mechanical efficiency decreased slightly at the highest concentration of levosimendan. CONCLUSIONS: At clinical concentrations in the present model, levosimendan increases right ventricular contractility and performance without significantly influencing pulmonary vascular tone. Further studies are required in a model of pulmonary vasoconstriction to disclose possible pulmonary vasodilator effects of levosimendan.

Animals↗
PubMed2005

Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs.

OBJECTIVE: The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (muHbo(2)) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (Do(2)) and/or oxygen consumption (Vo(2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. DESIGN: Laboratory experiment. SETTING: University animal research laboratory of experimental anesthesiology. SUBJECTS: Chronically instrumented dogs with flow probes for cardiac output measurement. INTERVENTIONS: Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10 microg.kg, followed by four infusion steps: 0.125-1.0 microg.kg.min), milrinone (5.0 microg.kg, followed by 1.25-10 microg.kg.min), or dobutamine (2.5-10.0 microg.kg.min). Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 mL.kg). MEASUREMENTS AND MAIN RESULTS: We measured muHbo(2) (reflectance spectrophotometry), Do(2), Vo(2), and systemic hemodynamics. Levosimendan significantly increased muHbo(2) from baseline (approximately 55% for all groups) to 64 +/- 4% and further to 69 +/- 2% with volume challenge (mean +/- sem). At the systemic level, levosimendan alone only slightly increased Do(2) at a Vo(2). Milrinone elicited similar systemic effects (Do(2), Vo(2), hemodynamics) but failed to increase muHbo(2). Dobutamine, conversely, increased muHbo(2) to a similar extent as levosimendan; however, this was accompanied by marked increases in Do(2) and Vo(2). The gastric mucosa selectivity of these interventions, expressed as slope of the muHbo(2)/Do2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). CONCLUSIONS: Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectively (i.e., at only moderately increased Do(2) and stable Vo(2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.

Adrenergic beta-Agonists↗