The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Camilla Schinner - One of the best experts on this subject based on the ideXlab platform.
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the Inotropic Agent digitoxin strengthens desmosomal adhesion in cardiac myocytes in an erk1 2 dependent manner
Basic Research in Cardiology, 2020Co-Authors: Camilla Schinner, Silvana Olivaresflorez, Angela Schlipp, Sebastian Trenz, Manouk Feinendegen, Heinrich Flaswinkel, Ellen Kempf, Desalegn Tadesse Egu, Sunil YeruvaAbstract:Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive adhesiotropy", was demonstrated to be a function of sympathetic signaling and to be relevant for a sufficient Inotropic response. We used the Inotropic Agent digitoxin to investigate the link between inotropy and adhesiotropy. In contrast to wild-type hearts, digitoxin failed to enhance pulse pressure in perfused mice hearts lacking the desmosomal protein plakoglobin which was paralleled with abrogation of plaque thickening indicating that positive Inotropic response requires intact desmosomal adhesion. Atomic force microscopy revealed that digitoxin increased the binding force of the adhesion molecule desmoglein-2 at cell-cell contact areas. This was paralleled by enhanced cardiac myocyte cohesion in both HL-1 cardiac myocytes and murine cardiac slices as determined by dissociation assays as well as by accumulation of desmosomal proteins at cell-cell contact areas. However, total protein levels or cytoskeletal anchorage were not affected. siRNA-mediated depletion of desmosomal proteins abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, digitoxin caused activation of ERK1/2. In line with this, inhibition of ERK1/2 signaling abrogated the effects of digitoxin on cell-cell adhesion and desmosomal reorganization. These results show that the positive Inotropic Agent digitoxin enhances cardiac myocyte cohesion with reorganization of desmosomal proteins in an ERK1/2-dependent manner. Desmosomal adhesion seems to be important for a sufficient positive Inotropic response of digitoxin treatment, which can be of medical relevance for the treatment of heart failure.
Sunil Yeruva - One of the best experts on this subject based on the ideXlab platform.
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the Inotropic Agent digitoxin strengthens desmosomal adhesion in cardiac myocytes in an erk1 2 dependent manner
Basic Research in Cardiology, 2020Co-Authors: Camilla Schinner, Silvana Olivaresflorez, Angela Schlipp, Sebastian Trenz, Manouk Feinendegen, Heinrich Flaswinkel, Ellen Kempf, Desalegn Tadesse Egu, Sunil YeruvaAbstract:Desmosomal proteins are components of the intercalated disc and mediate cardiac myocyte adhesion. Enhancement of cardiac myocyte cohesion, referred to as "positive adhesiotropy", was demonstrated to be a function of sympathetic signaling and to be relevant for a sufficient Inotropic response. We used the Inotropic Agent digitoxin to investigate the link between inotropy and adhesiotropy. In contrast to wild-type hearts, digitoxin failed to enhance pulse pressure in perfused mice hearts lacking the desmosomal protein plakoglobin which was paralleled with abrogation of plaque thickening indicating that positive Inotropic response requires intact desmosomal adhesion. Atomic force microscopy revealed that digitoxin increased the binding force of the adhesion molecule desmoglein-2 at cell-cell contact areas. This was paralleled by enhanced cardiac myocyte cohesion in both HL-1 cardiac myocytes and murine cardiac slices as determined by dissociation assays as well as by accumulation of desmosomal proteins at cell-cell contact areas. However, total protein levels or cytoskeletal anchorage were not affected. siRNA-mediated depletion of desmosomal proteins abrogated increase of cell cohesion demonstrating that intact desmosomal adhesion is required for positive adhesiotropy. Mechanistically, digitoxin caused activation of ERK1/2. In line with this, inhibition of ERK1/2 signaling abrogated the effects of digitoxin on cell-cell adhesion and desmosomal reorganization. These results show that the positive Inotropic Agent digitoxin enhances cardiac myocyte cohesion with reorganization of desmosomal proteins in an ERK1/2-dependent manner. Desmosomal adhesion seems to be important for a sufficient positive Inotropic response of digitoxin treatment, which can be of medical relevance for the treatment of heart failure.
Anders Perner - One of the best experts on this subject based on the ideXlab platform.
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Scandinavian SSAI clinical practice guideline on choice of Inotropic Agent for patients with acute circulatory failure
Acta anaesthesiologica Scandinavica, 2018Co-Authors: Morten Hylander Møller, Anders Granholm, E. Junttila, Michael Haney, A. Oscarsson-tibblin, A. Haavind, Jon Henrik Laake, Erika Wilkman, K. O. Sverrisson, Anders PernerAbstract:BACKGROUND: Adult critically ill patients often suffer from acute circulatory failure and those with low cardiac output may be treated with Inotropic Agents. The aim of this Scandinavian Society of ...
Hiroyuki Fujiki - One of the best experts on this subject based on the ideXlab platform.
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opc 18790 a novel positive Inotropic Agent has both arterial and venous vascular dilating actions in the dog
European Journal of Pharmacology, 1996Co-Authors: Hiroyuki Fujiki, Toyoki Mori, Kenji Yoshida, Takashi Imaizumi, Michiaki TominagaAbstract:OPC-18790, (±)6-[3-(3,4-dimethoxybenzylamino)-2- hydroxypropoxy]-2(1H)-quinolinone, is a novel positive Inotropic Agent with a moderate vasodilating action. We examined the vasodilating action of OPC-18790 in detail in the pentobarbital-anesthetized dogs using a colored microsphere technique for resistance vessels and a mean circulatory filling pressure method for capacitance vessels. Intravenously (i.v.) infused OPC-18790 increased the first derivative of left ventricular pressure (LVdP/dt max), cardiac output, heart rate and decreased total peripheral resistance but did not affect mean blood pressure. OPC-18790 significantly increased arterial blood flow distribution to heart and decreased vascular resistance in heart. OPC-18790 at 300 μg/kg i.v. and nitroglycerin at 50 μg/kg i.v. did not affect mean circulatory filling pressure in intact anesthetized dogs, but both compounds decreased mean circulatory filling pressure in spinally anesthetized dogs. OPC-18790 also decreased resistance to venous return but nitroglycerin did not. These results suggest that OPC-18790 has both arterial and venous vasodilating actions in addition to its positive Inotropic action. These actions may produce an improvement of cardiohemodynamics in heart failure.
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Effects of Toborinone (OPC-18790), a New Positive Inotropic Agent, on Action Potential in Guinea Pig Sinoatrial Node: Compared with Milrinone and E-4031
Japanese journal of pharmacology, 1996Co-Authors: Kensuke Orito, Hiromichi Takase, Hiroyuki Fujiki, Toyoki MoriAbstract:Abstract The effects of toborinone ([(±)-6-[3-(3,4-dimethoxybenzylamino)-2-tiydroxypropoxy]-2(1H)-quinolinone], OPC-18790), milrinone and E-4031 (1-(2-(6-methyl-2-pyridil)-1-ethyl)-4-(4-methanesulfonyl-amino-l-benzoyl)piperidine dihydrochloride) on membrane potential were examined in isolated guinea pig sinoatrial node preparations. Toborinone, a new positive Inotropic Agent, prolonged cycle length (CL), depolarized maximum diastolic potential (MDP) and decreased maximum upstroke velocity (V-,) and action potential amplitude (APA). On the other hand, milrinone, a peak III phosphodiesterase (PDE III) inhibitor, increased Vmax and APA and shortened CL and action potential duration. E-4031, an IK blocker, prolonged CL, depolarized MDP and decreased Vmax and APA. These results suggest that toborinone modulates the action potential like an IK blocker rather than a PDE III inhibitor in a sinoatrial node.
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effects of opc 18790 a new positive Inotropic Agent on energetics in the ischaemic canine heart a 31p mrs study
Cardiovascular Research, 1995Co-Authors: Makoto Ishikawa, Hiroyuki Fujiki, Toyoki Mori, Michiaki Tominaga, Shuji Itoh, Keiko Koga, Youichi YabuuchiAbstract:Objective: Effects of OPC-18790, a novel positive Inotropic Agent, on cardiohaemodynamics and cardiac energetics were assessed simultaneously in dogs with cardiac ischaemia using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and compared with those of amrinone, a pure cGMP-inhibited PDE inhibitor. Methods: Cardiac ischaemia was produced by partial stenosis of the coronary artery. Dogs with cardiac ischaemia were instrumented for the determination of regional coronary blood flow (non-radioactive coloured microsphere method), regional contractile function (sonomicrometry), and haemodynamics. Myocardial phosphate compounds were measured simultaneously by 31P-MRS. Results: Coronary stenosis produced regional dyskinesis, a slight decrease in cardiac output (CO), intracellular acidosis, an increase in the inorganic phosphate (Pi)/creatine phosphate (PCr) ratio concomitantly with a decrease in regional coronary blood flow (CBF) in the ischaemic region. OPC-18790 dose-dependently produced an increase in contractility (measured by peak LVdP/dt) and CO, with only slight changes in heart rate (HR) and mean blood pressure (mBP). OPC-18790 did not change regional dyskinesis, but improved the Pi/PCr ratio at the high dose compared with ischaemic values (before drug administration). Amrinone produced an increase in CO comparable to that of OPC-18790; however, the increase in peak LVdP/dt was smaller while the increase in HR and decrease in mBP were larger than those seen with OPC-18790. Amrinone worsened the Pi/PCr ratio and intracellular acidosis only at the high dose. Conclusion: These observed differences in energy metabolism between OPC-18790 and amrinone at the high dose may be due to the ability of OPC-18790 to increase CBF in the ischaemic region and which may attributed to its differing effect on overall haemodynamics. Thus, OPC-18790 may be useful in the management of ischaemic heart failure.
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Cardiovascular actions of OPC-18790: A novel positive Inotropic Agent with little chronotropic action
Heart and Vessels, 1992Co-Authors: Tetsumi Hosokawa, Hiroyuki Fujiki, Toyoki Mori, Takashi Imaizumi, Michiaki Tominaga, Shizuo Kinoshita, Kazumi Takemoto, Teruo Noda, Makoto Ohura, Youichi YabuuchiAbstract:OPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1 H ) - quinolinone], a novel positive Inotropic Agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10^−6 to 10^−4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive Inotropic effect of OPC-18790 was not affected by β-blockade. OPC-18790 (10^−5 to 10^−4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na^+, K^+-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC_50 = 0.41 × 10^−6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.
Michiaki Tominaga - One of the best experts on this subject based on the ideXlab platform.
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opc 18790 a novel positive Inotropic Agent has both arterial and venous vascular dilating actions in the dog
European Journal of Pharmacology, 1996Co-Authors: Hiroyuki Fujiki, Toyoki Mori, Kenji Yoshida, Takashi Imaizumi, Michiaki TominagaAbstract:OPC-18790, (±)6-[3-(3,4-dimethoxybenzylamino)-2- hydroxypropoxy]-2(1H)-quinolinone, is a novel positive Inotropic Agent with a moderate vasodilating action. We examined the vasodilating action of OPC-18790 in detail in the pentobarbital-anesthetized dogs using a colored microsphere technique for resistance vessels and a mean circulatory filling pressure method for capacitance vessels. Intravenously (i.v.) infused OPC-18790 increased the first derivative of left ventricular pressure (LVdP/dt max), cardiac output, heart rate and decreased total peripheral resistance but did not affect mean blood pressure. OPC-18790 significantly increased arterial blood flow distribution to heart and decreased vascular resistance in heart. OPC-18790 at 300 μg/kg i.v. and nitroglycerin at 50 μg/kg i.v. did not affect mean circulatory filling pressure in intact anesthetized dogs, but both compounds decreased mean circulatory filling pressure in spinally anesthetized dogs. OPC-18790 also decreased resistance to venous return but nitroglycerin did not. These results suggest that OPC-18790 has both arterial and venous vasodilating actions in addition to its positive Inotropic action. These actions may produce an improvement of cardiohemodynamics in heart failure.
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effects of opc 18790 a new positive Inotropic Agent on energetics in the ischaemic canine heart a 31p mrs study
Cardiovascular Research, 1995Co-Authors: Makoto Ishikawa, Hiroyuki Fujiki, Toyoki Mori, Michiaki Tominaga, Shuji Itoh, Keiko Koga, Youichi YabuuchiAbstract:Objective: Effects of OPC-18790, a novel positive Inotropic Agent, on cardiohaemodynamics and cardiac energetics were assessed simultaneously in dogs with cardiac ischaemia using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and compared with those of amrinone, a pure cGMP-inhibited PDE inhibitor. Methods: Cardiac ischaemia was produced by partial stenosis of the coronary artery. Dogs with cardiac ischaemia were instrumented for the determination of regional coronary blood flow (non-radioactive coloured microsphere method), regional contractile function (sonomicrometry), and haemodynamics. Myocardial phosphate compounds were measured simultaneously by 31P-MRS. Results: Coronary stenosis produced regional dyskinesis, a slight decrease in cardiac output (CO), intracellular acidosis, an increase in the inorganic phosphate (Pi)/creatine phosphate (PCr) ratio concomitantly with a decrease in regional coronary blood flow (CBF) in the ischaemic region. OPC-18790 dose-dependently produced an increase in contractility (measured by peak LVdP/dt) and CO, with only slight changes in heart rate (HR) and mean blood pressure (mBP). OPC-18790 did not change regional dyskinesis, but improved the Pi/PCr ratio at the high dose compared with ischaemic values (before drug administration). Amrinone produced an increase in CO comparable to that of OPC-18790; however, the increase in peak LVdP/dt was smaller while the increase in HR and decrease in mBP were larger than those seen with OPC-18790. Amrinone worsened the Pi/PCr ratio and intracellular acidosis only at the high dose. Conclusion: These observed differences in energy metabolism between OPC-18790 and amrinone at the high dose may be due to the ability of OPC-18790 to increase CBF in the ischaemic region and which may attributed to its differing effect on overall haemodynamics. Thus, OPC-18790 may be useful in the management of ischaemic heart failure.
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Cardiovascular actions of OPC-18790: A novel positive Inotropic Agent with little chronotropic action
Heart and Vessels, 1992Co-Authors: Tetsumi Hosokawa, Hiroyuki Fujiki, Toyoki Mori, Takashi Imaizumi, Michiaki Tominaga, Shizuo Kinoshita, Kazumi Takemoto, Teruo Noda, Makoto Ohura, Youichi YabuuchiAbstract:OPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1 H ) - quinolinone], a novel positive Inotropic Agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10^−6 to 10^−4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive Inotropic effect of OPC-18790 was not affected by β-blockade. OPC-18790 (10^−5 to 10^−4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na^+, K^+-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC_50 = 0.41 × 10^−6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.