Effects of Ca2+ Sensitizers on Contraction, [Ca2+]i Transient and Myofilament Ca2+ Sensitivity in Diabetic Rat Myocardium: Potential Usefulness as Inotropic Agents

Article

Author: Kemmotsu, O ; Sakuraya, F ; Onozuka, H ; Hattori, Y ; Matsuda, N ; Gando, S ; Makino, T ; Ishitani, T

The purpose of the present study was to investigate the effects of Ca2+ sensitizers EMD 57033, MCI-154, and EGIS-9377 in cardiac preparations from streptozotocin-induced diabetic rats. In enzymatically dissociated ventricular myocytes loaded with the Ca2+ probe indo 1, these Ca2+ sensitizers caused an increase in cell shortening without a significant effect on the intracellular Ca2+ ([Ca2+]i) transient. The contractile responses were substantially similar in myocytes from diabetic and age-matched control rats. In contrast, the contractile and [Ca2+]i responses to pimobendan and isoproterenol were significantly less in diabetic myocytes. The Ca2+ sensitivity of tension in beta-escin-skinned trabeculae from diabetic hearts was not significantly different from that of controls. The effect of EMD 57033 on myofilament responsiveness to Ca2+ was identical in control and diabetic preparations. The slower time course of relaxation observed in diabetic papillary muscles was further prolonged in the presence of EMD 57033. However, the extent of the increase in relaxation produced by EMD 57033 did not differ between control and diabetic muscles, and the detrimental effect on resting tension was less pronounced in the two groups. In anesthetized rats, echocardiography showed that intra-duodenal administration of EMD 57033 increased left ventricular systolic function without affecting variables of diastolic filling in both groups. Taken together, the present results suggest that Ca2+ sensitizers, unlike conventional inotropic agents, have the potential to increase in force of contraction to the same extent in nondiabetic and diabetic myocardium, possibly without exaggerating extremely the impairment of diastolic function in diabetes.

01 Feb 2000·Coronary Artery DiseaseQ4 · MEDICINE

Effects of pimobendan and EGIS 9377, cardiotonic agents, and OG-VI, a nucleoside–nucleotide mixture, administered during reperfusion after ischemia on stunned myocardium in dogs

Q4 · MEDICINE

Article

Author: Ogoshi, S ; Ichihara, K ; Satoh, K ; Fukutomi, T

BACKGROUNDPimobendan is a so-called calcium sensitizer that exerts a positive inotropic action. EGIS 9377 is synthesized as a calcium sensitizer. OG-VI is a nucleoside-nucleotide mixture that ameliorates the myocardial dysfunction (myocardial stunning) after ischemia.OBJECTIVETo determine whether administration of these agents after the onset of reperfusion after ischemia improves the condition of stunned myocardium.METHODSDogs anesthetized with pentobarbital were subjected to 20 min ligation of left anterior descending coronary artery and then 60 min reperfusion. The corresponding vehicle, 0.3 and 1 mg/kg pimobendan, or 1 and 3 mg/kg EGIS 9377 was injected intravenously 30 min after the onset of reperfusion. Saline solution or 1.2 mumol/kg per min OG-VI was infused for 30 min, starting 30 min after the reperfusion. Shortening of myocardial segment was measured by sonomicrometry. The tissue levels of energy and carbohydrate metabolites in the 60 min-reperfused hearts were determined.RESULTSShortening of myocardial segments significantly decreased during ischemia, and returned toward preischemic level after reperfusion for all groups, although the contractile dysfunction still remained. Injections and infusion of pimobendan, EGIS 9377, and OG-VI after the onset of reperfusion ameliorated the contractile dysfunction. Systemic vascular resistance was decreased by administrations of pimobendan and OG-VI. The levels of high-energy phosphates in 60 min-reperfused heart were not changed by either treatment.CONCLUSIONAdministration of pimobendan, EGIS 9377, and OG-VI ameliorate the myocardial contractile dysfunction after ischemia even when these agents are administered after the onset of reperfusion. The increase in contractile function due to these agents did not worsen the myocardial energy balance.

01 Jan 2000·Progress in Experimental Cardiology

Ca2+ Transients, Contractility, and Inotropic Responses in Rabbit Volume-Overloaded Cardiomyocytes

Author: Sugawara, Hiromi ; Endoh, Masao ; Atsumi, Hiroyuki ; Tomoike, Hitonobu ; Nakada, Shigekazu ; Sakurai, Kiyoharu ; Watanabe, Tomoo

Left ventricular hypertrophy occurs as an adaptation prior to chronic congestive heart failure caused by pressure or volume overload.We examined the modulation of the effects of Ca²⁺ sensitizers, namely, Org 30029 [N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride] and JTV-704 (EGIS-9377) [2-(1-methylthio)-5-(2-morpholinoethylamino)-8,9-dihydro-7H-thiopyrano [3,2-d] [1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride], in comparison with those of β-adrenoceptor agonists in cardiomyocytes isolated from volume-overloaded rabbits.We isolated ventricular cardiomyocytes by means of collagenase perfusion 12 wk after the shunt formation, when ventricular weight, aortic flow, left ventricular pressure, and diastolic pressure had been increased significantly.Cell shortening and Ca²⁺ transients were measured in cardiomyocytes loaded with indo-I.In cardiomyocytes isolated from the volume-overloaded heart, cell length and width were increased proportionally.The duration of Ca²⁺ transients and cell shortening was significantly prolonged in volume-overloaded cardiomyocytes compared with that in normal (isolated from sham-operated rabbit) cardiomyocytes.The response of Ca²⁺ transients and cell shortening to the Ca²⁺ sensitizers, namely, Org 30029 and JTV-704, was unaltered in volume-overloaded cardiomyocytes.By contrast, the response to dobutamine and isoproterenol was significantly attenuated in volume-overloaded cardiomyocytes compared with the response in normal cardiomyocytes.These results indicate that in volume-overloaded rabbit cardiomyocytes, the response to the Ca²⁺ sensitizers was maintained when the responsiveness to β-adrenoceptor stimulation had been reduced, an indication that the Ca²⁺ sensitizer may be beneficial for improvement of contractile dysfunction even when β-agonists lose their effectiveness in volume-overloaded cardiomyocytes with hypertrophy.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Preclinical	Japan	-	-
Heart Failure	Preclinical	Japan	-	-

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