Modulation of Anti-Glomerular Basement Membrane Nephritis in Rats by ONO-1301, a Non-Prostanoid Prostaglandin I2 Mimetic Compound with Inhibitory Activity against Thromboxane A2 Synthase

Article

Author: Kohtarou Kodama ; Hideyuki Adachi ; Toshiaki Ogawa ; Hideto Ohhara

We compared the antianginal effect of E4080, a novel bradycardiac agent with coronary vasodilating properties, with those of a bradycardiac agent and some coronary vasodilators in vasopressin-induced anginal model of guinea pigs. An i.v.-administration of vasopressin (0.2 IU/kg) produced an ST segment elevation on electrocardiograms (ECG) of 0.30 +/- 0.05 mV from the baseline within 30 sec in anesthetized guinea pigs. The ST segment elevation on ECG was used as an index of myocardial ischemia. E4080 and other drugs were injected i.v. 5 min before the administration of vasopressin. E4080 at 5 mg/kg depressed the ST segment elevation induced by vasopressin to 0.06 +/- 0.01 mV (20% of control, n = 6, P < 0.001). However, alinidine (5 mg/kg), which produced the same bradycardic action (reduction of heart rate by 50%) as that of E4080, tended to inhibit the ST segment elevation, but this was not statistically significant. On the other hand, other vasodilators such as isosorbide dinitrate (0.3 mg/kg), nifedipine (0.1 mg/kg) and lemakalim (1 mg/kg) also significantly reduced the ST segment elevation to 0.16 +/- 0.03, 0.08 +/- 0.04 and 0.09 +/- 0.03 mV, respectively. These results suggest that the inhibitory effect of E4080 on the ST segment elevation induced by vasopressin is due to the coronary vasodilating effect rather than the bradycardiac effect, and that E4080 would be useful as an antianginal agent.

01 Jan 1994·The Journal of pharmacology and experimental therapeutics

Effects of E4080, a novel bradycardic agent with a coronary vasodilating property, on coronary and systemic hemodynamics in conscious dogs.

Article

Author: Adachi, H

The effects of E4080 ((E)-N-[3-((N'-(2-(3,5-dimethoxyphenyl)-ethyl)-N'- methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl)-phenyl)-3-butenamide dihydrochloride dihydrate), a novel bradycardic agent with a coronary vasodilating property, on coronary and systemic hemodynamics were compared with those of pinacidil and nifedipine in chronically instrumented conscious dogs. A pair of piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery. Intravenous infusions of 30, 100 and 300 micrograms/kg/min of E4080 at 30-min intervals to six conscious dogs increased coronary blood flow and decreased total coronary resistance in a dose-dependent fashion, whereas coronary diameter tended to be increased. Although E4080 at a rate of 300 micrograms/kg/min decreased maximally mean aortic pressure by 27 +/- 3% (n = 6, P < .05 vs. base-line value), there was no significant change in the maximal rate of rise in left ventricular pressure or heart rate. Both pinacidil (3, 10 and 30 micrograms/kg/min) and nifedipine (1, 3 and 10 micrograms/kg/min) also tended to increase coronary diameter, and caused an increase in coronary blood flow and decreases in mean aortic pressure and total coronary resistance. In contrast to E4080, however, these changes caused by pinacidil and nifedipine were accompanied by a marked increase in heart rate. All of the drugs tested produced a significant and dose-dependent increase in plasma noradrenaline level. It is concluded that E4080 produces coronary and peripheral vasodilation, without inducing a reflex tachycardia despite sympathetic neural activation. These results suggest that E4080 exerts actions on the cardiovascular system which may be useful in the treatment of angina pectoris.

01 Dec 1993·European Journal of PharmacologyQ3 · MEDICINE

Selective inhibition by E4080, a novel bradycardic agent, of positive chronotropic responses to norepinephrine in isolated dog hearts

Q3 · MEDICINE

Article

Author: Takeshi Oguchi ; Shigetoshi Chiba ; Yasuyuki Furukawa ; Shoji Sawaki ; Yasurou Inoue

E4080, a novel bradycardic agent acts on various ionic currents including the hyperpolarization-activated inward current (I(f)), L-type Ca2+ current (ICa) and ATP-sensitive K+ (K+ATP) current in mammalian heart and vascular tissues. We thus investigated the chronotropic and inotropic effects of E4080 and its interaction with the positive cardiac responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left ventricles. E4080 (0.01-1 mumol) decreased the sinus rate and atrial and ventricular contractile forces in a dose-related manner. Glibenclamide (3 mumol) partly blocked the decrease in atrial force but not the decreases in sinus rate and ventricular force induced by E4080. Atropine (10 nmol) did not affect the negative cardiac responses to E4080. E4080 (0.01-1 mumol) inhibited the positive chronotropic responses to norepinephrine and IBMX dose dependently, but did not inhibit the positive inotropic ones in isolated atria. E4080 affected neither positive chronotropic nor inotropic responses to Bay k 8644. These results suggest that (1) the activation of K+ATP channels by E4080 is partly related to the decrease in atrial force but not the decreases in sinus rate and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotropic ones is probably due to the inhibition of I(f) rather than other properties, e.g., activation of K+ATP channels and inhibition of ICa in the dog heart.

100 Deals associated with E-4080

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	Preclinical	JP	Eisai Co., Ltd.	-
Arrhythmias, Cardiac	Preclinical	JP	Eisai Co., Ltd.	-

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