Hemodynamic and Myocardial Energetic Effects of CK-3197, a Selective Positive Inotropic Agent

Touhey

Hom

1991

Greenberg, S., 6. Touhey, and G. Horn: Ouabain pretreatment does not compromise the hemodynamic and myocardial energetic effects of CK-3197, a selective positive inotropic agent, in dogs with propranolol-induced heart failure. Drug Dev. Res. 22:37-50, 1991. We examined the interaction between ouabain and CK-3197, a new selective positive inotrope, on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol-induced heart failure (PIHF). Mongrel dogs (13-18 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i.v.) and instrumented for routine hemodynamic measurements using an open-chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dP/dT max by 50% from control values with an initial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2 ml, i.v., n = 8/group) or ouabain (25 Fg/kg, i.v., n = Wgroup). Thirty minutes later one-half of the

Section: Effects On Blood Flows and Vascular Resistancesmentioning

confidence: 99%

Ouabain pretreatment does not compromise the hemodynamic and myocardial energetic effects of CK‐3197, a selective positive inotropic agent, in dogs with propranolol‐induced heart failure

Touhey

Hom

1991

“…The narrow therapeutic margin between efficacy and toxicity for digitalis glycosides, the only selective positive inotropic agents approved for the treatment of congestive heart failure, has resulted in the development of non-digitalis, non-catecholamine compounds, such as amrinone, milrinone, enoximone, piroximone, and OPC-8212, as potential replacements for the digitalis glycosides [Alousi et al, 1983;Braunwald et al, 1979;Einzig et al, 1983;Greenberg and Touhey, 1990b,c;Greenberg et al, 1989a,b;Mikulic et al, 1977;Siegl, 1986;Steffen et al, 19861. However, most of these compounds, if not all, have exhibited vasodilator activity which may partially or completely account for their beneficial effects in this family of diseases [Alousi and Johnson, 1986;Braunwald et al, 1979;Einzig et al, 1983;Greenberg et al, 1990d;Mikulic et al, 1977;Siegl, 1986;Young and Ward, 19881. CK-2130 ( Fig. 1) was developed as a cardiotonic agent for the treatment of congestive heart failure.…”

Section: Introductionmentioning

confidence: 99%

General pharmacology of CK‐2130: A new selective positive inotrope

Paul

Luisi³

1990

CK-2130 is a new imidazolone developed to treat congestive heart failure. We compared CK-2130 to four inodilators and ouabain in several pharmacologic models. Intravenous (i.v.) administration of CK-2130 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) relatively selectively increased myocardial dP/dT when compared to the dual positive inotropic and vasodilator activity of milrinone, enoximone, imazodan, and piroximone. Milrinone and piroximone (600 mg/kg, P.o., and 30-300 mg/kg, i.p.) were central nervous system depressants in mice. CK-2130 (100 mg/kg, i.v. and 600 mg/kg, i.p. and p.0.) was not depressant. Gastric acid secretion in the guinea pig was not affected by CK-2130 (1 mg/kg, i.v.) and was inhibited by milrinone (1 mg/kg, i.v.) and enhanced by enoximone (1 mg/kg, i.v.). CK-2130 and milrinone (0.03-1 mg/kg, i.v.) did not affect rabbit sciatic nerve-gastrocnemius muscle function. CK-2130, piroximone, imazodan, and milrinone (100 pM) did not affect sympathetic neurotransmission, postsynaptic receptors, or guinea-pig nonvascular smooth muscles but relaxed canine arteries and veins. Ouabain (1-100 KM) initially facilitated, then inhibited, sympathetic neurotransmission, contracted vascular and non-vascular smooth muscles, enhanced the vas deferens contraction to norepinephrine, and inhibited uterine contractions to bradykinin (10 ELM). CK-2130, milrinone, piroximone, and imazodan (0.1 to 100 p,M) inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. Thus, CK-2130, a relatively selective positive inotrope, should be devoid of adverse central nervous system; neural, smooth, and skeletal muscle; and gastrointestinal side effects associated with digitalis and enoximone therapy.

Hemodynamic profile of the new cardiotonic agent CK‐2289 compared to milrinone and enoximone in the anesthetized dog

Paul

Touhey

1991

Greenberg, S.S., J. Paul, and B. Touhey: Hemodynamic profile of the new cardiotonic agent CK-2289 compared to milrinone and enoximone in the anesthetized dog. Drug Dev. Res. 23:109-126. 1991. We examined the hemodynamic profile of CK-2289, a new imidazolone developed for the treatment of congestive heart failure, in the normal pentobarbital-anesthetized dog. Mongrel dogs (10-18 kg) of either sex were anesthetized with pentobarbital sodium (35 mgikg, intravenously [i.v.]) and instrumented for routine hemodynamic measurements using an open-chest, artificially ventilated preparation. Intravenous administration of CK-2289 (3, 10, 30, and 100 pg/kg) to pentobarbital-anesthetized dogs increased left ventricular (LV) dP/ d T , , by 9, 26, 73, and 80%, respectively, and decreased mean arterial pressure (MAP) by 2, 6, 18, and 34%. CK-2289 was 2.7 times more potent as a positive inotropic agent than as a vasodilator. Heart rate (HR) increased by 2, 10, 18, and 28% after these doses of CK-2289, while left ventricular end diastolic pressure (LVEDP) decreased by 4.5 mmHg after the highest dose of compound. CK-2289 increased coronary blood flow (CBF) after each dose of compound. However, the increased CBF was less than that produced by milrinone for equivalent increases in LV dP/ dT, , , .Renal blood flow increased while vertebral blood flow was reduced after administration of the two highest doses of CK-2289. However, vertebral vascular resistance decreased slightly from control values. Milrinone and enoximone behaved qualitatively similar to, but were 6 and 27 times less potent than