Cutaneous arterial and venous alpha receptor blocking activity following intraduodenal indoramin to dogs

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.

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

Paul

Luisi³

1990

CK‐2289 and milrinone in dogs with propranolol‐induced heart failure: Effect of ouabain

Touhey

Hom³

1991

Self Cite

Greenberg, S.S., B. Touhey, and G. Horn: CK-2289 and milrinone in dogs with propranolol-induced heart failure: Effect of ouabain. Drug Dev. Res. 22:273-292, 1991. We examined the interaction between ouabain and CK-2289, a new bivalent inodilator, and compared their effect with that of milrinone on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol-induced heart failure (PIHF). Mongrel dogs (13-19 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, , , 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 = 12igroup) or ouabain (25 pg/kg, i.v., n = 12/group). These studies were performed in accordance with the Guide for the Care and Use ofLaboratory Animals as adopted by the US Department of Agriculture. Berlex is an accredited member in good standing of American Association of Laboratory Animal Care.Abbreviations used: MAP, mean arterial pressure; CO, aortic flow; TPR, total peripheral resistance; CVR, coronary vascular resistance; HR, heart rate; dP/dT,,, and the maximum rate of rise and rate of relaxation of the left ventricular pressure pulse; CBF, coronary blood flow, SCBF, coronary blood flowibeat; MVO,, myocardial oxygen utilization; SMO,, myocardial oxygen utilization/beat; CHF, congestive heart failure; PIHF, propranolol-induced heart failure; LVEDP, left ventricular end diastolic pressure; PAP, pulmonary artery pressure.0 1991 Wiley-Liss, Inc. 274Greenberg et al. CK-2289MlLRlNONE Thirty min later saline and ouabain-treated animals (4Igroup) were given 2 doses of saline (1 and 2 ml, i.v.), CK-2289 (0.01 and 0.03 mg/kg, i.v.) or milrinone (0.03 and 0.1 mgikg, i.v.) 30 min apart. Hemodynamic parameters were monitored continuously. Myocardial oxygen consumption (MVO,) was monitored 15 and 30 min after each dose cf drug. CK-2289 increased LV dP/ dT, , , and LV dP/dTmi, by 60 and 120% and 42 and 43%, respectively.Mean arterial pressure decreased by 12% after the high dose of CK-2289. CK-2289 did not affect heart rate, while LV end diastolic pressure decreased by 5 mmHg. CK-2289 increased LV work and did not affect or decrease LV contractile efficiency. Ouabain enhanced the myocardial energetic profile of CK-2289 by allowing CK-2289 to stimulate more work at a lower MVO,, thereby increasing myocardial efficiency. Milrinone had a profile similar to CK-2289 but in ouabain-pretreated animals with PlHF milrinone stimulated less work at the same MVO,, thus decreasing contractile efficiency. Thus, ouabain may enhance the myocardial energetic effects of CK-2289.

General pharmacology of CK‐1649C: A new quaternary class III antiarrhythmic agent

Luisi

Long

et al. 1992

CK-1649C is a new quaternary ammonium class Ill antiarrhythmic agent undergoing clinical trials. The side effect profile of a class Ill antiarrhythmic agent is generally unknown. This study compared CK-1649C with quinidine and lidocaine (class I), acecainide (class l/lll), and clofilium (class Ill), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK-1649C was devoid of neuropharmacologic activity in the mouse and rat. CK-I 649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenaninduced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK-1649C was devoid of activity on transmural nerve stimulation and did not exhibit a,-muscarinic, nicotinic, or p-adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK-1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water-loaded dogs. CK-1649C (30 mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK-1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic doses of 1-3 mg/kg in man.