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PubMed1987

Mode of vasorelaxing action of 5-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate (KT-362), a new intracellular calcium antagonist.

In rabbit aorta, pretreatment with KT-362 (KT; 10(-6) and 10(-5) M) inhibited contractile responses to norepinephrine (NE; 3 X 10(-9)-10(-5) M) and methoxamine (10(-7)-10(-4) M) but failed to affect responses to potassium (10-70 mM). KT (10(-5) M) partially inhibited Ca++-induced contractions in K+-depolarized aorta pre-equilibrated in a Ca++-free medium. After incubation of tissues for 30 min in a Ca++-free medium containing EGTA (0.2 mM), residual responses to NE and methoxamine were inhibited by KT (10(-6)-10(-4) M) and nitroglycerin (10(-5) M), but not by nifedipine, verapamil or diltiazem (all 10(-5) M). The inhibitory action of a combined treatment with KT and nitroglycerin (both 10(-5) M) on the residual response to NE was also much greater than that of either agent alone. In a Ca++-free medium, the residual caffeine-induced contraction of rabbit iliac artery was inhibited by KT (10(-5)-10(-4) M) but not by nifedipine (10(-5) M). The inhibitory action of KT on the residual responses to methoxamine and caffeine in a Ca+-free medium was much greater than that of nitroglycerin. In a Ca++-free medium with low EGTA (0.01 mM), D600 (10(-5) M) and NE (3 X 10(-7) M), the addition of Ca++ (2 mM) resulted in a tonic contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Pharmacologic profile of fezolamine fumarate: a nontricyclic antidepressant in animal models.

Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.

Animals↗
PubMed1979

Cardiovascular profile of 2-(3,4-diethyoxy-beta-methoxyphenethyl) imino-1-methylpyrrolidine fumarate (McN-2840-46), a preferential atrial anti-arrhythmic agent.

McN-2840-46, 2.5 mg/kg, i.v., protected against atrial tachyarrhythmias induced by three different methods in dogs and monkeys. The compound was inactive against ventricular arrhythmias produced by ouabain and by chloroform-epinephrine interaction at a four-fold higher dose. Significant reversal of ventricular arrhythmias produced by occlusion of the left anterior descending coronary artery in dogs was achieved by infusion of 8.8 +/- 2.4 mg/kg, i.v. of McN-2840-46. Myocardial electrogram studies confirm that the atrium is preferentially affected. McN-2840-46 does not possess beta 1- or beta 2-adrenergic blocking activity when evaluated on isolated rabbit atrial and guinea-pit tracheal chain preparations. McN-2840-46 is vagolytic but not anticholinergic. The vagolytic activity is attributed to its local anesthetic effect. Depression of myocardial function was observed in anesthetized dogs and in the heart-lung preparation. However, the isolated cat papillary muscle was stimulated by McN-2840-46 and doses considerably above the effective anti-arrhythmic dose did not significantly decrease cardiac output in the non-anesthetized dog. The results of these experiments suggest that McN-2840-46 is a potent "preferential" atrial anti-arrhythmic agent.

Acetylcholine↗