Effects of Chlorpromazine, Imipramine, and Quinidine on the Mechanical Activity of Single Skeletal Muscle Fibres of the Frog

Abstract

ANDERSSON, K.-E. Effects of chlorpromazine, imipramine, and quinidine on the mechanical activity of single skeletal muscle fibres of the frog. Acta physiol. scand. 1972. 85. 532-546. Chlorpromazine ( 8~ 10-0-3 x M), imipramine, and quinidine (5x 10-j-10-4 M )prolonged the relaxation phase of potassium induced contractures in single skeletal muscle fibres of the frog without affecting the maximum tension amplitude. These drugs also shifted the curve, which relates peak contracture tension to external potassium concentration, to lower potassium values and lowered the mechanical threshold. This is in contrast to other membrane stabilizers such as tetracaine, cocaine, and procaine, which have been reported to shift the curve to higher potassium values and .to increase the mechanical threshold. In high concentrations, chlorpromazine (lo-* M), imipramine, and quinidine (> M) produced slowly developing and only partially reversible contractures. Similar contractures could be evoked in fibres that were depolarized in isotonic potassium methyl sulphate solution and in fibres that had been soaked for 10-30 min in a calcium-free medium. The results support the idea that the contractile effects produced by chlorpromazine, imipramine, and quinidine are mediated by action upon intracellular calcium storing structures.

On the calcium receptor activating exocytosis: inhibitory effects of calmodulin‐interacting drugs on rat mast cells.

“…Moreover, our findings that thioridazine inhibits exocytosis by a non-competitive action and that high Ca fails to overcome the inhibition of exocytosis parallel observations on contraction in smooth muscle (Hidaka, Asano, Iwadare, Matsumoto, Totsuka & Aoki, 1978;Crosby & Diamond, 1980) and calmodulin in vitro (Weiss et al 1980). It may be noted further that the various drugs we tested bind rather selectively to calmodulin (Weiss et al 1980): by way of illustration, they bind only weakly to the Ca-receptive protein of striated muscle, troponin C Weiss et al 1980), and this is reflected in the refractoriness of contraction in striated muscle to inhibition by the phenothiazines (Andersson, 1972;Kerrick et al 1981). On these various grounds, the target of 241 neuroleptic drugs and W-7 in the mast cell seems likely to be some Ca-binding protein that closely resembles calmodulin if it is not calmodulin itself: and the results can be taken as indicating the involvement of this protein as the Ca receptor activating exocytosis in the mast cell.…”

Calmodulin‐antagonist Drugs and Porcine Malignant Hyperpyrexia

“…Due to the hydrophobic nature of calmodulin-antagonists (Seeman 1977;Levin & Weiss 1979), non-specific effects must also be considered. These effects may include disruption of sarcoplasmic reticulum Ca2+ transport (Balzer et al 1968;Balzer & Hellenbrecht 1969;Anderson 1972;Collins et al 1987) and effects on the contractile proteins themselves (Levin & Weiss 1978;Takagi 1981).…”

Pharmacological Investigations of Excitation‐Contraction Coupling

“…Furthermore quinidine lowers the contractile threshold for K contractures in frog single muscle fibers (12). Thus the active state is prolonged by two mechanisms, one affecting the duration of the action potential and the other affecting the contractile threshold.…”

“…At a concentration of 5 X 10-5 M it prolongs the time course of K contractures of single muscle fibers; at 3 X 10-3 M it effectively elicits quinidine contractures whose peak tension amounts to about one half of tetanic tension. The quinidine contractures occur whether the fibers are depolarized by high K concentrations or bathed in a Ca-free medium (12). Quinine at 1 mM induces twitch potentiation in whole frog muscle and causes a marked increase in Ca outflow and uptake (174).…”

“…Figure 7 shows how it can be shortened in the presence of low Ca 2 + concentrations or local anesthetics. High Ca 2 + concentrations (122,201) or drugs like caffeine (52), imipramine (12), and La (see Lanthanum, p. 400) can also prolong the responses, indicating that the exhaustion of a fixed store of activator does not determine the spontaneous relaxation during a K contracture, since the amount released can be modulated in different ways. Another explanation of the transient nature of these prolonged responses is that Ca release is activated when the fibers are depolarized and then is inactivated at a rate dependent on the membrane potential (51).…”