Abstract

Equimolar doses of two antimalarial agents, chloroquine diphosphate (CQ; WR-1544) and bis[(chloro-7"-quinolyl-4") amino-2'propyl]-1,4-piperazine (RP-12278; WR-3863), produced quantitatively similar neuromuscular blockades in the rabbit gastrocnemius preparation. In this animal, RP-12278, but not CQ, was found to produce apnea. In the rat phrenic nerve-diaphragm preparation, both CQ and RP-12278 produced complete neuromuscular blockade at concentrations as low as 1O^-5 M. CQ depressed muscle contractions immediately in nerve-stimulated preparations and later in muscle-stimulated preparations. When RP-12278 was added to the bath, a proteinaceous foam appeared, accompanied by an increase in muscle contractility and a contracture. As the contracture developed, contractions lessened and finally disappeared. The RP-12278-induced contracture was found to be dose-related and produced by a direct effect on the diaphragm. This effect was not acetylcholine-like, since the stimulatory effect of RP-12278 was not blocked by neuromuscular antagonists (d-tubocurarine, 10^-4 M; succinylcholine, 10³ M), nor did RP-12278 produce an acetylcholine-like effect on the isolated rabbit ileum. Neither K⁺-nor Mg⁺⁺-free Tyrode's affected the RP-12278 contracture. On the other hand, Ca⁺⁺-free Tyrode's completely blocked the RP-12278 contracture. The effects of RP-12278 on stimulated and nonstimulated diaphragms bathed in Ca-free Tyrode's for different intervals were measured. The stimulating effects of RP-12278 disappeared in stimulated muscle before they disappeared in nonstimulated muscle, suggesting that RP-12278 may produce its action by releasing bound intracellular calcium.