INVITRO EVALUATION OF THE ACTION OF CHLOROQUINE AND RELATED COMPOUNDS ON CONTRACTILE PROCESSES IN SMOOTH MUSCLE

Abstract

In this study, the effect of chloroquine on the contractions of isolated guinea-pig ileum (GPI), rat stomach strip (RSS), and endothelium free-rat aortic is strip (RAS) were investigated. These muscles exhibit contractions suggesting differences in sources of activator calcium. The main agonists used were histamine (HIS), Acetylcholine (ACH), Noradrenalin (NA) and Potassium (K+). A wide range of doses of CQ were used. The following drugs were also investigated: Amodiaquine (AMDQ), Mepacrine (MPC), Quinine (QUIN), Halofantrine (HFT) and Mefloquine (MFO), in order to examine the pattern, if any, of structure-action relationships. The effect of CQ on Ach induced contractions ranged from a potentiation in low CQ concentrations (10-12 -10-7M), to inhibition at concentrations > 10-5M. In this regard, drugs were classified into groups: I. CQ, AMDQ, MPC, QUIN, which consistently potentiated and inhibited at low and high concentrations respectively. II. HFT and MFQ, which showed neither marked potentiation nor inhibition. Potassium induced contractions were less affected by CQ than receptor mediated contractions. Varying the concentrations of Ca2+ in the physiological salt solution (PSS) bathing the muscle, greatly affected the action of CQ. In the RSS, Group I compounds at (10-7M) potentiated ACH-induced contractions in PSS containing 1.8mM Ca2+ while the inhibitory effect of concentrations > 10-5M was enhanced. Similar effects were observed in GPI and RAS. Thus potentiation of agonist contraction decreased in parallel with decrease in external Ca2+, whereas inhibitory effects increased. In PSS containing zero calcium and 0.5mM EGTA, contractions in GPI rapidly disappeared whereas in RSS and RAS residual contractions persisted. Low doses of antimalarial failed to potentiate the residual response but high doses completely abolished it. The action of CQ in RAS, pre-contracted with NA or K+ was studied. The relaxant effect of CQ was more marked on NA- than K+ induced contractions. This effect was unaffected by methylene blue (10-3M). Thus the mechanism of the relaxant action of CQ in RAS was unlike those of Ca2+ channel blockers or sodium nitroprusside. The possibility of the relaxant effect being due to K+ channel opening was investigated. The results suggested that K+ channel opening is not an adequate explanation for this action of CQ in RAS. These results show that : a) Two sites of action for CQ in smooth muscle. One site is the muscle-cell membrane where it may facilitate Ca2+ influx: this effect is more marked on receptor mediated than K-induced responses. The other site is intracellular, where the effect is observed at higher concentrations of antimalarial and manifests as inhibition of agonist contractions. b) The relaxant effect of CQ in arteries was most likely not due to calcium channel blockade nor opening of K+ channels: CQ probably interacted with intracellular contractile mechanism; c) The effect of CQ on muscle contraction depends on muscle type, agonist used, and the concentration of Ca2+ in the bathing fluid. These findings suggest that vascular relaxation by CQ may contribute to the cardiovascular collapse encountered with chloroquine therapy.