Calcium antagonistic and antiarrhythmic actions of CPU‐23, a substituted tetrahydroisoquinoline

Abstract

1 The effects of (1-{1-[(6-methoxyl)-naphth-2-yl]}-propyl-2-(1-piperidine)-acetyl-6,7-dimethyoxy-1,2,3,4-tetra-hydroisoquinoline) were studied on mechanical and electrical activities, and intracellular free calcium ([Ca2+]i) of isolated cardiac tissues in order to investigate its spectrum and mechanisms of action in the heart. Its antiarrhythmic and haemodynamic effects in pentobarbitone-anaesthetized rats subjected to coronary artery ligation were also evaluated. 2 CPU-23 at 10-6 10-4 M markedly inhibited slow action potential characteristics in guinea-pig papillary muscles and pace-maker action potential of rabbit sinoatrial node. It affected fast action potential only at 10-4 M. None of the effects of CPU-23 was reversed by washout for up to 2 h.3 Like nifedipine and diltiazem, CPU-23 decreased the heart rate of the isolated perfused heart of the rat. However, in contrast to these two classical calcium antagonists which dose-dependently inhibited the force of contraction, CPU-23 inhibited and stimulated the force of contraction at 10-7-3 x 10-6 M and 10-5 M, respectively. 4 CPU-23 at 10-6 10-5 M inhibited the KCl-induced [Ca2+], increase in the Ca2" medium, but did not affect the caffeine-induced [Ca21], increase in the Ca2'-free medium in isolated ventricular myocytes. 5 CPU-23 at 1-5 mg kg-' reduced dose-dependently ventricular arrhythmias including ventricular ectopic beats, VT and VF as well as mortality during coronary artery ligation. At 2.5-5 mg kg-' it even abolished VF, which was accompanied by 100% survival. 6 It is suggested that CPU-23 has calcium antagonistic properties in cardiac tissues. It selectively blocks the transmembrane influx of extracellular Ca2" through Ca2" channels, thus reducing the heart rate and developed tension, altering the slow action potential characteristics and producing antiarrhythmic effect against ischaemic arrhythmias.

Cardiovascular effects of CPU‐23, a novel L‐type calcium channel blocker with a unique molecular structure

“…As with previous studies in anaesthetized Sprague-Dawley (SD), spontaneously hypertensive (SHR) and normotensive (WKY) rats (Dong et al, 1992), CPU-23 lowered DBP and SBP; the decrease in SBP was short lived when compared to the decrease in DBP (Table 1). The haemodynamic pro®le of CPU-23 in vivo was consistent with our observations in vitro from cardiac tissue (Dong et al, 1993). Therefore we propose that the cardiodepressant eects of CPU-23 observed in the present study may be due in part to VGCC blockade.…”

“…In addition, CPU-23 inhibited KCl-induced Ca 2+ in¯ux and altered action potential characteristics of myocardial preparations. Consequently, we suggested that the cardiovascular eects of CPU-23 were due primarily to inhibition of calcium in¯ux via speci®c calcium channels, probably L-type VGCC (Dong et al, 1993). In the present study we have explored, in rat tail arterial rings, the mechanisms whereby CPU-23 induces either inhibition of KCl-and PE-induced contraction or vasodilation of a-adrenoceptor agonist-induced tone.…”

Antiarrhythmic Effect of Acupuncture Pretreatment in Rats Subjected to Simulative Global Ischemia and Reperfusion — Involvement of Adenylate Cyclase, Protein Kinase A, and L-Type Ca2+ Channel

“…Ventricular myocytes of male adult Sprague-Dawley rats were isolated using a collagenase perfusion method, as described previously [17]. Immediately after a 60 min perfusion (60 min normal perfusion in the NC and NCEA groups and 10 min normal perfusion + 40 min low flow perfusion + 10 min normal reperfusion in the SGIR and EA groups), the heart was then continuously perfused at a constant flow of 10 .…”

Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion1

“…Preparation of isolated ventricular myocytes Single ventricular myocytes were prepared from the hearts of male Sprague-Dawley rats by enzymatic dissociation [10] . The heart was perfused using a Langendorff apparatus with a 100% oxygenated, non-recirculating Ca…”

“…Loading of cells with Fura-2/AM was carried out as described previously [10] . After stabilization, isolated myocytes were incubated with 1 mmol/L Fura-2/AM at room temperature for 30 min.…”