Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: effects of pimozide, penfluridol, chlorpromazine, and haloperidol.

Abstract

This study was designed to determine whether neuroleptic drugs have calcium channel blocking activity in isolated rings of rabbit thoracic aorta. The results confirm previous findings that pimozide and penfluridol are calcium channel blockers. However, the data do not support the conclusion that these agents are selective for the voltage-sensitive calcium channel. The results also show that both haloperidol and chlorpromazine (which represent different classes of neuroleptic drugs) are also calcium channel blockers in vascular smooth muscle.It has been suggested (1) that neuroleptic drugs of the diphenylbutylpiperidine class (pimozide and penfluridol), which differ from other neuroleptics (phenothiazines and butyrophenones) in their ability to relieve both negative and positive symptoms of schizophrenia, owe their activity to an ability to antagonize voltage-dependent calcium channel activity in the brain. These neuroleptic drugs selectively inhibit the binding of [3H]nitrendipine to a rat cerebral cortical membrane fraction and also competitively antagonize potassium-induced calcium-dependent contractions in rat vas deferens. Inhibition of calcium-dependent contractile activity in smooth muscle can be attributed to effects on calcium-dependent mechanisms within the cell that are independent of calcium influx across the cell membrane (2).To test directly the hypothesis that drugs of the diphenylbutylpiperidine class are calcium influx blockers, we measured their effects on the rates of calcium influx in isolated rings of rabbit thoracic aorta (i) under control conditions, (it) during activation of a receptor-operated calcium channel (ROC) by norepinephrine (NE), and (iii) during activation of the potential-dependent calcium channel (PDC) by potassium chloride. Effects on isometric contractile force also were determined. Pimozide and penfluridol (diphenylbutylpiperidines) were compared to chlorpromazine (a phenothiazine), haloperidol (a butyrophenone), prazosin (an a, adrenergic ROC blocker), nifedipine (a PDC blocker), and lanthanum chloride (a nonselective calcium channel blocker). METHODSAll studies were conducted on tissue taken from male New Zealand White rabbits (2.2-2.4 kg), using previously described methods (3, 4).NE [(-)-arterenol bitartrate; Sigma] was dissolved in 20 ,ul of H20 and used in physiological salt (PS) solution (140 mM NaCl/5.9 mM KCl/1 mM MgCl2/10 mM D-glucose/5 mM Hepes/1.5 mM CaCl2, pH 7.3) containing 1.1 puM ascorbic acid (Hoffmann-LaRoche) to inhibit norepinephrine oxidation (ascorbic acid was added to the stock PS solution before pH adjustment). KCI (Fisher) was dissolved in 400 t.l of Isometric Tension. To record isometric tension, we placed each 3 mm long vascular ring across two stainless steel wires in a chamber containing 20 ml of fresh oxygenated PS solution at 370C. The lower wire was secured firmly to an oxygenator, while the upper wire was connected to a tension transducer. Each vascular ring was adjusted to maintain resting (base-line) tension of 1 g during a 60-min ...

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