Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat.
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1. The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded. 2. Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and 'background-EEG'. Drugs were administered i.v. 5 min before the onset of hypoxia. 3. Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses. 4. At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear-cut ventilatory drive did not occur with the other ineffective slow channel inhibitors. 5. It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect. (+info)
Comparative studies of cerebral vasodilators on relaxation activities in isolated basilar, mesenteric and pulmonary arteries of rabbits.
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Effects of cerebral vasodilators such as bencyclane, cinnarizine, and papaverine were comparatively studied using helically cut basilar and superior mesenteric arteries and radial muscle preparations of pulmonary arteries with the sympathetic nerve isolated from rabbits. The order of relaxation activities on high K+-induced contractures was cinnarizine>bencyclane>papaverine in basilar strips and cinnarizine>papaverine>bencyclane in mesenteric strips. Relaxation responses of basilar strips to cinnarizine and bencyclane were faster and more marked than those seen in mesenteric strips. Responses to papaverine were equipotent in both preparations. The action of cinnarizine alone was irreversible. In mesenteric strips, the order of the sensitivity of contractile responses to cumulatively applied biogenic amines was serotonin>noradrenaline>histamine. Cinnarizine produced an antihistaminergic action, while bencyclane produced an antiserotonergic action. In pulmonary arteries, 6 x 10(-6) g/ml papaverine inhibited contractile responses to 2, 5, and 25 Hz nerve stimulation in a frequency-independent manner together with inhibition of responses to noradrenaline. Bencyclane at 6 x 10(-6) and 10(-5) g/ml selectively inhibited in a dose-dependent manner contractile responses only to 25 Hz without inhibition of responses to noradrenaline. These results were discussed in comparison with findings of the cerebral vasodilators obtained using other experimental techniques. Spiral strips of basilar arteries from rabbits in combination with peripheral arteries may be used as a simple quantitative, and reproducible screening method in a preclinical stage for drug evaluation of cerebral vasodilators. (+info)