Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat

Abstract

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. 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. 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. 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. 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.

Plasma Concentration and CNS Effects of Ca Antagonists Darodipine and Nimodipine after Single-Dose Oral Administration to Healthy Volunteers

“…Inferentially, this observation also suggests possible interpretations for conflicting pharmacological effects obtained under similar treatment conditions and at apparently comparable drug doses. The observed EEG effects are qualitatively comparable to those reported in studies on animals or healthy volunteers [3,[23][24][25][26] and appear common to pharmacologically diverse (and often chemically unrelated) compounds interacting with voltage-operated Ca channels [41]. The differences among Ca channels that exist at the cellular level [42] are unlikely to be reflected in mass electrophysiological CNS activities such as the EEG, while the uneven brain regional distribution of binding sites and Ca uptake [43] may either account for the topographic distributions of the EEG effects of compounds with shared mechanism(s) of action or reflect drug action at selected CNS structures/subsystems.…”

“…Altered cellular calcium homeostasis and calcium overload are critical events in the pathogenesis and propagation of ischemic cell injury [1][2][3]. Some therapeutic efficacy of slow calcium channel blockers on symptoms of ischemic heart disease or in the treatment of patients with subarachnoid hemorrhage is indicated [4][5][6][7].…”