The effects of K(+)-channel blockers on the acetylcholine (ACh)-induced relaxation of vascular smooth muscle, intracellular free Ca2+ concentration ([Ca2+]i) elevation, and ACh-evoked outward K+ current of endothelial cells of rabbit aorta were studied using bioassay, spectrofluorimetry, and patch-clamp techniques, respectively. In bioassay experiments, ACh caused relaxation of endothelium-denuded aortic rings in a concentration-dependent manner when perfused through an endothelium-intact donor segment of aorta but not when perfused directly onto the recipient aortic ring. ACh-induced relaxation was inhibited by perfusion of tetraethylammonium ions (TEA; 5 mM) through the donor but not by perfusion directly onto the recipient segment. Glibenclamide had no effect on ACh-induced relaxation of the bioassay ring in either situation. ACh increased [Ca2+]i at the endothelial surface of aortic strips but not at the adventitial surface. TEA inhibited ACh-induced [Ca2+]i elevation, whereas glibenclamide had no effect. In patch-clamp experiments with freshly isolated endothelial cells, ACh evoked a biphasic outward current which was completely abolished by TEA (3 mM). It is concluded that Ca(2+)-dependent K+ channels are important for increasing [Ca2+]i during agonist stimulation and consequently for the synthesis/release of endothelium-derived relaxing factors (EDRFs). Furthermore, endothelial ATP-sensitive K+ channels do not contribute to ACh-induced relaxation or evoke an increase in endothelial [Ca2+]i of rabbit thoracic aorta.
In parallel with improvements in understanding pain neurophysiology, many chemicals have recently been investigated for spinal anaesthesia and analgesia. However, studies discussing the effects of these drugs on neural tissue indicate that knowledge about some aspects of neurotoxicity is limited. Forty-nine New Zealand albino rabbits, weighing 2.2±0.2 kg, were randomly assigned to seven groups of seven animals each. Single dose groups received intrathecally through the atlantooccipital membrane 0.9% saline 1.5 ml; midazolam 100 µg/kg (low dose midazolam group) or 500 µg/kg (high dose midazolam group); neostigmine 10 µg/kg (low dose neostigmine group) or 50 µg/kg (high dose neostigmine group). Two groups had seven days of repeated dosing with either midazolam 100 µg/kg/day (repeat midazolam group) or 10 µg/kg/day neostigmine (repeat neostigmine group). The animals were sacrificed on day 8, and two spinal cord sections from the fourth cervical level and fourth lumbar level were removed and prepared for histopathological study. Transmission electron microscopic evaluations were performed on transverse spinal cord sections by a neuropathologist blinded to the group allocation. Twenty myelinated axons and neurones in the cervical and lumbar sections were investigated for the histopathological study. This study indicates that midazolam and neostigmine have different neurotoxic effects that depend on the dose and the repetition of dosing when these drugs are administered intrathecally.
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