Volatile anaesthetics inhibit endothelium-dependent relaxation, but the underlying mechanism(s) have not been clarified. In an attempt to elucidate the mechanism(s), we determined the effects of halothane, isoflurane and sevoflurane on relaxation induced by acetylcholine and sodium nitroprusside (SNP) and the cGMP formation elicited by exogenous nitric oxide (NO) and SNP in rat aortas. Acetylcholine (10(-7)-10(-5) M)-induced relaxation was attenuated by halothane (2%), isoflurane (2%) and sevoflurane (4%). SNP (10(-8) M)-induced relaxation was reduced by halothane (2%), but not by isoflurane (2%) or sevoflurane (4%). The cGMP level of NO-stimulated aorta was reduced by halothane (2%) and sevoflurane (4%), but not by isoflurane (2%). The cGMP level of SNP (10(-7) M)-stimulated aorta was reduced by halothane (2%), but not by isoflurane (2%) and sevoflurane (4%). We conclude that the mechanisms responsible for the inhibition of endothelium-dependent relaxation differ among anaesthetics. Isoflurane inhibits the relaxation mainly by inhibiting the formation of NO in the endothelium. In contrast, the effect of halothane on endothelium-dependent relaxation may be largely due to the inhibition of action of NO in the vascular smooth muscle and the effect of sevoflurane may be to inactivate NO or to inhibit the action of NO.

Effects of amino acid substitutions in the first extracellular loop region of the ~-and p-opioid receptors were examined. Substitution of lysine-108 of the fi-receptor (~K108) with asparagine improved affinity to [D-Ala2,MePbe4,Gly-olSlenk ephalin (DAGO), a p-selective peptide agonist, to be comparable with that of the p-receptor. On the other hand, replacement of raN127 with lysine decreased the affinity to DAGO by ~ 15-fold. These results suggest that dK108 and mN127, which correspond to each other in the aligned amino acid sequences, mainly determine the difference in DAGO binding affinity between the ~-and p-receptors.

Since volatile anesthetics, barbiturates, and local anesthetics have been reported to inhibit endothelium-dependent relaxation, we hypothesized that any drug with anesthetic action would suppress this relaxation. In the present study, using rat thoracic aortae, we attempted to determine whether nonbarbiturate intravenous anesthetics, including midazolam, propofol, and ketamine, suppress endothelium-dependent relaxation, and to clarify the mechanism(s) involved. Acetylcholine-induced, endothelium-dependent relaxation was significantly attenuated by propofol and ketamine, but was unaffected by midazolam. Sodium nitroprusside (SNP)-induced relaxation was attenuated by propofol, but not by midazolam or ketamine. The acetylcholine-stimulated 3',5'-cyclic guanosine monophosphate (cGMP) level was reduced by pretreatment with propofol and ketamine but not by midazolam, and that stimulated by SNP was reduced by propofol but not by ketamine or midazolam. We conclude that propofol and ketamine suppress endothelium-dependent relaxation, whereas midazolam has no influence. Moreover, the suppressive effect of ketamine on endothelium-dependent relaxation is mediated by suppression of nitrous oxide (NO) formation, whereas that of propofol may be mediated at least partly by suppression of NO function.

ABSTRACT-Adrenomedullin is known to induce profound hypotension in vivo, but the direct effect of this peptide on isolated arteries has not been demonstrated. This study estimated the vasodilative effects of adrenomedullin in comparison with those of calcitonin gene-related peptide (CGRP) in basilar, mesenteric, coronary, renal and femoral arteries isolated from the dog. Adrenomedullin (3 to 100 nM) and CGRP (1 to 30 nM) induced concentration-dependent relaxation of these arteries with and without endothelium, and the relaxing effects were slightly greater in endothelium-intact arteries than in denuded ones. The vasodilative potency of adrenomedullin relative to CGRP was smaller in the femoral artery than in basilar, mesenteric, coronary and renal arteries.Keywords: Adrenomedullin, Calcitonin gene-related peptide, Vasodilatation Adrenomedullin was isolated from human pheochromocytoma cells as a peptide to increase cAMP levels in platelets (1), and it has been demonstrated to induce profound hypotension in vivo (1-4). Adrenomedullin shares structural homology with calcitonin gene-related peptide (CGRP) (1, 5), which is one of the most potent vasodilators known (6). Since the effect of adrenomedullin has been demonstrated to be inhibited by a CGRPreceptor antagonist, CGRP , it was first believed that adrenomedullin acts on CGRP receptors to exert its effects (2). However, recent investigations (7, 8) demonstrated adrenomedullin-specific binding sites in vascular smooth muscles, implying important roles of this peptide in the regulation of vascular tone. The findings that the adrenomedullin is secreted from the adrenal medulla (1, 9) and exists in considerable amount in plasma (1) suggested that this peptide works as a circulating hormone. Moreover, formation of adrenomedullin in vascular endothelial cell has been demonstrated recently (10), and it was suggested that this peptide may also act as one of the endothelium-derived regulators of vascular tone.Ishiyama et al. (3), using anesthetized rats, have demonstrated that cardiovascular depression induced by adrenomedullin is mediated mainly by a decrease of peripheral vascular resistance. Experiments using rat mesenteric bed (2), cat hindlimb vascular bed (11) and cat pulmonary vascular bed (12) have also revealed the potent vasodilative effect of adrenomedullin. However, the effect of this peptide on isolated arteries has not been demonstrated. The present study was conducted to evaluate the direct effects of adrenomedullin on the tension of canine peripheral arteries, to compare the effects with those of CGRP. Since effects of vasoactive agents often exhibit differences depending on organs, peripheral arteries including mesenteric, basilar, femoral, renal and coronary arteries were used to test possible organ differences in the vascular effects of these peptides. The experimental protocol was approved by the Kyoto University Animal Use Committee. Nine male mongrel dogs weighing 10-15 kg were anesthetized with ketamine were isolated. They were cut into rings 2-4 m...

Generalized clonic and tonic seizure-like movements were observed during emergence from anesthesia with sevoflurane in a 32-year-old man. The movements lasted 40 sec and necessitated no therapy. There were no significant effects of the incident on the cardiovascular system, such as hypotension, arrhythmia or bradycardia. No neurological abnormalities were obvious after the anesthesia. The movements may have been the result of seizure activity in the central nervous system, or myoclonus of the whole body.