Japanese journal of pharmacology
-
Although improving energy metabolism in ischemic brain has been accepted for the treatment of cerebrovascular diseases, administration of glucose, as an energy substrate, would aggravate ischemic brain damage via activating anaerobic glycolysis, which leads to lactate accumulation. Beta-hydroxybutyrate (BHB) is one of the ketone bodies that can be utilized as an energy source during starvation. The purpose of our study was to define the protective effects of BHB on brain damage induced by hypoxia, anoxia and ischemia. ⋯ BHB administered immediately after a bilateral carotid artery ligation at a dose of 30 mg x kg(-1) x h(-1) significantly suppressed the elevation of cerebral water and sodium contents as well as maintaining high ATP and low lactate levels. In contrast, glycerin, a hypertonic agent, substantially reduced the water content but did not show any significant effect on other parameters. We demonstrated that BHB, unlike glycerin, when used as an energy substrate in ischemic brain, has protective effects on cerebral hypoxia, anoxia and ischemia-induced metabolic change.
-
Comparative Study
TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys.
TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa-receptor agonist with pharmacological properties different from those produced by kappa1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degrees C and 55 degrees C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50 degrees C hot-water test. ⋯ The antinociception produced by the higher dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of kappa-opioid receptor different from the kappa-opioid receptor in cynomolgus monkeys.
-
Because it was still uncertain whether a stimulation of beta1-adrenoceptors accelerated alveolar fluid clearance in hyperoxic lung injury, the effect of denopamine, a selective beta1-adrenergic agonist, on alveolar fluid clearance was determined in rats exposed to 93% oxygen for 48 and 56 h. Alveolar fluid clearance was measured by the progressive increase in the concentration of Evans blue labeled albumin instilled into the alveolar spaces over 1 h at 37 degrees C in isolated rat lungs. The principle results were as follows: 1) Although lung water volume increased in rats exposed to hyperoxia for 48 and 56 h, basal alveolar fluid clearance did not change for up to 56 h; 2) Denopamine increased alveolar fluid clearance in rats exposed to hyperoxia as well as in rats without exposure to hyperoxia; 3) Denopamine primarily increased amiloride-insensitive alveolar fluid clearance in rats exposed to hyperoxia; 4) The potency of denopmaine was similar to that of terbutaline, a selective beta2-adrenergic agonist. In summary, denopamine is a potent stimulator of alveolar fluid clearance in rats exposed to hyperoxia.
-
A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. ⋯ It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.
-
Smooth muscle responsiveness of intrapulmonary small bronchi obtained from repeatedly antigen-challenged rats was compared with that from control animals to determine whether smooth muscle contractility of peripheral airways is augmented by such repeated challenge. In intact (non-permeabilized) smooth muscles of intrapulmonary bronchi, the acetylcholine (ACh)-induced contractile response was significantly augmented in the repeated challenge group, although 60-mM K+-induced contraction was within the normal level. In beta-escin-permeabilized muscles, no significant difference between groups was observed in the Ca2+-induced contractile responses. Thus, augmented ACh-induced contraction of intact intrapulmonary small bronchial smooth muscle might be, at least in part, due to an enhanced ACh-mediated Ca2+-sensitizing signal.