1.High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs.
Pelat M1, Verwaerde P, Galitzky J, Lafontan M, Berlan M, Senard JM, Montastruc JL. J Pharmacol Exp Ther. 2003 Jan;304(1):246-53.
The "in vivo" conditions for beta3-adrenoceptors (beta-AR) activation by isoproterenol were investigated in dog. Experiments were carried out in anesthetized dogs using isoproterenol as a nonselective beta-AR agonist. Intravenous infusion of isoproterenol (0.4 nmol/kg/min) induced arterial hypotension and tachycardia with a slight decrease in cutaneous blood flow. At this dose, isoproterenol increased glucose, glycerol, and nonesterified fatty acid plasma levels. The changes in cardiovascular and endocrine-metabolic parameters, induced by the low dose of isoproterenol, were suppressed by pretreatment with nadolol (1 mg/kg, i.v.). After nadolol administration, however, a 10-fold higher dose (4 nmol/kg/min) of isoproterenol was able to induce a decrease in arterial blood pressure with a slight tachycardia and an increase in cutaneous blood flow. This high dose of isoproterenol increased nonesterified fatty acid and glycerol plasma levels but failed to change glucose plasma levels.
2.Participation of peripheral group I and II metabotropic glutamate receptors in the development or maintenance of IL-1beta-induced mechanical allodynia in the orofacial area of conscious rats.
Jung CY1, Lee SY, Choi HS, Lim EJ, Lee MK, Yang GY, Han SR, Youn DH, Ahn DK. Neurosci Lett. 2006 Dec 6;409(3):173-8. Epub 2006 Oct 6.
The present study investigated the role of peripheral groups I and II metabotropic glutamate receptors (mGluRs) in interleukin (IL)-1beta-induced mechanical allodynia in the orofacial area of rats. Subcutaneous injection of 10 pg of IL-1beta decreased air-puff thresholds ipsilateral or contralateral to the injection site. The decrease in air-puff thresholds appeared 10 min after the injection of IL-1beta and IL-1beta-induced mechanical allodynia persisted for over 3 h. Pre-treatment with 7-(hydroxyimino) cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) or 2-methyl-6-(phenylethynyl)-pyridine hydrochloride (MPEP), a mGluR1 or mGluR5 antagonist, blocked IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia produced by a subcutaneous injection of 10 pg of IL-1beta. However, post-treatment with CPCCOEt or MPEP did not affect changes in behavioral responses, which were produced by the IL-1beta injection. Pre-treatment, as well as post-treatment with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), a group II mGluR agonist, blocked either IL-1beta-induced mechanical allodynia or mirror-image mechanical allodynia.
3.Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent.
Miller RR1, Doss GA, Stearns RA. Drug Metab Dispos. 2004 Feb;32(2):178-85.
Glucuronides of piperazine hydroxylamines are rarely reported in the literature, and even more rarely are their structures unambiguously identified. One major metabolite was detected by liquid chromatography/mass spectrometry-radioactivity in urine from monkeys treated with the aryl piperazine oral hypoglycemic agent 9-[(1S,2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(1-piperazinyl) purine hydrochloride (1). The mass spectrum of this metabolite indicated that it was both monooxygenated and glucuronidated on the piperazine ring. Possible structures included the N- or O-glucuronic acid conjugates of a carbinolamine, hydroxylamine, or N-oxide. Treatment with beta-glucuronidase gave a monooxygenated derivative of the parent compound. 1H NMR analysis of either the glucuronic acid conjugate or the monooxygenated product provided insufficient evidence to unambiguously determine their structures. Incubation of 1 with pig liver microsomes resulted in formation of the same monooxygenated derivative derived from beta-glucuronidase treatment of the glucuronide metabolite.
4.In vitro inhibition of human colonic motility with SR 59119A and SR 59104A: evidence of a beta3-adrenoceptor-mediated effect.
Bardou M1, Dousset B, Deneux-Tharaux C, Smadja C, Naline E, Chaput JC, Naveau S, Manara L, Croci T, Advenier C. Eur J Pharmacol. 1998 Jul 24;353(2-3):281-7.
The new beta3-adrenoceptor is present in the gastrointestinal tract of various species. This study aimed to show that this receptor modulates human colonic motility in vitro. We used circular muscle strips from the human colon suspended in single organ baths containing Krebs solution and subjected to an initial 1.5-2 g tension. We measured the effects of different beta3-adrenoceptor agonists, including SR 59104A (N-[(6-hydroxy-1,2,3,4-tetrahydronaphthalen-(2R)-2-yl)methyl]-(2 R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-(2R)-2-yl)methyl]-(2R) -2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), BRL 37344 (R,R + S,S) [4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl] phenoxy] acetic acid), and of isoprenaline and salbutamol in the absence or in the presence of propranolol alone or in combination with the beta3-adrenoceptor antagonist SR 59230A (3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydro-naphthalen-1- ylamino]-(2S)-2-propanol oxalate) on amplitude of spontaneous contractions.
