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Comparative Study
. 2009 Aug;157(8):1474-82.
doi: 10.1111/j.1476-5381.2009.00315.x.

Urethane, but Not Pentobarbitone, Attenuates Presynaptic Receptor Function in Rats: A Contribution to the Choice of Anaesthetic

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Free PMC article
Comparative Study

Urethane, but Not Pentobarbitone, Attenuates Presynaptic Receptor Function in Rats: A Contribution to the Choice of Anaesthetic

Cm Kurz et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: We examined whether cannabinoid CB(1) and histamine H(3) receptors resemble alpha(2)-adrenoceptors in that their presynaptically mediated cardiovascular effects are less marked in urethane- than in pentobarbitone-anaesthetized pithed rats.

Experimental approach: Effects of the cannabinoid agonist CP-55,940 and the H(3) receptor agonist imetit on electrically induced tachycardic and vasopressor responses, respectively, was compared in pithed rats anaesthetized with urethane or pentobarbitone. The affinity of urethane for the three receptors was measured by radioligand binding studies in rat brain cortex membranes and its potency assessed in superfused mouse tissues preincubated with (3)H-noradrenaline.

Key results: The neurogenic tachycardic response was less markedly inhibited by CP-55,940 in urethane- than in pentobarbitone-anaesthetized pithed rats. Imetit inhibited the neurogenic vasopressor response after pentobarbitone but not after urethane. The catecholamine-induced tachycardic and vasopressor response did not differ between rats anaesthetized with either compound. Urethane 10 mM (plasma concentration reached under anaesthesia) did not affect binding to CB(1) or H(3) receptors and alpha(2) adrenoceptors, nor did it alter the inhibitory effect of agonists at the three receptors on electrically evoked (3)H-noradrenaline release.

Conclusions and implications: Urethane, but not pentobarbitone, abolished the H(3) receptor-mediated vascular response in pithed rats and attenuated the CB(1) receptor-mediated cardiac response much more than pentobarbitone. The weaker effects of CB(1), H(3) and alpha(2) receptor agonists cannot be explained by antagonism by urethane at the three receptors in vitro. Pentobarbitone, but not urethane, is suitable as an anaesthetic for investigations of inhibitory presynaptic receptor function in pithed and anaesthetized rats.

Figures

Figure 1
Figure 1
Effect of CP-55,940 on the electrically induced tachycardia and of imetit on the electrically induced vasopressor response in urethane- and pentobarbitone-anaesthetized pithed and vagotomized rats. Five periods of electrical stimulation were administered, one 5 min before (S1) and another four 5, 10, 20 and 30 min after (S2–S5) i.v. injection of the drug under study. To quantify the effects of drugs, the ratios of S2, S3, S4 and S5 over S1 were determined (Sn/S1). Sn/S1 values are expressed as percentages of the corresponding ratios in controls (injection of vehicle; not shown). Means ± SEM of 4–10 experiments. *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control.
Figure 2
Figure 2
Inhibition of specific 3H-rimonabant (A), 3H-rauwolscine (B) and 3H-Nα-methylhistamine binding (C) to rat brain cortex membranes by urethane, pentobarbitone and selective ligands at the three labelled receptors. Details of the experimental protocols are given in Table 2. Means ± SEM of three to four experiments in triplicate (for some data points, SEM is smaller than symbols). The solid and interrupted line marked by P and U, respectively, represents the plasma concentration obtained under pentobarbitone administration in the study by Hatanaka et al. (1988) and under urethane administration in the studies by Boyland and Rhoden (1949) and O'Flaherty and Sichak (1983) (for further details, see Discussion).
Figure 3
Figure 3
Effect of three agonists on the electrically evoked tritium overflow from superfused mouse tissues preincubated with 3H-noradrenaline, and interaction with urethane or pentobarbitone. The effect of the cannabinoid receptor agonist WIN 55,212-2 was studied in pieces of vas deferens (A) whereas the effect of the α2-adrenoceptor agonist clonidine (B) and of histamine (C) was studied in cerebral cortex slices. The superfusion medium contained the respective agonist from 62 min of superfusion onward and urethane or pentobarbitone (and, when relevant, rauwolscine) throughout superfusion. Tritium overflow was evoked after 40 and 90 min of superfusion (S1, S2), and the ratio of the overflow evoked by S2 over that evoked by S1 was determined (S2/S1). S2/S1 values are expressed as percentages of the corresponding ratios in controls (not shown). Means ± SEM of 4–10 experiments. *P < 0.05, **P < 0.01, ***P < 0.001, compared with the corresponding control.

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