PubMed · 4599643
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A Boba. 1974. Enflurane toxicity.. https://doi.org/10.1097/00000542-197407000-00030
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The GABA(A) receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABA(A) receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABA(A) receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 A(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.
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It has previously been demonstrated in several species that stimulation of myelinated vagal efferent fibres evokes slowing of heart rate and atrio-ventricular (A-V) conduction and a decreased ventricular contractility but recruitment of non-myelinated fibres did not further increase the response. Only in rabbits was a significant bradycardia evoked on recruiting non-myelinated fibres. However, if stimulating myelinated fibres produced a near maximal response, then effects of further activation of non-myelinated fibres may have been missed. Indeed, selective stimulation of non-myelinated fibres alone now has been shown to evoke a slowing of heart rate independent of the effects of myelinated fibres. In the present study we tested in rabbits whether selective stimuli are also capable of slowing A-V conduction and changing ventricular contractility. In rabbits pretreated with the beta 1-adrenoceptor antagonist atenolol, ECG, arterial blood pressure, left ventricular pressure and dP/dt were recorded before and during stimulation of non-myelinated vagal efferent fibres using an anodal block technique (J. Physiol. 273 (1977) 539). R-R interval and A-V conduction times were computed off-line. Stimulation of non-myelinated vagal fibres increased R-R interval by 97.7 +/- 18.8 ms from a baseline of 315.3 +/- 7.7 ms, increased A-V conduction time by 9.9 +/- 1.1 ms from a baseline of 81.9 +/- 3.1 ms and decreased left ventricular dP/dtmax by 2486 +/- 362 mmHg s-1 from a baseline of 11,186 +/- 795 mmHg s-1. When hearts were paced at a rate about 10% higher than normal, A-V conduction time still increased by 13.3 +/- 1.9 ms from a baseline of 104.2 +/- 3.6 ms and dP/dtmax still fell by 2300 +/- 188 mmHg s-1 from a baseline of 11,200 +/- 777 mmHg s-1. Ganglionic blockade with hexamethonium (15-20 mg kg-1) always abolished the evoked increases in A-V conduction time, whilst there was still an increase in R-R interval in seven of the 12 animals tested. The data demonstrate that non-myelinated vagal efferent fibres can modulate chronotropic, dromotropic and inotropic actions on the heart.