In this project, we propose to study the relationship between the water solubility of a drug and the specificity of that drug for receptors that may mediate immobility and/or amnesia during general anesthesia. We have collected extensive preliminary data that suggest drug modulation of at least two anesthetic-sensitive receptors is predicted by a molar water solubility """"""""cut-off"""""""" value. We propose to confirm this solubility- specificity relationship using in vitro electrophysiological studies in frog oocytes (Specific Aim 1) and then to test whether these same relationships exist in vivo using pharmacologic studies in rats (Specific Aim 2).
In Specific Aim 1, we will express anesthetic-sensitive receptors (e.g., GABAA, NMDA, etc.) in frog oocytes and measure the inhibition or potentiation of currents produced by homologous hydrocarbon chains. Homologous hydrocarbons contain the same functional group, but differ by 1-2 carbons at the &-end of the hydrocarbon chain (e.g., 1-propanol vs. 1-hexanol). Utilizing a diverse range of hydrocarbons having vastly different vapor pressures and molecular sizes and charges, the effect of hydrocarbon water solubility as a single critical physical determinant of an in vitro cut-off effect on anesthetic-sensitive receptors can be demonstrated. This critical molar water solubility cut-off value will define in vitro specificity of a compound for one of two receptors. For example, in the case of NMDA and GABAA receptor modulation, the critical molar water solubility will predict whether a drug modulates GABAA receptors only or whether a drug is able to modulate both NMDA and GABAA receptors.
In Specific Aim 2, we aim to test whether the anesthetic solubility-specificity """"""""cut-off"""""""" described in the previous in vitro studies translate into specificity for GABAA versus NMDA receptor modulation in a whole-animal model. To this end, we will study the relative NMDA antagonism of 2 homologous inhaled anesthetic hydrocarbons (alkanes) and 2 homologous injectable anesthetic hydrocarbons (propofol and its halogenated analogue) using pharmacologic methods we have piloted in studies measuring the contribution of NMDA by isoflurane at minimum alveolar concentration (MAC) in rats. Since each homologous pair of anesthetics will have a water solubility value on either side of the specificity """"""""cut-off"""""""" value, we hypothesize that NMDA antagonism at MAC will exist only for the more soluble of the pair, whereas the less soluble compound should never exhibit evidence of NMDA receptor antagonism at any delivered concentration.
Anesthetics modulate multiple cell receptors, and these receptors can in turn mediate both desirable and undesirable effects. Validation of this novel solubility- specificity """"""""cut-off"""""""" phenomenon for cell receptors provides a mechanism for the development of safer anesthetics simply by altering the water solubility of existing agents. Decreasing water solubility of some drugs could increase receptor specificity and thus could potentially reduce undesirable drug side-effects. Increasing water solubility of other drugs might add desirable receptor modulation, with the potential to imbue a non- anesthetic with the immobilizing effects of a general anesthetic. The role of water solubility as a determinant of drug-receptor modulation would also add additional support to theories of anesthetic action at aqueous interfacial sites around cell receptor proteins.
|Brosnan, Robert J; Pham, Trung L (2014) Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation. BMC Pharmacol Toxicol 15:62|
|Brosnan, Robert J (2013) Inhaled anesthetics in horses. Vet Clin North Am Equine Pract 29:69-87|
|Brosnan, Robert J; Pypendop, Bruno H; Majewski-Tiedeken, Chalon R et al. (2013) Naltrexone does not affect isoflurane minimum alveolar concentration in cats. Vet Anaesth Analg 40:225-8|
|Brosnan, Robert J; Thiesen, Roberto (2012) Increased NMDA receptor inhibition at an increased Sevoflurane MAC. BMC Anesthesiol 12:9|
|Soares, Joao H N; Brosnan, Robert J; Fukushima, Fabiola B et al. (2012) Solubility of haloether anesthetics in human and animal blood. Anesthesiology 117:48-55|
|Brosnan, Robert J; Pham, Trung L (2011) Does anesthetic additivity imply a similar molecular mechanism of anesthetic action at N-methyl-D-aspartate receptors? Anesth Analg 112:568-73|
|Brosnan, Robert J (2011) GABA(A) receptor antagonism increases NMDA receptor inhibition by isoflurane at a minimum alveolar concentration. Vet Anaesth Analg 38:231-9|