Endothelium-dependent relaxation in response to ethanol in the porcine isolated pulmonary artery.
Many drugs cannot be dissolved in distilled water and so other solvents such as ethanol, dimethylsulphoxide and methanol are used. Because very little is known about the direct effects of these three solvents on the cardiovascular system, we have examined their effects on isolated pulmonary and coronary arteries from the pig. Increasing concentrations of ethanol, dimethylsulphoxide and methanol induced relaxation in porcine pulmonary (at 1.2% v/v, 59.9+/-9.0% (n =9), 55.9+/-9.0% (n =6) and 12.3+/-6.4% (n = 8), respectively, of U46619-induced tone) and coronary arteries (at 1.2% v/v, 69.9+/-7.1% (n = 10), 78.9+/-6.1% (n = 7) and 12.9+/-8.2% (n = 6) respectively, of U46619-induced tone). In the pulmonary arteries the relaxation in response to ethanol was found to be endothelium-dependent whereas the responses to dimethylsulphoxide and methanol were unaffected by removal of the endothelium. In the coronary arteries the relaxation to all three solvents was independent of the presence of the endothelium. Comparison of the sensitivity of the tissues to the solvents showed that ethanol and dimethylsulphoxide produced comparative responses in both the pulmonary and coronary arteries, whereas methanol was much less potent. The endothelium-dependent response to ethanol in the porcine pulmonary artery (maximum response, Emax, 67.1+/-9.3% of U46619-induced tone, n = 7) was attenuated by the cyclooxygenase inhibitor, flurbiprofen (Emax 31.9 +/- 12.0%, n=7), the nitric oxide synthase inhibitor, L-NAME (NG-nitro-L-arginine methyl ester; Emax 23.5+/-10.2%, n = 7)) and the combination of both inhibitors (Emax 18.3+/-7.8%, n = 7). The residual relaxatory response to ethanol was abolished, and converted into a contractile response, both by removal of the endothelium (at 1.7% v/v ethanol 27.3+/-11.5% of U46619-induced tone, n=7) and by the addition of a low concentration of KC1 (49.9-/+10.3%, n=6), suggesting the release of a non-prostanoid, non-nitric oxide factor from the endothelium. This response, however, was not attenuated by the cannabinoid receptor-antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide HCL; 52.5-/+4.3% relaxation, n =8), suggesting that the factor released in this preparation by ethanol is not a cannabinoid. The results of this study indicate that many solvents commonly used in pharmacological experiments have pronounced vasoactive properties. Methanol might be the vehicle of choice, because it was the least active solvent, whereas high concentrations of ethanol might influence vascular function at both the level of the smooth muscle and the endothelium, with the action on the endothelium involving the release of endothelium-derived relaxing factors.
Lawrence
R N
RN
School of Biomedical Science, University of Nottingham Medical School, Queens Medical Centre, UK.
Dunn
W R
WR
Wilson
V G
VG
D000818:Animals; D002186:Cannabinoids / Q000037:antagonists & inhibitors; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005480:Flurbiprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D000432:Methanol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D012997:Solvents / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D002186:Cannabinoids; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D012997:Solvents; D000431:Ethanol; D005480:Flurbiprofen; D000077285:Rimonabant; D019331:NG-Nitroarginine Methyl Ester; D000432:Methanol; D004121:Dimethyl Sulfoxide