ABSTRACT
We have previously observed an increase in nitric oxide (NO) content in rat brain cortex following halothane, sevoflurane or isoflurane anaesthesia. This study was undertaken in order to determine whether isoform-specific nitric oxide synthase (NOS) inhibitors and inducers could modify these increases in NO contents. Rats were subjected to isoflurane and sevoflurane anaesthesia with concomitant administration of neuronal nitric oxide synthase (nNOS) inhibitor 7-Nitro-indazole (7-NI), inducible nitric oxide synthase (iNOS) inhibitor 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT) or lipopolysaccharide. NO concentration in different organs was measured by electron paramagnetic resonance (EPR) spectroscopy. 7-NI significantly decreased NO concentration in cerebellum but not in brain cortex, whereas AMT decreased NO in all the organs studied. Anaesthesia significantly increased NO concentration in brain cortex and decreased that in cerebellum. AMT abolished the NO increase in brain cortex. Anaesthesia enhanced the drastic increase in NO concentration in brain cortex after intraventricular lipopolysaccharide administration. Isoflurane was found to inhibit recombinant nNOS and iNOS activities at high concentrations (EC50=20 mM). Our data suggest a putative role for iNOS in the increase in NO levels produced by isoflurane and sevoflurane, whereas nNOS activity is probably inhibited during anaesthesia.
Subject(s)
Anesthetics, Inhalation/pharmacology , Cerebellum/drug effects , Cerebral Cortex/drug effects , Isoflurane/pharmacology , Methyl Ethers/pharmacology , Nitric Oxide Synthase/physiology , Nitric Oxide/metabolism , Animals , Cerebellum/metabolism , Cerebral Cortex/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/physiology , Male , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/physiology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/chemistry , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Rats , Rats, Wistar , Recombinant Proteins/chemistry , SevofluraneABSTRACT
Mildronate [3-(2,2,2-trimethylhydrazine) propionate (THP)] is an antiischemic drug acting mainly via inhibition of fatty acid beta-oxidation. Some effects of the drug cannot be explained by the latter mechanism. We tested the eventual nitric oxide (NO) dependence of the mildronate action. Mildronate, gamma-butyrobetaine (GBB) and GBB methyl ester induced transient increases in nitric oxide (NO) concentrations in rat blood and myocardium. In vitro, these compounds neither modified the activities of purified neuronal and endothelial recombinant nitric oxide synthases (NOSs) nor were able to interact with their active site. GBB induced vasodilatation at high concentrations only (EC50 = 5 x 10(-5) M) while mildronate alone displayed no vasodilating effect although it enhanced the GBB vasodilating activity. GBB methyl and ethyl esters were found more potent vasodilators (EC50 = 2.5 x 10(-6) M). Pretreatment of aortic rings with NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) abolished vasodilating effects of the compounds. A hypothesis explaining NO and endothelium-dependent effects of mildronate and its analogues is proposed.
Subject(s)
Betaine/analogs & derivatives , Betaine/pharmacology , Carnitine/pharmacology , Endothelium/physiology , Methylhydrazines/therapeutic use , Nitric Oxide/physiology , Vasodilation/physiology , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Betaine/antagonists & inhibitors , Betaine/classification , Carnitine/antagonists & inhibitors , Carnitine/classification , Ditiocarb/pharmacology , Drug Combinations , Drug Evaluation, Preclinical , Drug Synergism , Electron Spin Resonance Spectroscopy/methods , Endothelium/drug effects , Male , Methylhydrazines/antagonists & inhibitors , Methylhydrazines/pharmacology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Myocardial Ischemia/drug therapy , Myocardial Ischemia/prevention & control , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide Synthase/drug effects , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type III , Rats , Rats, Wistar , Vasodilation/drug effectsABSTRACT
Production of nitric oxide was measured in lipopolysaccharide-treated rats (10 mg/kg, 4 hr) using the electron paramagnetic resonance method. As compared to the control animals, the nitric oxide level in liver of lipopolysaccharide-treated rats increased from 27.6+/-4.7 to 1485+/-129 ng/g tissue, in heart from 4.8+/-0.7 to 271+/-26 ng/g tissue, in blood from 33.6+/-12.4 to 638+/-136 ng/g tissue, in kidney from 3.3+/-0.5 to 356+/-31 ng/g tissue, in brain cortex from 46.0+/-3.4 to 227+/-27 ng/g tissue, in cerebellum from 27.7+/-2.6 to 218+/-30 ng/g tissue, and in testes from 13.8+/-1.1 to 86+/-8 ng/g tissue. Administration of the antiischaemic drug, mildronate (120 mg/kg) caused a significant twofold decrease of the nitric oxide level in brain cortex and cerebellum 1 hr after drug administration. Its natural analogue gamma-butyrobetaine (30 mg/kg) triggered a twofold decrease of the nitric oxide concentration in all studied tissues 30 min. after the administration. Nitric oxide reached the initial level 2 hr later. Neither mildronate nor gamma-butyrobetaine could inhibit the inducible nitric oxide synthase in vitro. Analogues of gamma-butyrobetaine appear to be prospective drugs for the treatment of circulatory complications of sepsis.
Subject(s)
Adjuvants, Immunologic/pharmacology , Betaine/analogs & derivatives , Betaine/pharmacology , Carnitine , Lipopolysaccharides , Methylhydrazines/pharmacology , Nitric Oxide/biosynthesis , Sepsis/metabolism , Animals , Male , Rats , Rats, WistarABSTRACT
Silacyclic derivatives of heteroaromatic sulfides have been prepared by using phase transfer catalytic (PTC) system thiol / silacyclopropyl iodide / solid K(2)CO(3) / 18-crown-6 / toluene. The target sulfides were isolated in yields up to 70 %. The S-derivatives of N-methylimidazolyl, benzoxazolyl and 1,3,4-triazolyl thiols selectively lowered the low density lipoprotein (LDL) level in mice with the high cholesterol diet in nutrition.