Urgosedin inhibits hypotension, hypoglycemia, and pro-inflammatory mediators induced by lipopolysaccharide.
Urgosedin is a newly synthesized compound especially with serotonergic and alpha-adrenergic blocking actions. In rat isolated thoracic aorta, urgosedin competitively antagonized norepinephrine-, clonidine-, and serotonin-induced vasocontractions in a concentration-dependent manner. In radioligand binding experiments, urgosedin had significant binding affinities on alpha1/alpha2, 5-HT1A, 5-HT1B and 5-HT2A receptors. Intravenous injection of lipopolysaccharide (LPS) produced a biphasic hypotension in normotensive rats. Although intravenous injection of urgosedin caused minor depressor actions in the normotensive Wistar rat, urgosedin significantly attenuated the secondary prolonged hypotension produced by LPS. The plasma levels of cytokines (IL-1beta, IL-6, TNF-alpha, and IFN-gamma) and hypoglycemia induced by LPS were also reduced by urgosedin. Moreover, the acute survival rates (350 minutes) of endotoxic shock increased from 0% (LPS group) to 100% in the groups pretreated with urgosedin. In RAW264.7 cells, urgosedin inhibited LPS-induced inducible nitric oxide synthase (iNOS) expression. In conclusion, our data suggest that urgosedin was a newly potent serotonergic and mild alpha-adrenergic blocking agent. Its prevention of LPS-induced hypotension and hypoglycemia might partially mediate through its inhibition activities on the iNOS expression and cytokines formation. Urgosedin might be an effective pharmacological agent against LPS-induced hypotension, hypoglycemia, and the formation of pro-inflammatory mediators.
Lo
Yi-Ching
YC
Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Wang
Ching-Chin
CC
Shen
Kuo-Pyng
KP
Wu
Bin-Nan
BN
Yu
Kwong-Leung
KL
Chen
Ing-Jun
IJ
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001786:Blood Glucose; D002460:Cell Line; D016207:Cytokines / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000145:classification; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007022:Hypotension / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D023382:Toxicity Tests, Acute / Q000379:methods
D000317:Adrenergic alpha-Antagonists; D001555:Benzene Derivatives; D001786:Blood Glucose; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010879:Piperazines; D011355:Prodrugs; D018490:Serotonin Agents; C494583:urgosedin; D012701:Serotonin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D009638:Norepinephrine