title: Atorvastatin prevents vascular hyporeactivity to norepinephrine in sepsis: role of nitric oxide and α₁-adrenoceptor mRNA expression.
abstract: Hyporeactivity to vasoconstrictors is one of the clinical manifestations of sepsis in man and experimental animals. The objective of the investigation was to examine whether atorvastatin can prevent hyporeactivity to norepinephrine (NE) in mouse aorta in sepsis, and if so, what are the mechanisms involved. Sepsis in mice was induced by cecal ligation and puncture. The aorta was harvested for tension experiment, nitric oxide (NO) and cyclic guanosine monophosphate measurements, and inducible NO synthase (iNOS) and α(1D)-adrenoceptor mRNA expression studies. In comparison with sham-operated controls, sepsis significantly decreased the contractile response to NE in the mouse aorta. Pretreatment with atorvastatin of septic animals completely restored NE-induced contractions to levels similar to those of sham-operated controls and significantly increased survival time and mean arterial pressure. Atorvastatin also attenuated iNOS-induced overproduction of NO, as well as iNOS mRNA expression. Accordingly, hyporeactivity to NE was not evident in tissues pretreated with selective iNOS inhibitor 1400W in sepsis. Although basal cyclic guanosine monophosphate accumulation in the aorta was reduced in sepsis, pretreatment of the tissues with soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) partially restored the reactivity to NE. Interestingly, hyporeactivity to NE in sepsis was associated with a decreased α(1D)-adrenoceptor mRNA expression in the mouse aorta. Atorvastatin pretreatment, however, prevented the decrease in α(1D)-adrenoceptor mRNA expression in septic animals. In conclusion, atorvastatin seems to prevent hyporeactivity to vasoconstrictor NE in the aorta from septic mice through attenuation of overproduction of NO as well as improved α(1D)-adrenoceptor mRNA expression. The findings of the present study may explain the beneficial effects of atorvastatin on improved hemodynamic functions in sepsis.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122 (Uttar Pradesh), India.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Kandasamy
authors.forename: Shahid
authors.initials: S
authors.lastname: Prawez
authors.forename: Soumen
authors.initials: S
authors.lastname: Choudhury
authors.forename: Amar Sunil
authors.initials: AS
authors.lastname: More
authors.forename: Azad Ahmed
authors.initials: AA
authors.lastname: Ahanger
authors.forename: Thakur Uttam
authors.initials: TU
authors.lastname: Singh
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006538:Heptanoic Acids / Q000627:therapeutic use*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D009638:Norepinephrine / Q000009:adverse effects* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000627:therapeutic use*; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics*; D018805:Sepsis / Q000188:drug therapy*; D014662:Vasoconstrictor Agents / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D010069:Oxadiazoles; D011758:Pyrroles; D011810:Quinoxalines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D000069059:Atorvastatin; D006162:Guanylate Cyclase; D009638:Norepinephrine