title: Vasomodulatory effect of novel peroxovanadate compounds on rat aorta: Role of rho kinase and nitric oxide/cGMP pathway.
abstract: The present study was undertaken to assess the role of reactive oxygen species (ROS) in rat aortic ring vasoreactivity and integrity by using various peroxovanadate (pV) compounds. All the pV compounds (1nM-300 μM) used in the present study exerted concentration-dependent contractions on endothelium intact rat aortic rings. All compounds with an exception of DPV-asparagine (DPV-asn) significantly altered vascular integrity as shown by diminished KCl responses. Phenylephrine (PE)-mediated contractions (3nM-300 μM) were unaltered in the presence of these compounds. Acetylcholine (Ach)-mediated relaxation in PE (1μM) pre-contracted rings was significantly reduced in presence of diperoxovanadate (DPV), poly (sodium styrene sulfonate-co-maleate)-pV (PSS-CoM-pV) and poly (sodium styrene 4-sulfonate)-pV (PSS-pV). However, no significant change in Ach-mediated responses was observed in the presence of poly (acrylate)-pV (PAA-pV) and DPV-asn. DPV-asn was thus chosen to further elucidate mechanism involved in peroxide mediated modulation of vasoreactivity. DPV-asn (30nM - 300 μM) exerted significantly more stable contractions, that was found to be catalase (100U/ml) resistant in comparison with H(2)O(2) (30nM-300 μM) in endothelium intact aortic rings. These contractile responses were found to be dependent on extracellular Ca(2+) and were significantly inhibited in presence of ROS scavenger N-acetylcysteine (100 μM). Intracellular calcium chelation by BAPTA-AM (10μM) had no significant effect on DPV-asn (30nM-300 μM) mediated contraction. Pretreatment of aortic rings by rho-kinase inhibitor Y-27632 (10μM) significantly inhibited DPV-asn-mediated vasoconstriction indicating role of voltage-dependent Ca(2+) influx and downstream activation of rho-kinase. The small initial relaxant effect obtained on addition of DPV-asn (30nM-1 μM) in PE (1 μM) pre-contracted endothelium intact rings, was prevented in the presence of guanylate cyclase inhibitor, methylene blue (10 μM) and/or nitric oxide synthase (NOS) inhibitor, l-NAME (100 μM) suggesting involvement of nitric oxide and cGMP. DPV-asn, like H(2)O(2), exerted a response of vasoconstriction in normal arteries and vasodilation at low concentrations (30nM-1 μM) in PE-pre contracted rings with overlapping mechanisms. These findings suggest usefulness of DPV-asn having low toxicity, in exploring the peroxide-mediated effects on various vascular beds. The present study also convincingly demonstrates role of H(2)O(2) in the modulation of vasoreactivity by using stable peroxide DPV-asn and warrants future studies on peroxide mediated signaling from a newer perspective.
authors.affiliation: Pharmacology Division, Central Drug Research Institute (CSIR), Chattar Manzil Palace, M G Marg, Lucknow 226 001, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Khanna
authors.forename: Manish
authors.initials: M
authors.lastname: Jain
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Barthwal
authors.forename: Diganta
authors.initials: D
authors.lastname: Kalita
authors.forename: Jeena Jyoti
authors.initials: JJ
authors.lastname: Boruah
authors.forename: Siva Prasad
authors.initials: SP
authors.lastname: Das
authors.forename: Nashreen S
authors.initials: NS
authors.lastname: Islam
authors.forename: Tangirala
authors.initials: T
authors.lastname: Ramasarma
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010545:Peroxides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D010545:Peroxides; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C091767:diperoxovanadate; C069276:peroxovanadate; D010656:Phenylephrine; D009569:Nitric Oxide; D014638:Vanadates; D054460:rho-Associated Kinases; D006152:Cyclic GMP; D000109:Acetylcholine; D000111:Acetylcysteine