title: Pharmacological analysis of hemodynamic responses to Lachesis muta (South American bushmaster) snake venom in anesthetized rats.
abstract: In this work, we examined some mechanisms involved in the hypotension caused by Lachesis muta (South American bushmaster) venom in anesthetized rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was maximal after 5 min and gradually returned to baseline over 60 min. Pretreatment of rats with the non-selective nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) did not attenuate the early phase of venom-induced hypotension, but abolished the recovery phase and resulted in rapid death; a similar effect was observed with the soluble guanylate cyclase (sGC) inhibitor ODQ. In contrast, the hemodynamic responses to venom were not attenuated by the non-selective NOS inhibitor NG-monomethyl-L-arginine, the inducible NOS inhibitor aminoguanidine, the phosphodiesterase 5 inhibitor sildenafil, the adenylate cyclase (AC) inhibitor SQ-22.536, the non-selective muscarinic receptor antagonist atropine, the bradykinin B2 receptor antagonist HOE-140 and the non-selective cyclooxygenase inhibitor indomethacin. Preincubation of venom with the PLA2inhibitor pBPB had no effect on the immediate hypotension but tended to improve the recovery phase. Neither AEBSF (a serine proteinase inhibitor) nor EDTA (a metalloproteinase inhibitor) prevented the venom-induced hypotension, but AEBSF and not EDTA protected against the lethality of a high dose (3.0 mg/kg, i.v.). There were no marked changes in the ECG parameters with the various treatments, except with L-NAME and ODQ that increased the RR interval. Pulmonary thrombus formation was markedly enhanced by L-NAME and ODQ, and to a lesser extent by pBPB, especially in small vessels, whereas AEBSF and EDTA inhibited thrombus formation. Venom relaxed phenylephrine-precontracted thoracic aorta and pulmonary artery in vitro, with the latter being more sensitive. The relaxation was endothelium-dependent and was inhibited by ODQ but not by H-89, a protein kinase A (PKA) inhibitor. Together, these findings indicate involvement of the NO/sGC/cGMP, but not the AC/cAMP/PKA signaling pathway, in the hemodynamic responses to L. muta venom in rats. Muscarinic mechanisms, kinins and arachidonic acid metabolites are apparently not involved.
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Dias
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Mariana A P
authors.initials: MA
authors.lastname: Rodrigues
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Bruna R
authors.initials: BR
authors.lastname: Inoue
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Renata L
authors.initials: RL
authors.lastname: Rodrigues
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: André L
authors.initials: AL
authors.lastname: Rennó
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Valéria B
authors.initials: VB
authors.lastname: de Souza
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Torres-Huaco
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Norma C
authors.initials: NC
authors.lastname: Sousa
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stroka
authors.affiliation: Setor de Biologia, Divisão de Zoologia Médica, Instituto Vital Brazil, Niterói, RJ, Brazil.
authors.forename: Anibal R
authors.initials: AR
authors.lastname: Melgarejo
authors.affiliation: Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil. Electronic address: hyslop@fcm.unicamp.br.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyslop
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced; D066298:In Vitro Techniques; D007705:Kinins / Q000378:metabolism / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D010275:Parasympathetic Nervous System / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D017208:Rats, Wistar; D015398:Signal Transduction; D012909:Snake Bites / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D014757:Viper Venoms / Q000633:toxicity*; D017819:Viperidae
chemical_list: D004791:Enzyme Inhibitors; D007705:Kinins; D014757:Viper Venoms; D019331:NG-Nitroarginine Methyl Ester
keywords: Cholinergic neurotransmission; Hypotension; Kinin; Lachesis muta venom; Nitric oxide; Pulmonary thrombosis