Isatin (1H-indole-2,3 dione) is an endogenous compound with biological activities. Many of its derivatives have pharmacological effects, including inhibition of cyclic guanosine monophosphate levels in cardiac tissue; sedative-hypnotic profiles; anticonvulsant, analgesic, antithermic, and anti-inflammatory activities; and anxiolytic, antimicrobial, and proapoptotic effects. Carbamates derived from isatin have a vasorelaxant profile. This study investigated the activity of 2 novel 2-hydroxyacetophenone derivatives of isatin (named MB101 and MB130) on the contractility of rat aorta and papillary muscles. Both compounds induced a concentration-dependent relaxation (5-100 μM) in the endothelium-intact aorta that was abolished by N-nitro-L-arginine methyl ester. Atropine, a muscarinic receptor antagonist, significantly prevented vasodilatation of 100 μM MB101. In contrast, atropine caused no significant alteration in MB130-induced vasorelaxation. Naloxone, a nonselective opioid receptor antagonist, completely prevented the relaxing effect of MB101 and MB130 at all concentrations. In papillary muscles, only MB130 induced a significant depression, and this contractile response was not altered by propranolol and atropine. Both the compounds reduced systolic and diastolic pressures in a dose-dependent manner in anesthetized rats. The 2-hydroxyacetophenones produced direct effects on vascular tonus through either muscarinic or opioid pathways. MB130 produced cardiac depression by opioid receptors and bradykinin because pretreatment HOE140 or with naloxone, an antagonist of type-2, bradykinin were able to partially block the decrease in twitch amplitude in papillary muscles induced by MB130. These findings provide information for designing new strategies for the treatment of cardiovascular disorders.
From the *Programa de Desenvolvimento de Fármacos, Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Rio de Janeiro, Brazil; and †Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Brazil.
Received for publication March 12, 2010; accepted September 16, 2010.
Supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Universitária Jose Bonifácio (FUJB), Instituto Nacional de Ciência e Tecnologia/Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)/Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq). In addition, this work was supported, in part, by fellowships from CAPES (L. B. Pontes), FAPERJ (D. Gabriel), and CNPq (G. Zapata-sudo and R. T. Sudo).
Reprints: Gisele Zapata-Sudo, MD, PhD, Departamento de Farmacologia Basica e Clinica, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Ciências Biomédicas, Bloco J, Sala 14, Rio de Janeiro, Brazil, 21941-590 (e-mail: email@example.com).