title: Increased cavernosal relaxation by Phoneutria nigriventer toxin, PnTx2-6, via activation at NO/cGMP signaling.
abstract: Erectile dysfunction (ED) mechanisms in diabetic patients are multifactorial and often lead to resistance to current therapy. Animal toxins have been used as pharmacological tools to study penile erection. Human accidents involving the venom of Phoneutria nigriventer spider are characterized by priapism. We hypothesize that PnTx2-6 potentiates cavernosal relaxation in diabetic mice by increasing cyclic guanosine monophosphate (cGMP). This effect is neuronal nitric oxide synthase (nNOS) dependent. Cavernosal strips were contracted with phenylephrine (10(-5) M) and relaxed by electrical field stimulation (20 V, 1-32 Hz) in the presence or absence of PnTx2-6 (10(-8) M). Cavernosal strips from nNOS- and endothelial nitric oxide synthase (eNOS)-knockout (KO) mice, besides nNOS inhibitor (10(-5) M), were used to evaluate the role of this enzyme in the potentiation effect evoked by PnTx2-6. Tissue cGMP levels were determined after stimulation with PnTx2-6 in presence or absence of N-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) and ω-conotoxin GVIA (10(-6) M), an N-type calcium channel inhibitor. Results showed that PnTx2-6 enhanced cavernosal relaxation in diabetic mice (65%) and eNOS KO mice, but not in nNOS KO mice. The toxin effect in the cavernosal relaxation was abolished by nNOS inhibitor. cGMP levels are increased by PnTx2-6, however, L-NAME abolished this enhancement as well as ω-conotoxin GVIA. We conclude that PnTx2-6 facilitates penile relaxation in diabetic mice through a mechanism dependent on nNOS, probably via increasing nitric oxide/cGMP production.
authors: Department of Biochemistry, Biological Science Institute, Federal University of Minas Gerais, Gerais, Belo Horizonte, Brazil. keniapedrosa@gmail.com
authors: K P
authors: KP
authors: Nunes
authors: B M
authors: BM
authors: Wynne
authors: M N
authors: MN
authors: Cordeiro
authors: M H
authors: MH
authors: Borges
authors: M
authors: M
authors: Richardson
authors: R
authors: R
authors: Leite
authors: M E
authors: ME
authors: DeLima
authors: R C
authors: RC
authors: Webb
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013111:Spider Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D020866:omega-Conotoxin GVIA
chemical_list: D010455:Peptides; D013111:Spider Venoms; C540367:Tx2-6 protein, Phoneutria nigriventer; D009569:Nitric Oxide; D020866:omega-Conotoxin GVIA; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester