Effect of early exposure to the pollutant 1,2-naphthoquinose on the vascular and cardiac functions: Role of Transient Receptor Potential ionic channels.

A poluição do ar ambiente (PAA) e do material particulado (MP2,5) estão sendo associados à efeitos adversos na saúde, embora pouco se sabe sobre os efeitos de PAA contaminantes do MP, como a 1,2-naftoquinona (1,2-NQ). Objetivou-se neste estudo avaliar o efeito in vitro e da exposição inalatória precoce da 1,2-NQ sobre a função atrial e cardiovascular (CV) de camundongos, além de investigar potenciais mecanismos, com ênfase em receptores de potencial transitório (TRP). No átrio direito (AD) isolado de camundongos, a adição in vitro da 1,2-NQ elevou a frequência atrial (FA) espontânea e reduziu o cronotropismo positivo frente a agonistas b-adrenérgico, sendo este revertido pelo bloqueio de receptores b1. Na artéria mesentérica (AM) ou pulmonar (AP) de camundongos selvagens, a 1,2-NQ causou vasocontração concentração-dependente, que foi abolida na AM do animal KO TRPA1, e exacerbada pelo bloqueio do TRPV1 (capsazepina; CPZ) e TRPV4 (HC-067047). Na AP de animais selvagens e KO para TRPV1 e TRPA1, a 1,2-NQ reduziu o relaxamento evocado por acetilcolina (ACh). Na AM, a 1,2-NQ reduziu a sensibilidade (pD2) a ACh, sendo este efeito abolido na AM de animais KO TRPA1 e inalterada em KO TRPV1. No AD de animais expostos a 1,2-NQ, a FA (pD2) frente a NE foi reduzida, sendo este efeito revertido pelo bloqueio do TRPV1, e exacerbado pelo antagonista TRPV4. No AD desses animais, a FA (Emax) frente a NE foi reduzida pelo bloqueio do TRPC5, ML-204, e observou-se um aumento na expressão (RNAm) dos receptores HCN4, TRPA1, TRPV1, b2 e b3, mas não de canais/proteínas envolvidas na homeostase do Ca2+ (ex.: RyR2, Serca2a, Cav1.2). Na AP destes, observou-se aumento Pb-adrenergic agonists, which was reversed by b1 receptor blockade. In the mesenteric (MA) or pulmonary (PA) arteries of wild mice, 1,2-NQ caused concentration-dependent vasoconstriction, which was abolished in MA of KO TRPA1 animal, and exacerbated by TRPV1 (capszepine; CPZ) and TRPV4 (HC-067047). In wildtype PA and KO for TRPV1 and TRPA1, 1,2-NQ reduced acetylcholine evoked relaxation (ACh). In MA, 1,2-NQ reduced the sensitivity (pD2) to ACh, and this effect was abolished in MA of TRPA1 KO animals and unchanged in TRPV1 KO. In RA of animals exposed to 1,2- NQ, FA (pD2) evoked by NE was reduced; such effect was reversed by TRPV1 blockade, and exacerbated by the TRPV4 antagonist. In RA of these animals, FA (Emax) evoked by NE was reduced by TRPC5 blockade, ML-204, and an increase in the expression (mRNA) of the receptors HCN4, TRPA1, TRPV1, b2 and b3 was observed but not of channels / proteins involved in Ca2+ homeostasis (eg, RyR2, Serca2a, Cav1.2). In the PA of these, a significant increase of the expression (mRNA) for factor Nrf2 was observed, and this effect was potentiated by TRPV1 blockade. Mice exposed to 1,2-NQ had no changes in caudal blood pressure, but exhibited changes in RR, SDRR, RMSSD, LF/HF ECG parameters, and phenylephrine (Phe) and ACh sensitivity in PA. Blockade of TRPV1 and TRPV4 exacerbated the effect of Phe and inhibited ACh response, respectively, in the PA of animals exposed to 1,2-NQ, and stimulated atrial fibrillation in the ouabain-induced model. In conclusion, these results show, for the first time, the molecular potential of TRP receptors (TRPV1) and b1 in functional alterations in RA and murine CV system in vitro incubation or in vivo neonatal exposure to 1,2-NQ, revealing the vulnerability of age to the adverse effects of 1,2-NQ. These functional and molecular findings also serve as indicators of susceptibility to the onset of CV dysfunctions elicited by 1,2- NQ