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Medial prefrontal cortex TRPV1 and CB1 receptors modulate cardiac baroreflex activity by regulating the NMDA receptor/nitric oxide pathway

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Abstract

The ventral medial prefrontal cortex (vMPFC) facilitates the cardiac baroreflex response through N-methyl-d-aspartate (NMDA) receptor activation and nitric oxide (NO) formation by neuronal NO synthase (nNOS) and soluble guanylate cyclase (sGC) triggering. Glutamatergic transmission is modulated by the cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid type 1 (TRPV1) receptors, which may inhibit or stimulate glutamate release in the brain, respectively. Interestingly, vMPFC CB1 receptors decrease cardiac baroreflex responses, while TRPV1 channels facilitate them. Therefore, the hypothesis of the present study is that the vMPFC NMDA/NO pathway is regulated by both CB1 and TRPV1 receptors in the modulation of cardiac baroreflex activity. In order to test this assumption, we used male Wistar rats that had stainless steel guide cannulae bilaterally implanted in the vMPFC. Subsequently, a catheter was inserted into the femoral artery, for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. The increase in tachycardic and bradycardic responses observed after the microinjection of a CB1 receptors antagonist into the vMPFC was prevented by an NMDA antagonist as well as by the nNOS and sGC inhibition. NO extracellular scavenging also abolished these responses. These same pharmacological manipulations inhibited cardiac reflex enhancement induced by TRPV1 agonist injection into the area. Based on these results, we conclude that vMPFC CB1 and TRPV1 receptors inhibit or facilitate the cardiac baroreflex activity by stimulating or blocking the NMDA activation and NO synthesis.

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Acknowledgments

The authors wish to thank Camargo, L.H.A. and Mesquita O. for technical help. This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Protocol number 461/2009); the Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq) (Protocol number 156718/2012-0); the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) fellowship (Protocol number 2011/19494-8), and the Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da FMRP-USP (FAEPA).

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  1. Davi C. Lagatta, Luciana B. Kuntze and Nilson C. Ferreira-Junior contributed equally to this work.

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  1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Davi C. Lagatta, Luciana B. Kuntze, Nilson C. Ferreira-Junior & Leonardo B. M. Resstel

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  1. Davi C. Lagatta
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The experiments were all performed in the Laboratory of Neuropharmacology, School of Medicine of Ribeirão Preto, University of São Paulo. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D. C. L., N. C. F-J., L. B. K., and L. R. conceived the study and designed the research; D. C. L., N. C. F-J., and L. B. K. performed the experiments; D. C. L. and L. R. analyzed the data; D. C. L., N. C. F-J., L. B. K., and L. R. interpreted results of experiments; D. C. L. prepared figures; D. C. L. drafted the manuscript; D. C. L. and L. R. edited and revised the manuscript; all the authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. In addition, all people designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Correspondence to Leonardo B. M. Resstel.

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Lagatta, D.C., Kuntze, L.B., Ferreira-Junior, N.C. et al. Medial prefrontal cortex TRPV1 and CB1 receptors modulate cardiac baroreflex activity by regulating the NMDA receptor/nitric oxide pathway. Pflugers Arch - Eur J Physiol 470, 1521–1542 (2018). https://doi.org/10.1007/s00424-018-2149-5

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