Role of the "calcium paradox" in sympathetic function in hypertensive animals and their possible implications for antihypertensive pharmacologic strategies

• Grant number: 14/10274-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2015
• End date: December 31, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Afonso Caricati Neto
• Grantee: Leandro Bueno Bergantin
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Study of our laboratory recently published in the british journal specialized in the studyof the role of Ca2+ in cell function Cell Calcium ( vol. 54 , 2013 ) unraveled themechanisms involved in the cellular process called "calcium paradox ." Elected as oneof the most accessed papers in all existence in this journal(http://top25.sciencedirect.com/subject/biochemistry-genetics-and-molecularbiology/3/journal/cell-calcium/01434160/archive/47), the study showed that thereduction of Ca2+ influx through L-type Ca2+- voltage-dependent channel ( VDCC ) bythe use of verapamil combined with increased of cytosolic cAMP concentration by theuse of rolipram promoted enhancement , rather than inhibition, of contractile activity ofsmooth muscle stimulated by neurotransmitters released from sympathetic nerves.This potentiation of contraction was abolished by inhibition of adenylyl cyclase activityand depletion of Ca2+ from the sarco - endoplasmic (SER ) reticulum , suggesting thatthe reduction of cytosolic Ca2+ concentration due to blockage of L-type VDCC couldstimulate adenylyl cyclase, increasing the cytosolic concentration of cAMP that , inresponse , could exacerbate the release of Ca2+ from the SER, resulting inhypersecretion of transmitters of the sympathetic nerves , and consequently increasingthe contractile response of muscle cells . Thus, co-administration of antihypertensivedrugs of the class of VDCC blockers with anti -depressants drugs of the class ofstimulants of cytosolic cAMP concentration could have undesirable clinical implicationsas increase of hypertension due to increased vasoconstrictor response caused byhypersecretion of neurotransmitters of vascular sympathetic nerves . Based on thisproposal , in this project we decided to investigate the role of the interaction betweenthe signaling pathways mediated by Ca2+ and cAMP on sympathetic function inhypertensive animals .

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CARICATI-NETO, AFONSO; GARCIA, ANTONIO G.; BERGANTIN, LEANDRO BUENO. Pharmacological implications of the Ca2+/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. PHARMACOLOGY RESEARCH & PERSPECTIVES, v. 3, n. 5, OCT 2015. (14/10274-3)

BERGANTIN, LEANDRO BUENO; CARICATI-NETO, AFONSO. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular signalling interaction. European Journal of Pharmacology, v. 788, p. 255-260, OCT 5 2016. (14/10274-3)