Pharmacological implications of the Ca2+/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders

Author(s)

Caricati-Neto, Afonso ^[1] ; Garcia, Antonio G. ^[2] ; Bergantin, Leandro Bueno ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Autonoma Madrid, Inst Teofilo Hernando ID Medicamento, Madrid - Spain

• Document type: Review article
• Source: PHARMACOLOGY RESEARCH & PERSPECTIVES; v. 3, n. 5 OCT 2015.
• Web of Science Citations: 6

Abstract

In this review, we discussed pharmacological implications of the Ca2+/cAMP signaling interaction in the antihypertensive and neurological/psychiatric disorders therapies. Since 1975, several clinical studies have reported that acute and chronic administration of L-type voltage-activated Ca2+ channels (VACCs) blockers, such as nifedipine, produces reduction in peripheral vascular resistance and arterial pressure associated with an increase in plasma noradrenaline levels and heart rate, typical of sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this apparent sympathomimetic effect of the L-type VACCs blockers remained unclear for decades. In addition, experimental studies using isolated tissues richly innervated by sympathetic nerves (to exclude the influence of adjusting reflex) showed that neurogenic responses were completely inhibited by L-type VACCs blockers in concentrations above 1 mu mol/L, but paradoxically potentiated in concentrations below 1 mu mol/L. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical increase in sympathetic activity produced by L-type VACCs blocker is due to interaction of the Ca2+/cAMP signaling pathways. Then, the pharmacological manipulation of the Ca2+/cAMP interaction produced by combination of the L-type VACCs blockers used in the antihypertensive therapy, and cAMP accumulating compounds used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to increase in sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. (AU)

• FAPESP's process: 14/10274-3 - Role of the "calcium paradox" in sympathetic function in hypertensive animals and their possible implications for antihypertensive pharmacologic strategies
• Grantee: Leandro Bueno Bergantin
• Support Opportunities: Scholarships in Brazil - Post-Doctoral