Insights for Antihypertensive pharmacotherapy from the “Calcium Paradox” due to Ca2+/camp Interaction

Abstract

Several experimental studies performed since 1975, using smooth muscles richly innervated by sympathetic nerves to exclude the autonomic influence of adjusting reflex (rodent vas deferens), showed that L-type voltage-activated Ca2+ channels (VACC) blockers completely inhibited neurogenic contractions induced by electrical field stimulation (EFS) in high concentrations (>10-6 M), but paradoxically increased these EFS-contractions in low concentrations (<10-6 M), suggesting that other mechanisms than only autonomic adjusting reflex are involved in these paradoxical effects. In 2013, we showed that these paradoxical effects of L-type VACC blockers, named by us “calcium paradox” phenomenon, were potentiated by drugs which increase cytosolic cAMP concentration ([cAMP] c-enhancers), such as rolipram, IBMX and forskolin, indicating that this sympathetic hyperactivity drug-induced is due to interaction of the Ca2+/cAMP intracellular signaling pathways (Ca2+/cAMP interaction). Then, the pharmacological manipulation of this interaction produced by combination of the L-type VACC blockers used in the antihypertensive therapy, and [cAMP] c-enhancers used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to sympathetic hyperactivity. Then, we discussed the role of Ca2+/cAMP interaction for antihypertensive pharmacotherapy.