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 infl uence of adjusting refl ex (rodent vas deferens), showed that L-type voltageactivated Ca 2+ channels (VACC) blockers completely inhibited neurogenic contractions induced by electrical fi eld 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 refl ex 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 druginduced is due to interaction of the Ca 2+ /cAMP intracellular signaling pathways (Ca 2+ /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 Ca 2+ /cAMP interaction for antihypertensive pharmacotherapy.