Research Article

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

Leandro Bueno Bergantin* and Afonso Caricati-Neto

Published: 03/27/2017 | Volume 1 - Issue 1 | Pages: 006-009


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.

Read Full Article HTML DOI: 10.29328/journal.ach.1001002 Cite this Article


  1. Grossman E, Messerli FH. Effect of calcium antagonists on sympathetic activity. Eur Heart J. 1998; 19: 27-31. Ref.:
  2. Kreye VA, Luth JB. Proceedings: Verapamil-induced phasic contractions of the isolated rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 1975.  Ref.:
  3. French AM, Scott NC. A comparison of the effects of nifedipine and verapamil on rat vas deferens. Br J Pharmacol. 1981; 73: 321-323. Ref.:
  4. Moritoki H, Iwamoto T, Kanaya J, Maeshiba Y, Ishida Y, et al. Verapamil enhances the non-adrenergic twitch response of rat vas deferens. Eur J Pharmacol. 1987; 140: 75-83. Ref.:
  5. Rae GA, Calixto JB. Interactions of calcium antagonists and the calcium channel agonist Bay K 8644 on neurotransmission of the mouse isolated vas deferens. Br J Pharmacol. 1989; 96: 333-340. Ref.:
  6. Bergantin LB, Souza CF, Ferreira RM, Smaili SS, Jurkiewicz NH, et al. Novel model for “calcium paradox” in sympathetic transmission of smooth muscles: role of cyclic AMP pathway. Cell Calcium. 2013; 54: 202-212. Ref.:
  7. Bergantin LB, Jurkiewicz A, García AG, Caricati-Neto A. A Calcium Paradox in the Context of Neurotransmission. Journal of Pharmacy and Pharmacology. 2015; 3: 253-261. Ref.:
  8. Caricati-Neto A, García AG, Bergantin LB. Pharmacological implications of the Ca2+/cAMP signalling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol Res Perspect. 2015; 3: 181. Ref.:
  9. Pohar B, Grad A, Mozina M, Rakovec P, Horvat M. Paradoxical elevation of pulmonary vascular resistance after nifedipine in primary pulmonary hypertension. A case study. Cor et vasa. 1989; 31: 238-241. Ref.:
  10. Ruzicka M, Coletta E, Floras J, Leenen FH. Effects of low-dose nifedipine GITS on sympathetic activity in young and older patients with hypertension. J Hypertens. 2004; 22: 1039-1044. Ref.:
  11. Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens.Greenwich. 2011; 13: 687-689. Ref.:
  12. Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular signalling interaction. Eur J Pharmacol. 2016; 788: 255-260. Ref.: