Acute hypoxia modifies cAMP levels induced by inhibitors of phosphodiesterase‐4 in rat carotid bodies, carotid arteries and superior cervical ganglia

Abstract

Background and purpose: Phosphodiesterase (PDE) inhibitors are useful to treat hypoxia-related diseases and are used in experiments studying the effects of oxygen on 3′-5′-cyclic adenosine monophosphate (cAMP) production. We studied the effects of acute hypoxia on cAMP accumulation induced by PDE inhibitors in oxygen-specific chemosensors, the carotid bodies (CBs) and in non-chemosensitive CB-related structures: carotid arteries (CAs) and superior cervical ganglia (SCG). Experimental approach: Concentration-response curves for the effects of a non-specific PDE inhibitor [isobutylmethylxanthine (IBMX) ], PDE4 selective inhibitors (rolipram, Ro 20-1724) and a PDE2 selective inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine) on cAMP levels were obtained in normoxic (20% O2/5% CO2) or hypoxic (5% O2/5% CO2) conditions. Key results: Responses to the PDE inhibitors were compatible with the presence of PDE4 in rat CBs, CAs and SCG but in the absence of PDE2 in CAs and CBs. Acute hypoxia enhanced the effects of IBMX and PDE4 inhibitors on cAMP accumulation in CAs and CBs. In SCG, acute hypoxia reduced cAMP accumulation induced by all the four PDE inhibitors tested. Differences between the effects of Ro 20-1724 and rolipram on cAMP were found in CAs and CBs during hypoxia. Conclusions and implications:The effects of PDE4 inhibitors could be potentiated or inhibited by acute hypoxia depending on the PDE isoforms of the tissue. The similarities between the characterization of PDE4 inhibitors at the CBs and CAs, under normoxia and hypoxia, did not support a specific role for cAMP in the oxygen-sensing machinery at the CB and suggested that no direct CB-mediated, hyperventilatory, adverse effects would be expected with administration of PDE4 inhibitors.

Effect of Oxygen on Phosphodiesterases (PDE) 3 and 4 Isoforms and PKA Activity in the Superior Cervical Ganglia

“…This finding adds to the literature by identifying PDE3 isoforms in this ganglion and is consistent with previous reports that characterize PDE4 by the effects of their specific inhibitors (Giorgi et al 1994; Lakics et al 2010; Li and Horn 2006; Nunes et al 2010). We found that PDE3a, PDE4b and PDE4d were the most abundant isoforms in the SCG.…”

“…We have recently observed that acute hypoxia decreased cAMP levels induced by PDE inhibitors in these ganglia, an opposite effect to that observed in the CB (Nunes et al 2010). …”

“…We had previously observed that acute hypoxia induced a decrease in cAMP levels in the presence of the non-specific PDE inhibitor, IBMX and specific PDE2 and PDE4 inhibitors, in whole SCG of adult Wistar rats (Nunes et al 2010). In the present work, hypoxia did not modulate either the levels of gene expression or PDE inhibition induced PKA activity.…”

The role of CAMP-dependent signaling systems in regulation of electrical and contractile properties of smooth muscles of the ureter in hypoxia in guinea pigs

“…Полученные результаты свидетельствуют, что активация аденилатциклазной системы посредством β-адреномиметика, форсколина, IBMX c последующим увеличением внутриклеточного содержания цАМФ приводят к подавлению активирующего действия гипоксии на параметры ýлектрической и, в большей степени, констрикторной активности ГМК мочеточника морской свинки. Согласно литературным данным, активация цАМФ-зависимого сигнального пути, с одной стороны, связана с повышением калиевой проводимости мембраны гладких мышц [2], а с другойуменьшением цитоплазматической концентрации ионов Са 2+ вследствие активации кальциевых насосов плазмалеммы, саркоплазматического ретикулума и (или) натрий-кальциевого обмена в ГМК [3,11].…”

Experimental Observations on the Biological Significance of Hydrogen Sulfide in Carotid Body Chemoreception

“…When PO 2 diminishes in the internal milieu bathing chemoreceptor cells, the molecular putative O 2 -sensor(s), through ill-defi ned coupling mechanisms, diminish the opening probability of diverse O 2 -sensitive K + channels leading to cell depolarization, activation of voltage operated Ca 2+ channels, entry of Ca 2+ and triggering of the release of several neurotransmitters which, in addition to activating the sensory nerve endings of the CSN, feedback control chemoreceptor cell activity via autoreceptors (Gonzalez et al 1994 ;Conde et al 2009 ;Nurse 2010 ). At every step from O 2 -sensing to the release of neurotransmitters, there are second messengers which fi ne shape the exocytosis and other neurotransmitter releasing mechanisms, and therefore the level of activity generated in the CSN (e.g., Pérez-García et al 1990, 1991Gómez-Niño et al 1994a , b ;Rocher et al 2009 ;He et al 2007 ;Nunes et al 2010 ;Kemp and Telezhkin 2014 ). Among these second messengers there is one, namely hydrogen sulfi de, whose potential capacity to modulate chemoreceptor activity, mechanisms of action, and physiological signifi cance are not well defi ned (Anichkov and Belen'kii 1963 ;Telezhkin et al 2009 ;Li et al 2010 ;Peng et al 2010 ;Fitzgerald et al 2011 ;Olson 2011 ;Haouzi et al 2011 ;Buckler 2012 ;Makarenko et al 2012 ;Kemp and Telezhkin 2014 ).…”