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


METHODS
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% O(2)/5% CO(2)) or hypoxic (5% O(2)/5% CO(2)) conditions.


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
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.
Nunes
Ana R
AR
Department of Pharmacology and CEDOC, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria, 130, Lisbon, Portugal.
Batuca
Joana R
JR
Monteiro
Emília C
EC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D002344:Carotid Body / Q000187:drug effects* / Q000378:metabolism; D015687:Cell Hypoxia; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010100:Oxygen / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000187:drug effects* / Q000378:metabolism
D058988:Phosphodiesterase 4 Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D000242:Cyclic AMP; D020889:Rolipram; D010100:Oxygen; D015056:1-Methyl-3-isobutylxanthine