Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production.
Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 μg·min(-1)·kg(-1) iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 μM) and cGMP analog 8-Br-cGMP (100 μM) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production.
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands;
Zhichao
Z
Zhou
Vincent J
VJ
de Beer
Shawn B
SB
Bender
A H
AH
Jan Danser
Daphne
D
Merkus
M Harold
MH
Laughlin
Dirk J
DJ
Duncker
D000818:Animals; D003243:Consciousness / Q000502:physiology*; D003331:Coronary Vessels / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D008297:Male; D023421:Models, Animal; D010805:Physical Conditioning, Animal; D011725:Pyridines / Q000494:pharmacology; D012146:Rest / Q000502:physiology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D016232:Endothelins; D011725:Pyridines; D013777:Tetrazoles; C016276:8-bromocyclic GMP; C120582:tezosentan; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
Big ET; ET; ETA/ETB blockade; PDE5 inhibition; coronary vasomotor tone