title: Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction.
abstract: The balance between the production and removal of cGMP in coronary vascular smooth muscle is of critical importance in determining coronary vasomotor tone and thus in the regulation of coronary blood flow. cGMP production by soluble guanylyl cyclase is activated by nitric oxide (NO), whereas cGMP breakdown occurs through phosphodiesterase 5 (PDE5). We hypothesized that myocardial infarction (MI) alters the balance between the production and removal of cGMP in the coronary vasculature and thereby alters the control of coronary vasomotor tone. Chronically instrumented swine with and without a 2-wk-old MI were exercised on a treadmill in the absence and presence of the PDE5 inhibitor EMD-360527 (300 μg·kg(-1)·min(-1) iv). Inhibition of PDE5 produced coronary resistance vessel dilation, which was more pronounced at rest than during exercise in normal swine. PDE5 gene expression was markedly reduced in coronary resistance vessels isolated from the remote myocardium of MI swine, which was accompanied by a similarly marked attenuation of coronary vasodilation by PDE5 inhibition in MI swine. The coronary vasoconstriction produced by inhibition of NO synthesis with N(ω)-nitro-L-arginine (20 mg/kg iv) was only slightly smaller in swine with MI. Interestingly, inhibition of NO synthesis reduced the vasodilator response to subsequent PDE5 inhibition in normal swine but not in MI swine. Conversely, PDE5 inhibition enhanced the coronary vasoconstriction produced by NO synthesis inhibition in normal swine but not in MI swine, suggesting that downregulation of PDE5 mitigated the loss of NO vasodilator influence. In conclusion, the expression and vasoconstrictor influence of PDE5 are markedly attenuated in coronary resistance vessels in the remote myocardium after MI, which appears to serve as a compensatory mechanism to mitigate the loss of NO vasodilator influence.
authors.affiliation: Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. d.merkus@erasmusmc.nl
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: Marleen
authors.initials: M
authors.lastname: Visser
authors.forename: Birgit
authors.initials: B
authors.lastname: Houweling
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jessica
authors.initials: J
authors.lastname: Nelson
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009203:Myocardial Infarction / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: coronary circulation; myocardial infarction; nitric oxide; phosphodiesterase 5; vasodilation