Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction

Abstract

DJ. Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction. Am J Physiol Heart Circ Physiol 304: H1370 -H1381, 2013. First published March 15, 2013 doi:10.1152/ajpheart.00410.2012The 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 g·kg Ϫ1 ·min Ϫ1 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 -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. coronary circulation; myocardial infarction; nitric oxide; phosphodiesterase 5; vasodilation LEFT VENTRICULAR (LV) function critically depends on an adequate oxygenation of the myocardium. Since myocardial O 2 extraction (ME O 2 ) is already high under resting conditions, any substantial increase in myocardial O 2 demand must be met by an increase in O 2 supply and hence an increase in coronary blood flow (CBF) (15,20). This tight matching of CBF to myocardial metabolism is the result of a delicate balance between a myriad of vasomotor signals stemming from cardiomyocytes, autonomic nerve terminals, and the endothelium (11,15,20,56).The endothelium-derived vasodilator nitric oxide (NO) produces coronary vasodilation through the activation of soluble guanylyl cyclase (sGC) and formation of cGMP in vascular smooth muscle (21). cGMP signaling is terminated through breakdown of cGMP by phosphodiesterase 5 (PDE5) and, to a lesser extent, by PDE1 (46). Th...

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

“…EMD360527 in a dose of 300 g·kg Ϫ1 ·min Ϫ1 iv results in plasma drug concentrations of 15.4 M (31), indicating that this dose reaches concentrations that are well above the IC50 for PDE5 and are at least an order of magnitude below the IC 50 of other PDE isoforms. Selectivity for PDE5 inhibition is also supported by our observation that EMD360527 has negligible effects on LV dP/dt max compared with the PDE3 inhibitor pimobendan (31).…”

“…In the present study, PDE5 inhibition, ET A /ET B blockade, and their combination resulted in decreases in mean aortic pressure, which are the result of systemic vasodilation (23,29,31) and which require autoregulatory adjustments in coronary vascular resistance. In addition, the baroreceptor reflex-mediated increases in heart rate and contractility, together with the decrease in aortic blood pressure, will result in changes in myocardial metabolism, requiring adjustments of myocardial oxygen supply and hence coronary blood flow.…”

“…Ninety minutes after completing a control exercise trial as described above, swine received a continuous intravenous infusion of EMD360527 in a dose of 300 g·kg Ϫ1 ·min Ϫ1 . Ten minutes after the infusion was started, the five-stage exercise trial was repeated, while infusion of EMD360527 was continued (23,31). Upon completion of the exercise trial, EMD360527 infusion was halted, and animals were allowed to rest for another 90 min.…”

“…PDE5 is present in vascular smooth muscle cells in the coronary vascular bed and thus has the potential to regulate coronary blood flow by exerting a vasoconstrictor influence. Indeed, PDE5 inhibition resulted in relaxation of coronary conduit arteries in swine in vitro (45) and in vivo (1), and produced coronary resistance vessel dilation, thereby increasing coronary blood flow in humans (24) and swine (31).…”

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

“…In the coronary circulation, interpretation of the data is even more complex as systemic administration of pharmacological antagonists of endogenous vasoactive substances results not only in alterations in coronary resistance vessel tone, but often also produce pronounced changes in systemic hemodynamic variables 7,14,17,19 . These altered hemodynamics influence cardiac work, and thereby cause changes in coronary blood flow resulting from changes in metabolic requirements of the heart or from autoregulation, rather than as a direct effect of the intervention on coronary vascular tone.…”