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...

Conditions in the body during aerobic exercise increase the level of lipid peroxidation (LP). LP is associated with elevated concentration of modified low-density lipoproteins that are implicated in development of cardiovascular disease. Supplementation with antioxidant vitamin E to athletes at 267 mg (400 IUs) or greater has been reported to reduce levels of LP associated with exercise. Little is currently known about the effects of modest supplementation of vitamin E on previously sedentary adults who initiate an aerobic fitness program. In the present study, sedentary subjects (n = 14) kept 24-hour diet records to establish antioxidant intake of vitamins E and C and collected 24-hour urine samples that were used to determine baseline urinary malondialdehyde (MDA) concentrations, one measure of in vivo LP. No significant differences were noted in the parameters between groups. Seven subjects were randomly selected and supplemented daily with 133 mg (200 IUs) of vitamin E. All subjects participated in moderate-intensity aerobic training for 8 weeks. Post-training, non-supplemented subjects excreted significantly more MDA (p<0.05) and consumed significantly fewer antioxidants than the supplemented group. Vitamin E supplementation appears to suppress elevated LP associated with beginning an aerobic exercise regimen in previously sedentary subjects.