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Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.

Prevention and treatment of type 2 diabetes includes recommendation to perform aerobic exercise, but evidence indicates that high-intensity exercise training may confer greater benefit. Unique motor recruitment patterns during exercise elicit spatially focused increases in blood flow and subsequent adaptations. Therefore, using 20-wk-old Otsuka Long Evans Tokushima fatty (OLETF) rats with advanced insulin resistance, we examined whether 12 wk of exercise protocols that elicit different motor unit recruitment patterns, endurance exercise (EndEx), and interval sprint training (IST) induce spatially differential effects on endothelial-dependent dilation to acetylcholine (ACh; 1 nM-100 μM) and vasoreactivity to insulin (1-1,000 μIU/ml) in isolated, pressurized skeletal muscle resistance arterioles. Compared with sedentary OLETF rats, EndEx enhanced sensitivity to ACh in second-order arterioles perfusing the "red" (G2A-R) and "white" (G2A-W) portions of the gastrocnemius (EC(50): +36.0 and +31.7%, respectively), whereas IST only increased sensitivity to ACh in the G2A-R (+35.5%). Significant heterogeneity in the vasomotor response to insulin was observed between EndEx and IST as mean endothelin-1 contribution in EndEx was 27.3 ± 7.6 and 25.9 ± 11.0% lower in the G2A-R and G2A-W, respectively. These microvascular effects of exercise were observed in conjunction with training-related improvements in glycemic control (HbA1c: 6.84 ± 0.23, 5.39 ± 0.06, and 5.30 ± 0.14% in sedentary, EndEx, and IST, respectively). In summary, this study provides novel evidence that treatment of advanced insulin resistance in the OLETF rat with exercise paradigms that elicit diverse motor recruitment patterns produce differential adaptive responses in endothelial-dependent dilation and in the complex vascular actions of insulin.

Activation of ADP-sensitive P2Y(1) receptors has been proposed as an integral step in the putative "nucleotide axis" regulating coronary blood flow. However, the specific mechanism(s) and overall contribution of P2Y(1) receptors to the control of coronary blood flow have not been clearly defined. Using vertically integrative studies in isolated coronary arterioles and open-chest anesthetized dogs, we examined the hypothesis that P2Y(1) receptors induce coronary vasodilation via an endothelium-dependent mechanism and contribute to coronary pressure-flow autoregulation and/or ischemic coronary vasodilation. Immunohistochemistry revealed P2Y(1) receptor expression in coronary arteriolar endothelial and vascular smooth muscle cells. The ADP analog 2-methylthio-ADP induced arteriolar dilation in vitro and in vivo that was abolished by the selective P2Y(1) antagonist MRS-2179 and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester. MRS-2179 did not alter baseline coronary flow in vivo but significantly attenuated coronary vasodilation to ATP in vitro and in vivo and the nonhydrolyzable ATP analog ATPγS in vitro. Coronary blood flow responses to alterations in coronary perfusion pressure (40-100 mmHg) or to a brief 15-s coronary artery occlusion were unaffected by MRS-2179. Our data reveal that P2Y(1) receptors are functionally expressed in the coronary circulation and that activation produces coronary vasodilation via an endothelium/nitric oxide-dependent mechanism. Although these receptors represent a critical component of purinergic coronary vasodilation, our findings indicate that P2Y(1) receptor activation is not required for coronary pressure-flow autoregulation or reactive hyperemia.

Coronary blood flow (CBF) is reduced and transiently reversed during systole via cardiac contraction. Cardiac contractility, coronary tone, and arterial pressure each influence systolic CBF (CBF(SYS)), particularly by modulating the retrograde component of CBF(SYS). The effect of concurrent changes in these factors on CBF(SYS) during dynamic exercise has not been examined. Using chronically instrumented swine, we hypothesized that dynamic exercise enhances retrograde CBF(SYS). Phasic CBF was examined at rest and during treadmill exercise [2-5 miles/h (mph)]. Absolute values of mean CBF over the cardiac cycle (CBF(CYCLE)) as well as mean CBF in diastole (CBF(DIAS)) and mean CBF(SYS) were increased by exercise, while relative CBF(DIAS) and CBF(SYS) expressed as percentage of mean CBF(CYCLE) were principally unchanged. Early retrograde CBF(SYS) was present at rest and increased in magnitude (-33 +/- 4 ml/min) and as a percent of CBF(CYCLE) (-0.6 +/- 0.1%) at 5 mph. This reversal was transient, comprising 3.7 +/- 0.3% of cardiac cycle duration at 5 mph. Our results also reveal that moderately intense exercise (>3 mph) induced a second CBF reversal in late systole before aortic valve closure. At 5 mph, late retrograde CBF(SYS) amounted to -53 +/- 11 ml/min (-3.1 +/- 0.7% of CBF(CYCLE)) while occupying 11.1 +/- 0.3% of cardiac cycle duration. Wave-intensity analysis revealed that the second flow reversal coincided with an enhanced aortic forward-going decompression wave (vs. rest). Therefore, our data demonstrate a predictable increase in early-systolic CBF reversal during exercise and additionally that exercise induces a late-systolic CBF reversal related to the hemodynamic effects of left ventricular relaxation that is not predictable using current models of phasic CBF.

Current evidence indicates that the ability of physical activity to sustain a normal phenotype of arterial endothelial cells (ECs) plays a central role in the beneficial effects of exercise (Ex) on atherosclerotic disease. Here we evaluate the strength of evidence that shear stress (SS) and/or circumferential wall stress (stretch) are the primary signals, produced by bouts of Ex, that signal altered gene expression in arterial ECs, thereby resulting in a less atherogenic EC phenotype. Current literature indicates that SS is a signal for expression of antiatherogenic genes in cultured ECs, in ECs of isolated arteries, and in ECs of arteries in intact animals. Furthermore, SS levels in the arteries of humans during Ex are in the range that produces beneficial changes. In contrast, complex flow profiles within recirculation zones and/or oscillatory flow patterns can cause proatherogenic gene expression in ECs. In vivo evidence indicates that Ex decreases oscillatory flow/SS in some portions of the arterial tree but may increase oscillatory flow in other areas of the arterial tree. Circumferential wall stress can increase expression of some beneficial EC genes as well, but circumferential wall stress also increases production of reactive oxygen species and increases the expression of adhesion factors and other proatherogenic genes. Interactions of arterial pressure and fluid SS play an important role in arterial vascular health and likely contribute to how Ex bouts signal changes in EC gene expression. It is also clear that other local and circulating factors interact with these hemodynamic signals during Ex to produce the healthy arterial EC phenotype. We conclude that available evidence suggests that exercise signals formation of beneficial endothelial cell phenotype at least in part through changes in SS and wall stretch in the arteries.