Exercise Training‐Induced Adaptations in Mediators of Sustained Endothelium‐Dependent Coronary Artery Relaxation in a Porcine Model of Ischemic Heart Disease

Abstract

Objective Test the hypothesis that exercise training enhances sustained relaxation to persistent endothelium-dependent vasodilator exposure via increased nitric oxide contribution in small coronary arteries of control and ischemic hearts. Methods Yucatan swine were designated to a control group or a group in which an ameroid constrictor was placed around the proximal LCX. Subsequently, pigs from both groups were assigned to exercise (5 days/week; 16 weeks) or sedentary regimens. Coronary arteries (~100–350 μm) were isolated from control pigs and from both nonoccluded and collateral-dependent regions of chronically-occluded hearts. Results In arteries from control pigs, training significantly enhanced relaxation responses to increasing concentrations of bradykinin (10−10 to 10−7 M) and sustained relaxation to a single bradykinin concentration (30 nM), which were abolished by NOS inhibition. Training also significantly prolonged bradykinin-mediated relaxation in collateral-dependent arteries of occluded pigs, which was associated with more persistent increases in endothelial cellular Ca2+ levels, and reversed with NOS inhibition. Protein levels for eNOS and p-eNOS-(Ser1179), but not caveolin-1, Hsp90, or Akt, were significantly increased with occlusion, independent of training state. Conclusions Exercise training enhances sustained relaxation to endothelium-dependent agonist stimulation in small arteries of control and ischemic hearts by enhanced nitric oxide contribution and endothelial Ca2+ responses.

Adaptations of the Endothelin System After Exercise Training in a Porcine Model of Ischemic Heart Disease

“…These data are consistent with our more recent findings that endothelial nitric oxide synthase protein is significantly increased in collateral-dependent compared with nonoccluded arteries of exercise-trained pigs [23]. We have also reported enhanced bradykinin-mediated relaxation in collateral-dependent arteries of exercise-trained pigs that is reversed by NOS inhibition [23]. Furthermore, others have reported that nitric oxide synthase inhibition decreases blood flow into the collateral-dependent region more so during exercise than at rest [53], providing evidence that the contribution of nitric oxide increases as coronary metabolic demand rises in the compromised myocardial region.…”

“…Indeed, we have previously reported that NOS inhibition results in a significant increase in sensitivity (EC 50 ) to ET-1 in collateral-dependent but not nonoccluded arteries of exercisetrained pigs [46]. These data are consistent with our more recent findings that endothelial nitric oxide synthase protein is significantly increased in collateral-dependent compared with nonoccluded arteries of exercise-trained pigs [23]. We have also reported enhanced bradykinin-mediated relaxation in collateral-dependent arteries of exercise-trained pigs that is reversed by NOS inhibition [23].…”

“…Taken together with our previous data [46], these findings suggest that upregulation of a signaling pathway initiated at the ET A receptor, such as that mediated by PKC, may be the primary mechanism underlying exercise-training-enhanced ET-1 contractile responses in collateral-dependent arteries. Previous data from our laboratory also demonstrate enhanced vasodilatory mechanisms in these small collateral-dependent arteries of exercisetrained pigs [23,46], suggesting adaptations in both vasoconstrictor and vasodilator pathways that may interact to optimize control of coronary blood flow into the compromised myocardium.…”

“…Numbers in parentheses represent number of animals. RT L 95 , arterial RT, where L 95 = 0.95* L 100 and L 100 is the internal circumference that the artery would have been under a transmural pressure of 100 mmHg, as previously described. No significant differences exist.…”

Roles of sarcoplasmic reticulum Ca2+ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

“…Intracellular Ca 2+ levels were measured using fura-2AM in phenol-free DMEM media as described [65][66][67] . LMCs were plated in glass bottom chamber and treated when LMCs reached 60% confluence.…”