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Impaired Coronary Endothelial Vasorelaxation in a Preclinical Model of Peripheral Arterial Insufficiency.

Arce-Esquivel AA, Bunker AK, Simmons GH, Yang HT, Laughlin MH, Terjung RL - J Heart Cardiol (2015)

Bottom Line: Vasorelaxation to ADP was reduced in LADs from Occl-Sed and Occl-Ex pigs (P<0.001) as compared to Non-Occl-Con pigs; however, Occl-Ex pigs exhibited partial recovery (P<0.001) intermediate to the other two groups.In addition, SNP, PE, Ang II, and ET-1 responses were not significantly different among the groups.Our results indicate that 'simple' occlusion of the femoral arteries induces vascular dysfunction in conduit vessels distinct from the affected hindlimbs, as evident in blunted coronary vasorelaxation responses to ADP and BK.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri ; Department of Health and Kinesiology, The University of Texas at Tyler, Tyler, Texas.

ABSTRACT

The present study was designed to determine whether adult swine with peripheral artery insufficiency (PAI) would exhibit vascular dysfunction in vessels distinct from the affected distal limbs, the coronary conduit arteries. Moreover, we sought to evaluate the effect of exercise training on coronary vasomotor function in PAI. Eighteen female healthy young Yucatan miniature swine were randomly assigned to either occluded exercise trained (Occl-Ex, n=7), or occluded-sedentary (Occl-Sed, n=5), or non-occluded, non-exercised control (Non-Occl-Con, n=6) groups. Occl-Ex pigs were progressively trained by running on a treadmill (5days/week, 12 weeks). The left descending artery (LAD) and left circumflex (LCX) coronary arteries were harvested. Vasorelaxation to adenosine diphosphate (ADP), bradykinin (BK), and sodium nitro-prusside (SNP) were assessed in LAD's; while constrictor responses to phenylephrine (PE), angiotensin II (Ang II), and endothelin-1 (ET-1) were assessed in LCX's. Vasorelaxation to ADP was reduced in LADs from Occl-Sed and Occl-Ex pigs (P<0.001) as compared to Non-Occl-Con pigs; however, Occl-Ex pigs exhibited partial recovery (P<0.001) intermediate to the other two groups. BK induced relaxation was reduced in LADs from Occl-Ex and Occl-Sed pigs (P<0.001), compared to Non-Occl-Con, and exercise modestly increased responses to BK (P<0.05). In addition, SNP, PE, Ang II, and ET-1 responses were not significantly different among the groups. Our results indicate that 'simple' occlusion of the femoral arteries induces vascular dysfunction in conduit vessels distinct from the affected hindlimbs, as evident in blunted coronary vasorelaxation responses to ADP and BK. These findings imply that PAI, even in the absence of frank atherogenic vascular disease, contributes to vascular dysfunction in the coronary arteries that could exacerbate disease outcome in patients with peripheral artery disease. Further, regular daily physical activity partially recovered the deficit observed in the coronary arteries.

No MeSH data available.


Related in: MedlinePlus

Concentration-response curves for adenosine diphosphate (ADP)-induced relaxation of isolated left descending coronary artery rings from non-occluded control (Non-Occl-Con, n=6); occluded exercise trained (Occl-Ex, n=7); and occluded sedentary (Occl-Sed, n=5) pigs. Data were obtained for Intact vesssels (panel A); in the presence of L-NAME (panel B); in the presence of Indo (panel C); in the presence of both, L-NAME + Indo (panel D); in the presence of L-NAME + Indo + 30 MM KCl (panel E); and denuded vessels (panel F). Values are means ± SE.*Non-Occl-Con greater than both Occl-Sed and Occl-Ex (p<0.001);** Occl-Ex greater than Occl-Sed (P<0.001);¥(P < 0.05);L-NAME decreased values in all groups (P<0.001);ΩIndo increased values in all groups (P<0.001), in a dose-dependent manner, but retained the relative differences among groups;£L-NAME + Indo eliminated the differences between groups (cf., panel A) by decreasing values of Non-Occl-Con group (P<0.001) and increasing values in Occl-Sed group (P<0.05) with dose-group interaction (p<0.001);§L-NAME added to Indo decreased values in all groups (P<0.001); ØIndo added to L-NAME elevated values in Occl-Sed and Occl-Ex (P<0.001) and eliminated the training effect observed with L-NAME only.
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Figure 2: Concentration-response curves for adenosine diphosphate (ADP)-induced relaxation of isolated left descending coronary artery rings from non-occluded control (Non-Occl-Con, n=6); occluded exercise trained (Occl-Ex, n=7); and occluded sedentary (Occl-Sed, n=5) pigs. Data were obtained for Intact vesssels (panel A); in the presence of L-NAME (panel B); in the presence of Indo (panel C); in the presence of both, L-NAME + Indo (panel D); in the presence of L-NAME + Indo + 30 MM KCl (panel E); and denuded vessels (panel F). Values are means ± SE.*Non-Occl-Con greater than both Occl-Sed and Occl-Ex (p<0.001);** Occl-Ex greater than Occl-Sed (P<0.001);¥(P < 0.05);L-NAME decreased values in all groups (P<0.001);ΩIndo increased values in all groups (P<0.001), in a dose-dependent manner, but retained the relative differences among groups;£L-NAME + Indo eliminated the differences between groups (cf., panel A) by decreasing values of Non-Occl-Con group (P<0.001) and increasing values in Occl-Sed group (P<0.05) with dose-group interaction (p<0.001);§L-NAME added to Indo decreased values in all groups (P<0.001); ØIndo added to L-NAME elevated values in Occl-Sed and Occl-Ex (P<0.001) and eliminated the training effect observed with L-NAME only.

Mentions: As illustrated in (Fig. 2), ADP-induced relaxation was significantly reduced by femoral artery occlusion, as the relaxation curve for the intact Occl-Sed group coronary vessels was much less (P<0.001), and exhibited a greater EC50 (Table 3), than the Non-Occl-Con group. Interestingly, the ADP-induced relaxation curve of the Occl-Ex group (Fig. 2A) was intermediate (P<0.001) from the deficit of the Occl-Sed group. ADP-induced relaxation was in part inhibited by L-NAME in all groups (Fig. 2B), although the relative relationships among the curves remained. The response of the Occl-Sed group remained below (P<0.001) that of the Non-Occl-Con group with the relaxation curve of the Occl-Ex intermediate (P<0.05) in a dose-dependent manner (Fig. 2B). Further, there was an increase in dilatation in all groups (P<0.001), in a dose-dependent manner, when Indo was added to the bath (Fig. 2C). The Non-Occl-Con group was greater than both other groups (P<0.001) and the Occl-Ex group greater than the Occl-Sed group (P<0.05) in a dose-dependent manner. Consistently, the relative sensitivities to ADP, as evident in EC50 (Table 3), were unchanged by either L-NAME or Indo. However, in the presence of both L-NAME and Indo ADP-induced relaxation became similar among all three groups (Fig. 2D), due in part to decreasing values in the Non-Occl-Con group (P<0.001) and increasing values in the Occl-Sed group (P<0.05) with dose-group interactions (P<0.001). It should be recognized that the ADP-induced relaxation remained rather robust for all three groups (i.e., different from zero), indicating that pathways different from NOS and COX are important for vasorelaxation. In contrast, ADP-induced relaxation was markedly inhibited by L-NAME + Indo + KCl (Fig. 2E) leading to a reduced sensitivity to ADP (Table 3); however, some vasorelaxation remained implying that additional mechanisms might play a role. When the endothelium was removed from the LAD rings, ADP-induced relaxation was robust and similar among all three groups; this indicates that ADP works on both endothelial and vascular smooth muscle cells (Fig. 2F). Importantly, following removal of the endothelium there were no longer any differences in the responses of the three different groups indicating that all of the effects of femoral artery occlusion and exercise training were mediated through the endothelium.


Impaired Coronary Endothelial Vasorelaxation in a Preclinical Model of Peripheral Arterial Insufficiency.

Arce-Esquivel AA, Bunker AK, Simmons GH, Yang HT, Laughlin MH, Terjung RL - J Heart Cardiol (2015)

Concentration-response curves for adenosine diphosphate (ADP)-induced relaxation of isolated left descending coronary artery rings from non-occluded control (Non-Occl-Con, n=6); occluded exercise trained (Occl-Ex, n=7); and occluded sedentary (Occl-Sed, n=5) pigs. Data were obtained for Intact vesssels (panel A); in the presence of L-NAME (panel B); in the presence of Indo (panel C); in the presence of both, L-NAME + Indo (panel D); in the presence of L-NAME + Indo + 30 MM KCl (panel E); and denuded vessels (panel F). Values are means ± SE.*Non-Occl-Con greater than both Occl-Sed and Occl-Ex (p<0.001);** Occl-Ex greater than Occl-Sed (P<0.001);¥(P < 0.05);L-NAME decreased values in all groups (P<0.001);ΩIndo increased values in all groups (P<0.001), in a dose-dependent manner, but retained the relative differences among groups;£L-NAME + Indo eliminated the differences between groups (cf., panel A) by decreasing values of Non-Occl-Con group (P<0.001) and increasing values in Occl-Sed group (P<0.05) with dose-group interaction (p<0.001);§L-NAME added to Indo decreased values in all groups (P<0.001); ØIndo added to L-NAME elevated values in Occl-Sed and Occl-Ex (P<0.001) and eliminated the training effect observed with L-NAME only.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696773&req=5

Figure 2: Concentration-response curves for adenosine diphosphate (ADP)-induced relaxation of isolated left descending coronary artery rings from non-occluded control (Non-Occl-Con, n=6); occluded exercise trained (Occl-Ex, n=7); and occluded sedentary (Occl-Sed, n=5) pigs. Data were obtained for Intact vesssels (panel A); in the presence of L-NAME (panel B); in the presence of Indo (panel C); in the presence of both, L-NAME + Indo (panel D); in the presence of L-NAME + Indo + 30 MM KCl (panel E); and denuded vessels (panel F). Values are means ± SE.*Non-Occl-Con greater than both Occl-Sed and Occl-Ex (p<0.001);** Occl-Ex greater than Occl-Sed (P<0.001);¥(P < 0.05);L-NAME decreased values in all groups (P<0.001);ΩIndo increased values in all groups (P<0.001), in a dose-dependent manner, but retained the relative differences among groups;£L-NAME + Indo eliminated the differences between groups (cf., panel A) by decreasing values of Non-Occl-Con group (P<0.001) and increasing values in Occl-Sed group (P<0.05) with dose-group interaction (p<0.001);§L-NAME added to Indo decreased values in all groups (P<0.001); ØIndo added to L-NAME elevated values in Occl-Sed and Occl-Ex (P<0.001) and eliminated the training effect observed with L-NAME only.
Mentions: As illustrated in (Fig. 2), ADP-induced relaxation was significantly reduced by femoral artery occlusion, as the relaxation curve for the intact Occl-Sed group coronary vessels was much less (P<0.001), and exhibited a greater EC50 (Table 3), than the Non-Occl-Con group. Interestingly, the ADP-induced relaxation curve of the Occl-Ex group (Fig. 2A) was intermediate (P<0.001) from the deficit of the Occl-Sed group. ADP-induced relaxation was in part inhibited by L-NAME in all groups (Fig. 2B), although the relative relationships among the curves remained. The response of the Occl-Sed group remained below (P<0.001) that of the Non-Occl-Con group with the relaxation curve of the Occl-Ex intermediate (P<0.05) in a dose-dependent manner (Fig. 2B). Further, there was an increase in dilatation in all groups (P<0.001), in a dose-dependent manner, when Indo was added to the bath (Fig. 2C). The Non-Occl-Con group was greater than both other groups (P<0.001) and the Occl-Ex group greater than the Occl-Sed group (P<0.05) in a dose-dependent manner. Consistently, the relative sensitivities to ADP, as evident in EC50 (Table 3), were unchanged by either L-NAME or Indo. However, in the presence of both L-NAME and Indo ADP-induced relaxation became similar among all three groups (Fig. 2D), due in part to decreasing values in the Non-Occl-Con group (P<0.001) and increasing values in the Occl-Sed group (P<0.05) with dose-group interactions (P<0.001). It should be recognized that the ADP-induced relaxation remained rather robust for all three groups (i.e., different from zero), indicating that pathways different from NOS and COX are important for vasorelaxation. In contrast, ADP-induced relaxation was markedly inhibited by L-NAME + Indo + KCl (Fig. 2E) leading to a reduced sensitivity to ADP (Table 3); however, some vasorelaxation remained implying that additional mechanisms might play a role. When the endothelium was removed from the LAD rings, ADP-induced relaxation was robust and similar among all three groups; this indicates that ADP works on both endothelial and vascular smooth muscle cells (Fig. 2F). Importantly, following removal of the endothelium there were no longer any differences in the responses of the three different groups indicating that all of the effects of femoral artery occlusion and exercise training were mediated through the endothelium.

Bottom Line: Vasorelaxation to ADP was reduced in LADs from Occl-Sed and Occl-Ex pigs (P<0.001) as compared to Non-Occl-Con pigs; however, Occl-Ex pigs exhibited partial recovery (P<0.001) intermediate to the other two groups.In addition, SNP, PE, Ang II, and ET-1 responses were not significantly different among the groups.Our results indicate that 'simple' occlusion of the femoral arteries induces vascular dysfunction in conduit vessels distinct from the affected hindlimbs, as evident in blunted coronary vasorelaxation responses to ADP and BK.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri ; Department of Health and Kinesiology, The University of Texas at Tyler, Tyler, Texas.

ABSTRACT

The present study was designed to determine whether adult swine with peripheral artery insufficiency (PAI) would exhibit vascular dysfunction in vessels distinct from the affected distal limbs, the coronary conduit arteries. Moreover, we sought to evaluate the effect of exercise training on coronary vasomotor function in PAI. Eighteen female healthy young Yucatan miniature swine were randomly assigned to either occluded exercise trained (Occl-Ex, n=7), or occluded-sedentary (Occl-Sed, n=5), or non-occluded, non-exercised control (Non-Occl-Con, n=6) groups. Occl-Ex pigs were progressively trained by running on a treadmill (5days/week, 12 weeks). The left descending artery (LAD) and left circumflex (LCX) coronary arteries were harvested. Vasorelaxation to adenosine diphosphate (ADP), bradykinin (BK), and sodium nitro-prusside (SNP) were assessed in LAD's; while constrictor responses to phenylephrine (PE), angiotensin II (Ang II), and endothelin-1 (ET-1) were assessed in LCX's. Vasorelaxation to ADP was reduced in LADs from Occl-Sed and Occl-Ex pigs (P<0.001) as compared to Non-Occl-Con pigs; however, Occl-Ex pigs exhibited partial recovery (P<0.001) intermediate to the other two groups. BK induced relaxation was reduced in LADs from Occl-Ex and Occl-Sed pigs (P<0.001), compared to Non-Occl-Con, and exercise modestly increased responses to BK (P<0.05). In addition, SNP, PE, Ang II, and ET-1 responses were not significantly different among the groups. Our results indicate that 'simple' occlusion of the femoral arteries induces vascular dysfunction in conduit vessels distinct from the affected hindlimbs, as evident in blunted coronary vasorelaxation responses to ADP and BK. These findings imply that PAI, even in the absence of frank atherogenic vascular disease, contributes to vascular dysfunction in the coronary arteries that could exacerbate disease outcome in patients with peripheral artery disease. Further, regular daily physical activity partially recovered the deficit observed in the coronary arteries.

No MeSH data available.


Related in: MedlinePlus