Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries

Juan Carlos Robles, Michael Sturek, Janet L. Parker, Cristine L. Heaps

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca2+-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca2+ sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (~150 (μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca2+ concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (Nω-nitro-L-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca2+ concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca2+ sensitization. Inhibition of PKC (calphostin C; 1 (μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 (μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca2+ sensitization.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Coronary Vessels
Swine
Exercise
Arteries
Endothelin-1
Phorbol 12,13-Dibutyrate
rho-Associated Kinases
Coronary Occlusion
Vasodilation
Nitric Oxide Synthase
Endothelium
Myocardium
Perfusion

Keywords

  • Coronary artery disease
  • Coronary circulation
  • Endothelin
  • Protein kinase C
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries. / Robles, Juan Carlos; Sturek, Michael; Parker, Janet L.; Heaps, Cristine L.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 300, No. 4, 04.2011.

Research output: Contribution to journalArticle

@article{07b36bf07d644211b07822ffd28bffb7,
title = "Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries",
abstract = "Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca2+-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca2+ sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (~150 (μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca2+ concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (Nω-nitro-L-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca2+ concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca2+ sensitization. Inhibition of PKC (calphostin C; 1 (μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 (μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca2+ sensitization.",
keywords = "Coronary artery disease, Coronary circulation, Endothelin, Protein kinase C, Vascular smooth muscle cell",
author = "Robles, {Juan Carlos} and Michael Sturek and Parker, {Janet L.} and Heaps, {Cristine L.}",
year = "2011",
month = "4",
doi = "10.1152/ajpheart.00957.2010",
language = "English",
volume = "300",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Ca2+ sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries

AU - Robles, Juan Carlos

AU - Sturek, Michael

AU - Parker, Janet L.

AU - Heaps, Cristine L.

PY - 2011/4

Y1 - 2011/4

N2 - Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca2+-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca2+ sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (~150 (μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca2+ concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (Nω-nitro-L-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca2+ concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca2+ sensitization. Inhibition of PKC (calphostin C; 1 (μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 (μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca2+ sensitization.

AB - Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca2+-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca2+ sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (~150 (μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca2+ concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition (Nω-nitro-L-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca2+ concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca2+ sensitization. Inhibition of PKC (calphostin C; 1 (μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 (μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca2+ sensitization.

KW - Coronary artery disease

KW - Coronary circulation

KW - Endothelin

KW - Protein kinase C

KW - Vascular smooth muscle cell

UR - http://www.scopus.com/inward/record.url?scp=79955069541&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955069541&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00957.2010

DO - 10.1152/ajpheart.00957.2010

M3 - Article

C2 - 21297028

AN - SCOPUS:79955069541

VL - 300

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 4

ER -