Copyright © 2005, European Society of Cardiology
Exaggerated coronary vasoreactivity to endothelin-1 in aged rats: Role of protein kinase C
aDepartment of Kinesiology, The Pennsylvania State University, 106 Noll Laboratory, University Park, PA 16802, United States
bDepartment of Kinesiology, Texas A&M University, College Station TX, United States
cBiomedical Sciences, University of Missouri, Columbia MO, United States
* Corresponding author. Tel.: +1 814 865 5679; fax: +1 814 865 4602. Email address: dhk102{at}psu.edu
Objective: The interaction between advanced age and increased susceptibility to ischemic insult is well documented. Age-related increases in coronary vascular resistance, in part due to impaired dilator responses, have been reported. Our aim was to determine the role of endothelin-1 (ET-1) on enhanced constrictor responses in aged coronary arteries (CAs) and whether protein kinase C (PKC) signaling mechanisms impact ET-1 responses.
Methods: Vasoreactivity was assessed in CAs isolated from aged (24 months; n=16) and adult (4 months; n=21) male F344 rats following ET-1 (10–10–10–8) with and without specific ETA/ETB receptor antagonists (BQ-123, 1 µM; BQ-788, 30 nM) or the PKC inhibitor bisindolylmaleimide (Bis; 10–6 M). Constrictor responses to KCl (80 mM) were also measured and voltage-gated Ca2+ channel (VGCC) determined in isolated coronary smooth muscle cells. Dilator responses to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed.
Results: Passive diameter was greater (357 ± 19 vs. 309 ± 9; p<0.02) while spontaneous tone was similar in 24 months vs. 4 months. ET-1 resulted in greater constriction in 24 months vs. 4 months (79% vs. 67%; p<0.01). Group differences persisted following selective ETB inhibition with BQ-788 (p<0.02), while BQ-123 abolished contractile responses to ET-1. Importantly, inhibition of ET-1 constriction by Bis occurred in 24 months but not 4 months (p<0.01). Constrictor responses to KCl and peak VGCC current density were similar in 24 months vs. 4 months (48% vs. 50%). No age-related differences were observed in ACH- or SNP-mediated dilation. Western blotting revealed increases in Ca2+-sensitive PKC
, -βI, and -βII levels with age, while eNOS and ETA receptor protein levels were unchanged.
Conclusion: Aberrant ETA constrictor responses and directional changes in PKC are likely to contribute to coronary vascular pathology with advanced age.
KEYWORDS Senescence; Vascular smooth muscle; Endothelium; ETA and ETB receptors; eNOS
Time for primary review 18 days
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