Exaggerated coronary vasoreactivity to endothelin-1 in aged rats: Role of protein kinase C

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Abstract
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; ppB inhibition with BQ-788 (pp2+-sensitive PKCα, -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.

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