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Cardiovascular Research 1999 41(3):554-562; doi:10.1016/S0008-6363(98)00253-3
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Coronary vasoconstriction to endothelin-1 increases with age before and after ischaemia and reperfusion

Andrew T Goodwin, Mohamed Amrani, Adrian J Marchbank, Caroline C Gray, Jay Jayakumar and Magdi H Yacoub*

Department of Cardiac Surgery, Heart Science Centre, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK

* Corresponding author. Tel.: +44-1895-828-893; Fax: +44-1895-828-902.

Objective: Ageing is known to be associated with changes within the heart. We investigated whether the coronary response to endothelin-1 (ET) and sarafotoxin S6c (S6c) is altered with increasing age, before and after cardioplegic arrest. Methods: Using an isolated rat heart model, increasing concentrations of ET and S6c were administered to rats of different ages (group I=one month; group II=five months; group III=21 months). An identical series of experiments was performed following the addition of indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) to the Krebs perfusion fluid. In a third series of experiments, increasing doses of ET-1 were added to hearts following 4 h of cardioplegic arrest at 4°C. Results: Coronary flows are expressed as a percentage of initial coronary flow±SEM. There was a greater decrease in coronary flow in the older rats for all doses of ET-1. ET-1 (10–9 M) reduced coronary flows to 72.8±3.7, 53.2±6.7 and 56.5±10.7% for groups I–III respectively (P=0.01 I vs. II; P=0.1 I vs. III). A similar response to ET-1 was seen in hearts perfused with indomethacin and L-NAME when compared to those perfused without (P=NS). Perfusion with ET-1 (10–9 M) following 4 h of cardioplegic arrest reduced coronary flows to 40.5±4.9, 26.8±4.8 and 24.1±3.9%, respectively (P=0.08 I vs. II; P=0.03 I vs. II P=0.03 I vs. III). Perfusion with S6c (10–10 M) produced coronary flows of 93.3±5.5, 77.0±3.5 and 73.9±3.9% for groups I–III, respectively (P=0.03 I vs. II; P=0.01 I vs. III). Perfusion with S6c (10–9 M) in the presence of L-NAME and indomethacin reduced coronary flows to 85.7±3.0, 81.6±2.2 and 74.6±3.6% (P=NS I vs. II; P=0.03 I vs. III). Conclusions: The coronary vasoconstrictor response to ET-1 and S6c increases with age. The increased vasoconstriction in response to ET-1 is independent of the decrease in NO release seen with ageing.

KEYWORDS Endothelin; Sarafotoxin; Ageing; Rat hearts; Coronary artery


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