title: Coronary vasoconstriction to endothelin-1 increases with age before and after ischaemia and reperfusion.
abstract: 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 degrees 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. 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.
authors.affiliation: Department of Cardiac Surgery, Heart Science Centre, Harefield Hospital, Middlesex, UK.
authors.forename: A T
authors.initials: AT
authors.lastname: Goodwin
authors.forename: M
authors.initials: M
authors.lastname: Amrani
authors.forename: A J
authors.initials: AJ
authors.lastname: Marchbank
authors.forename: C C
authors.initials: CC
authors.lastname: Gray
authors.forename: J
authors.initials: J
authors.lastname: Jayakumar
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D006324:Heart Arrest, Induced; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011184:Postoperative Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin