Role of endogenous endothelin in the regulation of basal coronary tone in the rat.
1. Coronary vascular tone is a vital factor that regulates the delivery of oxygen to cardiac muscle. We tested the hypothesis that basal coronary tone may depend on the release of an endogenous vasoconstrictor peptide, endothelin (ET). 2. Using an isolated, Krebs solution-perfused rat heart we measured the changes in coronary flow following the administration over a 30 min period of the ET antagonists Ro61-0612 (mixed ETA/ETB), PD155080 (ETA) and BQ788 (ETB). 3. In a second series of experiments, hearts were randomly assigned to perfusion with plain Krebs solution, or with Krebs solution to which L-NAME and/or indomethacin had been added. The effect on coronary flow following the addition of Ro61-0612 was then measured. 4. Perfusion with Ro61-0612 (10-4 M) alone increased coronary flow by 57.8 % vs. control (P = 0.00001). PD155080 (10-4 M) increased coronary flow by 28.9 % (P = 0.009), whereas BQ788 had no effect on coronary flow. 5. In the second series of experiments, Ro61-0612 increased coronary flow by 6.6 +/- 0.8 ml min-1 in hearts perfused with plain Krebs solution, by 3.8 +/- 0.8 ml min-1 in hearts to which both L-NAME and indomethacin had been added, by 3.3 +/- 0.7 ml min-1 in hearts to which L-NAME had been added, and by 6. 9 +/- 0.5 ml min-1 in hearts to which indomethacin had been added to the Krebs buffer. 6. In hearts perfused with Krebs solution alone, nitric oxide (NO) release into the coronary sinus increased from 219. 8 to 544.9 pmol min-1 g-1 following the addition of Ro61-0612 (P = 0. 06). There was no detectable release of NO from hearts perfused with L-NAME alone or in combination with indomethacin either before or after the addition of Ro61-0612. 7. We conclude that endogenous ET plays a role in coronary tone mediated via ETA receptors. This vasodilatation is partially due to an increase in endogenous NO release. However, a significant vasodilatation is still seen following the inhibition of NO synthesis. We propose that basal coronary tone depends on a balance between the endogenous release of vasodilators such as NO and vasoconstrictors such as ET.
Department of Cardiac Surgery, Heart Science Centre, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK.
A T
AT
Goodwin
M
M
Amrani
C C
CC
Gray
J
J
Jayakumar
M H
MH
Yacoub
D000818:Animals; D003331:Coronary Vessels / Q000502:physiology*; D004558:Electric Stimulation; D004594:Electrophysiology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011464:Epoprostenol; D019001:Nitric Oxide Synthase