Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide, and K ATP channels

• Published in: American journal of physiology. Heart and circulatory physiology 2022-12, Vol.323 (6), p.H1080-H1090
• Main Authors: Duncker, Dirk J, Sorop, Oana, van de Wouw, Jens, Fen, Gao, de Beer, Vincent J, Taverne, Yannick J, de Graaff, Henri J D, Merkus, Daphne
• Format: Article
• Language: English
• Subjects: Adenosine - pharmacology; Adenosine Triphosphate - pharmacology; Animals; Coronary Circulation - physiology; Coronary Vessels; Dogs; Glyburide - pharmacology; KATP Channels; Nitric Oxide - metabolism; Swine; Vasodilation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00109.2021

The interplay of mechanisms regulating coronary blood flow (CBF) remains incompletely understood. Previous studies in dogs indicated that CBF regulation by K channels, adenosine, and nitric oxide (NO) follows a nonlinear redundancy design and fully accounted for exercise-induced coronary vasodilation. Conversely, in swine, these mechanisms appear to regulate CBF in a linear additive fashion with considerable exercise-induced vasodilation remaining when all three mechanisms are inhibited. A direct comparison between these studies is hampered by the different doses and administration routes (intravenous vs. intracoronary) of drugs inhibiting these mechanisms. Here, we investigated the role of K channels, adenosine, and NO in CBF regulation in swine using identical drug regimen as previously employed in dogs. Instrumented swine were exercised on a motor-driven treadmill, before and after blockade of K channels (glibenclamide, 50 µg/kg/min ic) and combination of inhibition of NO synthase ( -nitro-l-arginine, NLA, 1.5 mg/kg ic) and adenosine receptors (8-phenyltheophylline, 8PT, 5 mg/kg iv) or their combination NLA + 8PT + glibenclamide. Glibenclamide and NLA + 8PT each produced coronary vasoconstriction both at rest and during exercise, whereas the combination of NLA + 8PT + glibenclamide resulted in a small further coronary vasoconstriction compared with NLA + 8PT that was, however, less than the sum of the vasoconstriction produced by NLA + 8PT and glibenclamide, each. Thus, in contrast to previous observations in the dog, ) the coronary vasoconstrictor effect of glibenclamide was not enhanced in the presence of NLA + 8PT and ) the exercise-induced increase in CBF was largely maintained. These findings show profound species differences in the mechanisms controlling CBF at rest and during exercise. The present study demonstrates important species differences in the regulation of coronary blood flow by adenosine, NO, and K channels at rest and during exercise. In swine, these mechanisms follow a linear additive design, as opposed to dogs which follow a nonlinear redundant design. Simultaneous blockade of all three mechanisms virtually abolished exercise-induced coronary vasodilation in dogs, whereas a substantial vasodilator reserve could still be recruited during exercise in swine.