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

Dirk J. Duncker*, Oana Sorop, Jens van de Wouw, Gao Fen, Vincent J. de Beer, Yannick J. Taverne, Henri J.D. de Graaff, Daphne Merkus*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The interplay of mechanisms regulating coronary blood flow (CBF) remains incompletely understood. Previous studies in dogs indicated that CBF regulation by KATP 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 KATP 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 KATP channels (glibenclamide, 50 µg/kg/min ic) and combination of inhibition of NO synthase (Nω-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, 1) the coronary vasoconstrictor effect of glibenclamide was not enhanced in the presence of NLA + 8PT and 2) 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.NEW & NOTEWORTHY The present study demonstrates important species differences in the regulation of coronary blood flow by adenosine, NO, and KATP 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.

Original languageEnglish
Pages (from-to)H1080-H1090
JournalAmerican journal of physiology. Heart and circulatory physiology
Volume323
Issue number6
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
This study was supported by Dutch CardioVascular Alliance (an initiative with support of the Dutch Heart Foundation) Grant 2020B008 RECONNEXT (to D.J.D. and D.M.) and German Center for Cardiovascular Research (DZHK) Grant 81Z0600207 (to D.M.).

Publisher Copyright:
Copyright © 2022 the American Physiological Society.

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