Objective: The mechanisms underlying hypercapnic coronary dilation remain unsettled. This study tests the hypothesis that flow dependent NO production is obligatory for the hypercapnic flow response.
Methods/results: In isolated, constant pressure (CP) perfused guinea pig hearts a step change of arterial pCO(2) from 38.6 to 61.4 mm Hg induced a bi-phasic flow response with an early transient (maximum 60 s) and a consecutive persisting flow rise (121.6+/-6.6 (S.D.) % after 10 min). In contrast, when perfused with constant flow (CF), perfusion pressure only transiently (2 min) fell by 7.4+/-4.8 % following the step change of arterial pCO(2). In CP perfused hearts L-NAME (100 micromol/l) specifically abolished the delayed flow rise during hypercapnic acidosis (102.37+/-2.9% after 10 min), whereas the inhibitor had no effect on perfusion pressure response in CF perfused hearts. Under CP perfusion arterial hypercapnia resulted in a transient rise of coronary cGMP release (from 0.69+/-0.35 to 1.12+/-0.68 pmol/ml), which was abolished after L-NAME. Surprisingly, the K(+)ATP channel blocker glibenclamide did not have any significant effect on the hypercapnic flow response but largely blunted reactive hyperemia after a 20 s flow stop.
Conclusions: The delayed steady state hypercapnic flow response in guinea pig heart requires intact NO production. The absence of a persisting decrease in coronary resistance under CF perfusion points to an important role of shear stress dependent NO production.