Longitudinal Gradients for Endothelium-Dependent and -Independent Vascular Responses in the Coronary Microcirculation

Abstract

Background Coronary microvessels (<300 μm in diameter) have been demonstrated to be important in the regulation of local resistance and flow. Recent studies also suggest that these microvessels are more responsive to physiological and pharmacological stimuli than conduit vessels. However, little is known regarding the relative sensitivity of different microvascular segments in response to flow (shear stress) and agonists. The goal of this study was to test the hypothesis that a longitudinal gradient for shear stress– and agonist-induced dilation exists in the coronary microcirculation. Methods and Results Experiments were performed in four different sizes of porcine subepicardial coronary arterial microvessels: small arterioles (40±1-μm ID with resting tone); intermediate arterioles (60±1 μm); large arterioles (106±4 μm); and small arteries (179±9 μm). Vessels were isolated and cannulated to allow luminal pressure and flow to be independently controlled. All vessels developed active tone (to ≈65% to 75% of maximum diameter) at their control luminal pressures and showed graded dilations to stepwise increases in shear stress (0 to 10 dynes/cm 2 ). For arterioles, the magnitude of the dilations increased as vessel size increased. The highest shear stress produced 21±3%, 32±2%, and 52±5% increases in diameter in small, intermediate, and large arterioles, respectively. Small arteries dilated only 22±6%. The endothelium-dependent vasodilator substance P (SP) produced dose-dependent dilation of all vessels with a threshold at 10 −16 mol/L. Arterioles were maximally dilated at 10 −9 mol/L SP. However, this dose produced only 80% dilation in small arteries. The ED 50 for SP was shifted to the right by two orders of magnitude in small arteries compared with the arterioles. Adenosine preferentially dilated small arterioles, and the dose-response curves shifted to the right for larger vessels. The thresholds for adenosine-induced dilation were 10 −12 , 10 −11 , and 10 −9 mol/L for small, intermediate, and large arterioles, respectively. The endothelium-independent vasodilator nitroprusside produced identical dose-dependent dilations in all vessel segments. Conclusions The results indicate that the pig coronary circulation exhibits a heterogeneity in physiological and pharmacological responses along the microvascular network. Small arterioles are more sensitive to adenosine, but large arterioles are more responsive to shear-stress stimulation. We speculate that site-specific preferential responses may play a crucial role in coordinating overall vascular function in the coronary microvascular network.