Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation. Restoration of endothelium-dependent responses by L-arginine
Related Experiment Videos
1Department of Medical Physiology, College of Medicine, Texas A&M University, College Station 77843-1114.
Insights
Atherosclerosis impairs blood vessel dilation, reducing blood flow. L-arginine supplementation restored normal vasodilation in coronary arterioles, suggesting it can counteract these effects.
Area of Science:
- Cardiovascular Research
- Endothelial Function
- Vascular Biology
Background:
- Atherosclerosis significantly impacts vascular health, particularly affecting endothelium-dependent responses.
- Endothelium-derived relaxing factor (EDRF) plays a crucial role in regulating vascular tone.
- Impaired vasodilation is a hallmark of large vessel disease.
Purpose of the Study:
- To quantify the effects of atherosclerosis on endothelium-dependent vasoactive responses in coronary arterioles.
- To investigate the potential of L-arginine to restore normal vasomotor function in atherosclerotic conditions.
- To elucidate the mechanisms underlying impaired vasodilation in the context of atherosclerosis.
Main Methods:
- Isolated, cannulated coronary arterioles from normal and atherosclerotic pigs were used for in vitro assessment.
- Dose-response curves to ADP, serotonin, and histamine were constructed to evaluate pharmacological responses.
- Flow-induced vasodilation was assessed by establishing different flow rates across the vessels.
- Vascular responses were measured before and after L-arginine administration and endothelial denudation.
Main Results:
- Arterioles from atherosclerotic pigs exhibited significantly blunted vasodilation to pharmacological stimuli (ADP, serotonin, histamine) compared to normal pigs.
- Flow-induced vasodilation, present in normal arterioles, was absent in those from atherosclerotic pigs.
- Administration of L-arginine for 40 minutes restored normal physiological and pharmacological endothelium-dependent vasodilation in atherosclerotic arterioles.
Conclusions:
- Atherosclerosis attenuates endothelium-dependent vasodilation to pharmacological agents and impairs flow-mediated dilation in downstream coronary arterioles.
- The observed abnormalities in vascular responsiveness are linked to impaired synthesis and/or release of endothelium-derived relaxing factor.
- L-arginine supplementation effectively restores normal endothelial function in the context of atherosclerosis, highlighting its therapeutic potential.
Abstract:
The goals of this study were 1) to quantitate the effects of atherosclerosis on physiological and pharmacological endothelium-dependent vasoactive responses in coronary arterioles downstream from arterial lesions and 2) to determine if administration of L-arginine, the precursor for endothelium-derived was induced in pigs, and vasomotor responses of isolated, cannulated coronary arterioles (30-70 microns in diameter) were assessed by measuring diameter changes in vitro. To assess pharmacological alterations of endothelium-dependent responses, dose-response curves were constructed to ADP, serotonin, and histamine. To assess physiological alterations in endothelial function, different flow rates were established across the vessel. Arteriolar diameters were measured in vessels from normal and atherosclerotic pigs under control conditions, after administration of L-arginine, and after endothelial denudation. In arterioles from normal pigs, administration of serotonin, histamine, or ADP produced dose-dependent vasodilation, which was abolished by endothelial denudation. In arterioles from atherosclerotic pigs, administration of histamine, serotonin, and ADP produced dilation at only the highest doses (10(-6)-10(-7) M), and the extent of dilation was only 20-30% of that observed in arterioles from normal pigs. Initiation of flow also produced vasodilation in arterioles from normal pigs that was completely abolished after endothelial denudation. In arterioles from atherosclerotic pigs, flow-induced responses were absent. These abnormal physiological and pharmacological responses (i.e., blunted vasodilation to pharmacological stimulation and to flow) were restored after administration of L-arginine for 40 minutes. The vascular responses after administration of L-arginine were not different from those observed under control conditions in arterioles from normal pigs. In addition, L-arginine did not restore vasodilation to the endothelium-dependent agonists in denuded segments. From these data in arterioles downstream from atherosclerotic lesions, we conclude that 1) the ED50 and maximal responses of endothelium-dependent vasodilation to ADP, histamine, and serotonin are attenuated; 2) the physiological response to flow, that is, flow-mediated endothelium-dependent vasodilation, is absent; and 3) the abnormality in arteriolar responsiveness during large vessel disease involves an impairment of the synthesis and/or release of endothelium-derived relaxing factor.