Vasoactive mediators underlying coronary tone regulation and dysregulation
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Date
2014-12-29
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Johns Hopkins University
Abstract
This dissertation illustrates the role of nitric oxide (NO) in regulating coronary tone and how impairment of NO bioavailability not only influences coronary vasoregulation but also the roles of other vasoactive mediators, namely the endothelial-derived hyperpolarizing factor (EDHF), hydrogen sulfide (H2S).
To investigate coronary function in a physiological setting, a novel technique using high-resolution ultrasound was developed to measure coronary vasodilatory response in vivo. With this method, coronary vasodilatory function was evaluated in terms of increase in coronary blood flow velocity. Vasorelaxation was induced by intravenous infusion of adenosine triphosphate and by increasing myocardial demand with β-adrenergic receptor agonist dobutamine. This approach was further adapted to measure ascending aortic stiffness in vivo, a systemic parameter that influences coronary function. Aortic diameter was measured by ultrasound while aortic pressure was measured invasively by pressure catheter. Vasoactive drugs were infused to modulate aortic pressure to obtain a pressure-diameter relationship of the ascending aorta.
These ultrasound-based techniques were then applied to investigating the effects of ionizing radiation exposure on coronary artery function. Rats exposed to ionizing radiation exhibited reduced coronary flow in vivo. Decreased coronary flow was associated with both decreased aortic diastolic pressure and elevated superoxide content in the coronary artery. Reduced diastolic pressure was attributed to decreased heart rate. Reduction of superoxide production by xanthine oxidase inhibition partially restored basal coronary flow and coronary superoxide content. However, in vivo vasodilatory response was not improved. Moreover, endothelial function was preserved in irradiated rats. These findings support that radiation-associated coronary artery disease is initiated by an increase in superoxide level, which leads to reduced NO bioavailability and diminished coronary vasodilatory response in vivo. The data further suggest that excess superoxide production precedes coronary endothelial dysfunction characteristic of coronary artery disease.
Next, the role of endogenously produced H2S in coronary tone vasoregulation and the interaction between NO and H2S were examined. Both cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), the enzymatic producers of H2S in the vasculature, were detected in human coronary endothelial cells and rat coronary arteries. In vitro measurement of H2S production showed that the rat coronary artery can produce H2S through the MPST pathway but not through the CSE pathway. Both pharmacologic inhibition and genetic deletion of CSE did not alter coronary vasodilatory function in vivo, supporting that CSE-produced H2S does not have a significant role in coronary vasoregulation. Ex vivo coronary vasoreactivity response to MPST substrate 3-mercaptopyruvate (3-MP) was similar to the vasoreactivity response to H2S donor sodium hydrosulfide (NaHS), supporting that vasoactive effects of 3-MP were through MPST-mediated production of H2S. The data demonstrate that H2S production in the coronary artery is mediated by MPST and not CSE, contrary to other vascular beds where CSE has a significant role. The data further show that the vasoactive effect of H2S is NO dependent: H2S induces coronary vasoconstriction in the presence of NO and vasorelaxation in the absence of NO. Vasoconstrictive effects of H2S appear to be due to its scavenging of NO and the resulting decrease in NO bioavailability.
This dissertation illustrates how altering the bioavailability of NO not only influences coronary vasodilatory function but also the roles of other vasoactive mediators in coronary vasoregulation. This dissertation further demonstrates the significance of in vivo influences on vascular function and the power of implementing a multi-level approach in studying vascular function. Changes in cellular signaling can be correlated to changes in physiological function, providing a more complete representation of vascular function after the introduction of a pathogenic stimulus.
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Coronary vasoregulation, coronary function