Login to view PhD Thesis

Enter your username and password here in order to log in on the website:


Forgot your password?

Coronary artery receptor changes following myocardial ischemia-reperfusion and organ culture

Gry Freja Skovsted

Summary

Ischemic heart disease is a condition where the coronary blood supply is insufficient to meet the energy demands of the myocardium. Myocardial ischemia causes a number of complications which, depending on the severity, include impaired cardiac contractility (heart failure), arrhythmias and acute myocardial infarction (AMI). Ischemic heart disease carries high morbidity and mortality worldwide, and is the most common cause of death in most Western countries. 

Blood supply to the myocardium is regulated by coronary arteries, which by vasodilation and vasoconstriction increase and reduce blood flow, respectively. The balance between vasodilation and constriction is controlled by the availability of vasoactive substances and by the ability to transduce their signal into the smooth muscle cells. This transduction is mediated by several mechanisms including G-protein coupled receptors (GPCRs), and can be altered by changes in the density and function of the receptors, including intracellular mediators and second messengers. 

Experimental animal studies have shown that ischemic conditions in the brain can lead to alteration in the function and expression of contractile GPCRs in the smooth muscle cells of the ischemic arteries. These changes are furthermore associated with reduced blood flow in the affected areas. Similar changes in receptor expression are seen in patients with ischemic heart disease. Studies have shown that coronary arteries from patients with ischemic heart disease had altered mRNA and protein levels of contractile endothelin ETB and angiotensin II AT1 receptors. But since these studies were performed on arteries taken from the hearts of 10- 24 hours post-mortem, these results must be interpreted with caution. Accordingly, it is still unclear whether acute myocardial ischemia leads to upregulation of ETB and angiotensin II AT1 receptors in coronary artery smooth muscle cells, the mechanisms involved in the putative receptor upregulation leading to changes in the contractile function of the coronary arteries. Experimental myocardial ischemia can be performed in anesthetized rats by ligation of the left coronary artery (LAD). This operation is used as an in vivo model in this work. Ischemia-reperfusion induced an increase in AT1 and ETB receptor-mediated contractile responses in LAD 24 hours after surgery. These changes were dependent on the location of segments in relation to ligation. The increased AT1 response occurred in the coronary artery above (proximal) ligation, while increased ETB response occurred in coronary arteries downstream (distal) to ligation. The mechanisms underlying these increased receptor responses were generally different: While the increased ETB response was associated with increased ETB receptor protein levels in the smooth muscle cells; increased AT1-mediated contraction involved activation of α1-adrenoceptors, and we did not observe changes in AT1 receptor protein levels. Organ culture of isolated coronary arteries from healthy (nonoperated) rats induced a rapid increase in ETB receptor-mediated contractile response. Organ culture was used as an in vitro model to show that the MEK/ERK signalling pathway as well as a transcriptional mechanism in this receptor upregulation. 

We hope that these studies have increased understanding of the pathological mechanisms that occur in coronary arteries after myocardial ischemia. It is conceivable that an increased receptor-mediated contraction in the post-ischemic coronary arteries as seen here, can lead to decreased blood flow to the heart and cause further deterioration of cardiac ischemia-induced damage. Further studies will clarify the significance of these receptor changes in a pathophysiological perspective.