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Role of the endothelium in regulation of contractility in porcine retinal arterioles

Thomas Dalsgaard

Summary

This PhD thesis is based on studies performed at the Department of Pharmacology, Faculty of Health Sciences, Aarhus University, during the period January 2007 to March 2010, interrupted by a stay at the Department of Pharmacology, University of Vermont, Vermont, USA, from March 2009 to September 2009.
Disturbance in the blood supply to the retina is a common finding in retinal diseases leading to blindness. Thus, in both diabetic retinopathy and glaucoma, alterations in the retinal blood flow are involved in the disease pathogenesis. Therefore, a prerequisite for developing new treatment modalities and improving existing treatments for these diseases is to gain a profound knowledge of the underlying mechanisms regulating retinal blood flow under normal physiological and patophysiological circumstances.
The retinal blood flow is determined by perfusion pressure and vascular resistance. The vascular resistance is determined by the contractile state of vascular smooth muscle cells in the resistance arteries, and several different mechanisms exist for regulating vascular smooth muscle contractility. The perivascular tissue, the smooth muscle cells themselves, and the vascular endothelium are important for regulation of smooth muscle contractility. The vascular endothelium regulates smooth muscle contraction level through the release of vasodilating agents, such as nitric oxide (NO), prostaglandins, and the endothelium‐derived hyperpolarising factor (EDHF). This study investigated the mechanisms underlying endothelium‐dependent vasodilatation in porcine retinal arterioles. Using the wire myograph as the principal method, this study found that the endotheliumdependent vasodilatation was mediated by NO and prostaglandins. Surprisingly, no EDHF‐type relaxation was observed. However, blocking the channels commonly recognised as a part of the EDHF‐type relaxation, the small (SK) and intermediate (IK) conductance calcium‐activated potassium channels, reduced the endothelium‐dependent vasodilatation. This reduction was mainly mediated by blocking the SK channel and a reduced NO bioavailability. Furthermore, opening of SK channels enhanced endothelium‐dependent vasodilatation through increased NO bioavailability, and this enhanced vasodilatation may involve increased uptake of L‐arginine, the substrate for endothelial NO synthase. No involvement of the large (BK) conductance calcium‐activated potassium channel in vascular smooth muscle cell relaxation was observed in retinal arterioles.
This study concludes that in porcine retinal arterioles, endothelium‐dependent vasodilatation is enhanced through opening of SK channels, and that opening of SK channels increase NO bioavailability possibly through enhanced uptake of L‐arginine. These results implicate that treatment with specific SK channel openers and/or in combination with L‐arginine supplement may improve endothelium‐dependent vasodilatation and restore retinal blood flow in patients with retinal diseases that experience a reduced retinal blood flow as a part of the disease pathogenesis.