Please use this identifier to cite or link to this item:
|Title:||A Structural Basis for the Genesis of Hypertension in the Spontaneously Hypertensive Rat|
|Authors:||Dickhout, Jeffrey G.|
|Keywords:||Medical Sciences;Medical Sciences|
|Abstract:||<p>The spontaneously hypertensive rat (SHR) was used as a model of human essential hypertension. The overall hypothesis was that hypertrophy of the smooth muscle layer of small muscular arteries in essential hypertension results in greater contractility of these vessels that then results in elevated total peripheral resistance and higher blood pressures. Elevated total peripheral resistance and small artery hypertrophy are well documented in the SHR, however, it remains unknown if these changes are the cause of result of elevated blood pressure. For this reason, we have focused our studies on young SHR during the initiation of hypertension to attempt to separate cause from effect. Studies were done to determine when SHR's blood pressure begins to differ from its normotensive control the Wistar-Kyoto rat (WKY). We found that blood pressure began to diverge between SHR and WKY at four weeks of age. Structural and functional differences between small muscular arteries from the mesenteric vascular bed of 4-week old SHR and age matched WKY controls were studied using a new morphometric protcol involving confocal microscopy and a pressurized artery myograph. Arteries from SHR had a larger medial volume, increased number of smooth muscle cell layers, but similar lumen size when compared with WKY in the maximally relaxed condition. Functional studies showed that SHR arteries contracted more in response to stimulation by KC1 and norepinephrine, resulting in significantly smaller lumen size in these vessels as compared to WKY. We concluded that structural and functional differences in SHR arteries were primary changes which may contribute to the development of hypertension. Further studies were conducted to determine if a differential incidence of apoptosis during the development of SHR and WKY arteries contributes to the structural differences. One to two week old animals were used for these studies since at this time the structure was similar between the strains. To measure the incidence of apoptosis, we used both DNA laddering and end labeling. It was found that SHR had a significantly decreased incidence of apoptosis over WKY. The cellular nature of the medial layer hypertrophy in SHR at 4-weeks was also assessed. Numerical density of smooth muscle cell nuclei in the medial layer was measured with a three dimensional disector method under confocal microscopy. We found that the numerical density of medial smooth muscle cells was significantly less in SHR than WKY, and the number of smooth muscle cells was significantly less in SHR than WKY, and the number of smooth muscle cells was similar between the strains. The smooth muscle cell length from SHR was significantly longer than WKY. We concluded that increased smooth muscle cell length in prehypertensive SHR is responsible for their increased medial volume. These studies have shown that medial layer hypertrophy due to smooth muscle cell lengthening in the small muscular arteries of SHR which increases their contractile ability, occurs at the initiation of hypertension. This evidence demonstrates that structural and functional changes in these SHR arteries can not be the result of increased blood pressure but may be a factor causing hypertension by increasing the total peripheral resistance in these animals.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.