Essential hypertension is the leading contributor to premature death worldwide. Endoplasmic reticulum (ER) stress has recently been implicated in diseased blood vessels and hypertension. It is unclear whether ER stress is a cause or a consequence of hypertension. We hypothesized that ER stress inhibition would prevent the development of hypertension in the young spontaneously hypertensive rat (SHR) by improving vascular structure and function. The SHR was used as a genetic model of human essential hypertension, and the Wistar Kyoto (WKY) rat as its normotensive control. The first study conducted involved assessing the levels of ER stress in young SHRs, before they developed hypertension. The second study conducted involved treating rats with 1g/kg/day of the sodium salt of 4-phenylbutyric acid (4-PBA) orally for 8 weeks from 5 weeks of age. Blood pressure was measured weekly, noninvasively via radiotelemetry. Mesenteric arteries were collected at sacrifice. Finally, the third study conducted involved treating rats with 1g/kg/day 4-PBA orally for eight weeks from five weeks of age, and then withdrawing the drug for four weeks to determine if drug treatment created a sustained lowering of blood pressure. In the first study, ER stress markers were observed to be significantly increased in the young SHR when compared to the WKY. In the second study, blood pressure was observed to be significantly lower in the 4-PBA-treated SHR groups than in the untreated SHRs. In addition, mesenteric arteries from the 4-PBA treated SHRs had a significant decrease in media/lumen ratio, ER stress marker expressions, as well as improved vasodilatory response to carbachol and reduced contractile responses to phenylephrine. In the third study, 4-PBA was able to keep the blood pressure low for one week after withdrawal, however, blood pressure returned to similar levels as untreated SHRs by the end of three weeks. Overall, ER stress inhibition, via 4-PBA, blunted the development of hypertension in the SHR. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22174 |
| Date | 06 1900 |
| Creators | Naiel, Safaa |
| Contributors | Dickhout, Jeffrey, Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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