UBC Theses and Dissertations
The effects of phentolamine on fructose-fed rats Zhou, Kangbin
The present project was designed to establish a pharmacological profile of phentolamine, a non-selective α adrenergic receptor antagonist, to provide information as to whether phentolamine might be effective on preventing the blood pressure elevation in fructose fed rats, a well-established rodent model of metabolic syndrome. Male Wistar rats fed with a 60% fructose diet for 14 weeks were found to have elevated blood pressure and insulin resistance. Phentolamine treatment prevented this increase in blood pressure without affecting insulin resistance. To further investigate the mechanism of action of phentolamine in preventing the blood pressure elevation, the levels of plasma noradrenaline and angiotensin II, two proposed contributors to the development of elevated blood pressure, were examined. Neither noradrenaline nor angiotensin II was affected by phentolamine. Phentolamine is known to cause tachycardia mediated by indirect β adrenergic receptor activation. Cardiac tissue apoptosis was used as a marker to evaluate the extent of possible cardiac toxicity. The results suggest that there was no significant increase of apoptosis caused by in the phentolamine-treated rats. To examine the effects of phentolamine on cardiac β receptors, the activities of the dominant β receptors (β₁) were examined by measuring the phosphorylation of two downstream effectors, protein kinase A (PKA) and phospholamban since both proteins are activated through phosphorylation upon β₁ receptor activation. The phosphorylation levels of PKA were similar among all four animal groups while those of phospholamban were decreased significantly by phentolamine, suggesting chronic administration of phentolamine may have desensitized these receptors leading to a decrease in their activities. Plasma 8-isoprostane and total nitrate/nitrite were chosen as markers to evaluate the state of oxidative stress, a proposed mechanism of fructose-induced elevated blood pressure and insulin resistance. Plasma levels of 8-isoprostane were similar among all four animal groups while those of total nitrate/nitrite (an index of total nitric oxide production) index of were about 7 folds higher in the fructose fed animals regardless of the treatment of phentolamine. This suggests an increased level of oxidative stress since overproduction of nitric oxide has been shown to lead to an elevation in peroxynitrite which can cause oxidative damage.
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