Prevention of cardiovascular damage in rat models of hypertension and diabetes mellitus by resveratrol and nebivolol

Cardiovascular disease is highly prevalent within todays society, costing the Australian public $5.9 billion and placing a significant amount of strain on the health care system. Both diabetes and hypertension are significant risk factors for the development of cardiovascular disease as they have the potential to result in major maladaptive damage occuring to not only the heart, but also to the vasculature. Research has focused on finding compounds which may help to either prevent or reverse the damaging effects of these two disorders on the body. Both pharmaceutical and nutraceutical compounds which are able to decrease inflammation and oxidative stress and/or increase nitric oxide are of particular interest. Resveratrol and nebivolol are two such compounds.

Resveratrol is a naturally occuring polyphenol which has demonstrated numerous benefical biological effects such as influencing actions at a cellular level, preventing or slowing various disease process such as cancer and diabetes, as well as displaying positive effects of inflammation, oxidative stress and nitric oxide release. Nebivolol, on the other hand, is a pharmaceutical compound used for the treatment of hypertension. Its mechanism of action has been well documented as a B-adrenoceptor receptor antagonist (B-blocker) which is highly specific for the B₁-adrenoceptor receptor. The major aim of this project was to examine both the acute and chronic effects of resveratrol and nebivolol of the cardiovascular system in an animal based model. The first two studies aimed at examining the acute effects of these two compounds on isolated cardiovascular tissues and the efficacy of nebivolol and resveratrol at decreasing blood pressure at various doses. Studies three and four aimed at investigating whether resveratrol or nebivolol could effectively prevent the maladaptive cardiovascular alterations which occur in both diabetes and hypertension and to examine the potential role of nitric oxide using animal models of both disease processes.

The results gained from the acute studies indicate that resveratrol and nebivolol decrease the action potential duration and induce mild vasorelaxation in aortic and mesenteric segments. Relaxation induced by resveratrol was prevented by the addition of a L-type calcium channel inhibitor (verapamil), a nitric oxide synthase inhibitor (Nw-nitro-L-arginine methyl ester) and a non-selective potassium channel inhibitor (4-aminopyridine). This suggests that nebivolol and resveratrol act as putative anti-arrhythmic and vasodilatory agents in vitro through possible indirect nitric oxide mechanisms. It was also established that in a rodent model of genetic hypertension, high doses of both resveratrol and nebivolol display a hypotensive effect six hours post-administration. There was also a time and dose dependent effect on heart rate seen in the nebivolol treated, but not in resveratrol treated animals. Chronic administration of either resveratrol or nebivolol in induced models of diabetes and hypertension demonstrated that both compounds provide some cardio-protective effects. Resveratrol was found to extert anti-inflammatory and antioxidant effects in both disease models and this is thought to account for the anti-arrhythmic effects seen in the cardiovasular tissues. Nebivolol exerted similar anti-arrhythmic effects on cardio-vascular tissue. It was concluded that nebivolol may exert favourable metabolic and some cardioprotective effects via the activation of the B₃-adrenoceptor and direct scavenging of free radicals.

Overall, this project demonstrates that both resveratrol and nebivolol have benefical antioxidant and anti-inflammatory actions that were found to slow the maladaptive cardiovascular alterations in animal models of diabetes and hypertension.