The concept of mild chronic vascular inflammation as part of the pathophysiology of cardiovascular disease, most importantly hypertension and atherosclerosis, has been well accepted. Indeed there are links between vascular inflammation, endothelial dysfunction and oxidative stress. However, there are still gaps in our understanding regarding this matter that might be the cause behind disappointing results of antioxidant therapy for cardiovascular risk factors in large-scale long-term randomised controlled trials. Apart from the limitations of our knowledge, limitations in methodology and assessment of the body's endogenous and exogenous oxidant-antioxidant status are a serious handicap. The pleiotropic effects of antioxidant and anti-inflammation that are shown by some well-established antihypertensive agents and statins partly support the idea of using antioxidants in vascular diseases as still relevant. This review aims to provide an overview of the links between oxidative stress, vascular inflammation, endothelial dysfunction and cardiovascular risk factors, importantly focusing on blood pressure regulation and atherosclerosis. In view of the potential benefits of antioxidants, this review will also examine the proposed role of vitamin C, vitamin E and polyphenols in cardiovascular diseases as well as the success or failure of antioxidant therapy for cardiovascular diseases in clinical trials.
In this study, we report the effects of a non-antioxidant flavonoid flavone on vascular reactivity in Wistar-Kyoto (WKY) rat isolated aortae. Whether flavone directly modulates vascular reactivity in spontaneously hypertensive rat (SHR) and streptozotocin-induced diabetic-WKY rat isolated aortae was also determined. Thoracic aortic rings were mounted in organ chambers and exposed to various drug treatments in the presence of flavone (10 microM) or its vehicle (DMSO), which served as control. Pretreatment with flavone enhanced relaxant effects to endothelium-dependent vasodilator acetylcholine (ACh) and attenuated contractile effects to alpha(1)-receptor agonist phenylephrine (PE) in WKY aortae compared to those observed in control aortic rings. Flavone had no effect on relaxations to ACh in WKY aortae incubated with either L-NAME or methylene blue, but enhanced relaxations to ACh in WKY aortae incubated with indomethacin or partially depolarized with KCl. Relaxations to ACh are totally abolished in both control or flavone pretreated endothelium-denuded WKY aortae. Flavone attenuated the inhibition by beta-NADH of ACh-induced relaxation in WKY aortae, but it had no significant effect on the transient contractions induced by beta-NADH nor the pyrogallol-induced abolishment of ACh-induced relaxation in WKY aortae. Flavone enhanced endothelium-independent relaxation to sodium nitroprusside (SNP) in both endothelium-intact and -denuded WKY aortae. Flavone enhanced relaxation to ACh and SNP as well as attenuated contractile effects to PE in SHR and diabetic aortae, a finding similar to that observed in normal WKY aortae. From these results, we conclude that flavone modulates vascular reactivity in normal as well as hypertensive and diabetic aortae. These effects of flavone results probably through enhanced bioactivity of nitric oxide released from the endothelium.
The seeds of Swietenia macrophylla King (SM) (Meliaceae) are used as a folk medicine for the treatment of hypertension in Malaysia. However, the antihypertensive and vasorelaxant effects of SM seeds are still not widely studied. Thus, this study was designed to investigate the in vivo antihypertensive effects and in vitro mechanism of vasorelaxation of a 50% ethanolic SM seed extract (SM50) and the fingerprint of SM50 was developed through tri-step Fourier transform infrared (FTIR) spectroscopy. The vasorelaxant activity and the underlying mechanisms of SM50 were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats in the presence of antagonists. The pharmacological effect of SM50 was investigated by oral administration of spontaneously hypertensive rats (SHRs) with three different doses of SM50 (1000, 500, and 250 mg/kg/day) for 4 weeks and their systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were measured weekly using tail-cuff method. The tri-step FTIR macro-fingerprint of SM50 showed that SM50 contains stachyose, flavonoids, limonoids, and ester, which may contribute to its vasorelaxant effect. The results showed that the vasorelaxant activity of SM50 was mostly attributed to channel-linked receptors pathways through the blockage of voltage-operated calcium channels (VOCC). SM50 also acts as both potassium channels opener and inositol triphosphate receptor (IP3R) inhibitor, followed by β2-adrenergic pathway, and ultimately mediated through the nitric oxide/soluble guanylyl cyclase/cyclic 3',5'-guanosine monophosphate (NO/sGC/cGMP) signaling pathways. The treatment of SM50 also significantly decreased the SBP and DBP in SHRs. In conclusion, the antihypertensive mechanism of SM50 was mediated by VOCC, K+ channels, IP3R, G-protein-coupled β2-adrenergic receptor, and followed by NO/sGC/cGMP signaling mechanism pathways in descending order. The data suggested that SM50 has the potential to be used as a herbal medicament to treat hypertension.