## 3 Effect of PS on Components of MetS
### Effect of PS on Hypertension  
Increased blood pressure is regarded as a critical component of MetS. Even in the absence of diabetes, more than 85% of individuals with MetS have high blood pressure (BP) or hypertension [92]. Oxidative stress and inflammation have been implicated in the pathogenesis of hypertension. Oxidative stress and inflammation increase ROS accumulation, which reduces the bioavailability of the protective vasodilator NO and modulates endothelial function, vascular tone, and cardiac function [93; 94]. Furthermore, ROS has been linked to pathological processes, such as inflammation, hypertrophy, apoptosis, fibrosis, and vessel rarefaction. These factors contribute to the development of endothelial dysfunction and cardiovascular remodelling, which are hallmarks of hypertension [95; 96]. As a result, reducing oxidative stress, primarily using antioxidant molecules, may be beneficial in preventing and treating hypertension. Several studies reported the hypotensive effect of PS. In male Wistar rats with Nu-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension, the aqueous leaf extract of PS (125, 250, and 500 mg/kg/day for 4 weeks) reduced systolic, diastolic, and mean arterial blood pressure [97]. Similar observations were obtained in dexamethasone-induced [98,99] and spontaneously hypertensive rats treated with PS [24,100,101]. The hypotensive effect of PS could be attributed to its ability to increase vasodilation and decrease vasoconstriction. Endothelin-1 (ET-1) is a potent vasoconstrtictor that increases blood pressure and contributes to the development of hypertension [102,103]. The aqueous leaf extract of PS (500 mg/kg/day for 28 days) reduced the ET-1 level in the mesenteric artery, suggesting that it reduced vasoconstriction in hypertensive rats. Endothelial nitric oxide synthase (eNOS) is the major enzyme responsible for NO production in the blood vessels. NO is a powerful vasodilator and its reduction can negatively impact endothelial-dependent vasodilation, leading to increased peripheral resistance and blood pressure [104]. The aqueous extract of PS increased the expression and activity of eNOS in the thoracic aorta, increased the serum level of eNOS and increased the levels of NO in the serum and mesenteric artery of L-NAME and dexamethasone-induced and spontaneously hypertensive rats [24,97,98,100,101]. This is suggestive of a vasodilatory effect of PS in hypertensive rats. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of NO synthase, and elevated levels of ADMA inhibits NO synthesis [105]. PS supplementation reduced the plasma ADMA levels in spontaneously hypertensive rats [101], thus preventing the inhibition of NO production in hypertensive rats and helped vasodilation. The circulating MDA level was reduced by PS supplementation in L-NAME-induced hypertensive rats (125, 250, and 500 mg/kg/day of the aqueous leaf extract of PS for 4 weeks) [97] and spontaneously hypertensive rats (SHR) (0.5, 1, and 2 mg/kg/day of aqueous extract of PS for 28 days) [24]. These observations indicate that the antioxidant effects of PS were related to its anti-hypertensive properties. However, supplementation with the aqueous leaf extract of PS did not change the heart rate, lactate dehydrogenase, and creatine phosphokinase in SHRs. These observations suggest that it was ineffective in preventing hypertension-induced cardiac tissue injury [24]. The action of PS could be  
Figure 3: Protective effect of PS supplementation against hyperglycemia and T2 DM: current knowledge and future area of investigation. List of abbreviations: PS, _Piper symmetosum_; \(\uparrow\), increase; \(\downarrow\), decrease; \(+\), in combination with. nullified because oxidative stress is not involved in the development of hypertension in SHRs. Results from gene expression studies on the brain of SHRs suggest that albumin and chymase in the presence of angiotensin and prostaglandin E receptor 4 are responsible for causing hypertension in SHRs [106].