The potential antihypertensive and antidiabetic activities of stevia in preventing chronic cardiovascular disease in rat models of hypertension and diabetes: Comparison to the calcium channel antagonist verapamil

Diabetes and hypertension are major contributors to cardiovascular disease which is the leading causes of death worldwide. The impact of diabetes on the cardiovascular system is high, with almost 75% of diabetic deaths being directly attributed to some form of heart or blood vessel disorder. Diabetes and hypertension induce significant damage to the heart, blood vessels and kidney. Stevia, Stevia rebaudiana Bertoni, a naturally sweet herb, has been used for several hundred years as an anti-diabetic and cardiotonic in South America. In limited human and rat trials, stevia reduced hypertension, improved insulin-sensitivity and decreased blood lipids following hypertension and diabetes. The current study aimed to identify any cardioprotective benefits of stevia in reversing and/or preventing further cardiovascular damage in animal models of type 1 diabetes and hypertension compared to the calcium channel antagonist verapamil. A mechanistic study on normal healthy tissues was also performed to establish a putative mechanism of action of stevia. The mechanistic study showed that stevia could reduce cardiac action potential duration (APD) at 20%, 50% and 90% of repolarisation, dilate vascular beds and decrease isolated ileum contraction induced by electrical field stimulation (EFS) and M3 receptor agonist carbachol. In short, our results suggested that the mechanism of action of stevia is multimodal since stevia showed beneficial modulatory effects on cardiovascular and gastrointestinal tissues which can be related to calcium channel antagonism, activation of M2 muscarinic receptor function, and via enhanced nitric oxide (NO) release. The second study examined the chronic effects of hypertension in the spontaneously hypertensive rat (SHR). Chronic dosing (8 weeks) of stevia (200 mg/kg/day) or verapamil (4 mg/kg/day) were compared in the SHR to establish if either compound could reduce the severity of cardiovascular remodelling and peripheral neuropathy following hypertension. Stevia treatment prevented maladaptive left ventricular changes, restored cardiac contractility and end systolic pressure and reduced diastolic stiffness in the hypertensive rats. Stevia also normalised liver and kidney weights compared to body weight/tibial length ratio in the SHR rats. Stevia reduced oxidative stress and inflammation as observed by significant increase in TAC and serum NO levels comopared to the unrtreated SHR. Verapamil improved systolic and diastolic functions, except for the heart rate which was significantly reduced in the SHR. The final study utilized the streptozotocin (STZ)-induced type 1 diabetic rat model with the effect of stevia and verapamil again investigated for an eight-week treatment period. The results showed that both stevia and verapamil treatment improved the maximal contractile and relaxation responses of thoracic aortic rings and mesenteric arteries, improved serum NO synthesis, total anti-oxidant capacity and malondialdehyde (MDA) levels following diabetes. Electrophysiological studies showed that stevia prevented prolongation of the action potential at 20%, 50% and 90% of repolarisation suggesting that stevia might restore sinus rhythm and reduce ventricular arrhythmogenesis following diabetes. Verapamil showed similar results invithese electrophysiological studies. In the isolated ileum, stevia prevented the gastrointestinal dysmotility following chronic diabetes. In summary, this study established that stevia can prevent the cardiovascular remodelling following diabetes and hypertension with putative mechanisms thought to be through multiple pathways such as calcium channel blockade, reduction in insulin resistance, increased NO synthesis and reduction of oxidative damage. Verapamil was also shown to be effective in these animal models acting as an anti-inflammatory, antioxidant and NO promoting treatment in addition to its primary pharmacological role.