R. Vella

Resveratrol Prevents Cardiovascular Complications in the SHR/STZ Rat by Reductions in Oxidative Stress and Inflammation

The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrols antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes.

Resveratrol shows neuronal and vascular-protective effects in older, obese, streptozotocin-induced diabetic rats.

Diabetes-induced CVD is the most significant complication of prolonged hyperglycaemia. The aim of this study was to determine whether resveratrol, a polyphenol antioxidant compound, when administered at a dose that can be reasonably obtained through supplementation could prevent the development of cardiovascular complications in older, obese, diabetic rats. Diabetes was induced in 6-month old, obese, male Wistar rats via a single intravenous dose of streptozotocin (65 mg/kg). Randomly selected animals were administered resveratrol (2 mg/kg) via oral gavage daily for 8 weeks. Body weights, blood glucose levels, food intake and water consumption were monitored, and assessments of vascular reactivity, tactile allodynia and left ventricular function were performed. Resveratrol therapy significantly improved tactile allodynia and vascular contractile functionality in diabetic rats (P<0·05). There were no significant changes in standardised vasorelaxation responses, plasma glucose concentrations, water consumption, body weight, left ventricular hypertrophy, kidney hypertrophy, heart rate or left ventricular compliance with resveratrol administration. Resveratrol-mediated improvements in vascular and nerve function in old, obese, diabetic rats were associated with its reported antioxidant effects. Resveratrol did not improve cardiac function nor mitigate the classic clinical symptoms of diabetes mellitus (i.e. hyperglycaemia, polydypsia and a failure to thrive). This suggests that supplementation with resveratrol at a dose achievable with commercially available supplements would not produce significant cardioprotective effects in people with diabetes mellitus.

The effect of lipophilicity and dose on the frequency of statin-associated muscle symptoms: A systematic review and meta-analysis

&NA; Addressing the factors which lead to the development of statin‐associated muscle symptoms (SAMS) is vital for maintaining patient compliance with these pharmaceuticals, and thus improving patient outcomes. This study aimed to clarify the relationship between statin lipophilicity, or dose, and the frequency of adverse muscle symptoms using a systematic review of randomised controlled trials (RCTs). RCTs, including statin monotherapy and placebo groups, which reported data on muscle adverse events were identified through the PubMed and Scopus databases. Risk ratios (RRs) and 95% confidence intervals (CI) were pooled using a random‐effects meta‐analysis. A total of 135 RCTs were included in this review. Statin therapy was associated with a significant, but modest, increase in the risk of adverse muscle symptoms compared to placebo (RR = 1.050; 95% CI = 1.014–1.089; P = 0.007; I2 = 3.291%). This significant association was primarily due to the inclusion of RCTs recruiting participants with a history of statin intolerance. Lipophilic statins had no appreciable impact on the development of SAMS compared to hydrophilic formulations. A univariate meta‐regression of dose (standardised to atorvastatin dose equivalents) and the risk of musculoskeletal complaints also showed no significant association. The results obtained from this meta‐analysis indicate that there is a slight increase in the risk of SAMS, especially in individuals with a history of statin intolerance. There is limited evidence to suggest that the risk of SAMS would differ between the use of lipophilic and hydrophilic statins, or high‐ and low‐dose therapy.

Investigation of long chain omega-3 PUFAs on arterial blood pressure, vascular reactivity and survival in angiotensin II-infused Apolipoprotein E knockout mice

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease. Long chain omega‐3 polyunsaturated fatty acids (LC n‐3 PUFAs) decrease inflammation and oxidative stress in an angiotensin II‐infused apolipoprotein E‐knockout (ApoE−/−) mouse model of AAA. This study investigated the effects of LC n‐3 PUFAs on blood pressure and vascular reactivity in fourteen angiotensin II‐infused ApoE−/− male mice. Blood pressure was obtained using a non‐invasive tail cuff method and whole blood was collected by cardiac puncture. Vascular reactivity of the thoracic aorta was assessed using wire myography and activation of endothelial nitric oxide synthase (eNOS) was determined by immunohistochemistry. A high LC n‐3 PUFA diet increased the omega‐3 index and reduced the n‐6 to n‐3 PUFA ratio. At day 10 post‐infusion with angiotensin II, there was no difference in systolic blood pressure or diastolic blood pressure in mice fed the high or low n‐3 PUFA diets. The high LC n‐3 PUFA diet resulted in a non‐significant trend for delay in time to death from abdominal aortic rupture. Vascular reactivity and eNOS activation remained unchanged in mice fed the high compared to the low LC n‐3 PUFA diet. This study argues against direct improvement in vascular reactivity in ApoE−/− mice that were supplemented with n‐3 PUFA for 8 weeks prior to infusion with angiotensin II.

Δ9-Tetrahydrocannabinol Prevents Cardiovascular Dysfunction in STZ-Diabetic Wistar-Kyoto Rats

The aim of this study was to determine if chronic, low-dose administration of a nonspecific cannabinoid receptor agonist could provide cardioprotective effects in a model of type I diabetes mellitus. Diabetes was induced in eight-week-old male Wistar-Kyoto rats via a single intravenous dose of streptozotocin (65 mg kg−1). Following the induction of diabetes, Δ9-tetrahydrocannabinol was administered via intraperitoneal injection (0.15 mg kg−1 day−1) for an eight-week period until the animals reached sixteen weeks of age. Upon completion of the treatment regime, assessments of vascular reactivity and left ventricular function and electrophysiology were made, as were serum markers of oxidative stress and lipid peroxidation. Δ9-Tetrahydrocannabinol administration to diabetic animals significantly reduced blood glucose concentrations and attenuated pathological changes in serum markers of oxidative stress and lipid peroxidation. Positive changes to biochemical indices in diabetic animals conferred improvements in myocardial and vascular function. This study demonstrates that chronic, low-dose administration of Δ9-tetrahydrocannabinol can elicit antihyperglycaemic and antioxidant effects in diabetic animals, leading to improvements in end organ function of the cardiovascular system. Implications from this study suggest that cannabinoid receptors may be a potential new target for the treatment of diabetes-induced cardiovascular disease.

Validation of a clinically-relevant rodent model of statin-associated muscle symptoms for use in pharmacological studies

&NA; Various rodent models of statin‐associated muscle symptoms (SAMS) have been used to investigate the aetiology of statin myotoxicity. Variability between these models, however, may be contributing to the ambiguity currently surrounding the pathogenesis of SAMS. Furthermore, few studies have assessed the reproducibility of these models. The aim of this study was to compare two established rodent models of statin myotoxicity, differing in treatment duration and dose, to determine which reproducibly caused changes characteristic of SAMS. Isolated skeletal muscle organ bath experiments, biochemical analyses, real‐time quantitative‐PCR and biometric assessments were used to compare changes in skeletal muscle and renal integrity in statin‐treated animals and time‐matched control groups. The SIM80 model (80 mg kg−1 day−1 simvastatin for 14 days) produced fibre‐selective skeletal muscle damage characteristic of SAMS. Indeed, fast‐twitch gastrocnemius muscles showed increased Atrogin‐1 expression, reduced peak force of contraction and decreased Myh2 expression while slow‐twitch soleus muscles were unaffected. Contrastingly, the SIM50 model (50 mg kg−1 day−1 simvastatin for 30 days) produced little evidence of significant skeletal muscle damage. Neither statin treatment protocol caused significant pathological changes to the kidney. The results of this study indicate that the SIM80 model induces a type of SAMS in rodents that resembles the presentation of statin‐induced myalgia in humans. The findings support that the SIM80 model is reproducible and can thus be reliably used as a platform to assess the aetiology and treatment of this condition. HighlightsDifferent SAMS models produce different changes in skeletal muscle integrity.The SIM80 model produces myotoxicity characteristic of SAMS.The effects of the SIM80 model are fibre‐selective.The SIM80 model should be used for pharmacological studies of SAMS.

(−)-Epicatechin Reduces Blood Pressure and Improves Left Ventricular Function and Compliance in Deoxycorticosterone Acetate-Salt Hypertensive Rats

(−)-Epicatechin (E) is a flavanol found in green tea and cocoa and has been shown to attenuate tumour necrosis factor alpha (TNF-α)-mediated inflammation, improve nitric oxide levels, promote endothelial nitric oxide synthase (eNOS) activation and inhibit NADPH oxidase. This study investigated the effect of 28 days of low epicatechin dosing (1 mg/kg/day) on the cardiovascular function of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Wistar rats (n = 120, 8 weeks of age) underwent uninephrectomy and were randomised into four groups (uninephrectomy (UNX), UNX + E, DOCA, DOCA + E). DOCA and DOCA + E rats received 1% NaCl drinking water along with subcutaneous injections of 25 mg deoxycorticosterone-acetate (in 0.4 mL of dimethylformamide) every fourth day. UNX + E and DOCA + E rats received 1 mg/kg/day of epicatechin by oral gavage. Single-cell micro-electrode electrophysiology, Langendorff isolated-heart assessment and isolated aorta and mesenteric organ baths were used to assess cardiovascular parameters. Serum malondialdehyde concentration was used as a marker of oxidative stress. Myocardial stiffness was increased and left ventricular compliance significantly diminished in the DOCA control group, and these changes were attenuated by epicatechin treatment (p < 0.05). Additionally, the DOCA + E rats showed significantly reduced blood pressure and malondialdehyde concentrations; however, there was no improvement in left ventricular hypertrophy, electrophysiology or vascular function. This study demonstrates the ability of epicatechin to reduce blood pressure, prevent myocardial stiffening and preserve cardiac compliance in hypertrophied DOCA-salt rat hearts.