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Therapeutic Implications of Nitrite in Hypertension

Ling WC, Mustafa MR, Murugan DD

J Cardiovasc Pharmacol, 2020 02;75(2):123-134.
PMID: 31651673 DOI: 10.1097/FJC.0000000000000771

Nitrite, an anion produced from the oxidative breakdown of nitric oxide (NO), has traditionally been viewed as an inert molecule. However, this dogma has been challenged with the findings that nitrite can be readily reduced to NO under pathological conditions, hence representing a physiologically relevant storage reservoir of NO either in the blood or tissues. Nitrite administration has been demonstrated to improve myocardial function in subjects with heart failure and to lower the blood pressure in hypertensive subjects. Thus, extensive amount of work has since been carried out to investigate the therapeutic potential of nitrite in treating cardiovascular diseases, especially hypertension. Studies done on several animal models of hypertension have demonstrated the efficacy of nitrite in preventing and ameliorating the pathological changes associated with the disease. This brief review of the current findings aims to re-evaluate the use of nitrite for the treatment of hypertension and in particular to highlight its role in improving endothelial function.

Matched MeSH terms: Endothelium, Vascular/physiopathology
Lipid peroxidation in the descending thoracic aorta of rats deprived of REM sleep using the inverted flowerpot technique

Nawi A, Eu KL, Faris ANA, Wan Ahmad WAN, Noordin L

Exp Physiol, 2020 08;105(8):1223-1231.
PMID: 32539237 DOI: 10.1113/EP088667

NEW FINDINGS: What is the central question of this study? Deprivation of rapid eye movement (REM) sleep is associated with increased oxidative stress, but its effects on the blood vessels are poorly documented. We investigated whether REM sleep deprivation induces oxidative stress and causes lipid peroxidation in the aorta. What is the main finding and its important? We demonstrate that REM sleep deprivation induces oxidative stress and mediates lipid peroxidation in the aorta. This can cause endothelial changes and increased blood pressure. These findings will contribute to the growing body of literature on the mechanism underlying the effects of sleep deprivation on cardiovascular disease.
ABSTRACT: Oxidative stress-mediated lipid peroxidation is a known cause of endothelial injury or dysfunction. Deprivation of rapid eye movement (REM) sleep is associated with oxidative stress. To date, the pathogenesis of increased blood pressure after sleep deprivation remains poorly understood, particularly in the REM sleep phase. Our aim was to investigate the effects of REM sleep deprivation on blood vessels in the REM sleep-deprived rat model. Twenty-eight male Sprague-Dawley rats were divided into four equal groups: free-moving control rats, rats deprived of REM sleep for 72 h (REMsd), tank control rats and 72 h sleep-recovered rats after 72 h of REM sleep deprivation. The rats were deprived of REM sleep using the inverted flowerpot technique. Food consumption, body weight gain and systolic blood pressure were monitored. At the end of the experiment, the descending thoracic aorta was isolated for the measurement of oxidative stress markers. Despite a significant increase in food consumption in the REMsd group compared with the other groups, there was a significant reduction in body weight gain. Systolic blood pressure also showed a significant increase in the REMsd group compared with the other groups. Superoxide dismutase activity was significantly lower and malondialdehyde concentrations significantly higher in the REMsd group compared with the other groups. Increased levels of malondialdehyde are suggestive of lipid peroxidation in the blood vessels, and oxidative stress may be attributed to the initiation of the process. The changes after REM sleep deprivation revert during sleep recovery. In conclusion, the findings of the present study provide convincing evidence that REM sleep deprivation induced lipid peroxidation, leading to endothelial damage.

Matched MeSH terms: Endothelium, Vascular/physiopathology*
Fulltext Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

Azemi AK, Mokhtar SS, Rasool AHG

Oxid Med Cell Longev, 2020;2020:7572892.
PMID: 32879653 DOI: 10.1155/2020/7572892

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.

Matched MeSH terms: Endothelium, Vascular/physiopathology*
Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation

Wee CL, Mokhtar SS, Banga Singh KK, Rasool AHG

Microvasc Res, 2021 Nov;138:104227.
PMID: 34324883 DOI: 10.1016/j.mvr.2021.104227

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 μg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.

Matched MeSH terms: Endothelium, Vascular/physiopathology
Fulltext Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress

Wee CL, Mokhtar SS, Singh KKB, Yahaya S, Leung SWS, Rasool AHG

Oxid Med Cell Longev, 2021;2021:3109294.
PMID: 33623633 DOI: 10.1155/2021/3109294

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 μg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Matched MeSH terms: Endothelium, Vascular/physiopathology*