Deuterium oxide prevents hypertension and elevated cytosolic calcium in hypertensive rats.

Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium, has been implicated in the pathophysiology of hypertension. This study examined the dose-dependent effect of deuterium oxide (5%, 10%, or 20% in drinking water) on systolic blood pressure, aortic calcium uptake, and platelet cytosolic free calcium in spontaneously hypertensive rats. Starting at age 8 weeks, spontaneously hypertensive rats were divided into four groups of six animals each. The drinking water of groups 1, 2, 3, and 4 was replaced by 100% water and 5%, 10%, and 20% deuterium oxide in water, respectively, for another 7 weeks. Ten Wistar-Kyoto rats, age 8 weeks, were given 100% water for the next 7 weeks. The usual increase in systolic blood pressure and the associated increase in aortic calcium uptake and platelet cytosolic free calcium in spontaneously hypertensive rats at age 15 weeks was lowered in a dose-dependent manner by deuterium oxide. Deuterium oxide also prevented renal vascular changes in spontaneously hypertensive rats. A minimum dose of 10% deuterium oxide was needed to completely prevent the development of hypertension, elevated aortic calcium uptake, platelet cytosolic free calcium, and renal vascular changes in spontaneously hypertensive rats.

Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats.

BACKGROUND AND OBJECTIVES: In spontaneously hypertensive rats (SHRs), excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether a dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound that is known to increase tissue cysteine and glutathione, can lower blood pressure and normalize associated biochemical and histopathological changes in SHRs. METHODS AND RESULTS: Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the Wistar- Kyoto (WKY) rat control group and the SHR control group were given a normal diet, and the SHR-lipoic acid group was given a diet supplemented with lipoic acid (500 mg/kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared with WKY rat controls and the SHR lipoic acid group. SHR controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. CONCLUSIONS: Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.

Deuterium oxide normalizes blood pressure and elevated cytosolic calcium in rats with ethanol-induced hypertension.

This study examined the effect of 10% deuterium oxide (D2O) in drinking water on systolic blood pressure, platelet cytosolic free calcium, aortic calcium uptake and renal vascular changes in rats with ethanol-induced hypertension. Eighteen male Wistar-Kyoto rats, age seven weeks, were divided into three groups of six animals each. Group I was given water and groups II and III, 5% ethanol in drinking water for the next seven weeks. After one week, systolic blood pressure in the ethanol-treated rats was significantly higher (P < 0.01) than in rats drinking water. After seven weeks, animals in group I were continued on water, group II on 5% ethanol, group III on 5% ethanol but with the addition of 10% D2O in their drinking water for the next seven weeks. After 14 weeks, systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake was significantly higher (P < 0.01) in group II rats (given ethanol for 14 weeks) compared with rats from other groups. Ethanol-treated rats also showed smooth muscle hyperplasia with some thickening of the wall and narrowing of the lumen in small arteries and arterioles of the kidney. D2O given to ethanol-treated rats normalized their blood pressure, platelet cytosolic free calcium, aortic calcium uptake and attenuated renal vascular changes.

Ethanol- and threonine-induced hypertension in rats: a common mechanism.

OBJECTIVE: To investigate the effects of oral L-threonine and ethanol, precursor of endogenous acetaldehyde, on systolic blood pressure, cystolic free calcium ([Ca2+]i) and vascular calcium uptake in Wistar-Kyoto (WKY) rats. METHODS: Twenty-four male WKY rats aged eight weeks were divided into four groups of six animals each. Animals were given either water or 5% ethanol, 8% L-threonine or 8% L-glycine in drinking water for 15 weeks, animals were sacrificed, aortic rings were incubated in physiological buffer containing 45Ca2+ and uptake was measured after 20 mins. ([Ca2+]i in platelets was measured with a fluorescence [Ca2+]i indicator, FURA-2. Tissues were processed for morphological investigation. RESULTS: After 15 weeks, systolic blood pressure, platelet [Ca2+]i and aortic calcium uptake were all significantly higher (P < 0.001) in rats given either threonine or ethanol than in control rats given water or glycine. Animals in threonine or ethanol group also showed smooth muscle cell hyperplasia, with some thickening of the wall and narrowing of the lumen in small arteries and arterioles of the kidney. Glycine treatment did not cause any of these changes in rats. CONCLUSION: These results suggest that acetaldehyde may be a common cause of both ethanol- and threonine-induced hypertension.

IgA nephropathy in adults: immunohistologic findings and clinical course.

Laboratory examination of specimens from 123 consecutive renal biopsies performed at Victoria General Hospital, Halifax revealed six cases of mesangial deposition, predominantly of IgA, unassociated with systemic disorders. Immunohistologic examination showed deposits of only IgA in one specimen, IgA and IgG in two and IgA, IgG and IgM in three. Glomerular deposits of C3 were seen in five of the specimens, and properdin was seen in three. Glomeruli in all the specimens showed increased matrix and increased numbers of cells in the mesangium. Electron microscopy revealed deposits in the mesangium or capillary wall in all five of the specimens so studied. All six patients had proteinuria, four had microscopic hematuria, and three had hypertension; in one patient the disease progressed to renal failure.

Argentaffin cells, intestinal metaplasia and antral metaplasia in carcinoma of the gall bladder.

The occurrence of argentaffin cells, intestinal metaplasia, and antral metaplasia has been studied in 20 gall bladders with carcinomas, in a papilloma, and in 20 specimens of cholelithiasis. Argentaffin cells were present in six carcinomas, but in only one specimen were they present in large numbers. Only one adenocarcinoma contained occasional argyrophil cells and no argentaffin or argyrophil cells were seen in the papilloma. Five of the 20 specimens of cholelithiasis contained occasional argentaffin cells. Intestinal and antral metaplasia were found in four carcinomas, in the papilloma, and in seven of the 20 specimens of cholelithiasis. It is suggested that metaplastic changes may play a role in the pathogenesis of carcinoma of the gall bladder.

Hashimoto's thyroiditis with medullary carcinoma.

The association of Hashimoto's thyroiditis with lymphoma and papillary carcinoma has been recognized, but there have been few reports of an association between Hashimoto's thyroiditis and medullary carcinoma of the thyroid gland, especially in Canada. The authors report three cases, seen in an 18-month period, of Hashimoto's thyroiditis and medullary carcinoma in patients whose relatives had multiple endocrine neoplasia type II. The findings support the view that the thyroiditis occurred in response to the tumour process and not vice versa.

Oral heparin prevents hypertension and elevated cytosolic calcium in salt-sensitive rats.

This study examined the effect of oral heparin on systolic blood pressure, platelet cytosolic free calcium, aortic calcium uptake and renal vascular changes in Dahl salt-sensitive (DS) rats on low (0.4% NaCl) and high (8% NaCl) salt diet. Twenty-four male DS rats, age 8 weeks, were divided into four groups of 6 animals each. Groups I and II were on low salt diet and groups III and IV on the high salt diet. Additionally, groups I and III were placed on 100% H2O and groups II and IV on sodium heparin 0.5 mg/ml in H2O as their drinking water for a period of 6 weeks. At 14 weeks, systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake were significantly higher in rats on high salt diet and water compared with rats from all other groups. Oral heparin treatment prevented the increase in systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in rats on high salt diet. Heparin also prevented or attenuated the onset of adverse renal vascular changes observed in Dahl salt-sensitive rats on high salt diet. Oral heparin treatment did not cause abnormal hematological, biochemical or pathological changes in rats.

Dietary vitamin E supplementation lowers blood pressure in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin E increases tissue glutathione levels--a storage form of cysteine. The aim of the present study was to investigate whether a dietary supplementation of vitamin E lowers blood pressure and prevents renal vascular changes by normalizing tissue aldehyde conjugates and cytosolic [Ca2+] in SHRs. Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin E group a diet supplemented with vitamin E (34 mg/ kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin E group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Dietary vitamin E supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+], tissue aldehyde conjugates and attenuated adverse renal vascular changes.

Dietary vitamin E and C supplementation prevents fructose induced hypertension in rats.

In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound N-acetyl cysteine prevents fructose-induced hypertension by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether dietary supplementation of vitamin E and vitamin C which are known to increase tissue glutathione, a storage form of cysteine, prevents this hypertension and its associated biochemical and histopathological changes. Starting at 7 weeks of age, animals were divided into four groups of six animals each and treated as follows: control group, normal diet and normal drinking water; fructose group, normal diet and 4% fructose in drinking water; fructose + vitamin E group, diet supplemented with vitamin E (34 mg/ kg feed) and 4% fructose in drinking water; fructose + vitamin C group, diet supplemented with vitamin C (1,000 mg/kg feed) and 4% fructose in drinking water. At 14 weeks, systolic blood pressure, platelet [Ca2+]i and kidney and aortic aldehyde conjugates were significantly higher in the fructose group. These animals also displayed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin E and C supplementation in fructose-treated WKY rats prevented the increase in systolic blood pressure by normalizing cytosolic [Ca2+]i and kidney and aortic aldehyde conjugates and preventing adverse renal vascular changes.

Fructose-induced hypertension, hypertriglyceridemia and elevated cytosolic calcium in rats: prevention by deuterium oxide.

We examined the effect of 5% deuterium oxide (D20) in drinking water on systolic blood pressure, platelet cytosolic free calcium, aortic calcium uptake and plasma insulin, glucose and triglycerides in rats with fructose-induced hypertension. Eighteen male Wistar-Kyoto (WKY) rats, age 8 weeks, were divided into 3 groups of 6 animals each. Animals in group I were given water; group II, 8% fructose and group III, 8% fructose + 5% D20 as their drinking water for the next 15 weeks. Systolic blood pressure in the fructose treated rats was significantly higher (p < 0.01) than in animals on water after 2 weeks and remained higher throughout the study. At 15 weeks, systolic blood pressure, platelet cytosolic calcium, aortic calcium uptake and plasma glucose, insulin and triglycerides were significantly higher (p < 0.01) in the fructose treated rats compared with rats from other groups. Deuterium oxide given together with fructose prevented development of high blood pressure and the associated increase in platelet cytosolic calcium, aortic calcium uptake and plasma triglycerides. D20 treatment did not prevent fructose induced increases in plasma insulin and glucose. The parallel increase in systolic blood pressure, cytosolic free calcium, and in vascular calcium uptake suggests that an increased cytosolic free calcium is involved in the pathophysiology of hypertension. D20 prevents this hypertension by normalizing cytosolic free calcium.

Oral heparin normalizes blood pressure and elevated cytosolic calcium in hypertensive rats.

Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium has been implicated in the pathophysiology of hypertension. This study examined the effect of oral heparin on systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Starting at age 12 weeks, each strain of rats were divided into 2 groups (6 animals in each group); the control group was placed on H2O (100%) and the experimental group was placed on H2O with heparin (0.5 mg sodium heparin/ml H2O) for a period of nine weeks. At 21 weeks, systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake were significantly higher in spontaneously hypertensive rats on water compared with spontaneously hypertensive rats on heparin and Wistar-Kyoto rats on water and on heparin. Oral heparin treatment normalized the elevated platelet cytosolic free calcium, aortic calcium uptake and systolic blood pressure in spontaneously hypertensive rats but had no effect on Wistar-Kyoto rats. Heparin also prevented onset of adverse renal vascular changes observed in spontaneously hypertensive rats. Oral heparin treatment did not cause abnormal hematological, biochemical or pathological changes in rats.

Dietary vitamin C supplementation lowers blood pressure in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin C can increase tissue cysteine and glutathione levels. The aim of the present study was to investigate whether a dietary supplementation of vitamin C can lower tissue aldehydes and blood pressure and normalize associated biochemical and histopathological changes in SHRs. Starting at 12 weeks of age, animals were divided into 3 groups of 6 animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin C group a diet supplemented with vitamin C (1000 mg/kg feed) for the next 9 weeks. After nine weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin C group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin C supplementation in SHRs lowered the systolic blood pressure, tissue aldehyde conjugates and attenuated adverse renal vascular changes.

Aldehyde induced hypertension in rats: prevention by N-acetyl cysteine.

Methylglyoxal, a highly reactive endogenous aldehyde is formed in the tissue of humans and animals as an intermediate of glucose and fructose metabolism. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet [Ca2+]i, circulating nitric oxide levels, tissue aldehyde conjugates and renal vascular changes in chronic methyglyoxal treated Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals, age seven weeks, were divided into three groups of six animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-methylglyoxal (chow diet and methyglyoxal in drinking water); WKY-methyglyoxal + NAC (1.5% NAC in diet and methylglyoxal in drinking water) for the next 18 weeks. Methylgyoxal in drinking water was given at a concentration of 0.2% during weeks 0-5; 0.4%, weeks 6-10; and 0.8%, weeks 11-18. After 18 weeks systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were significantly higher and serum nitric oxide levels lower in methylglyoxal treated rats. Methylglyoxal treated rats also showed smooth muscle cell hyperplasia in the small artery and arterioles of the kidney. N-acetyl cysteine, an aldehyde binding thiol compound, prevented these changes.

Ethanol induced hypertension in rats: reversibility and role of intracellular cytosolic calcium.

This study examined the reversibility of chronic ethanol induced increase in systolic blood pressure, elevated platelet cytosolic free calcium and aortic calcium uptake in rats and the effect of a calcium channel blocker on these changes. Twenty-four male Wistar-Kyoto rats, age 7 weeks, were divided into 4 groups of 6 animals each. Animals in group I were given water and group II, III and IV, 5% ethanol in drinking water for the next 7 weeks. Systolic blood pressure in the ethanol treated rats was significantly higher (p < 0.01) than in controls after 1 week and remained higher. After 7 weeks, group I was continued on water, group II on ethanol, group III was continued on ethanol but with the addition of verapamil 5 mg/100 ml in their drinking water and group IV was returned to normal drinking water for the next 7 weeks. After 14 weeks, systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake was significantly higher (p < 0.01) in rats given ethanol for 14 weeks and also in rats given ethanol for 7 weeks followed by water for 7 weeks as compared to controls. These two groups also showed smooth muscle cell hyperplasia with some thickening of the wall and narrowing of the lumen in small arteries and arterioles of kidney. Verapamil given to the ethanol treated rats normalized their blood pressure, platelet cytosolic free calcium, aortic calcium uptake and attenuated renal vascular changes. Discontinuation of ethanol treatment for 7 weeks did not reverse the hypertension or the adverse renal vascular changes in ethanol induced hypertensive rats.

Oral treatment with low molecular weight heparin normalizes blood pressure in hypertensive rats.

Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium has been implicated in the pathophysiology of hypertension. This study examined the effect of oral low molecular weight heparin (Logiparin) on systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in spontaneously hypertensive rats. Starting at age 12 weeks, spontaneously hypertensive rats were divided into three groups of six animals each. The drinking water of groups 1, 2 and 3 was replaced by 100% H2O, 0.5 mg (low dose) or 1 mg (high dose) low molecular weight heparin/ml H2O, respectively, for next 11 weeks. Six normotensive Wistar-Kyoto rats (age 12 weeks) on H2O and six on low dose heparin in H2O were used as controls. At age 23 weeks, increase in systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in spontaneously hypertensive rats was significantly lowered by low dose LMW heparin as compared to spontaneously hypertensive rats on H2O, but was significantly higher than Wistar-Kyoto rats on H2O and LMW heparin. This dose of heparin did not have any effect on these parameters in normotensive Wistar-Kyoto rats. High dose LMW heparin normalized the elevated platelet cytosolic free calcium, aortic calcium uptake and systolic blood pressure in spontaneously hypertensive rats, but it had a limited effect on adverse renal vascular changes. Oral low molecular weight heparin did not cause any abnormal hematological, biochemical or pathological changes in rats.

N-acetyl cysteine attenuates ethanol induced hypertension in rats.

All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. N-acetyl cysteine, an analogue of the dietary amino acid cysteine, binds acetaldehyde, thus preventing its damaging effect on physiological proteins. This study examined the effect of oral N-acetyl cysteine on the increased blood pressure, platelet cytosolic free calcium, blood acetaldehyde and adverse renal vascular changes induced by chronic ethanol treatment in rats. Twenty-four male Wistar-Kyoto (WKY) rats, age 7 weeks were divided into four groups of six animals each. Animals in group I were given water and group II 5% ethanol in water for the next 14 weeks. Animals in group III were given 5% ethanol + 1% N-acetyl cysteine for 4 weeks followed by 5% ethanol + 2% N-acetyl cysteine for the next 10 weeks. Animals in group IV were given 5% ethanol for 7 weeks; at that time ethanol was withdrawn and animals were placed on water with 2% N-acetyl cysteine for the next 7 weeks. After 14 weeks systolic blood pressure and platelet cytosolic free calcium were all significantly higher (p<0.001) in rats given ethanol as compared to rats in other groups. N-acetyl cysteine treatment, along with ethanol, significantly (p<0.001) attenuated the increased blood pressure and platelet cytosolic free calcium and adverse renal vascular changes. Discontinuation of ethanol treatment for 7 weeks along with N-acetyl cysteine supplementation also significantly lowered the blood pressure and platelet cytosolic free calcium and attenuated adverse renal vascular changes. There was no significant difference in aortic malonaldehyde among four groups. Increase in blood acetaldehyde with ethanol treatment was significantly attenuated with N-acetyl cysteine treatment. These results suggest that acetaldehyde may be the cause of ethanol-induced hypertension and elevated cytosolic free calcium and renal vascular changes.

Antihypertensive effect of low ethanol intake in spontaneously hypertensive rats.

Light to moderate drinking in humans lowers the risk of coronary heart disease and may lower blood pressure. We examined the effect of chronic low daily alcohol consumption on blood pressure, platelet cytosolic free calcium [Ca2+]i, tissue aldehyde conjugates and renal vascular changes in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). We also examined the effects of the same weekly amount of alcohol consumption over a one day period each week simulating weekend drinking in humans. Animals, age 7 weeks, were divided into six groups of six animals each and were treated as follows: WKY and SHR control, normal drinking water; WKY and SHR, 0.5% ethanol in drinking water; WKY and SHR, 3.5% ethanol in drinking water one day/week. After 14 weeks systolic blood pressure, platelet [Ca2+]i, liver, kidney and aortic aldehyde conjugates were significantly higher (p < 0.05) in untreated SHRs as compared to untreated WKYs. Daily 0.5% ethanol consumption in SHRs significantly (p < 0.05) attenuated these changes and also attenuated smooth muscle cell hyperplasia and narrowing of the lumen in small arteries and arterioles of the kidney. WKY rats treated with 0.5% ethanol had lower aldehyde conjugates without any significant effect on blood pressure and platelet [Ca2+]i as compared to WKY controls. Consumption of 3.5% ethanol one day/week did not affect blood pressure and associated changes in normotensive WKY rats or hypertensive SHRs as compared to their respective controls. These results suggest that chronic daily low ethanol intake lowers blood pressure in SHRs by lowering tissue aldehyde conjugates and cytosolic free calcium.

Dietary vitamin B6 supplementation attenuates hypertension in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels, increasing cytosolic free calcium and blood pressure. N-acetyl cysteine normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. It is known that dietary vitamin B6 supplementation can increase the level of endogenous cysteine. Our objective was to investigate whether a dietary supplementation of vitamin B6 can prevent hypertension and associated changes in SHRs. Starting at 7 weeks of age, animals were divided into three groups of six animals each. Animals in WKY-control group and SHR-control group were given a normal vitamin B6 diet; and SHR-vitamin B6 group, a high vitamin B6 diet (20 times the recommended dietary intake; RDA) for the next 14 weeks. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls compared to WKY controls. These animals also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation attenuated the increase in systolic blood pressure, tissue aldehyde conjugates and associated changes. These results further support the hypothesis that aldehydes are involved in increased systolic blood pressure in SHRs and suggest that vitamin B6 supplementation may be an effective antihypertensive.