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Plant sterols have been incorporated into nutritional fats to achieve cholesterol lowering, but studies using enrichment of low-fat foods with plant sterols have not been reported. Our study was aimed at determining the effect of dietary intake of low-fat foods containing natural nonesterified plant sterols together with recommended doses of calcium, magnesium, and potassium on serum cholesterol and low-density lipoprotein (LDL) cholesterol-lowering in persons with mild to moderate hypercholesterolemia. This was a randomized, double-blind, placebo-controlled feeding trial lasting 15 weeks and performed in 2 university hospital centers. Seventy-eight subjects aged 25 to 75 years with serum cholesterol concentrations varying between 6 mmol/L (232 mg/dl) and 8 mmol/L (310 mg/dl) were randomly allocated to active treatment consisting of intake of bread, meat products, and jam enriched with 1.25 to 5.0 g/day of plant sterols and the slightly elevated concentrations of mineral nutrients, or the corresponding placebo food items. Serum lipid, high-density lipoprotein cholesterol and calculated LDL cholesterol concentrations were determined. Seventy-one persons completed the trial. Reduction in serum total cholesterol was 8% in the active treatment group and 3% in the placebo group (p = 0.0071) and that of LDL cholesterol was 13% in the active treatment group and 5% in the placebo group (p = 0.0070). In conclusion, natural nonesterified plant sterols contained in low-fat food items and ingested in moderate doses reduced serum total and LDL cholesterol concentrations to the same extent as reported previously for esterified plant sterol derivatives added to nutritional fats. The presence of mineral nutrients in doses recommended for blood pressure-lowering did not interfere with the cholesterol-lowering efficacy of the sterols, providing a promising approach to dietary prevention of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Galactoglucomannans (GGM) recovered from abundant forest industry side-streams has been widely recognized as a renewable hydrocolloid. The low molar mass and presence of O-acetyl side-groups results in low viscous dispersions and weak intermolecular interactions that make GGM unsuitable for hydrogel formation, unless forcefully chemically derivatized and/or crosslinked with other polymers. Here we present the characterization of hydrogels prepared from GGM after tailoring the degree of acetylation by alkaline treatment during its recovery. Specifically, we investigated gel characteristics of low-acetyl GGM dispersions prepared at varied solid concentrations (5, 10 and 15 %) and pH (4, 7 and 10), and then subjected to ultrasonication. The results indicated that low-acetyl GGM dispersions formed gels (G' > G″) at all other studied solid concentration and pH level combinations except 5 % and pH 4. High pH levels, leading to further removal of acetyl groups, and high solid concentration facilitated the gel formation. GGM hydrogels were weak gels with strong shear-thinning behavior and thixotropic properties, and high hardness and water holding capacity; which were enhanced with increased pH and solid concentration, and prolonged storage time. Our study showed the possibility to utilize low-acetyl GGM as mildly processed gelling or thickening agents, and renewable materials for bio-based hydrogels., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In current diets, the level of sodium is very high, whereas that of potassium, calcium, and magnesium is low compared with the level in diets composed of unprocessed, natural foods. We present the biologic rationale and scientific evidence that show that the current salt intake levels largely explain the high prevalence of hypertension. Comprehensive reduction of salt intake, both alone and particularly in combination with increases in intakes of potassium, calcium, and magnesium, is able to lower average blood pressure levels substantially. During the past 30 years, the one-third decrease in the average salt intake has been accompanied by a more than 10-mm Hg fall in the population average of both systolic and diastolic blood pressure, and a 75% to 80% decrease in both stroke and coronary heart disease mortality in Finland. There is no evidence of any harmful effects of salt reduction. Salt-reduction recommendations alone have a very small, if any, population impact. In the United States, for example, the per capita use of salt increased by approximately 55% from the mid-1980s to the late 1990s. We deal with factors that contribute toward increasing salt intakes and present examples of the methods that have contributed to the successful salt reduction in Finland.

Because dietary fat appears to be an effective vehicle for dispensing plant sterols into the diet, a special plant-sterol-containing ingredient has recently been developed. This ingredient is a plant sterol suspension in oil in which the sterols are in microcrystalline form. The objective of the present study was to analyse the cholesterol-lowering effects and safety of two different plant sterol preparations, an orally administered microcrystalline plant sterol suspension (MPS) in rapeseed oil and a powdered plant sterol supplement, in obese Zucker rats. Dietary plant sterol supplements (0.5%, w/w) were given concurrently with a high cholesterol diet (HCD, 1% cholesterol and 18% fat, w/w). No significant changes in serum triglyceride, blood glucose, serum glutamate oxaloacetic transaminase and glutamic pyruvic transaminase values or body and liver weights were observed. The powdered plant sterol supplement lowered the serum cholesterol by 25% (P < 0.05) and the MPS diet by 35% (P < 0.001) compared with HCD by the end of the 12-week experiment. Interestingly, the plant sterol supplements also produced a marked reduction in serum ubiquinone levels, suggesting a possible effect on isoprene synthesis. Unlike the powdered plant sterol, both MPS and plain rapeseed oil decreased the serum baseline diene conjugation values, suggesting that they protect against oxidative stress-induced lipid peroxidation in rats. This lipid peroxidation diminishing effect is probably due to some antioxidative components in rapeseed oil. These findings indicate that an unesterified plant sterol, such as the microcrystalline suspension in oil, effectively prevents cholesterol absorption in obese Zucker rats.

The regulation of both angiotensin receptors and bradykinin receptors during sodium intake is poorly understood. We hypothesized that an altered balance between renal angiotensin type 1 (AT1) receptors and bradykinin type 2 (B2) receptors might contribute to an increase in blood pressure during periods of high-sodium intake. We studied the effects of high-sodium intake on renal AT1 receptors and B2 receptors in 5-6-week-old spontaneously hypertensive rats (SHR) receiving high-sodium chloride (6% NaCl) or mineral salts (10.5%, composition: 57% NaCl, 28% KCl, 12% MgSO4) compared to those receiving a low-sodium (NaCl 0.125%) diet for 10 weeks. Mineral salt intake was included due to its beneficial effects on blood pressure and cardiac hypertrophy. Receptor densities were measured by quantitative autoradiography. AT1 receptors were quantified using incubation with 125I-Sar1-Ile8-angiotensin II and displacement was measured with PD123319 (10 micromol/l), whereas B2 receptors were quantified using 125I-HPP-icatibant and displacement was measured with icatibant (3 micromol/l). Compared to the SHR controls, a further increase in blood pressure occurred after 2 weeks in the 6% NaCl group and after 6 weeks in the mineral salt group. AT1 receptor density increased in the renal cortex by 41% (p<0.01) in the 6% NaCl group and by 26% (p<0.05) in the mineral salt group. B2 receptor density decreased in the renal medulla by 26% (p<0.01) in the 6% NaCl group, and decreased even more i.e., by 45% (p<0.001), in the mineral salt group. It was shown that a 6% NaCl or a 10.5% mineral salt loading was capable of increasing renal AT1 receptor density and decreasing renal B2 receptor density. An altered balance between these receptors might be associated with hypertension under conditions of sodium loading.

Ca may interfere with fat and cholesterol metabolism through formation of insoluble soaps with fatty and bile acids in the intestine. In the present study, we examined the effects of different dietary Ca levels on the serum lipid profile and cholesterol metabolism in obese Zucker rats fed a low-fat diet. We also tested whether dietary Ca interfered with the lipid-lowering effects of a pine oil-derived plant sterol mixture. Increase in dietary Ca intake from 0.2 to 0.8%, and further to 2.1% (w/w) dose-dependently decreased serum total cholesterol (r -0.565, P=0.002, n 27), LDL-cholesterol (r -0.538, P=0.006, n 25), and triacylglycerol (r -0.484, P=0.014, n 25) concentrations, and increased HDL-cholesterol (r -0.478, P=0.016, n 25) and HDL: LDL cholesterol (r 0.672, P<0.001, n 25) in rats fed a 1% cholesterol diet. Analysis of serum campesterol: cholesterol and sitosterol: cholesterol suggested that Ca dose-dependently increased intestinal cholesterol absorption (r 0.913, P<0.001, n 18), whereas serum desmosterol: cholesterol and lathosterol: cholesterol indicated that Ca dose-dependently increased endogenous cholesterol synthesis (r 0.691, P=0.003, n 18). Therefore, the decrease of serum LDL-cholesterol appeared to be due to Ca-induced increase in the conversion of cholesterol to bile acids. The increase in Ca intake did not interfere with the beneficial effects of plant sterols on serum total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. The high-Ca diet with plant sterol supplementation further increased the HDL-cholesterol concentration and HDL: LDL cholesterol. The present findings indicate that the beneficial effects of dietary Ca on the serum lipid profile during a low-fat diet are dose-dependent, and resemble those of bile acid sequestrants. Increased dietary Ca did not impede the lipid-lowering effects of natural plant sterols.

In most hypertensive rat models, serum total cholesterol is typically low and the cholesterol is primarily in the HDL rather than the LDL fraction. This difference from humans usually makes these animals unsuitable for experimental atherosclerosis studies. In the present study, we induced severe hypercholesterolemia including a 10-fold increase in serum LDL cholesterol, endothelial dysfunction and hypertension as well as vascular and renal damage in obese Zucker rats by feeding a human-type high fat, high cholesterol and high salt diet (butter 18, cholesterol 1 and NaCl 6 g/100 g dry weight). Supplementation of this atherogenic diet with plant sterols (1 g/100 g) and replacing the NaCl partially by calcium, magnesium and potassium effectively prevented the diet-induced increases in total and LDL cholesterols and 24-h systolic and mean blood pressures, and markedly improved endothelial function. Plant sterols and the minerals also protected against vascular and renal damage and extended the life span of the obese Zucker rats by 60% compared with the rats fed the atherogenic diet. Our findings suggest that human-type cardiovascular disorders can be induced in obese Zucker rats by feeding a human-type atherogenic diet. This seems to be a suitable animal model for experimental studies on atherosclerosis and hypertension as well as for evaluating new dietary approaches to reducing cardiovascular risk.

Background and Aim: Recent clinical studies have demonstrated that plant sterols moderately lower serum cholesterol levels in patients with mild hypercholesterolemia. Furthermore, there is evidence suggesting that mineral nutrients, such as calcium and magnesium, may also decrease serum cholesterol concentrations. In this study, we tested the hypothesis that supplementation with mineral nutrients may enhance the cholesterol-lowering effect of plant sterols in obese Zucker rats. Furthermore, we compared the lipid-lowering effects of monovalent sodium and potassium cations with those of divalent calcium and magnesium cations., Methods and Results: A Western-type high-fat/high-cholesterol diet increased serum cholesterol by 175% and liver cholesterol by 65% in comparison with a low-fat/low-cholesterol control diet. On the contrary, the high-fat/high-cholesterol diet decreased intestinal cholesterol absorption, as assessed by means of serum campesterol-, sitosterol-, and sitostanol-to-cholesterol ratios, thus indicating that it was under negative feedback regulation. Supplementation of the high-fat/high-cholesterol diet with plant sterols or mineral nutrients partially prevented the diet-induced increased in serum cholesterol and, when given concurrently, their cholesterol-lowering effect was enhanced. Their combination also effectively prevented the diet-induced increase in liver cholesterol concentration, and had beneficial effects on liver and myocardial hypertrophy, and the development of obesity. These beneficial effects were at least partially mediated by an enhanced blockade of intestinal cholesterol absorption. Interestingly, only divalent cations enhanced the cholesterol-lowering effect of plant sterols, thus supporting the idea that the lipid-lowering effect of divalent cations is related to the formation of insoluble and inabsorbable calcium and magnesium chelates with fatty acids., Conclusions: Our findings indicate that the cholesterol-lowering effect of plant sterols is enhanced by the co-administration of divalent calcium and magnesium cations but not by monovalent sodium and potassium cations.

Background: Cyclosporine A (CsA)-induced hypertension and nephrotoxicity are aggravated by high sodium intake. Accumulating evidence suggests that potassium and magnesium supplementation could protect against the detrimental effects of dietary salt. In the present study, we tested the hypothesis of whether concurrent supplementation with potassium and magnesium could protect against the development of CsA-induced hypertension and nephrotoxicity more effectively than supplementation with one mineral alone., Methods: Eight-week-old spontaneously hypertensive rats (SHRs) were divided into four groups (N = 10 in each group): (1) CsA group (5 mg/kg subcutaneously) receiving high-sodium diet (Na 2.6%, K 0.8%, Mg 0.2% wt/wt); (2) CsA group receiving a high-sodium, high-potassium diet (Na 2.6%, K 2.4%, Mg 0.2%); (3) CsA group receiving high-sodium, high-magnesium diet (Na 2.6%, K 0.8%, Mg 0.6%); and (4) CsA group receiving high-sodium, high-potassium, high-magnesium diet (Na 2.6%, K 2.4%, Mg 0.6%)., Results: CsA induced severe hypertension and deteriorated renal functions in SHRs on high-sodium diet. Histologically, the kidneys showed severe thickening of the media of the afferent artery with fibrinoid necrosis. Potassium supplementation lowered blood pressure (198 +/- 5 vs. 212 +/- 2 mm Hg, P < 0.05) and partially prevented the development of proteinuria (-25%, P < 0.05). Magnesium supplementation decreased blood pressure to the same extent but improved renal functions more effectively than potassium. The greatest protection against CsA toxicity was achieved when dietary potassium and magnesium supplementations were combined. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion, a marker for renal proximal tubular damage, increased progressively in CsA-treated SHRs on the high-sodium diet. Neither potassium nor magnesium influenced urinary NAG excretion. We also estimated the activity of the renal dopaminergic system by measuring 24-hour urinary dopamine excretion rates. CsA suppressed the renal dopaminergic system during high-sodium diet. Magnesium supplementation, alone and in combination with potassium, protected against the development of renal dopaminergic deficiency in CsA-treated SHRs on high-sodium diet. Magnesium supplementation increased plasma-free ionized magnesium (iMg) and bone magnesium by 50 and 16%, respectively., Conclusions: Our findings indicate that both potassium and magnesium supplementations showed beneficial effects against CsA-induced hypertension and nephrotoxicity. The protective effect of magnesium clearly exceeded that of potassium. The greatest protection against CsA toxicity was achieved when potassium and magnesium were combined. We also provide evidence that the development of CsA-induced glomerular, tubular, and vascular lesions are associated with renal dopaminergic deficiency.

Background: Cyclosporin A-induced hypertension is dependent on the level of dietary salt. We investigated whether dietary magnesium or potassium could protect against cyclosporin A-induced cardiac and renal damage in spontaneously hypertensive rats (SHRs) on high-sodium diet., Methods: Eight-week-old SHRs were divided into 4 groups: (1) receiving a high-sodium diet, (2) receiving a high-sodium, high-potassium diet, (3) receiving a high-sodium, high-magnesium diet, and (4) receiving a high-sodium, high-potassium, high-magnesium diet. The effects of cyclosporin A in SHRs on a relatively low-sodium diet and in normotensive Wistar-Kyoto rats were also examined. Cardiac and renal morphologic condition was assessed, and tissue damage was scored by light microscopy after 6 weeks of cyclosporin A treatment., Results: In SHRs on a high-sodium diet, cyclosporin A caused luminal narrowing of the coronary arteries, left ventricular scarring, and damage in the renal arterioli and glomeruli. Dietary magnesium supplementation alone and in combination with potassium protected against these changes, whereas potassium alone was less effective. Cyclosporin A treatment caused only minor histopathologic changes in SHRs receiving a low-sodium diet. Interestingly, the detrimental interaction between cyclosporin A and a high-sodium diet was also observed in normotensive Wistar-Kyoto rats., Conclusions: Dietary magnesium, especially in combination with potassium, protects against cyclosporin A-induced cardiac and renal damage.

There is an increased interest in the role of magnesium ions in clinical medicine, nutrition and physiology. The characteristics of the binding of magnesium and calcium ions to various components, macromolecules and biological membranes are described. Magnesium affects many cellular functions, including transport of potassium and calcium ions, and modulates signal transduction, energy metabolism and cell proliferation. The mechanism of cellular uptake and efflux of magnesium, its intracellular transport, intestinal absorption, renal excretion and the effect of hormones on these are reviewed. Magnesium deficiency is not uncommon among the general population: its intake has decreased over the years especially in the western world. The magnesium supplementation or intravenous infusion may be beneficial in various diseased states. Of special interest is the magnesium status in alcoholism, eclampsia, hypertension, atherosclerosis, cardiac diseases, diabetes, and asthma. The development of instrumentation for the assay of ionized magnesium is reviewed, as are the analytical procedures for total magnesium in blood and free magnesium in the cytosol. The improved procedures for the assay of different magnesium states are useful in understanding the role of magnesium in health and disease.

The cardiovascular and renal pathophysiology associated with chronic renal allograft rejection under triple drug immunosuppressive treatment was studied using a recently developed model (Brown Norway (BN) rats) in a 6-week experiment. Renal transplantation was performed to 10-week-old rats in a rat strain combination of Dark Agouti (DA) --> BN. The right kidney was removed from another group of BN rats (uninephrectomized). A triple drug treatment comprising cyclosporine (10 mg/kg subcutaneously, s.c.), azathioprine (2 mg/kg s.c.) and methylprednisolone (1.6 mg/kg s.c.) was given to each rat daily for 6 weeks. A control group underwent no operations nor drug treatment. After the transplantation, the systolic blood pressure in this group was increased from 116 +/- 2 to 166 +/- 2 mmHg, while in the uninephrectomized group the rise was from 115 +/- 4 to 146 +/- 4 mmHg, and no change was observed in the blood pressures of the control group. The vascular relaxation responses of mesenteric arterial rings in vitro to acetylcholine were inhibited in both the transplantation group and the uninephrectomized group as compared with the control group, but few significant differences were found in the contraction responses to noradrenaline and potassium chloride. Graft histology was examined after 6 weeks, quantified by using the chronic allograft damage index (CADI). Changes specific to a chronic rejection reaction were observed in the allografts (CADI mean 6.0) but no injuries were seen in the rats' own kidneys (CADI mean 1.2). Our findings show that allograft rejection in BN rats after renal transplantation is associated with the development of arterial hypertension. The combination of cyclosporine, methylprednisolone and azathioprine also rises blood pressure in uninephrectomized BN rats. The hypertensive effects of the drug treatment and graft rejection are associated with endothelial dysfunction.

Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the level of dietary salt. The present study assessed the role of the renin-angiotensin system in the development of CsA-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In addition, we examined whether ACE inhibition prevents the detrimental effects of CsA on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. Eight-week-old SHR were divided into three different groups (n = 8 in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of the dry weight of the chow), (ii) CsA group (5 mg/kg s.c.) on a high-sodium diet and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end of the six-week experimental period, systolic blood pressure in the CsA group was significantly higher compared to the control group (245+/-6 vs 208+/-9 mmHg, respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%, the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05 compared to controls). Histologically, the kidneys of CsA-treated SHR showed severe thickening of the media of the afferent arteriole and fibrinoid necrosis of the arteriolar wall. Interestingly, CsA induced vascular injury also in the small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension and deterioration of kidney function as well as CsA-induced vascular injuries in the kidneys and myocardium. Enalapril also decreased left ventricular weight-to body weight ratio and prevented CsA-induced increases in urinary calcium and phosphorus excretions. Our findings indicate that CsA has a detrimental effect on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and vascular injuries. Our findings thus suggest that increased activity of the renin-angiotensin system is involved in the pathogenesis of CsA-induced hypertension and nephrotoxicity in SHR on a high-sodium diet.

The influence of isosorbide-5-mononitrate (IS-5-MN) on the cardiovascular effects of high dietary salt intake (NaCl, 6.6% of dry weight of food) and that of a potassium, magnesium and l-lysine-enriched salt alternative (Pansalt 10.5%, producing a 6.6% content of NaCl) was studied in spontaneously hypertensive rats in an 8-week experiment. Common salt produced a marked rise in blood pressure and induced cardiac and renal hypertrophy, while the salt alternative, although containing the same amount of NaCl, neither increased blood pressure nor caused any significant cardiac hypertrophy. IS-5-MN treatment at a daily dose of approximately 60-70 mg/kg (mixed with food) attenuated the rise in blood pressure induced by common salt, but did not prevent the cardiac or renal hypertrophy. IS-5-MN did not offer any additional benefit to the use of the salt alternative diet alone in treatment of high blood pressure. Mesenteric arterial responses in vitro were examined at the end of the study. IS-5-MN treatment during the moderately low-salt (NaCl 0.7%) control diet tended to decrease the contractile response to noradrenaline and increase the relaxation to acetylcholine. Common salt, but not the salt alternative, induced a 50% increase in the 24-h urinary excretion of cyclic GMP. Both salt supplements induced an 8-9-fold increase in the excretion of calcium, and about a 2-fold increase in the excretion of phosphorus. Common salt also increased the excretion of magnesium by 50%. IS-5-MN treatment had no significant effect on the excretion of the mineral elements. Our findings show that increased intake of potassium and magnesium reduces the harmful effects of common salt. Pressure-independent mechanisms are involved in salt-induced left ventricular and renal hypertrophy, since they remained unaffected despite the prevention of the salt-induced rise in blood pressure by IS-5-MN treatment.

1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated alpha-adrenoceptor-mediated vascular contractile responses.

The cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt were studied in 9-wk-old spontaneously hypertensive rats (SHR). N omega-nitro-L-arginine methyl ester (L-NAME, 0.025% in food, about 20 mg/kg/d) was given to rats receiving diets containing low, moderate, and high salt levels (NaCl 0.2%, 1.1%, and 6.0% of the dry weight of the chow) for 3 wk, L-NAME increased systolic blood pressure by 50 to 60 mmHg in all treated groups, as compared with an average rise of 10 to 20 mmHg in the control SHR. The high-salt diet did not further increase blood pressure. L-NAME also induced cardiac and renal hypertrophy, and these changes were aggravated by the high-salt diet. In addition, 19 of the 30 rats treated with L-NAME suffered strokes and all of them had several myocardial infarctions and renal damage, while the rats not treated with L-NAME had no evidence of stroke or myocardial or renal injury. Responses of mesenteric arterial rings in vitro were studied at the end of the experiment. The vascular contractile responses to noradrenaline were increased, and the relaxation responses to acetylcholine were inhibited in the L-NAME treated groups. In addition, the high-salt diet alone tended to inhibit the response to acetylcholine. Plasma renin activity was markedly increased by L-NAME treatment and decreased by the high-salt diet. The 24-h urine protein excretion was increased both by the L-NAME treatment and by the high-salt diet. The combination of L-NAME and the high-salt diet markedly raised the serum creatinine concentration. Our findings show that the coronary and renal functions are particularly vulnerable in SHR during impaired nitric oxide synthesis, and that the end-organ damage is worsened by an increased intake of dietary salt. We suggest that dysfunction of the endothelium is the primary cause of the effects observed in this study.

Recent studies have shown that increased intake of dietary sodium chloride produces blood pressure-independent increase in cardiac and renal mass even in young normotensive rats. With advancing age the harmful cardiovascular effects of increased dietary sodium are not so well known. In the present study the influence of advancing age on the cardiovascular effects of increased intake of sodium (control diet, 0.3% and high-sodium diet, 2.6% sodium in the chow) were examined in young and aged (3 and 18 months old, respectively, at the beginning of the experiment) male normotensive Wistar rats in a six-week study. Moreover, the potential role of renin-angiotensin system in ageing during normal and a high-sodium intake was studied using a pharmacological tool, angiotensin converting enzyme (ACE) inhibitor ramipril. Ageing did not significantly modify basal systolic blood pressure measured by the tail cuff method. A high intake of sodium chloride increased blood pressure significantly only in aged rats, while in young rats it increased renal weight. Left ventricular weight was not affected by high-sodium diet in either age group. The ACE inhibition during control diet lowered blood pressure and decreased left ventricular weight in young rats only and these effects were completely blocked by a high-sodium diet. The maximal vascular contraction force of mesenteric arterial rings to noradrenaline was decreased with ageing while endothelium-dependent and -independent relaxation responses were unaltered with ageing. The sensitivity to sodium nitroprusside was impaired by the high-sodium diet in young rats. In both age groups the urinary excretion of calcium was increased during the high-sodium diet. In conclusion, the increased intake of sodium produced different changes in cardiovascular function in normotensive rats depending on age. With advancing age, the sensitivity to sodium-induced increase in blood pressure was increased. In aged rats a high intake of dietary sodium elevated blood pressure, while in young rats it increased renal mass without increase in blood pressure. In both age groups sodium did not affect left ventricular hypertrophy. Both high-sodium intake and ageing attenuated or even abolished the cardiovascular effects of ACF inhibition.

The influence of common salt (NaCl) and a novel potassium-, magnesium-, and L-lysine-enriched mineral salt on the cardiovascular and renal effects of the selective imidazoline I1-receptor agonist moxonidine was examined in spontaneously hypertensive rats (SHR). Common salt was added at the level of 6% of the dry weight of the chow, and mineral salt at a 75% higher level of 10.5% thereof to produce the same NaCl concentration of 6% as in the common salt group. During the control diet an 8-week oral treatment with moxonidine (117 mg/1000 g of the dry weight of the chow producing an approximate daily dose of 10 mg/kg), lowered blood pressure by 13 mmHg. The common salt diet alone raised blood pressure by 27 mmHg. Moxonidine lowered blood pressure by 21 mmHg during the common salt diet, but the blood pressure remained 19 mmHg higher than in the moxonidine-treated SHR receiving the control diet (P<0.05). Unlike common salt, mineral salt alone did not raise blood pressure nor did it interfere with the antihypertensive effect of moxonidine. Moxonidine showed a kidney-protective effect during the control diet measured as decreased urinary protein excretion, but it did not affect the development of left ventricular hypertrophy. Moxonidine increased plasma renin activity during the control diet and it raised the serum aldosterone level both during the control and mineral salt diets. The vascular relaxation responses of the mesenteric arterial rings to both acetylcholine (an indicator of endothelium-dependent vascular relaxation) and nitroprusside and nitroprusside (an indicator of endothelium-independent vascular relaxation) were attenuated by the common salt diet alone but maintained during the moxonidine treatment. Our findings are consistent with the concept that moxonidine is able to improve the excretion of sodium. This effect might explain the maintenance of normal vascular relaxation during a high intake of common salt. These effects may partly account for the antihypertensive effect of moxonidine.

1. Cardiovascular effects of submaximal antihypertensive doses of the angiotensin converting enzyme inhibitor, ramipril (0.25 mg kg-1 day-1 in the food), and the calcium channel blocker, felodipine (0.4 mg kg-1 day-1 subcutaneously by osmotic minipump), both alone and in combination, were examined in spontaneously hypertensive rats (SHR) in a four-week study. 2. Both ramipril and felodipine as monotherapy decreased systolic blood pressure. The antihypertensive effect of the drug combination was more than that of ramipril treatment alone, but not significantly better than that of felodipine monotherapy. Ramipril or felodipine treatments did not significantly affect the heart rate, either alone or in combination. 3. The beneficial effect of ramipril monotherapy on left ventricular hypertrophy was more prominent than that of felodipine. The cardioprotective effect of felodipine was improved when combined to ramipril. The systolic blood pressure at the end of the experimental period correlated only weakly with left ventricular hypertrophy. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the four-week study. Ramipril and felodipine monotherapies as well as their combination markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine. The combination of ramipril and felodipine slightly enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside. Ramipril treatment alone slightly diminished the vascular contractile responses to noradrenaline. Neither ramipril nor felodipine alone or in combination affected the vascular contractile responses to potassium chloride. 5. Ramipril treatment, both alone and in combination with felodipine, caused a three fold increase in plasma renin activity. Serum aldosterone, fasting blood glucose level, serum insulin and the 24 hour urinary excretions of sodium, potassium, magnesium, calcium, phosphorus or protein were not significantly affected by the drug treatments. 6. Our findings suggest that a better overall control of hypertension and end-organ damages, without an increase in adverse effects, can be achieved by the combination of submaximal antihypertensive doses of felodipine and ramipril than by monotherapy with either drug alone.

The aim of the present study was to investigate the influence of age and an increased intake of dietary sodium on the cardiovascular and renal effects of the angiotensin converting enzyme inhibitor, ramipril. Male spontaneously hypertensive rats (SHR) aged 10 and 60 weeks received either control or a high level of sodium (0.3% vs. 2.6% Na) and ramipril (2 mg/kg/day) mixed in the chow for 6 weeks. Blood pressure was measured weekly by tail-cuff method. Arterial functions were determined by measuring vascular contractile and relaxation responses of mesenteric arterial rings in vitro at the end of the study. An age-related increase in systolic blood pressure, left ventricular (LVH) and renal hypertrophy (RH) as well as proteinuria were found in SHR. The vascular relaxation to nitroprusside was impaired in aged SHR. The high sodium intake accelerated the development of hypertension only in young SHR but increased LVH and RH in both age groups. Ramipril effectively lowered blood pressure in both age groups, but decreased the LVH significantly only in young rats. Ramipril markedly improved the vascular relaxation to acetylcholine and nitroprusside only in young rats. The vascular contractile responses to noradrenaline and potassium chloride were not affected by age, sodium intake or ramipril treatment. The high sodium intake markedly attenuated the cardiovascular effects of ramipril. The high-sodium diet enhanced the urinary excretion of cyclic GMP in both age groups, while it increased urinary excretion of protein in young SHR only. In conclusion, the cardiovascular effects of ramipril were impaired with advanced age even in the presence of a control intake of sodium. A high sodium intake attenuated or even abolished the cardiovascular effects of ramipril in both young and aged SHR.

Plasma from spontaneously hypertensive rats (SHR) and from patients with essential hypertension has been suggested to contain a substance with a delayed pressor effect, parathyroid hypertensive factor (PHF), associated with salt-sensitive forms of hypertension. In order to study whether high sodium intake would increase plasma levels of PHF-like activity, determined by bioassay, SHR received either a high-sodium (2.6% Na in the chow) or a normal-sodium (0.3% Na) diet for 6 weeks. Intravenous injection of plasma from SHR on a high-sodium diet (6 ml/kg) to urethane-anaesthetized Wistar rats induced a delayed increase in mean arterial blood pressure 70-80 min after bolus injection. No delayed pressor effects could be demonstrated by plasma from SHR or Wistar rats on a normal-sodium diet. It is concluded that a factor with a delayed blood pressure-increasing effect appears to be present in plasma from SHR on a high-sodium diet but not in plasma from normotensive Wistar rats or SHR on a normal-sodium diet. Further studies to characterize this factor and its possible relation to salt-induced hypertension are warranted.

In the present study the influence of dietary salt on the cardiovascular and renal effects of the calcium channel blocker felodipine (1.2 mg/kg sc) and the beta 1-adrenoceptor blocking drug metoprolol (250 mg/kg po), alone and in combination, was examined in the spontaneously hypertensive rats (SHRs) in a 4-week study. In addition, the influence of different diet and drug regimens on vascular functions was assessed by measuring the vascular relaxation and contractile responses of mesenteric arterial rings in vitro at the end of the experimental period. In SHRs, a high-salt diet caused a marked rise in blood pressure, impaired the endothelium-dependent vascular relaxation responses to acetylcholine and induced left ventricular hypertrophy (LVH) and renal hypertrophy. Metoprolol had little if any effect on salt-induced changes in blood pressure, endothelium-dependent vascular relaxation or renal hypertrophy, but it partially prevented the development of salt-induced LVH. Felodipine during the high-salt diet lowered blood pressure to normotensive level and completely prevented salt-induced left ventricular and renal hypertrophy as well as endothelial dysfunction. Felodipine produced tachycardia, especially at the beginning of drug treatment. The combination of felodipine and metoprolol abolished the effects of the individual drugs on heart rate. The drug combination also completely prevented the detrimental cardiovascular and renal effects induced by a high salt intake. Although salt restriction did not further enhance the profound antihypertensive effect of the combination of metoprolol and felodipine, it enhanced the effects of the drug combination on LVH and renal hypertrophy. Our findings indicate that felodipine treatment, alone and in combination with metoprolol, normalizes blood pressure and prevents the development of salt-induced LVH and renal hypertrophy. During the high-salt diet the beneficial vascular effects of felodipine as well as those of the combination of felodipine and metoprolol are mediated, at least in part, by prevention of salt-induced endothelial dysfunction. The only apparent benefit from the use of metoprolol in combination with a relatively high dose of felodipine was the prevention of tachycardia.

Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.

The cardiovascular effects of a partially purified extract of fish oil, enriched in the n-3 series fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were studied in stroke-prone spontaneously hypertensive rats (SHR-SP) fed with high- and low-sodium diets during 5 weeks. Addition of salt to the low-salt control diet at a level commonly found in human food items (6% NaCl of the dry weight of the diet) produced a remarkable rise in blood pressure, an increase in left ventricular weight-to-body weight ratio (LVH-index) and an increase in kidney weight-to-body weight ratio (RH-index). Fish oil (20% of the dry weight of the diet) did not significantly influence the blood pressure or LVH-index or RH-index during the low-salt control diet. However, fish oil completely prevented the remarkable rise in blood pressure and clearly antagonized the rise of both LVH- and RH-indices, induced by the high-salt diet. The fish oil supplementation increased the levels of the polyunsaturated fatty acids of the n-3 series and decreased those of the n-6 series in plasma and kidney, irrespective of the salt content of the diet. Fish oil lowered serum thromboxane B2 concentration by approximately 75%. During the high-salt diet, fish oil markedly decreased water intake and urine volume, and increased urinary sodium concentration by about 60%. Our findings show that, in addition to an antihypertensive effect, fish oil also decreases LVH and RH. These effects appear to be due to an improved ability to excrete sodium and could be explained by the observed changes in the fatty acid composition and metabolism.

Efforts in Finland to implement the recommended non-pharmacological and pharmacological principles for the control of hypertension, stroke and ischaemic heart disease have been accompanied by an approximately 10 mm Hg fall in the population average of diastolic blood pressure, and about 60% decrease in deaths from both stroke and ischaemic heart disease among 30-59-year-old men and women from 1972 to 1992. Adherence to antihypertensive drug therapy has been quite good. However, the drug treatment does not seem to account for more than 5-6% of the observed fall of blood pressure, and 10-15% of the decrease in deaths from strokes and ischaemic heart disease. There has been no overall adherence to several non-pharmacological recommendations, and marked increases in the intake of alcohol, obesity among men, and smoking among women have been observed. However, the population adherence to recommendations to decrease the intakes of sodium and saturated fats, and to reduce the sodium-to-potassium ratio and the saturated-to-unsaturated fat ratio, has been good. These dietary changes appear to account for a major part of the fall of blood pressure and the decrease in the cardiovascular diseases. Currently a rapid further population-wide decrease in the dietary sodium-to-potassium ratio is taking place, due to a decrease in the use of salt and replacement of common salt by a novel sodium-reduced, potassium-, magnesium-, and l-lysine HCI-enriched salt, both in home kitchens and in the food industry.

Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide-type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration. In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide.

1. The influence of sodium chloride (NaCl)-enrichment of the diet (6% of the dry weight) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of the beta 1-adrenoceptor blocking drug, metoprolol, was studied in stroke-prone spontaneously hypertensive rats. 2. Increased dietary sodium chloride intake produced a marked rise in blood pressure and induced left ventricular and renal hypertrophy. By contrast, the salt alternative did not increase blood pressure and caused remarkably less cardiac and renal hypertrophy than did sodium chloride. 3. Metoprolol treatment at a daily dose of 250 mg kg-1 lowered blood pressure and decreased left ventricular hypertrophy index during the control diet. Sodium chloride-enrichment blocked the antihypertensive effect of metoprolol, while a partial protective effect on left ventricular and renal hypertrophy persisted. In the presence of the salt alternative-enrichment both at the level of 6% and 10.5% (corresponding to a NaCl level of 6%), metoprolol was fully able to exert its beneficial cardiovascular and renal effects. 4. Both salt supplementations, irrespective of metoprolol treatment, induced a 3 to 4 fold increase in the urinary excretion of calcium. There was a linear correlation between the urinary excretions of sodium and calcium. The urinary excretion of magnesium rose by 90% and that of potassium by 110% in the salt alternative group. 6. Our findings suggest that replacement of common salt by a potassium-, and magnesium-enriched salt alternative in the diet produces beneficial cardiovascular effects and improves the antihypertensive efficacy of metoprolol in stroke-prone spontaneously hypertensive rats. Increased intake of potassium and/or magnesium and L-lysine from the salt alternative is involved in the beneficial effects of the salt alternative. The NaCl-induced myocardial and renal hypertrophies appear to be partially mediated by Beta-adrenoceptor activation.

1. The influence of salt (sodium chloride; NaCl) (an additional 6% in the diet) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of ramipril was studied in stroke-prone spontaneously hypertensive rats in a 6-week study. The intake of sodium chloride was adjusted to the same level by adding the salt alternative at a 1.75 times higher amount than regular salt. 2. Salt produced a marked rise in blood pressure and induced cardiac hypertrophy and significant mortality, while the salt alternative neither increased blood pressure nor caused any mortality and produced less cardiac hypertrophy than salt. 3. Ramipril treatment at a daily dose of 3 mg kg-1 normalized blood pressure and prevented the development of cardiac hypertrophy of rats on control diet. These effects of ramipril were blocked by the addition of salt but were only slightly attenuated by the addition of the salt alternative. The mortality in the salt group was prevented by ramipril. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Salt, but not the salt alternative, increased vascular contractile responses to noradrenaline. Ramipril treatment improved the arterial relaxation responses to acetylcholine and to sodium nitroprusside. The vascular relaxation enhancing effect of ramipril was blocked by salt but only slightly attenuated by the salt alternative. 5. Ramipril treatment did not significantly increase plasma renin activity in the presence or in the absence of salt supplementation. The salt alternative did not cause hyperkalaemia, either alone or in combination with ramipril treatment. 6. Both salt supplementations, irrespective of ramipril treatment, induced a six to eight fold increase in the urinary excretion of calcium. There was an expected 90 to 140% rise in the urinary excretion of magnesium and 200% rise in the urinary excretion of potassium in the salt alternative group. Salt also produced an approximately 50% increase in magnesuria.7. Our findings suggest that replacement of salt by the potassium-, magnesium- and L-lysine-enriched salt alternative improves the cardiovascular effects of ramipril. In the present study the beneficial effect was related to the increased intakes of potassium and/or magnesium and L-lysine from the salt alternative because the amount of sodium chloride was the same.

Increased dietary intake of regular salt (sodium chloride) interferes markedly with the therapeutic effects of angiotensin converting enzyme inhibitors. To study further the interactions between dietary salt intake and antihypertensive drug treatment, we examined the effects of felodipine, a dihydropyridine derivative Ca2+ channel antagonist with natriuretic properties, on blood pressure and the development of left ventricular hypertrophy in the stroke-prone spontaneously hypertensive rats during different levels of sodium chloride in the diet. We also compared the influence of regular salt on the cardiovascular effects of felodipine with that of a novel K(+)-, Mg(2+)- and l-lysine-enriched and Na(+)-reduced salt alternative, which in previous studies markedly improved the therapeutic effects of enalapril and ramipril. During the 28-day experiment regular salt produced a marked rise in blood pressure and induced left ventricular hypertrophy, while the salt alternative neither induced any rise of blood pressure nor caused cardiac hypertrophy. Felodipine had an enhanced antihypertensive effect during the increased intake of sodium chloride, and lowered the blood pressure to the same normotensive level as it did during the control and the salt alternative diets. Felodipine also completely blocked the development of the sodium chloride-induced cardiac hypertrophy. The heart rate of the felodipine-treated animals was significantly increased during the first two study weeks but thereafter it did not differ from that of the controls. Hence, unlike regular salt, the novel Na(+)-reduced, K(+)-, Mg(2+)-, and l-lysine-enriched salt alternative did not raise blood pressure and produced little if any left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

The mineral elements sodium, potassium, calcium and magnesium play a central role in the normal regulation of blood pressure. In particular, these mineral elements have important interrelationships in the control of arterial resistance. These elements, especially sodium and potassium, also regulate the fluid balance of the body and, hence, influence the cardiac output. Evidence shows that the present levels of intake of mineral elements are not optimum for maintaining normal blood pressure but predispose to the development of arterial hypertension. Research results suggest that without sodium chloride (common salt) and other sodium compounds being added to the diet arterial hypertension would be virtually non existent. Moreover, blood pressure would not rise with age. In communities with a high consumption of added sodium, a high intake of potassium and, possibly, magnesium seem to protect against the development of arterial hypertension and the rise of blood pressure with age. A marked reduction of sodium intake is effective in treating even severe hypertension. A moderate restriction of sodium intake or an increase in potassium intake exert remarkable antihypertensive effects, at least in some hypertensive patients. Magnesium and possibly also calcium supplements may be effective in reducing blood pressure in some hypertensives. In hypertensive patients treated with drugs sodium restriction and potassium and magnesium supplementation enhance the therapeutic effect, reduce the number and dosage, and lessen the adverse effects of prescribed antihypertensive drugs. Hence, a fall in sodium consumption and increases in potassium and magnesium consumption are useful in preventing and treating arterial hypertension.

Cardiovascular effects have been attributed to the amino acids which are precursors of catecholamines or other neurotransmitters. To study if even other amino acids may exert cardiovascular or ventilatory effects, a number of various acidic, basic and neutral L-amino acids were injected intravenously to anaesthetised normotensive rats at the doses of 0.2-1.6 mmol/kg. All amino acids were able to produce either blood pressure, heart rate or ventilation rate changes. Hence, in this study the production of cardiovascular or ventilatory effects was not limited to the known precursors of neurotransmitters. Therefore, in addition to increased formation and release of neurotransmitters, other mechanisms are apparently involved in the cardiovascular and ventilatory effects of various L-amino acids.

Tyrosine exerts potent cardiovascular effects: smaller doses induce tachycardia and hypertension while higher doses induce bradycardia and hypotension. However, the direct cardiac effects of this amino acid have not been characterised. In the present study increasing doses of L-tyrosine were administered to the perfusate of isolated rat (0.01-10.0 mg) and rabbit (0.5-40.0 mg) hearts. Heart rate and isometric force of contraction or amplitude of contractions, and either perfusion pressure or flow of perfusate were recorded. In rat hearts L-tyrosine decreased heart rate and isometric force of contraction. In rabbit hearts L-tyrosine also decreased heart rate and amplitude of contractions. The effects on coronary vasculature were variable. In rat hearts, high doses of L-tyrosine induced bi-phasic changes with initial coronary dilatation, followed by vasoconstriction. In rabbit hearts the predominant effect of L-tyrosine was coronary artery constriction. These results show that the inhibitory cardiovascular effects of L-tyrosine in vivo may be at least in part, explained by direct cardiac effects of this amino acid.

The purpose of the present study was to test the hypothesis that an increased digitalis-like activity, induced by excessive intake of Na, is involved in the development and maintenance of hypertension. In normotensive rats prolonged administration of digitoxin alone induced only a mild and transient rise of blood pressure. Increased intake of NaCl did not affect the blood pressure of these rats. However, simultaneous administration of both digitoxin and NaCl produced a sustained elevation of blood pressure. In SHR the effect of the addition (6% of the weight of the pellets) of 1) NaCl or 2) a mixture containing 50% NaCl and 50% KCl or 3) a mixture containing 65% NaCl, 25% KCl, and 10% MgSO . 7H2O, was examined. A marked fall of blood pressure occurred during the use of the mixtures containing K and Mg. The results suggests that both an increased intake of Na and an increased digitalis-like activity are needed for the development of hypertension. The results on SHR confirm the previous findings demonstrating that the use of salt mixtures in which a part of the NaCl is replaced by K and Mg salts is beneficial compared to the use of NaCl. Furthermore, since K and Mg are effective antagonists of digitalis the results could suggest the involvement of an increased digitalis-like activity in the maintenance of hypertension.

Catecholamines are formed, released and metabolized in the cerebral regions known to regulate the cardiovascular system. The release of catecholamines in these brain areas is associated with changes in cardiovascular function. Injections of exogenous catecholamines into certain brain regions induce cardiovascular changes and mimic the effects of the release of endogenous catecholamines in the same regions. In addition, drugs with selective effects on cerebral catecholamine functions also induce cardiovascular changes. Changes in cerebral catecholamines have also been found in arterial hypertension. Taken together, these observations provide strong evidence that cerebral catecholaminergic mechanisms have a crucial role in both the normal and pathological control of circulation. Cerebral catecholaminergic mechanisms also mediate, at least in part, the therapeutic effects of clonidine, alpha-methyldopa and some other antihypertensive drugs. Recent findings suggest that histaminergic mechanisms in the brain may also be important in the control of circulation and in the mediation of drug effects. Since the cerebral mono-aminergic systems are necessary for the physiological control of circulation, it is likely that the cerebral catecholaminergic and possibly histaminergic pathways are also involved in the mediation of the effects of psychological stress factors on the cardiovascular system.

The stomach of urethane-anaesthetised rats was perfused with 10% (v/v) ethanol. At 40 min, the secretion of acid was strongly inhibited and the contents of cyclic AMP and ATP were lowered in the superficial mucosa, but not in whole gastric mucosa. After discontinuation of the ethanol perfusion, the rate of gastric acid output as well as the cyclic AMP and ATP levels recovered. Most of the acid-secreting parietal cells were found in the superficial mucosa where the changes of cyclic AMP and ATP took place. The results suggest that lowering of the mucosal contents of cyclic AMP and ATP may be involved in the ethanol-induced inhibition of the gastric acid output.

beta-Adrenergic agents are used to inhibit preterm labor and glucocorticoids to accelerate fetal pulmonary maturation. A study was designed to investigate the metabolic effects of intravenous infusion of ritodrine (150 to 100 microgram/min) or isoxsuprine (200 to 150 microgram/min) in a series of 28 patients with gestations of 28 to 40 weeks, with and without concomitant dexamethasone therapy. Ritodrine was more potent than isoxsuprine in increasing the circulating levels of cyclic AMP, glucose, insulin, and triglycerides. The diabetogenic effect of both ritodrine and isoxsuprine was so slight that it did not have any clinical significance in women with normal glucose tolerance. The results were similar when these beta-adrenergic tocolytics were given to women concomitantly with intramuscular dexamethasone therapy, although dexamethasone appeared to minimally impair carbohydrate metabolism. Both ritodrine and isoxsuprine caused a significant fall in serum iron and potassium, and this effect was unaltered by dexamethasone. Serial serum potassium levels should be obtained during long-term infusion of beta-mimetics.