Why and how to implement sodium, potassium, calcium, and magnesium changes in food items and diets?

The present average sodium intakes, approximately 3000-4500 mg/day in various industrialised populations, are very high, that is, 2-3-fold in comparison with the current Dietary Reference Intake (DRI) of 1500 mg. The sodium intakes markedly exceed even the level of 2500 mg, which has been recently given as the maximum level of daily intake that is likely to pose no risk of adverse effects on blood pressure or otherwise. By contrast, the present average potassium, calcium, and magnesium intakes are remarkably lower than the recommended intake levels (DRI). In USA, for example, the average intake of these mineral nutrients is only 35-50% of the recommended intakes. There is convincing evidence, which indicates that this imbalance, that is, the high intake of sodium on one hand and the low intakes of potassium, calcium, and magnesium on the other hand, produce and maintain elevated blood pressure in a big proportion of the population. Decreased intakes of sodium alone, and increased intakes of potassium, calcium, and magnesium each alone decrease elevated blood pressure. A combination of all these factors, that is, decrease of sodium, and increase of potassium, calcium, and magnesium intakes, which are characteristic of the so-called Dietary Approaches to Stop Hypertension diets, has an excellent blood pressure lowering effect. For the prevention and basic treatment of elevated blood pressure, various methods to decrease the intake of sodium and to increase the intakes of potassium, calcium, and magnesium should be comprehensively applied in the communities. The so-called 'functional food/nutraceutical/food-ceutical' approach, which corrects the mineral nutrient composition of extensively used processed foods, is likely to be particularly effective in producing immediate beneficial effects. The European Union and various governments should promote the availability and use of such healthier food compositions by tax reductions and other policies, which make the healthier choices cheaper than the conventional ones. They should also introduce and promote the use of tempting nutrition and health claims on the packages of healthier food choices, which have an increased content of potassium, calcium, and/or magnesium and a lowered content of sodium. Such pricing and claim methods would help the consumers to choose healthier food alternatives, and make composition improvements tempting also for the food industry.

Increased kidney xanthine oxidoreductase activity in salt-induced experimental hypertension.

Clinical and experimental studies have established an association between high sodium intake and arterial hypertension. The renal mechanisms resulting in impaired sodium excretion in hypertension-prone subjects are not clear. In hypertension-prone rats, high blood pressure results in increased renal mass and hemodynamic changes, both of which may alter renal oxygen distribution. Xanthine oxidoreductase (XOR) oxidizes ATP metabolites hypoxanthine and xanthine to urate. Because XOR is induced by hypoxia, we assessed kidney XOR activity in 2 models of salt-sensitive hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. Increasing sodium intake from basal (0.08%) to high (2.56% wt/dry wt in the diet) increased renal XOR activity dose-dependently from 68+/-8 to 143+/-21 microU/mg protein in the Dahl S (P<0.05) but not in Dahl salt-resistant (Dahl R) rats. On basal and high sodium diets, SHR had higher renal XOR activity (101+/-10 and 134+/-26 microU/mg protein, respectively) than normotensive Wistar-Kyoto rats (55+/-2 and 58+/-6 microU/mg protein, P<0.05). Sodium restriction (0.02% wt/wt) downregulated kidney XOR activity in both Dahl S and R rats by nearly 40%. In SHR, allopurinol treatment totally inhibited renal XOR activity, but neither systolic blood pressure nor renal mass changed. The results suggest that renal XOR induction is a consequence of increased salt intake or the resulting hypertension. However, further studies on renal XOR activity during the development of hypertension are needed to assess the importance of XOR in the pathophysiology of arterial hypertension.

Beneficial effects of a potassium- and magnesium-enriched salt alternative.

The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.

Effects of dietary sodium and magnesium on cyclosporin A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats.

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.

Analeptic effect of centrally administered histamine H2-receptor agonist dimaprit but not impromidine in urethane-anesthetized rats.

Intracerebroventricularly administered dimaprit decreased the depth of urethane anaesthesia. Ventilatory stimulation, positive corneal reflex and increased susceptibility to pain were observed. Furthermore, dimaprit decreased the lethal effect of large doses of urethane. The analeptic property of dimaprit was not shared by the potent H2-receptor agonist, impromidine, Histamine increased ventilatory tidal volume but no other stimulatory effects were observed. These findings suggest that the analeptic effects of dimaprit were not mediated by H2-receptors. Among the analeptic effects of dimaprit, only the protection against urethane toxicity was antagonized by metiamide. However, this phenomenon appeared to be due to the nonspecific interaction between the three bradypnoeic drugs metiamide, dimaprit and urethane. The histamine-induced increase in ventilatory tidal volume was not antagonized by diphenhydramine or metiamide, suggesting the existence of a novel histaminergic mechanism in the central nervous system.

Synthesis and antihypertensive activity of some new quinazoline derivatives.

A series of substituted 2-piperidino-4-amino-6,7-dimethoxyquinazolines was synthesized and screened as potential antihypertensive agents. The hypotensive effect of all the new compounds was studied after intravenous administrations in urethane-anesthetized normotensive rats. The furoylpiperazine moiety in the prazosin molecule could be replaced by a more stable substituted piperidine group without loss of the blood pressure lowering activity. However, the nature of the substituent profoundly influenced the hypotensive potency as well as the duration of the hypotensive action. Some of the new compounds were found to be as potent as prazosin. On the basis of potency and the duration of the hypotensive action in the anesthetized rats, five of the most promising compounds were selected for further studies. Each of these agents exerted an antihypertensive effect upon oral administrations in conscious spontaneously hypertensive rats. At small doses, the new compounds appeared to be somewhat less potent than prazosin, but at the higher doses of 10-100 mumol/kg, two of them appeared to be even more efficacious antihypertensive agents than prazosin.

Effect of a diet based on low-fat foods enriched with nonesterified plant sterols and mineral nutrients on serum cholesterol.

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.

Improvement of cardiovascular effects of metoprolol by replacement of common salt with a potassium- and magnesium-enriched salt alternative.

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.

Cardiovascular effects of a low-dose combination of ramipril and felodipine in spontaneously hypertensive rats.

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.

Influence of dietary salts on the cardiovascular effects of low-dose combination of ramipril and felodipine in spontaneously hypertensive rats.

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.

Replacement of salt by a novel potassium- and magnesium-enriched salt alternative improves the cardiovascular effects of ramipril.

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.

Ischaemic heart disease. An epidemiological perspective with special reference to electrolytes.

Ischaemic heart disease (IHD) is a major public health problem in most industrialised countries. In the death rates from IHD, marked differences exist between various countries and also between different areas of individual countries. Unfavourable dietary factors appear to play an important role in the aetiology of IHD, and thus differences in dietary habits and the quality of food may be mainly responsible for the geographic differences in the prevalence of IHD. The present liberal use of salt as well as the refining and other industrial processing of food increase the content of sodium and decrease the content of potassium and magnesium in the diet. The high intake of sodium and the inadequately low levels of potassium and magnesium in the diet predispose to the development of arterial hypertension. Since arterial hypertension is a major risk factor of IHD, the distorted electrolyte composition of our present diet can be considered an important aetiological factor of this disease. To decrease the body burden of sodium, diuretic agents are frequently used. Unfortunately, in the presence of the relatively low content of potassium and magnesium in the diet, the diuretic-induced increases in the excretion of these electrolytes commonly decrease the potassium and magnesium levels in the body. The falls in potassium and magnesium may increase the death rate from IHD by predisposing the heart to fatal arrhythmias, and also by other mechanisms. The likelihood of magnesium deficiency also appears to be influenced by the area of residence. The higher-than-average death rates from IHD in the so-called North Karelia area in eastern Finland and in some other areas with exceptionally high death rates from this disease may be at least partly due to the very low levels of magnesium in the soil and drinking water. It can be concluded that electrolyte disturbances have important implications in the aetiology and pathogenesis of IHD.

Down-regulation of renal glutathione synthesis by systemic nitric oxide synthesis inhibition in spontaneously hypertensive rats.

Nitric oxide stimulates in vitro the synthesis of glutathione, an abundant thiol with a number of functions such as detoxification of xenobiotics and reactive oxygen species. In order to study this relationship in an animal model of hypertension, we treated spontaneously hypertensive rats (SHR) either with a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) or with a nitric oxide donor isosorbide-5-mononitrate (IS-5-MN). Inhibition of nitric oxide synthesis led to malignant hypertension and to a marked decrease in glutathione synthesis through down-regulation of the rate-limiting enzyme gamma-glutamylcysteine synthetase (GCS). The reduction in GCS activity was further augmented in SHR on a high sodium diet. Renal GCS activity in untreated SHR was 234 +/- 14 and 240 +/- 18 nmol/min/mg protein (mean +/- SD) on a low and high sodium diet, respectively. When L-NAME was included in the diet, the activities dropped to 173 +/- 28 and 123 +/- 28 for the low and high sodium diets, respectively. IS-5-MN attenuated the rise in blood pressure induced by sodium chloride, but did not affect the GCS activity. The mechanism of GCS stimulation by nitric oxide is not known, but our results combined with the literature suggest that a relatively high concentration of nitric oxide is needed.

Beneficial effects of dietary magnesium and potassium on cardiac and renal morphologic features in cyclosporin A-induced damage in spontaneously hypertensive rats.

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.

Effects of ritodrine and isoxsuprine with and without dexamethasone during late pregnancy.

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.

Cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt in spontaneously hypertensive rats.

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.

Cardiovascular effects of L-tyrosine in normotensive and hypertensive rats.

There are conflicting reports on the blood pressure effects of tyrosine. The aim of this study was to establish complete dose-response relationships and to compare the effects of various modes of administration of L-tyrosine in anaesthetised normotensive and spontaneously hypertensive rats. The intravenous injection of L-tyrosine, 0.2-0.4 mmol/kg, produced tachycardic and hypertensive effects in both species. The higher doses (0.8-1.6 mmol/kg) produced marked bradycardiac and hypotensive responses. Intracerebroventricular administration of L-tyrosine, 0.005-0.1 mmol/kg, had no statistically significant effects. Chronic dietary administration of L-tyrosine at the approximate daily doses of 0.7-55 mmol/kg was also without any significant effects. These results suggest that the controversies in the earlier studies could be due mainly to differences in doses and modes of administration. Our results also suggest that the cardiovascular effects of tyrosine are peripheral rather than central in origin although a central site of action cannot be excluded.

Cardiovascular effects of L-tyrosine: influence of blockade of tyrosine metabolism.

Tyrosine is the precursor of catecholamines. Small doses of tyrosine produce tachycardia and hypertension while higher doses produce bradycardia and hypotension in anaesthetised rats. The mechanism of these effects has not been established. An increased synthesis and release of catecholamines has been suggested to be the mechanism. Various pretreatments were given to anaesthetised Wistar rats to study the influence of a blockade of L-tyrosine metabolism and thus a blockade of catecholamine synthesis, on these cardiovascular effects: valine, which inhibits tyrosine uptake into brain, alpha-methyl-p-tyrosine, which blocks the rate-limiting enzyme, tyrosine hydroxylase, carbidopa and benserazide, which both inhibit dopa decarboxylase, and desipramine, which blocks catecholamine re-uptake. Benserazide and alpha-methyl-p-tyrosine partially blocked the stimulatory effects of tyrosine. None of the pretreatments were able to block effectively the inhibitory effects of L-tyrosine. Therefore, the metabolism of tyrosine to form catecholamines may be involved in the stimulatory but not in the inhibitory cardiovascular effects of L-tyrosine. Valine pretreatment did not antagonize the depressant effects of tyrosine. Since valine blocks the uptake of L-tyrosine into the brain, the depressant effects of L-tyrosine might be peripheral rather than central in origin.

Ethanol, indomethacin and gastric acid secretion in the rat.

In the anesthetized rat, 10% ethanol in the gastric lumen causes a total cessation of the secretion of gastric acid within 30--60 min. This effect is inhibited by pretreatment with indomethacin, which is a potent inhibitor of prostaglandin synthesis. Therefore, the inhibitory effect of local ethanol on gastric acid secretion in the rat may be mediated, at least partly, by increased synthesis of prostaglandins.

Xylazine-induced sedation in chicks is inhibited by opiate receptor antagonists.

The sedative effect of xylazine and its interaction with antagonists of alpha-adrenoceptors or opiate receptors was examined in chicks. The duration of the sleep-like behavioral state induced by xylazine was determined by measuring the time interval during which the chicks failed to exhibit the righting reflex. In these chicks, intramuscular administration of xylazine (0.3-4.8 mg/kg) induced a loss of the righting reflex, the duration of which was dose-dependent. Both alpha-adrenoceptor antagonists of the alpha2 type, i.e. yohimbine (0.1-1.0 mg/kg) and compound 170150 (0.1-1.0 mg/kg) (a benzodioxane derivative), and opiate receptor antagonists, i.e. naloxone (0.4-1.6 mg/kg) and nalorphine (3.0-30.0 mg/kg), effectively inhibited the sedative effect of xylazine while prazosin (0.1-10.0 mg/kg), an alpha 1-adrenoceptor antagonist, failed to antagonize xylazine-induced sedation. These findings suggest that in addition to the stimulation of central alpha 2-adrenoceptors, activation of an endogenous opiate mechanism may be involved in the sedative effect of xylazine.