Arterial smooth muscle contractions in spontaneously hypertensive rats on a high-calcium diet.

OBJECTIVE: To study the effects of a high-calcium diet upon blood pressure, vascular smooth muscle contractions and intracellular free calcium in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: Eight-week old animals were placed on a normal-calcium diet (1.1% calcium; SHR and WKY rat groups) or a high-calcium diet (2.1% calcium; Ca-SHR and Ca-WKY rat groups) and observed for 12 weeks. METHODS: Blood pressure was measured indirectly by the tail-cuff method and in vitro smooth muscle responses were studied using a standard organ bath chamber. Platelets were used as a cell model for analysis of intracellular free calcium concentration, measured by the fluorescent indicator Quin-2. RESULTS: The blood pressure of Ca-WKY and WKY rats did not differ, but increased systolic blood pressure was attenuated in Ca-SHR compared with SHR. The concentration-response curves of mesenteric arterial rings for potassium chloride and noradrenaline were not affected by the high-calcium diet in either SHR or WKY rats. The time required for total relaxation after washout of contractile agents (washout time) was shortest in WKY and Ca-WKY rats after both agonists, and shorter in Ca-SHR than in SHR after noradrenaline. Smooth muscle responses were also studied by contracting the preparations with noradrenaline and potassium chloride in a calcium-free solution, after which, calcium was added to the organ bath in increasing concentrations. Calcium contraction responses were similar in WKY and Ca-WKY rats; SHR displayed an attenuated response to calcium addition in mesenteric rings stimulated by both agonists. After potassium chloride as agonist, the responses of SHR and Ca-SHR did not deviate but, after noradrenaline, a significant shift in the calcium contraction curve towards the normotensive curve was observed in Ca-SHR. Intracellular free calcium was clearly lower in WKY rats than in SHR, and was significantly reduced by calcium supplementation in the hypertensive but not the normotensive animals. CONCLUSIONS: A reduction in intracellular free calcium concentration and an effect upon receptor-mediated vascular smooth muscle contraction and excitation-contraction coupling may participate in the blood pressure lowering effect of a high-calcium diet.     

Effects of a high calcium diet and deoxycorticosterone on vascular smooth muscle responses in spontaneously hypertensive rats

The effects of calcium and deoxycorticosterone (DOC) were studied in four groups of spontaneously hypertensive rats (SHR): control, calcium, DOC and DOC + calcium. Calcium was administered in drinking fluid as 1.5% calcium chloride, and DOC was injected weekly (25 mg/kg subcutaneously). During the 9-week study the increase in systolic blood pressure was enhanced in the DOC and attenuated in the calcium group, but did not differ from control values in the DOC + calcium group. DOC augmented in vitro contractions of aortic and mesenteric arterial rings induced by noradrenaline and impaired relaxations in response to nitroprusside and acetylcholine. Calcium alone enhanced the relaxation in response to nitroprusside in the mesenteric artery. In the DOC + calcium group vascular contractions did not differ from control values, but the relaxations caused by nitroprusside and acetylcholine were augmented in the mesenteric artery. The activity of erythrocyte Ca2(+)-ATPase increased in both calcium groups. The Na+:K+ ratio of tail artery tissue was reduced in the calcium group. In conclusion, calcium supplementation attenuates the development of hypertension, and prevents DOC-induced blood pressure increases in SHR by altering vascular reactivity. Changes in smooth muscle electrolyte ratios and Ca2(+)-ATPase activity may account for these alterations.     

High calcium diet reduces blood pressure in exercised and nonexercised hypertensive rats

The effects of long-term high calcium diet and physical exercise and their combined effects on the development of hypertension, plasma and tissue atrial natriuretic peptide, and arterial function were studied in spontaneously hypertensive rats with Wistar-Kyoto rats serving as normotensive controls. Hypertensive rats were made to exercise by running on a treadmill up to 900 m/day. Calcium supplementation was instituted by increasing the calcium content of the chow from 1.1% to 2.5%. During the 23-week study, calcium supplementation attenuated the rise in blood pressure in both trained and nontrained hypertensive animals, whereas exerise training had no significant effect on blood pressure. The high calcium diet alone was associated with reduced plasma and ventricular tissue contents of atrial natriuretic peptide, both of which were increased by exercise. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Neither increased dietary calcium nor endurance training affected the contractile sensitivity of endothelium-intact preparations to potassium chloride or norepinephrine. However, a high calcium diet enhanced the arterial relaxation induced by the return of potassium to the organ bath upon precontraction with potassium-free solution, and also moderately augmented relaxations to acetylcholine, sodium nitrite, and isoproterenol. Exercise training did not affect the potassium relaxation rate, but enhanced responses to acetylcholine isoproterenol, and sodium nitrite. In conclusion, enhanced arterial potassium relaxation, a response reflecting the function of the vascular sodium pump, paralleled well the long-term blood pressure lowering action of increased dietary calcium intake in exercised and nonexercised hypertensive rats. However, augmented arterial relaxation to agonists could also be observed in the absence of reduced blood pressure following regular physical exercise.     

Na+, K(+)-adenosine triphosphatase regulation in hypertrophied vascular smooth muscle cells.

Vascular smooth muscle cell hypertrophy is a normal compensatory state that may play a pathogenic role in hypertension. Angiotensin II stimulates a hypertrophic response in cultured vascular smooth muscle cells. As part of the growth response, angiotensin II rapidly activates the Na(+)-H+ exchanger, increasing Na+ influx. Because Na+, K(+)-ATPase is the major cellular mechanism for regulating intracellular Na+, we studied the effects of angiotensin II-induced hypertrophy on Na+, K(+)-ATPase expression and activity. Angiotensin II caused rapid increases in both steady-state Na+, K(+)-ATPase activity (ouabain-sensitive 86Rb uptake) and intracellular [Na+]. Angiotensin II also caused a sustained increase in Na+, K(+)-ATPase at 24 hours with a 73% increase in maximal 86Rb uptake per milligram protein and a fourfold increase in Na+, K(+)-ATPase alpha-1 messenger RNA levels. Thus, angiotensin II hypertrophy was associated with rapid increases in Na+, K(+)-ATPase activity due to increased Na+ entry and sustained increases due to a specific increase in Na+, K(+)-ATPase expression. These data demonstrate dynamic regulation of Na+, K(+)-ATPase at the functional and molecular level and suggest that similar compensatory mechanisms should be present in vivo. Alterations in such compensatory pathways may be fundamental to the pathogenesis of hypertension.     

Potassium augments vascular relaxation mediated by nitric oxide in the carotid arteries of hypertensive Dahl rats

The present study was designed to determine whether and how potassium supplementation improves the endothelial function of carotid arteries of hypertensive Dahl rats. Dahl salt-sensitive rats were fed a high sodium diet, a high sodium plus potassium-supplemented diet, a normal rat chow, or a potassium-supplemented diet for 4 weeks. High sodium intake significantly increased the blood pressure, which was attenuated by potassium supplementation. The isometric tension of rat-isolated carotid rings was measured. In norepinephrine-precontracted rings, the relaxation in response to acetylcholine, adenosine 5′-diphosphate (ADP), and isoproterenol were significantly attenuated in hypertensive Dahl rats, which was improved by potassium supplementation. Pretreatment with N^G-nitro-l-arginine methyl ester blocked the responses to acetylcholine and ADP, and eliminated the difference in relaxation in response to isoproterenol. The endothelium-independent relaxation in response to forskolin, S-nitroso-N-acetyl-dl-penicillamine, and sodium nitroprusside was significantly attenuated in hypertensive Dahl rats, which was not affected by potassium supplementation. The results indicated that salt-induced hypertension was associated with marked alterations in the endothelial and vascular smooth muscle functions of the carotid arteries of Dahl rats. Potassium supplementation ameliorated the endothelial but not the smooth muscle function. The protective effect of potassium appeared to be achieved through increased endothelial nitric oxide production. The current studies, in conjunction with our recent studies on nitric oxide synthase activity in the kidney, strongly suggest that potassium attenuates development of hypertension by increasing nitric oxide production in Dahl rats.     

Effects of high potassium or low sodium diet on vascular Na+,K+-ATPase activity and blood pressure in young spontaneously hypertensive rats

These studies were designed to investigate whether the antihypertensive effects of high potassium or low sodium diets are related to changes in vascular Na+,K+-adenosine triphosphatase (ATPase) activity. Vascular Na+,K+-ATPase was measured as ouabain-sensitive rubidium uptake in aorta incubated in buffer or plasma from spontaneously hypertensive rats (SHR) fed either a high potassium, a low sodium, or a normal diet for 2 weeks. The high potassium diet significantly increased Na+,K+-ATPase activity, whereas the low sodium diet significantly decreased activity. There was no evidence of a ouabainlike factor in plasma. The increased pump activity on the high potassium diet appeared to be due to an increase in maximum activity (Vmax) of the enzyme, rather than to an increased affinity for potassium. Potentially, an increase in Na+,K+-ATPase activity could contribute to the antihypertensive effect of potassium by hyperpolarizing the cell membrane. The decrease in vascular Na+,K+-ATPase activity on a low sodium diet probably is unrelated to its depressor effect, but it may be a homeostatic mechanism for maintaining sodium balance in the animal.     

Platelet and erythrocyte Mg2+, Ca2+, Na+, K+ and cell membrane adenosine triphosphatase activity in essential hypertension in blacks.

OBJECTIVE: To assess the relationship between intracellular Mg2+, Ca2+, Na+ and K+ and cell membrane adenosine triphosphatase (ATPase) activity in normotensive and hypertensive blacks. DESIGN: Intracellular cations and cell membrane ATPase activity were studied in black patients with untreated essential hypertension and age-, weight- and height-matched normotensive controls. Platelet, erythrocyte and serum Mg2+, Ca2+, Na+ and K+ levels as well as platelet and erythrocyte membrane Na+,K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase activities were measured in all subjects. METHODS: Intracellular Na+ and K+ were measured by flame photometry and Mg+ and Ca+ by atomic absorption spectrophotometry. Cell membrane ATPase activity was determined by a colorimetric method. RESULTS: The hypertensive group consistently demonstrated depressed activity of each ATPase studied, with significantly lower serum Mg2+, serum K+, erythrocyte Mg2+ and platelet Mg2+ levels compared with the normotensive group. Platelet Na+ and Ca2+ and erythrocyte Ca2+ were significantly elevated in the hypertensive group. In the hypertensive group, mean arterial pressure (MAP) was inversely correlated with platelet and erythrocyte membrane Na+,K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase. Serum Mg2+, serum Ca2+ and platelet Mg2+ were negatively correlated with MAP in the hypertensive group whilst erythrocyte and platelet Ca2+ were positively correlated. In the normotensive group, platelet Mg2+ and MAP were negatively, and erythrocyte Ca2+ and MAP, positively correlated. CONCLUSIONS: Black patients with essential hypertension have widespread depression of cell membrane Na+,K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase activities with serum and intracellular Mg2+ depletion and cytosolic Na+ and Ca2+ overload, which may reflect an underlying membrane abnormality in essential hypertension. These cellular abnormalities may be related to the defective transport mechanisms that in turn may be aggravated by Mg2+ depletion.     

Effect of dietary calcium supplementation on blood pressure and calciotropic hormones in mineralocorticoid-salt hypertension

In order to determine the effect of dietary calcium supplementation on blood pressure and calciotropic hormones, we studied two groups (n = 12 each) of mineralocorticoid [deoxycorticosterone (DOC)]-salt hypertensive rats, one receiving a normal-calcium diet (0.6% calcium, as calcium carbonate) and the other a high-calcium diet (2.5% calcium), over an 8-week period. Dietary calcium supplementation significantly attenuated the rise in blood pressure. Serum ionized calcium concentrations were significantly decreased from baseline levels in both groups but tended to be higher among the calcium-supplemented rats. Serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-D) were significantly higher in the DOC-salt rats than in normotensive rats fed normal rat chow [PTH: 49 +/- 4 versus 15 +/- 0.9 pg/ml (means +/- s.e.m.); 1,25-D: 108 +/- 7 versus 73 +/- 13 pg/ml, in DOC-salt and normotensive rats, respectively]. In the DOC-salt rats, dietary calcium supplementation did not significantly lower the elevated serum concentration of PTH (from 49 +/- 4 to 40 +/- 4 pg/ml; NS), but did significantly reduce that of 1,25-D (from 108 +/- 7 to 66 +/- 8 pg/ml; P less than 0.01). Since 1,25-D may increase vascular smooth muscle calcium uptake, dietary calcium supplementation may lower blood pressure in DOC-salt hypertension, in part, by suppressing 1,25-D.     

Calcium Supplementation Is Associated With Endothelium Dependent Attenuation of Vascular Smooth Muscle Reactivity in Normotensive Pregnant and Nonpregnant Rats

The study tests the hypothesis that the blood pressure lowering effect of a high calcium diet is mediated through attenuation of vascular reactivity and examined the mechanisms involved in both normotensive pregnant and nonpregnant rats. The contractile responses of aortic rings of Wistar rats fed on high (1.7%, 2.1%) and normal (0.9%) calcium diets to phenylephrine, angiotensin II, KCl, and CaCl₂ were studied. The relaxations to acetylcholine and potassium chloride, as well as the effects of endothelial denudation, pretreatment with indomethacin (10⁻⁶ mol/L), methylene blue (10⁻⁶ mol/L), and calcium free solution on the responses to phenylephrine were also examined.In both pregnant and nonpregnant rats, the contractile responses of aortic rings of animals fed a high calcium diet to all the agents were significantly attenuated, compared with those of controls. After endothelial denudation, or treatment with methylene blue, but not with indomethacin, the responses of the rings to phenylephrine were enhanced and not different from similarly treated rings from rats on a normal calcium diet. There was no difference in the contractile responses to phenylpehrine in calcium free solution. The relaxation to acetylcholine, but not to potassium chloride, was enhanced in rings from rats on a high calcium diet. The diminution in reactivity was not associated with corresponding changes in sensitivity of the tissues.It is concluded that in normotensive rats a high calcium diet is associated with diminished vascular smooth muscle reactivity that is endothelium dependent, and involves increased stimulation of the nitric oxide–guanylate cyclase pathway but not of the sodium–potassium ATPase or prostacyclin.     

Plasma digitalis-like activity and cytosolic Ca2+ in essential hypertension

Digitalis compounds are known to increase Ca2+ influx in various cells. As platelet cytosolic free [Ca2+] and plasma digitalis-like activity have been reported independently to be higher in some untreated hypertensive patients than in normotensive subjects, we have investigated a possible relationship between these two parameters. Platelet cytosolic free [Ca2+], determined using Quin-2, the capacity of plasma extracts to inhibit renal Na+, K(+)-ATPase activity and ouabain binding on human erythrocytes were measured in parallel in 25 untreated hypertensive patients and 11 normotensive subjects. Enhanced values for all 3 parameters were observed in the same hypertensive patient. Platelet cytosolic free [Ca2+] was positively correlated to the plasma digitalis-like activity, which was evaluated by the inhibition of Na+, K(+)-ATPase activity and ouabain binding (r = 0.430, P = .010 and r = 0.448, P = .006, respectively). These relationships were independent of age and blood pressure. These results indicate that endogenous digitalis-like compounds may participate in the control of cytosolic free [Ca2+], in agreement with their proposed hypertensive role.     

Sodium pump activity and calcium relaxation in vascular smooth muscle of deoxycorticosterone acetate-salt rats

The Na+-K+ pump activity was determined in femoral arterial smooth muscle from deoxycorticosterone acetate (DOCA)-salt hypertensive rats using potassium relaxation and ouabain-sensitive 86Rb uptake as indices. The membrane-stabilizing effect of calcium and its relation to Na+-K+ pump activity also were examined. Femoral arteries from DOCA-salt rats exhibited a greater relaxation in response to potassium addition after contraction with norepinephrine in a low potassium (0.6 mM) Krebs solution. The concentration of potassium required to produce a 50% relaxation was significantly less in DOCA-salt rats. Ouabain-sensitive 86Rb uptake was significantly greater at 3, 10, and 20 minutes of 86Rb incubation in femoral arteries from DOCA-salt rats. Linear regression analysis revealed a significant correlation between the uptake of 86Rb and time of incubation in both control and DOCA-salt rats. A significant difference in the slopes of the regression lines showed that the rate of uptake was greater in DOCA-salt rats. No difference was observed in ouabain-insensitive 86Rb uptake. A dose-dependent relaxation in response to increasing concentrations of calcium following contraction to norepinephrine was observed in femoral arteries from control and DOCA-salt rats. The relaxation was directly dependent on the level of extracellular potassium and was blocked by ouabain. Femoral arteries from DOCA-salt rats relaxed to a significantly greater extent in response to calcium at each level of potassium when compared with controls. These results provide further evidence for an increase in Na+-K+ pump activity in vascular smooth muscle from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for increased in vivo Na(+)-H+ antiporter activity and an altered skeletal muscle contractile response in the spontaneously hypertensive rat

We have assessed the in vivo activity of the Na(+)-H+ antiporter skeletal muscle in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls using phosphorus (31P) nuclear magnetic resonance spectroscopy to measure changes in cytosolic acid concentrations during isometric contraction. During contraction there was a small rate of rise in skeletal muscle cytosolic acid concentration to a smaller maximum concentration in SHR. This difference in acid response was removed by amiloride and was not attributable to differences in cell buffering or the rate of production of lactic acid, suggesting that the difference in acid response in SHR skeletal muscle is due to increased in vivo Na(+)-H+ antiporter activity. Amiloride reduced resting muscle glycogen concentration and increased muscle lactate concentration in the SHR. This could be related to altered in vivo calcium metabolism. The maximum tension produced by skeletal muscle during contraction in SHR was less than in WKY rats, and relaxation between twitches was significantly greater, consistent with the finding of increased vascular smooth muscle relaxation in essential hypertension. Since increased Na(+)-H+ antiporter activity occurs in association with increased relaxation of both skeletal and vascular smooth muscle, these data are not consistent with a relationship between increased Na(+)-H+ antiporter activity and increased maximal muscle tension development. However, they show that increase Na(+)-H+ antiporter activity is associated with increased muscle relaxation.     

Disturbed sodium and calcium exchange in erythrocytes of spontaneously hypertensive rats (author's transl)

In red blood cells of spontaneously hypertensive and of normotensive rats intracellular NA+ activity (a(i)Na), Na+ concentration (]Na+]i) and Ca2+ activity (a(i)Ca) were measured by ion-selective electrodes and flame photometry, respectively. In spontaneously hypertensive rats a(i)Na and a(i)Ca were significantly elevated as compared with the normotensive controls, whereas [Na+]i showed no significant difference. In hypertensive animals a(i)Na, exceeded [Na+]i, in normotensive rats a(i)Na was lower than [Naf+]i. From these results it can be concluded: (1) In spontaneously hypertensive rats the transmembraneous distribution of free Na+ is altered, (2) an elevation of intracellular free Ca2+ may contribute to increased vascular contractility in hypertensive animals, (3) the described abnormalities may be caused by a lowered binding-capacity of intracellular macromolecules for Na+ and Ca2+.     

The role of calcium in the regulation of normal vascular tone and in arterial hypertension

The vascular tone depends on periarterial neurogenic nerve stimulus and endothelial substances release. The most evident biochemical cause of the vascular smooth muscle contraction-relaxation process lies in the changing concentration of cytosolic Ca2+. Intracellular free calcium is the major determinant of vascular tone. The depolarization wave opens the slow calcium channels, which permit Ca2+ to enter in small quantities into the interior of the cell triggering the release of much larger quantities of calcium from the sarcoplasmic reticulum. The flux of Ca2+ to and from the cytosol is regulated by three principle mechanisms. The calcium voltage sensitive Ca2+ channel that are opened by the depolarization wave. The potassium channels (CK+) and the Na+/K(+)-ATPase pump. The CK+ opening permits the exit of potassium from the interior of the cell which tends to hyperpolarize the smooth muscle cell membrane and closes the calcium channel avoiding the entry of Ca2+. The activity of the sodium pump also produces membrane hyperpolarization. Thus, the activity of these two mechanisms counter-regulates the voltage dependent calcium channel. The massive release of Ca2+ from intracellular stores of the sarcoplasmic reticulum is done through two classes of channels. One is ryanodine sensitive, the other is the inositol 1,4,5-trisphosphate receptor. The endothelial cell dysfunction is accompanied by a decrease in the production and/or the release of nitric oxide and the increase of contracting factors. That induce a Ca2+ mobilization of extracellular and intracellular stores. Contraction of smooth muscle to hypoxia is mediated by an accumulation of intracellular Ca2+. The relaxant substances of vascular smooth muscle inhibit activation of the phospholipase C and open Ca2+ channels, or produce a stimulus to the exit of the Ca2+ through the plasmatic membrane, with a decrease of intracellular calcium. An endothelial dysfunction with decrease of nitric oxide release exists in different types of hypertension. Pregnancy-induced hypertension is associated with low calcium levels in the diet, improving with the treatment of calcium supplements.     

Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium

Alpha-adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na+,K+-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na+,K+-ATPase activity, and their Na+,K+-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na+,K+-ATPase because of adaptin-mu2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na+,K+-ATPase activity, mu2-subunit hyperphosphorylation, and impaired Na+,K+-ATPase endocytosis. Thus, increased renal Na+,K+-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na+,K+-ATPase endocytosis in response to natriuretic signals.     

Magnesium and hypertension

Magnesium status has a direct effect upon the relaxation capability of vascular smooth muscle cells and the regulation of the cellular placement of other cations important to blood pressure - cellular sodium:potassium (Na:K) ratio and intracellular calcium (iCa(2+)). As a result, nutritional magnesium has both direct and indirect impacts on the regulation of blood pressure and therefore on the occurrence of hypertension. Hypertension occurs when cellular Na:K ratios become too high, a consequence of a high sodium, low potassium diet or, indirectly, through a magnesium deficient state which causes a pseudo potassium deficit. Like wise, magnesium deficiency alters calcium metabolism, creating high iCa(2+), low serum calcium and low urinary calcium states even when calcium intake is adequate. High iCa(2 + ) and high cellular Na:K ratio both occur when cellular magnesium becomes too low and the Mg-ATP driven sodium-potassium pump and calcium pump become functionally impaired. High iCa(2+) has several vasoconstrictive effects which lead to hypertension, an indirect result of low magnesium status. Dietary calcium is directly proportional to dietary magnesium. Serum magnesium does not reflect true magnesium status as do intracellular magnesium measurements. Several studies on the effect of calcium on blood pressure need these added considerations of magnesium status to fully understand the impact of the Mg:Ca ratio as the primary cause of hypertension and other aspects of Syndrome X. Magnesium supplementation above 15 mmol per day are required to normalize high blood pressure in unmedicated hypertensive patients while 15 mmol per day will lower high blood pressure in patients treated with anti-hypertensive medications. In most humans, healthy blood pressure depends upon a balance of both Na:K and Mg:Ca ratios at both cellular and whole body levels which, in turn, require adequate, long-term intakes of nutritional magnesium. The knowledge that low magnesium causes imbalance in both cellular and physiological calcium widens our view of the studies showing hypertensives have abnormal calcium metabolism.     

Role of Na+,K(+)-ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats.

Several investigators have demonstrated the antihypertensive properties of potassium in various models of hypertension. The present studies were conducted to determine whether central mechanisms contribute to these salutary effects of potassium. In Inactin-anaesthetized rats, intracerebroventricular administration of KCl solutions (0.375, 0.75 and 1.25 mumol/5 microliters) produced concentration-dependent reductions in arterial pressure and heart rate. These effects were significantly attenuated by prior central administration of ouabain, a selective inhibitor of the sodium pump. In a separate series of experiments, prior central administration of alpha 1- and alpha 2-antagonist phentolamine, or the dopamine receptor (DA1 and DA2) antagonist RS-sulpiride, was also effective in inhibiting the hypotensive and bradycardiac effects of intracerebroventricular administration of potassium. Thus, these data suggest that activation of Na+,K(+)-ATPase and central noradrenergic and dopaminergic mechanisms are involved in the central actions of potassium and these central mechanisms may contribute to the salutary effects of a potassium-rich diet in hypertensive subjects. The present studies demonstrate a potentially important relationship between Na+,K(+)-ATPase activity in the central nervous system and neural regulation of arterial blood pressure.     

Effect of Dietary Calcium on In Vitro Aortic Tissue Responsiveness to a Hypertensive Factor

It has been proposed that calcium supplementation in the diet is associated with a reduction in blood pressure. In the present study, we investigated vascular tissue sensitivity to a hypertensive factor (HF) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) fed a high calcium diet, a low calcium diet and a food restricted diet. HF, which has been isolated from erythrocytes, increases blood pressure when injected into normotensive rats and stimulates calcium uptake by aortic rings in vitro. Five-week-old rats were divided into the following groups: SHR and WKY fed a regular diet (1% calcium), SHR and WKY fed a high calcium diet (4% calcium), SHR and WKY fed a low calcium diet (0.02% calcium) and SHR and WKY fed a regular diet (1% calcium) in which food intake was restricted to 65% of ad libitum intake. Food intake, body weight, urine phosphate excretion and blood pressure development were followed for 8 weeks. At sacrifice, plasma levels of calcium and phosphate were determined. Tissue responsiveness to HF was calculated by incubating aortic rings from the rats in the different groups with HF and measuring lanthanum-resistant calcium uptake. A 4-fold increase in dietary     

Effect of calcium antagonists on aortae isolated from normotensive and hypertensive rats: relaxation and calcium influx blockade

Verapamil and diltiazem were equally potent (ie, similar EC50s) in relaxing potassium-contracted aortas of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. The mechanical EC50s produced approximately 50% calcium influx blockade, suggesting a causal link between relaxation and calcium influx blockade. Nitrendipine was about 250 times more potent in relaxing aortic smooth muscle in SHR than in WKY rats (EC50s in -log [M] were 14.10 +/- 0.30 and 11.70 +/- 0.54, respectively). This difference was not affected by endothelial denudation, and was present when nitrendipine was used by preincubation rather than during established potassium chloride contractions. In spite of the different relaxant potency of nitrendipine in SHR and WKY rats, both strains showed similar EC50s for calcium influx blockade for this compound (9.21 +/- 0.36 in SHR and 8.75 +/- 0.26 in WKY). The dissociation between aortic smooth muscle relaxation and calcium influx blockade after nitrendipine was more pronounced in the SHR strain. This suggests that mechanisms other than or in addition to calcium influx blockade play a role in the relaxation of potassium-contracted vascular smooth muscle with dihydropyridine compounds, but not with other calcium antagonists.     

Mechanism of antihypertensive effect of dietary potassium in experimental volume expanded hypertension in rats

Dietary potassium supplementation lowers blood pressure (BP) and attenuates complications in hypertensive subjects, particularly those with the low renin volume expanded (LRVE) variety. We and others have shown that the plasma level of a digitalis like substance (DLS) is elevated in this type of hypertension. We therefore, examined the effect of increases in dietary potassium on the plasma level of endogenous DLS, myocardial and renal Na+, K+-ATPase (NKA) activities, BP, and renal excretory function in reduced renal mass (RRM)-salt hypertension in the rat, a classical model of LRVE hypertension. 70% RRM rats were divided in 4 groups, namely those consuming: 1) a sodium free and normal potassium (1.3% as KCl) diet (RRM-0 Na), 2) a normal sodium and normal potassium diet (RRM-NaK), 3) a normal sodium and high potassium (2 X normal) diet (RRM-Na2K), and 4) a normal sodium and 4 times normal potassium diet (RRM-Na4K). At the end of 4 weeks of dietary treatment, direct BP was recorded, plasma level of DLS determined by bioassay and with a radioimmunoassay for digoxin (DIF) and myocardial and renal NKA activities were measured. As expected, compared to RRM-0Na rats, RRM-NaK rats developed hypertension. BP increased significantly less in RRM-Na2K, whereas BP did not increase in RRM-Na4K rats. Hypertension in RRM-NaK rats was associated with an increase in plasma DLS and DIF and decrease in renal and myocardial NKA activities. DLS was increased (DIF was not changed) and myocardial NKA also decreased in rats consuming double potassium. However, quadrupling potassium in the diet (RRM-Na4K) normalized DLS and DIF and increased myocardial and renal NKA activities, compared to RRM-0Na rats. Also compared to RRM-0Na, water consumption, urinary volume excretion, sodium, and potassium increased in the other 3 groups, more so in RRM-Na4K rats. These data show that quadrupling the potassium in the diet prevents the BP increase in RRM rats and this is associated with diuresis/natriuresis and normalization of DLS, perhaps because the diuresis/natriuresis normalizes blood volume.