Effects of adenosine on transmembrane potential and sarcolemmal Na+-K+ ATPase activity of human atrial myocardium

Adenosine effects on the transmembrane potential characteristics and the sarcolemmal Na+-K+ ATPase activity of human atrial myocardium were studied in tissue from 20 patients who were divided into 2 groups based on the maximum diastolic potentials (MDP) greater than or less than -60 mV. Group A consisted of 10 patients with MDP of 70.84 +/- 4.20 mV and Na+-K+ ATPase activity of 15.37 +/- 0.46 mumole Pi/mg/hr. Ten patients with MDP of 44.54 +/- 6.24 mV and Na+-K+ ATPase activity of 12.55 +/- 0.42 mumole Pi/mg/hr were included in group B. Adenosine had no effects on the electrophysiological properties and the sarcolemmal Na+-K+ ATPase activity of atrial myocardium at concentrations below 1 X 10(-5) M in either group. Adenosine resulted in mildly altered atrial transmembranes potentials without significant effect on Na+-K+ ATPase activity at concentrations between 1 X 10(-5) M and 5 X 10(-4) M. However, a significant reduction of transmembrane potentials and an apparent inhibition of Na+-K+ ATPase activity were observed only in tissue from group B. These results suggest that: 1) adenosine has no effect on the electrophysiological properties and the sarcolemmal Na+-K+ ATPase activity of human atrial myocardium at physiological concentrations; 2) adenosine induced inhibition of the sarcolemmal Na+-K+ ATPase activity in slow channel-dependent atrial tissues may be a mechanism responsible for the alterations of transmembrane potentials under unphysiological conditions; and 3) adenosine contributes to the genesis of cardiac arrhythmias during acute myocardial ischemia, which can reduce transmembrane potentials of the myocardial cells and may increase the myocardial adenosine level above its effective concentration.     

Genetic and environmental regulation of Na/K adenosine triphosphatase activity in diabetic patients

Even if the pathogenesis of diabetic neuropathy is incompletely understood, an impaired Na/K adenosine triphosphatase (ATPase) activity has been involved in this pathogenesis. We previously showed that a restriction fragment length polymorphism (RFLP) of the ATP1-A1 gene encoding for the Na/K ATPase's alpha 1 isoform is associated with a low Na/K ATPase activity in the red blood cells (RBCs) of type 1 diabetic patients. We thus suggested that the presence of the variant of the ATP1A1 gene is a predisposing factor for diabetic neuropathy, with a 6.5% relative risk. Furthermore, there is experimental evidence showing that lack of C-peptide impairs Na/K ATPase activity, and that this activity is positively correlated with C-peptide level. The aim of this study was to evaluate the respective influence of genetic (ATP1-A1 polymorphism) and environmental (lack of C-peptide) factors on RBC's Na/K ATPase activity. Healthy and diabetic European and North African subjects were studied. North Africans were studied because there is a high prevalence and severity of neuropathy in this diabetic population, and ethnic differences in RBC's Na/K ATPase activity are described. In Europeans, Na/K ATPase activity was significantly lower in type 1 (285 +/- 8 nmol Pi/mg protein/h) than in type 2 diabetic patients (335 +/- 13 nmol Pi/mg protein/h) or healthy subjects (395 +/- 9 nmol Pi/mg protein/h). Among type 2 diabetic patients, there was a significant correlation between RBC's Na/K ATPase activity and fasting plasma C-peptide level (r = 0.32, P <.05). In North Africans, we confirm the ethnic RBC's Na/K ATPase activity decrease in healthy subjects (296 +/- 26 v 395 +/- 9 nmol Pi/mg protein/h, r < 0.05), as well as in type 1 diabetic patients (246 +/- 20 v 285 +/- 8 nmol Pi/mg protein/h; P <.05). However, there is no relationship between the ATP1A1 gene polymorphism and Na/K ATPase activity. ATP1A1 gene polymorphism could not explain the ethnic difference. We previously showed that Na/K ATPase activity is higher in type 1 diabetic patients without the restriction site on ATP1A1 than in those heterozygous for the restriction site. This fact was not observed in healthy subjects. In type 2 diabetic patients, association between ATP1A1 gene polymorphism and decreased enzyme activity was found only in patients with a low C-peptide level. Therefore, the ATP1-A1 gene polymorphism influences Na/K ATPase activity only in case of complete or partial C-peptide deficiency, as observed in type 1 and some type 2 diabetic patients, without any correlation with hemoglobin A1c (HbA1c). Correlation observed between C-peptide levels and RBC's Na/K ATPase suggests that the deleterious effect of C peptide deficiency on Na/K ATPase activity is worse in the presence of the restriction site. This may explain the high relative risk of developing the neuropathy observed in type 1 diabetic patients bearing the variant allele.     

糖尿病患者红细胞膜Na~ -K~ ATP酶的改变

测定了34例无并发症的非胰岛素依赖型糖尿病患者红细胞膜Na~( )-K~( )ATP酶活性,并与20例年龄相匹配的正常人作比较。结果表明糖尿病患者红细胞膜Na~( )-K~( )ATP酶活性比正常人明显降低,该酶活性与馒头餐胰岛素释放试验的最高胰岛素水平和胰岛素曲线下面积呈明显正相关,而与空腹血糖和糖化血红蛋白无明显相关。糖尿病者红细胞超氧化物歧化酶含量明显降低,但与Na~( )-K~( )ATP酶活性之间无明显相关。提示糖尿病时Na~( )-K~( )ATP酶活性受血中胰岛素水平的调节。     

Genetic hypertension in the SHR rat and circulating digitalis compounds

Circulating digitalis-like compounds have been found elevated in some experimental sodium--and volume--dependent hypertensions, as well as in human essential hypertension. As few studies have been undertaken to assess their enhancement in the genetic hypertension of Okamoto (SHR) we have investigated their presence in plasma using 4 criteria: their apparent immunoreactivity with antidigoxin antibodies, their competition with tritiated ouabain binding to the sodium pump of human red blood cells,-their ability to inhibit the Na+, K+ ATPase activity of rat kidney membranes, and the Na+ fluxes from rat red blood cells. When compared to ordinary Wistar (W) and Wistar Kyoto rats (WKY), SHR exhibited a markedly enhanced apparent immunoreactivity with antidigoxin-antibodies (138 +/- 8; 59 +/- 3; 61 +/- 4 pg/ml, n = 15, 6 et 15, p less than 0.001, and p less than 0.001 respectively). The inhibition of ouabain binding by plasma extracts of the three strains did not differ (10.3 +/- 1.6, 9.9 +/- 1.7 and 12.9 +/- 1.4 ng/ml, n = 9, 18 and 14 respectively). When compared to WKY, SHR plasma extracts inhibited the renal Na+, K+ ATPase activity (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumoles Pi . mg-1 . h-1, n = 11 and 10, p less than 0.01, respectively). When incubated in SHR plasma for one hour, net sodium effluxes from Wistar erythrocytes were inhibited compared to that measured in the presence of W or WKY plasma: (5.91 +/- 0.20 vs 7.68 +/- 0.25 and 7.52 +/- 0.15 mmol/l cells, n = 5, 3 and 5, p less than 0.001, and p less than 0.001 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

High sodium diet and circulating digitalis-like compound in the rat

The effects of a high salt diet (8% NaCl) on blood pressure and intra-erythrocytic Na+ content were studied in Wistar rats. The ability of the plasma to inhibit the renal Na+,K+-ATPase activity and to cross-react with digoxin antibodies was also investigated. After 1 week, neither systolic blood pressure nor intra-erythrocytic Na+ content were modified, but plasma extracts slightly inhibited renal Na+,K+-ATPase (70.9 +/- 1.7 versus 76.3 +/- 2.1 mumol Pi/mg per h, P = 0.05). After 2 weeks, the plasma inhibitory activity, systolic blood pressure and intra-erythrocytic Na+ content were higher than corresponding values in control animals (65.5 +/- 1.6 versus 79.1 +/- 2.8 mol Pi/mg per h, P less than 0.001; 132 +/- 2 versus 114 +/- 4 mmHg, P less than 0.001, and 4.95 +/- 0.32 versus 3.81 +/- 0.36 mmol/l cells, P less than 0.05, respectively). After 3 months, the plasma digoxin-like immunoreactivity and its ability to inhibit the Na+ pump were elevated (68.7 +/- 7.9 versus 48.2 +/- 5.4 pg/ml, P less than 0.02; 57.8 +/- 1.8 versus 72.9 +/- 1.8 mumol Pi/mg per h, P less than 0.001, respectively) whereas intra-erythrocytic Na+ content had returned to control levels. The results demonstrated that this high salt intake led to simultaneous increases in systolic blood pressure and in the activity of a digitalis-like compound present in plasma. The inhibition of Na+,K+-ATPase was correlated with systolic blood pressure and digoxin-like immunoreactivity (r = 0.569, n = 76, P less than 0.001 and r = 0.414, n = 34, P less than 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

(Na+ + K+) ATPase inhibitors and intracellular electrolytes in essential hypertension

White blood cell (WBC) Na+ and K+ concentrations, plasma (Na+ + K+)ATPase inhibition and blood pressure were determined in normotensive control subjects and patients with essential hypertension. While the untreated hypertensive group had significantly lower WBC K+ concentrations than the normotensive group (mean +/- SEM, 121.6 +/- 4.4 vs. 134.7 +/- 2.8 mEq/kg, p less than 0.05), no significant difference was observed in WBC Na+ concentrations between the 2 groups. The mean of plasma (Na+ + K+)-ATPase inhibition in untreated hypertensive patients was higher than that in normotensive controls (14.8 +/- 1.7 vs. 7.2 +/- 1.8%, p less than 0.05). The correlations between (Na+ + K+)ATPase inhibition and mean blood pressure and between WBC Na+/K+ ratio and mean blood pressure were significant (r = 0.278, p less than 0.05 and 0.270, p less than 0.05, respectively), but both were weak. However, untreated hypertensive patients with higher (Na+ + K+)ATPase inhibition had significantly higher WBC Na+/K+ ratios than untreated patients with less (Na+ + K+)ATPase inhibition. These results suggest a contribution of plasma (Na+ + K+)ATPase inhibition in the production of high blood pressure in a subset of patients with essential hypertension, which results in altered intracellular K+ concentrations.     

Oleic acid-induced lung injury in rats and effects of caffeic acid phenethyl ester

Caffeic acid phenethyl ester (CAPE) is a phenolic antioxidant and is an active anti-inflammatory component of honeybee propolis. The authors evaluated the effects of CAPE on oxidative stress and lung damage in an oleic acid (OA)-induced lung-injury model. Rats were divided into 5 groups as sham, OA, CAPE, pre-OA-CAPE, and post-OA-CAPE. Acute lung injury was induced by intravenous administration of 100 mg/kg of OA. Pre-OA-CAPE group received CAPE (10 micromol/kg. intravenously) 15 minutes before OA infusion and post-OA-CAPE group received CAPE 2 hours after OA administration. Malondialdehyde (MDA) level of plasma, bronchoalveolar lavage fluid (BALF), and lung tissue; myeloperoxidase activity of BALF and lung tissue; Na(+)-K(+) ATPase activity of lung tissue; and total protein content of BALF were measured. Light microscopic analyses of lung specimens were performed. The increased MDA levels in lung homogenates (47.98+/-13.75 nmol/mL), BALF (31.12+/-3.07 nmol/mL), and plasma (61.84+/-15.34 nmol/mL) decreased significantly to 24.33+/-3.09 nmol/mL (P = 0.000), 23.19+/-4.97 nmol/mL (P = 0.002), and 27.36+/-5.37 nmol/mL (P = 0.000), respectively, following CAPE administration in pre-OA-CAPE group. Another important finding was the restoration of the enzymatic activity of Na(+)-K(+) ATPase from a value of 203.89+/-32.18 nmol Pi/mg Protein/h in OA group, to a value of 302.17+/-51.90 nmol Pi/mg Protein/h (P = 0.012) in pre-OA-CAPE group with CAPE treatment. CAPE has been shown to have a clear attenuating effect on oxidative damage in experimental animal studies. However, further investigations are necessary to suggest CAPE as a treatment agent in critically ill patients with lung injury.     

Beneficial effects of propionyl L-carnitine on sarcolemmal changes in congestive heart failure due to myocardial infarction.

OBJECTIVE: Earlier studies have revealed sarcolemmal (SL) defects in congestive heart failure due to myocardial infarction; however, the mechanisms of SL changes in the failing heart are poorly understood. Since congestive heart failure is associated with various metabolic abnormalities including a deficiency of carnitine, we examined the effects of propionyl L-carnitine, a carnitine derivative, in animals with congestive heart failure. METHODS: For this purpose, heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated with 100 mg/kg (i.p. daily) propionyl L-carnitine for 4 weeks. The sham control group received saline injections. The animals were assessed for their left ventricular function. SL membranes were examined for Na(+)-K+ ATPase, Na(+)-Ca2+ exchange and adenylate cyclase activities. RESULTS: A marked improvement in the attenuated left ventricular function of the experimental animals was seen upon treatment with propionyl L-carnitine. The SL adenylyl cyclase activities in control, untreated failing hearts and treated failing hearts were 590 +/- 36, 190 +/- 22 and 320 +/- 21 pmol cAMP/mg/10 min, whereas the SL Na(+)-K+ ATPase activities were 35.7 +/- 2.8, 22.5 +/- 2.4 and 30.1 +/- 2.8 mumol Pi/mg/h, respectively. Furthermore, the SL Na(+)-dependent Ca(2+)-uptake activity, which decreased in the failing hearts (4.6 +/- 0.4 vs. 9.3 +/- 0.7 nmol Ca2+/mg/2 s for control), was improved (6.8 +/- 0.5 nmol Ca2+/mg/2 s) significantly following treatment with propionyl L-carnitine. CONCLUSION: These results indicate that metabolic therapy with propionyl L-carnitine may attenuate defects in the SL membrane and thus may improve heart function in congestive heart failure due to myocardial infarction.     

Digoxin and membrane sodium potassium ATPase inhibition in cardiovascular disease

Kerala has a high incidence of mucoid angiopathy, metabolic syndrome X and endomyocardial fibrosis. Magnesium deficiency has been reported in these disorders even though the Keralite diet has adequate magnesium. A possible cause of magnesium deficiency is the increased digoxin, a potent inhibitor membrane Na(+)-K+ ATPase which can lead to magnesium depletion. Digoxin is known to be synthesised by the hypothalamus and other tissues and can also be obtained from plant sources in the diet. Inhibition of Na(+)-K+ ATPase can cause intracellular magnesium depletion and increase in intracellular calcium. In view of these, a study has been carried out on the activity of membrane Na(+)-K+ ATPase, using RBC membrane, serum digoxin, magnesium and glycosaminoglycan levels in patients of mucoid angiopathy, endomyocardial fibrosis and syndrome X. Significant decrease in the membrane Na(+)-K+ ATPase was observed in patients while serum digoxin levels showed an increase. Serum magnesium was significantly lower while glycosaminoglycan levels were increased. The inhibition of Na(+)-K+ ATPase activity may be due to increase in endogenous and/or exogenous digoxin. This inhibition leads to depletion of intracellular magnesium and an increase in intracellular calcium load. The role of underlying magnesium-related insulin resistance and the consequence of this intracellular magnesium and calcium alteration in the pathogenesis of these disorders is discussed.     

Recovery of erythrocyte Na(+)-K(+)-Cl- cotransport activity by enalapril

We studied total exchangeable sodium, ion transport activity at maximal rate, and erythrocyte Na+ content in response to angiotensin converting enzyme inhibition in mild-to-moderate essential hypertensive patients with normal renal function. Twenty-five patients (mean age 56 years, range 40-62 years) who had abnormal red blood cell Na(+)-K(+)-Cl- cotransport or red blood cell Li(+)-Na+ countertransport were treated with either enalapril (20 mg daily) or hydrochlorothiazide (50 mg daily) during a 30-day period. During the period of enalapril treatment, Na(+)-K+ pump and Na(+)-K(+)-Cl- cotransport increased significantly from 4,282 +/- 255 to 5,236 +/- 325 mumol/l red blood cell/hr (p less than 0.01) and 166 +/- 21 to 220 +/- 24 mumol/l red blood cell/hr (p less than 0.05), respectively. Mean intracellular Na+ content in erythrocytes decreased from 11.4 +/- 0.40 to 10.0 +/- 0.33 mmol/l (p less than 0.01) and exchangeable Na+ from 39.8 +/- 0.6 mmol/kg to 35.6 +/- 0.6 mmol/kg (p less than 0.001). Sodium reduction correlated with the recovery of Na(+)-K(+)-Cl- cotransport activity (r = -0.65, p less than 0.01). During treatment, systolic and diastolic blood pressures were reduced significantly (p less than 0.01). In 12 patients treated with hydrochlorothiazide, Na(+)-K(+)-Cl- cotransport, Na(+)-K+ pump, Na(+)-Li+ countertransport, and Na+ permeability did not change significantly while Na+ content decreased from 11.7 +/- 0.3 to 10.3 +/- 0.2 mmol/l (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Red blood cell Na+,K+-ATPase in men with newly diagnosed or previously treated essential hypertension

Alterations of cellular function of Na+,K+-adenosine triphosphatase (ATPase; Na+-K+ pump) have been implicated in the pathophysiology of essential hypertension. Therefore, this aspect of red blood cell (RBC) Na metabolism was studied in black men with newly diagnosed, untreated essential hypertension (NEH) and a normotensive control group. RBC Na content, Na+-K+ pump number (ouabain binding sites), and pump activity were measured. No statistically significant differences were found between the two groups for any of these three parameters. However, a group of previously treated essential hypertensive subjects (PEH) who had been withdrawn from therapy in the preceding 6 weeks were also studied. This group differed significantly from the NEH subjects in regard to all RBC Na+-K+ pump parameters. Their RBC Na content (10.27 +/- 3.23 vs 7.77 +/- 2.52 mmol Na/LRBC; p = 0.006) was higher, and their Na+-K+ pump activity (166 +/- 50 vs 221 +/- 87 nmol inorganic phosphate/mg membrane protein/hr; p = 0.03) and Na+-K+ pump number (213 +/- 40 vs 284 +/- 85 binding sites/RBC; p = 0.001) were lower compared with those in NEH subjects. Although the PEH subjects were older and somewhat less hypertensive than their NEH counterparts, these factors were not found to influence the Na+-K+ pump parameters. These results indicate that chronic diuretic therapy of patients with essential hypertension is associated with a reduced number of RBC Na+-K+ pumps. Since RBCs are not considered target cells for diuretics, the effects of these drugs on RBC electrolyte metabolism may occur at the time of erythropoiesis by the production of RBCs with fewer Na+-K+ pumps.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathophysiological mechanisms of altered transmembrane potentials in diseased human atria

The pathophysiological mechanisms of altered transmembrane potentials in diseased human atria were investigated in 20 patients who were divided into group A (normal) and group B (diseased). The electrophysiological data of right atrial tissues measured with glass microelectrodes included maximum diastolic potentials (MDP), action potential amplitudes (APA) and action potential durations at the time required for 50% repolarization (ADP 50%) and 75% repolarization (APD 75%). The sarcolemma isolated from atrial tissues was used for determination of the sarcolemmal Na+-K+ ATPase activities. Anionic molecular sites distributed in the sarcolemmal complex were characterized by cationized ferritins (CF). The electrophysiological data in groups A and B were: MDP -80.74 +/- 1.94 mV and -44.54 +/- 6.24 mV, APA 92.72 +/- 9.25 mV and 57.74 +/- 10.85 mV, APD 50% 42.48 +/- 6.63 msec and 210.34 +/- 36.38 msec and APD 75% 56.47 +/- 8.55 msec and 281.66 +/- 42.18 msec respectively. The difference in the Na+-K+ ATPase activities between groups A (15.37 +/- 0.46 mumole Pi/mg/hr) and B (12.55 +/- 0.4 mumole Pi/mg/hr) was highly significant. CF molecules were frequently seen to be more irregularly and loosely distributed in the sarcolemmal surfaces of group B atrial myocytes. Based on these results we conclude that depression of the sarcolemmal Na+-K+ ATPase activity and derangement of the anionic binding sites in the sarcolemmal surfaces play an important role in altering transmembrane potentials in diseased human atria.     

Positive inotropic effects of the endogenous Na+/K(+)-transporting ATPase inhibitor from the hypothalamus.

Bovine hypothalamus contains a nonpeptidic substance that inhibits purified Na+/K(+)-transporting ATPase [ATP phosphohydrolase (Na+/K(+)-transporting), EC 3.6.1.37] reversibly with high affinity by a mechanism similar to, but not identical to, that of the cardiac glycosides. It possesses some of the characteristics ascribed to a putative endogenous "digitalis-like" compound that has been implicated in the control of renal sodium excretion and the pathogenesis of essential hypertension in man. To determine whether this hypothalamic Na+/K(+)-transporting ATPase inhibitor might have physiologic properties in cardiac tissues, its effects on Na+ pump inhibition, accumulation of cytosolic free calcium, and contractile response were studied in cultured, spontaneously contracting neonatal rat cardiocytes. The hypothalamic factor potently inhibited the Na+ pump in these cells, increased myoplasmic free calcium in a dose-dependent manner, and reversibly enhanced myocyte contractility by up to 40%, comparable in degree to maximal positive inotropic effects caused by the cardiac glycoside ouabain. Comparative studies further indicate that cardiotoxic effects of ouabain in the myocytes may be more complex than simple progressive elevation of intracellular free calcium concentration because at a free calcium concentration in excess of that produced by a toxic dose of ouabain, no toxicity with the hypothalamic Na+/K(+)-transporting ATPase inhibitor occurred.     

The effects ex vivo and in vitro of insulin and C-peptide on Na/K adenosine triphosphatase activity in red blood cell membranes of type 1 diabetic patients

The decrease in Na/K adenosine triphosphatase (ATPase) activity observed in several tissues of type 1 diabetic patients is thought to play a role in the development of long-term complications. Infusion of insulin may restore this enzyme activity in red blood cells (RBCs), and recent arguments have been developed for a similar role of C-peptide. The aims of this study were to determine whether insulin acts directly on the RBC enzyme and to evaluate the effect of C-peptide on Na/K ATPase activity. Thirty-nine C-peptide-negative type 1 diabetic patients were studied (blood glucose, 11.2 +/- 1.49 mmol/L; hemoglobin A1c [HbA1c], 8.9% +/- 0.1%, mean +/- SEM). Blood samples were obtained in the morning, before breakfast and insulin injection. Intact and living RBCs were resuspended in their own plasma and incubated with or without insulin (50 microU/mL) or C-peptide (6 nmol/L). Ex vivo by microcalorimetry, the heat produced after 1 hour by the enzyme-induced hydrolysis of adenosine triphosphate (ATP), was measured in a thermostated microcalorimeter at 37 degrees C. The results showed that Na/K ATPase activity was significantly increased by insulin (12.4 +/- 0.5 v 15.4 +/- 0.9 mW/L RBCs, P < .05, n = 23) but not by C-peptide (11.9 +/- 0.7 v 12.9 +/- 0.9 mW/L RBCs, NS, P = .26, n = 12). In another experiment, RBC suspensions were incubated at 37 degrees C in a water bath with or without insulin (50 microU/mL) or C-peptide (6 nmol/L) for 10 minutes. RBC membranes were isolated and Na/K ATPase activity was assessed by measuring inorganic phosphate release at saturating concentrations of all substrates. The results showed that insulin and C-peptide significantly increased RBC Na/K ATPase activity (342 +/- 25, P < .005 and 363 +/- 30, P < .005, respectively v255 +/- 22 nmol Pi x mg protein(-1) x h(-1), n = 14). We conclude that insulin and C-peptide act directly on RBC Na/K ATPase, thus restoring this activity in type 1 diabetic patients. The stimulatory effect of C-peptide observed in vitro on RBC Na/K ATPase activity confirms that C-peptide plays a physiological role.     

Platelet 5-HT content and uptake in essential hypertension: role of endogenous digitalis-like factors and plasma cholesterol

A decrease in platelet 5-HT content linked to partial inhibition of 5-HT uptake has been described in essential hypertension. Transport of 5-HT through platelet membrane is dependent upon transmembranal Na+ and K+ gradients. It is inhibited by Na+, K+-ATPase inhibitors such as ouabain and endogenous digitalis-like compounds isolated from hemodiafiltrate. The activity of such compounds in plasma extracts, measured by inhibition of Na+,K+-ATPase or ouabain binding to human erythrocytes, and platelet 5-HT content were determined in parallel in essential hypertensive patients. Significant negative correlations were observed between these parameters in men, suggesting that high levels of digitalis-like compounds can affect platelet 5-HT content. In addition, in essential hypertensive patients, total plasma cholesterol was inversely related to both platelet 5-HT content (n = 15, r = -0.594, P less than 0.02) and maximal velocity of 5-HT uptake (n = 15, r = -0.717, P less than 0.003). In normotensive control subjects, no variation of platelet 5-HT content with cholesterol was observed. This suggests that the platelet membranes of essential hypertensive patients are more sensitive to increases in plasma cholesterol than those of normotensive subjects.     

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.     

尼莫地平对老年高血压患者内分泌激素和离子转运的影响

目的　探讨血管紧张素Ⅱ (AngⅡ )、去甲肾上腺素 (NE)、内源性类洋地黄物质 (EDLS)和细胞离子转运在老年原发性高血压 (EH)发病及尼莫地平治疗中的作用。方法　测定 2 0例轻中度老年EH患者和 2 1例健康老年人血浆AngⅡ、NE和EDLS及淋巴细胞Na+ 、Ca2 + 转运 ,观察尼莫地平治疗 6个月后各项参数变化。结果　老年EH患者血浆AngⅡ、NE和EDLS升高 ;细胞Na+ K+ 腺苷三磷酸酶 (Na+ K+ ATPase)和Ca2 + 腺苷三磷酸酶 (Ca2 + ATPase)活性降低、Na+ 和Ca2 + 增高、K+ 下降 ;NE与AngⅡ、EDLS、Na+ 和Ca2 + 正相关、与Ca2 + ATPase负相关 ,EDLS与Na+ K+ ATPase负相关。尼莫地平干预后 ,血压、总外周阻力、血浆 3种激素、细胞Na+ 和Ca2 + 降低 ,两种ATPase活性增高。结论　循环内分泌升压激素含量变化和细胞Na+ 、Ca2 + 转运失常及其相互作用可能参与老年EH的发病过程 ;尼莫地平长期治疗 ,能降低老年EH血压并改善其异常的病理生理机制     

Kinetic abnormalities of the red blood cell sodium-proton exchange in hypertensive patients.

The present study was designed to examine the kinetics of Na(+)-H+ exchange in red blood cells of normotensive and hypertensive subjects and its relation to the previously reported abnormalities in Na(+)-Li+ exchange. The Na(+)-H+ antiporter activation kinetics were studied by varying cell pH and measuring net Na+ influx (mmol/l cell x hr = units) driven by an outward H+ gradient. The Na(+)-Li+ exchange was determined at pH 7.4 as sodium-stimulated Li+ efflux. Untreated hypertensive patients (n = 30) had a higher maximal rate of Na(+)-Li+ exchange (0.43 +/- 0.05 versus 0.26 +/- 0.02 units, p less than 0.0003), a higher maximal rate of Na(+)-H+ exchange (62.3 +/- 6.2 versus 47 +/- 4 units; p less than 0.02), but a similar affinity for cell pH compared with normotensive subjects (n = 46). The cell pH activation of the Na(+)-H+ antiporter exhibited a lower Hill coefficient than that of normotensive subjects (1.61 +/- 0.12 versus 2.56 +/- 0.14; p less than 0.0001). This index of occupancy of internal H+ regulatory sites was found reduced in most of the hypertensive patients (73%) whether their hypertension was untreated or treated. Hypertensive patients with Na(+)-Li+ exchange above 0.35 units (0.68 +/- 0.057 units, n = 16) did not exhibit elevated maximal rates of Na(+)-H+ exchange (57.3 +/- 10 units, NS) in comparison with those with Na(+)-Li+ exchange below 0.35 units (66.4 +/- 7.6 units, n = 26), but both groups exhibited reduced Hill coefficients. Hypertensive patients with enhanced Na(+)-H+ exchange activity (more than 90 units) had normal maximal rates of Na(+)-Li+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial inositol and sodium in diabetes.

Although inhibition of Na(+)-K+ ATPase has been described in the diabetic heart, K+ loss from myocardium has not been observed in a canine model of mild diabetes. The finding of tissue Na+ accumulation and a potential relation to alteration of left ventricular inositol as observed in other tissues in diabetes form the basis of this investigation. Diabetes was induced with alloxan in three groups of male mongrel dogs who were studied after 1 yr. In the initial experiment the tissue compartment volumes, determined with intravenous 51Cr EDTA as a marker, were found to be normal. Calculated cell sodium was increased to 32.8 +/- 2.6 mEq/kg cell H2O vs 18.7 +/- 1.1 in controls (p < 0.01). Cell potassium in diabetes was normal. In the second group, myocardial polyols were analyzed by gas-liquid chromatography. Inositol was diminished in diabetes to 0.61 +/- 23 microM/g of left ventricle, vs the respective control levels of 1.9 +/- 0.57 microM/g (p < 0.02). Sorbitol concentration was unaltered. Left ventricular sodium increments were not associated with altered tissue calcium. In group III the hypothesis that inhibition of Na(+)-K+ ATPase in diabetes might not elicit the expected alteration of K+ transport was assessed during intracoronary infusion of acetyl strophanthidin. No difference in cation responses from control was observed. It is postulated that a change in the conformation of Na(+)-K+ ATPase, with high affinity sodium binding sites facing the intracellular compartment, may render sodium less releasable from cell membrane.