Sodium-lithium countertransport and hypertension in Rochester, Minnesota

The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr, p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr, p less than 0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr, p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium-lithium countertransport in ambulatory hypertensive and normotensive patients

Numerous studies have reported the mean value for Na+-Li+ countertransport to be increased in red blood cells from patients with essential hypertension. Although concomitant variables including age, body size, national origin, geographic location, gender, and family history of hypertension may affect Na+-Li+ countertransport values, most case-control studies have failed to assess the contribution of these factors to the differences in Na+-Li+ countertransport between hypertensive and normotensive groups. The present study was undertaken to provide estimates of Na+-Li+ countertransport in hypertensive and normotensive subjects after taking into account these potentially confounding sources of variation. In 187 subjects undergoing medical evaluation at the Mayo Clinic, Rochester, MN, the combined effects of variation in age, height, and weight accounted for 20.6% of the interindividual variability in Na+-Li+ countertransport. After adjustment to remove variability due to these concomitants, differences in national origin, region of birth, and place of current residence made no additional contribution to variability in this trait. There was no significant difference in mean adjusted Na+-Li+ countertransport between men and women (0.41 +/- 0.17 vs 0.40 +/- 0.12 [SD] mmol Li efflux/L red blood cells/hr; n = 107). The mean value for adjusted Na+-Li+ countertransport was significantly greater (p less than or equal to 0.001) in subjects with essential hypertension (0.44 +/- 0.15 mmol/L red blood cell/hr; n = 104) compared with normotensive subjects (0.31 +/- 0.07 mmol/L red blood cells/hr; n = 39) or subjects with borderline blood pressure elevation (0.35 +/- 0.11 mmol/L red blood cells/hr; n = 21). Subjects with a family history of hypertension in at least one parent or full sibling had significantly higher (p less than 0.02) Na+-Li+ countertransport values (0.42 +/- 0.16 mmol/L red blood cells/hr; n = 111) than those with no family history of hypertension (0.37 +/- 0.13 mmol/L red blood cells/hr; n = 76). These results suggest that increased mean Na+-Li+ countertransport in hypertensive subjects in this sample cannot be attributed to confounding effects of variation in age, body size, gender, national origin, birthplace, or residence. Forty-eight percent of subjects with essential hypertension had adjusted Na+-Li+ countertransport values above the range observed in normotensive controls.     

Sodium-lithium countertransport and probability of hypertension in Caucasians 47 to 89 years old.

The objectives of the present study were to determine whether sodium-lithium countertransport contributes to predicting the probability of having hypertension and to determine whether it does so after other predictor traits have been considered. We used logistic regression to model the relation between sodium-lithium countertransport and the probability of having hypertension, estimated by the prevalence of hypertension among 172 men and 252 women, aged 47-89 years, from the Caucasian population of Rochester, Minn. When sodium-lithium countertransport was the only predictor trait considered, it made a statistically significant contribution to prediction both in men (model chi(2)1df = 20.50, p < 0.001) and in women (model chi(2)1df = 16.69, p < 0.001). For each standard deviation increase in sodium-lithium counter-transport, the expected odds of having hypertension increased 2.25 times in men (95% confidence interval [CI], 1.44-3.51) and 1.77 times in women (95% CI, 1.32-2.37). When sodium-lithium countertransport was not considered, the other traits identified as predictors were age, body mass index, and plasma apolipoprotein CII and CII squared; plasma apolipoprotein AI was an additional predictor in women but not in men. When sodium-lithium countertransport was added to models that included the other predictors, it improved prediction both in men (increase in model chi(2)1df = 12.29, p < 0.001) and in women (increase in model chi(2)1df = 4.86, p < 0.027). Based on these complete models, when the other predictors remained at their mean values, each standard deviation increase in sodium-lithium countertransport increased the expected odds of having hypertension 2.06 times in men (95% CI, 1.31-3.22) and 1.48 times in women (95% CI, 1.04-2.21). These results establish that sodium-lithium countertransport provides information that is helpful in predicting the probability of having hypertension and is not reflected in other identified predictor traits.     

Na+-Li+ countertransport in essential hypertension

Several studies on Na+-Li+ countertransport have reported higher rates in essential hypertensive than in normotensives, with a distribution pattern which is dependent on racial and ethnic background. However, it is not well established whether this abnormality in Na+ transport is associated with an abnormal clinical setting. In the present study we have performed a kinetic analysis of the interaction of the Na+-Li+ countertransport system with internal Na+ in erythrocytes from a sample of 72 essential hypertensives and 30 normotensive controls. A significant increase in mean values of the maximal rate of Li+-stimulated Na+ efflux (Vmax; 375.1 +/- 23.8 versus 213.7 +/- 8.5 mumol/l cells per h; mean +/- s.e.m.; Mann-Whitney test: U = 500; P less than 0.0001), as well as in the apparent affinity constant for internal Na+ (KNa; 10.03 +/- 0.08 versus 6 +/- 0.4 mmol/l cells; Mann-Whitney test: U = 718; P less than 0.0079), were observed in essential hypertensives with respect to normotensives. Using the 95% confidence interval of Vmax in normotensives as the normal range, 29 (40.3%) of the essential hypertensives exhibited values above the normal upper limit. The maximal rate (Vmax) and the internal Na+ content required for half-maximal stimulation (K50%) of Na+-K+ ATPase and outward Na+-K+ cotransport, and the rate constant of Na+ leak (KPNa) in this subset were similar to the values observed in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sodium-lithium countertransport activity in healthy, dyslipidemic, and hypertensive individuals

The aim of our study was to investigate the role of dyslipidemia on red blood cell sodium-lithium countertransport activity in healthy and hypertensive individuals. A total of 128 Caucasian individuals, aged 20 to 60 years old, were divided into 4 groups: dyslipidemic/ hypertensive, dyslipidemic/normotensive, normolipidemic/hypertensive, and normolipidemic/ normotensive (controls). Sodium-lithium countertransport activity was determined based on the Canessa et al method. Sodium-lithium countertransport activity was significantly higher in all patient groups compared with controls (P < .001) and similar in the 3 patient groups. Sodium-lithium countertransport activity was significantly and positively associated with triglyceride levels (P < .001), body mass index (P < .001), total cholesterol levels (P = .001), and systolic (P = .001) and diastolic blood pressure (P = .001). In multivariate regression analysis, triglycerides made the largest contribution to sodium-lithium countertransport variation among the variables tested (R(2) = 0.273). Our results suggest that dyslipidemia affects sodium-lithium countertransport activity independently of essential hypertension and even to a greater extent than hypertension.     

Sodium-lithium countertransport and blood pressure: the Gubbio Population Study

The relation of red blood cell sodium-stimulated lithium countertransport to blood pressure (BP) and prevalence of hypertension was assessed in univariate and multivariate analyses for 2,748 men and women aged 25-74 years who participated in the baseline examination of the Gubbio Population Study in north central Italy. Since age-specific countertransport values were consistently higher for men than women, all analyses were done for men and women separately. In simple correlation analyses, countertransport was significantly related to systolic and diastolic BP in both sexes (r values 0.107-0.163). In age-adjusted analyses, countertransport was significantly related to BP level of both men and women not receiving antihypertensive treatment; mean levels were high for hypertensive persons receiving antihypertensive therapy compared with normotensive persons. Age-adjusted prevalence rates of hypertension were progressively higher for both sexes in successively higher quintiles of countertransport, almost twice as high for those in the highest quintile compared with those in the lowest quintile. Correspondingly, age-adjusted logistic regression analyses showed countertransport to be related significantly to prevalence of hypertension for both men and women (p less than 0.001). Since age, body mass index, plasma total cholesterol, uric acid, glucose, urinary sodium/potassium excretion, pulse, and (for men) daily alcohol intake also were significantly correlated with BP, and in some instances with countertransport, relation of countertransport to BP was also assessed in multivariate analyses with control for these variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Red cell sodium-lithium countertransport and cardiovascular risk factors in essential hypertension

Human red blood cells possess a Na (+)H (+) antiporter in the plasma membrane that can exchange external Na(+) for intracellular H(+) when the intracellular pH falls below 7.0. The antiporter can also exchange Na(+) for Li(+) and that is named Na (+)Li (+) countertransport (SLC). This antiporter activity has been extensively investigated in essential hypertension and diabetes by clinical, epidemiologic, and genetic studies. Elevated values are found in patients with essential hypertension and diabetic nephropathy. In vitro studies in red cells of fasted individuals have demonstrated that physiologic doses of insulin increase the maximal transport rate and the K(m) for Na(+) of both Na (+)Li (+) and Na (+)H (+) exchanges. Ex vivo, SLC also exhibits elevated maximal activity and low affinity for Na(+) in insulin-resistant hypertensives. Patients with elevated antiporter activity manifest metabolic abnormalities (for example, high fasting insulin levels, hyperlipidemia, increased total body exchangeable Na(+), and renal and cardiac hypertrophy) that are part of the syndrome characterized by resistance to insulin-stimulated body glucose disposal. The coexistence of hypertension with insulin resistance and elevated SLC has suggested that a link between the metabolic and ion transport abnormalities may be mediated through chronic elevation of insulin levels. The association between circulating insulin concentrations and prevalence and severity of cardiovascular disease has been documented in many prospective population studies. Insulin modulation of this Na(+) antiporter might be an intermediate risk factor for cardiovascular disease that monitors chronic alterations of Na(+) homeostasis observed in hypertension and diabetes.     

Thiol protein defect in sodium-lithium countertransport in subset of essential hypertension

There is probably a heterogeneous etiology for essential hypertension (EHT), and abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is common in a subgroup of patients with a strong family history of hypertension and cardiovascular disease (EHT-FH patients). The aim of this study was to test the hypothesis that altering a membrane thiol protein could mimic the abnormal Na/Li CT observed in the patients and that a more refined understanding of the mechanism of abnormal Na/Li CT would facilitate a clearer identification of a subgroup of patients with a homogeneous biochemical abnormality. Na/Li CT kinetics were determined in untreated erythrocytes and after thiol group alkylation with N-ethylmaleimide (NEM). Compared with normal control erythrocytes, untreated erythrocytes from EHT-FH patients had a low K(m) of Na/Li CT, with a high ratio of maximum velocity to K(m). This kinetic pattern was reproduced in normal erythrocytes by treatment with NEM in sodium-free medium. The same treatment in EHT-FH erythrocytes caused a markedly abnormal effect with an increase in maximum velocity, indicating an increase in transporter turnover in contrast to the increase in sodium affinity seen in normal control erythrocytes. Frequency distributions of these kinetic changes showed a subgroup of approximately 75% of EHT-FH patients with abnormal kinetic changes with NEM. Therefore, the key Na/Li CT thiol group that is very reactive to NEM and causes the abnormal Na/Li CT in a subgroup of hypertensive patients may be a useful intermediate phenotype for a disease group within the syndrome of EHT. The single flux assay of Na/Li CT at 140 mmol/L sodium poorly discriminates this group. Identification of the thiol protein involved may lead to a molecular explanation of the altered membrane function in this subgroup of patients.     

Fibroblast Na+-Li+ countertransport rate is elevated in essential hypertension.

OBJECTIVES: Elevated erythrocyte Na+- Li+ countertransport (SLC) rates are commonly found in essential hypertension. We have recently shown that human skin fibroblasts functionally express a phloretin-sensitive Na+-H+ exchange (NHE) which may also be similar to erythrocyte SLC because of amiloride-insensitivity. DESIGN AND METHODS: We investigated whether elevations in fibroblast SLC parallel the known elevations in erythrocyte SLC and in cell NHE that characterize essential hypertension. RESULTS: Higher fibroblast SLC rates were found among hypertensive patients (n = 23, median 48.8 nmol Li+/ mg(protein) per min) than in 19 normotensive individuals of similar age and sex (median 14.8 nmol Li+/mg(protein) per min, P= 0.0002). As expected, erythrocyte SLC was elevated in patients with hypertension (median 411 versus 329 micromol/l(cell) per h, P= 0.0273), but was not quantitatively related to fibroblast SLC. Finally, fibroblast NHE exchange activity was higher in essential hypertension (median Vmax 14.2 versus 7.6 mmol H+/l(cell) per min, P= 0.002), but was unrelated to fibroblast SLC. CONCLUSIONS: These findings extend to human skin fibroblasts the notion of abnormal Li+ transport in essential hypertension, and appear to be in accordance with the hypothesis that fibroblast SLC may be independent of NHE. However, molecular studies will be required to understand whether distinct exchangers and/or regulation mechanisms underlie these dysregulations.     

Platelet membrane and calcium control abnormalities in essential hypertension

The mechanisms whereby intracellular calcium concentration is controlled are briefly reviewed. With the current knowledge of both calcium homeostasis and the function and properties of cellular Ca2+-target proteins/signal transduction systems, a dysfunction of cellular calcium metabolism is considered in relation to the pathogenesis of hypertension. Although the enhanced peripheral vascular resistance characteristic of hypertension is ultimately a function of Ca2+ availability for smooth muscle cell contraction, the platelet possesses many parallel biochemical and physiologic properties. Therefore, we have utilized the platelet as the cell model for investigating the role of Ca2+ in hypertension disorders. An overview of Ca2+-linked platelet processes altered in essential hypertension is presented, and an attempt is made to integrate these multiple aberrations in a fundamental membrane lesion.     

Cardiac diastolic abnormalities and atrial natriuretic factor in essential hypertension

Cardiac function and plasma levels of atrial natriuretic factor(ANF) were studied in a group of 38 patients with untreatedessential hypertension and in a group of 31 well matched normotensivecontrols. ANF was slightly but significantly higher in hypertensivesand was directly correlated with mean arterial pressure andinversely with plasma renin activity (PRA). Hypertensives showednormal systolic function and higher cardiac mass compared tocontrols. ANF was inversely correlated to echocardiographicindexes of left ventricular performance in the former group.At Doppler echocardiographic evaluation, hypertensives showedan impairment in diastolic function which was correlated tothe increase in ANF levels. Stepwise multiple regression analysisperformed with ANF as the dependent variable and several biohumoraland echocardiographic parameters as the independent variablesshowed that only cardiac diastolic function and PRA significantlyaffect ANF levels in hypertensives. In conclusion, an impairmentin cardiac diastolic function may be responsible together withother factors for the increased ANF levels encountered in essentialhypertension.     

Abnormal thiol reactivity of tropomyosin in essential hypertension and its association with abnormal sodium-lithium countertransport kinetics

OBJECTIVES: To identify a thiol protein that is abnormal in a subgroup of essential hypertensive (EHT) patients who have a strong family history of hypertension and cardiovascular disease and have a low Km of erythrocyte Na/Li countertransport (CT). METHODS: To detect biotin maleimide labelling of a key thiol protein to investigate its reaction with N-ethylmaleimide (NEM) in normal and EHT erythrocytes. RESULTS: The thiol protein of 33 kDa apparent molecular weight (p33) identified by the loss of labelling with biotin maleimide was identified as tropomyosin due to its retarded running in 6 mol/l urea gels and immunoblotting. The NEM reaction with p33 detected by loss of subsequent biotin maleimide labelling is biphasic in normal control erythrocytes with the rate in the first 30 s double that after 30 s. In EHT erythrocytes NEM reaction (1) after 30 s is faster than normal and (2) in the first 30 s causes a paradoxical increase in apparent biotin maleimide labelling. In normal control erythrocytes, the loss of biotin maleimide labelling with NEM reaction or the faster phenylmaleimide reaction follows the same time course as the decrease in Km of Na/Li CT. CONCLUSIONS: NEM reaction with p33 requires two thiols. Only the cytoskeletal form of tropomyosin from the TM3 gene has more than one thiol group and agrees with SDS-PAGE mobility. Tropomyosin is a strong candidate to explain the familial abnormality in EHT with abnormal Na/ Li CT and it could explain many of the characteristics of this disease.     

Structural abnormalities of small resistance arteries in essential hypertension

Regardless of the mechanisms that initiate the increase in blood pressure, the development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, the small arteries smooth muscle cells are restructured around a smaller lumen, and there is no net growth of the vascular wall, while in some secondary forms of hypertension, a hypertrophic remodeling may be detected. Also, in non-insulin-dependent diabetes mellitus, a hypertrophic remodeling of subcutaneous small arteries is present. The results from our own group have suggested that indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive patients, over and above all other known cardiovascular risk factors. Therefore, the regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure, both in human and in animal models of genetic and experimental hypertension. A complete normalization of small resistance artery structure is demonstrated in hypertensive patients, after long-term and effective therapy with ACE inhibitors, angiotensin II receptor blockers and calcium antagonists. Few data are available in diabetic hypertensive patients; however, blockade of the renin–angiotensin system seems to be effective in this regard. In conclusion, there are several pieces of evidence that suggest that small resistance artery structure may be considered an intermediate endpoint in the evaluation of the effects of antihypertensive therapy; however, there are presently no data available about the prognostic impact of the regression of vascular structural alterations in hypertension and diabetes.     

Parallel adrenal and renal abnormalities in young patients with essential hypertension

To determine whether the previously described abnormalities in adrenal secretion and renal blood flow in essential hypertension are associated, we examined the responses to the relevant systems in 18 patients with essential hypertension. Young patients, under 30 years of age, were studied to minimize the likelihood that the phenomena were secondary to long-standing hypertension. To achieve a wide span of sodium balance, studies were performed during a high (200 mEq) sodium intake, a restricted (10 mEq) sodium intake and a restricted sodium intake supplemented by a further short-term diuretic-induced volume deficit (furosemide, 180 to 300 mg, to reduce body weight by 1 to 1.5 kg). The indexes measured included cardiac output (indocyanine green indicator dilution), plasma volume (¹²⁵I albumin space), renal blood flow (radioxenon transit), plasma renin activity and aldosterone levels and aldosterone secretory rate. All of these variables, with the exception of Mood pressure and total peripheral resistance, were within the normal range during the two diets. However, the aldosterone secretory response to diureticinduced volume depletion on a low-sodium diet was clearly blunted in nine subjects. These nine subjects (abnormal responders) had a virtually absent aldosterone increment (23 ± 34 μg per 24 hours) compared with the normal responders (502 ± 70 μg per 24 hours). In addition, renal blood flow was significantly higher in these same nine subjects during both a high sodium intake (434 ± 19 versus 342 ± 26 ml/100 g per minute) and a restricted sodium intake (446 ± 11 versus 285 ± 39 ml/100 g per minute). Yet, there were no significant differences between these two groups in sodium or potassium balance, blood pressure, plasma volume, cardiac index or plasma renin activity during a high or low sodium intake. Normally, control of both aldosterone release by the adrenal and renal perfusion is dominated by angiotensin; an apparently blunted response of both systems suggests that there may be a generalized abnormality in the way angiotensin interacts with its target tissues in many young patients with essential hypertension.     

Apolipoprotein E gene polymorphism is related to metabolic abnormalities, but does not influence erythrocyte membrane lipid composition or sodium-lithium countertransport activity in essential hypertension

The aim of this study was to analyze the influence of the apolipoprotein E (apoE) gene polymorphism on insulin resistance and plasma lipid composition of essential hypertensive patients. A secondary objective was to analyze if differences regarding plasma lipids had an effect on the erythrocyte membrane lipid composition and the activity of the erythrocyte membrane sodium-lithium countertransport. We studied 128 untreated nondiabetic essential hypertensive patients enrolled from our outpatient clinic. We considered as hyperinsulinemic all subjects having more than 80 mU/L of plasma insulin 120 minutes after a 75-g oral glucose intake. The number of hyperinsulinemic subjects among carriers of the epsilon4 allele was higher that in epsilon4 noncarrier subjects (13 of 19 v45 of 109, P < .05; odds ratio [OR], 3.08; confidence interval [CI], 0.99-10.57). Plasma insulin at baseline and plasma insulin and glucose at 120 minutes after overload was higher in carriers of the epsilon4 allele (respectively, 17.5 +/- 6.9 v 12.4 +/- 4.9 mU/L, P < .01; 111.9 +/- 39.9 v 88.7 +/- 48.2, P < .05; and 143.8 +/- 29.3 v 121.2 +/- 30.8 mg/dL, P < .005). Subjects with the epsilon4 allele had a plasma lipid profile more atherogenic than those without this allele. This profile was mainly characterized by higher levels of low-density lipoprotein (LDL) cholesterol (150.1 +/- 31.2 v 133.0 +/- 34.3 mg/dL, P < .05) and very-low-density lipoprotein (VLDL) triglycerides (134.7 +/- 85.5 v 99.2 +/- 68.8 mg/dL, P < .05) and by lower levels of high-density lipoprotein (HDL) cholesterol (41.8 +/- 10.7 v 50.0 +/- 14.7 mg/dL, P < .05). There were no differences between groups regarding erythrocyte membrane cholesterol or phospholipids composition and sodium-lithium countertransport (SLC) activity.     

Increased red cell sodium-lithium countertransport and lymphocyte cytosolic calcium are separate phenotypes in patients with essential hypertension

Increased red blood cell sodium-lithium countertransport (SLC) activity and elevated intracellular calcium have been observed in hypertensive patients. The association of these ion transport abnormalities with each other and with another phenotype, insulin resistance, has been suggested. We investigated whether elevated SLC activity and increased lymphocyte cytosolic calcium (Ca(cyt)) occur in the same individuals and whether either is associated with hyperinsulinaemia. We measured SLC activity, lymphocyte Ca(cyt)and fasting insulin levels in hypertensive patients and normal subjects. Consistent with prior studies, SLC activity was significantly and positively correlated with fasting insulin levels (r = 0.45, P < 0.01). However, SLC activity and lymphocyte Ca(cyt) were significantly but inversely correlated (r = -0.42, P < 0.01) and lymphocyte Ca(cyt) was also inversely correlated with fasting insulin (r = -0.55, P < 0.001). When the study participants were instead separated into two groups based on fasting insulin levels, those above the median (15 microU/ml) had significantly higher SLC activity and significantly lower Ca(cyt). When separated by lymphocyte Ca(cyt) levels (above or below 120 nM) those patients with low lymphocyte Ca(cyt) had significantly higher SLC activity and significantly higher insulin levels. Multiple linear regression showed that fasting insulin was significantly predictive of SLC activity (P = 0.05) and Ca(cyt) (P < 0.01). Thus, elevated SLC activity and increased lymphocyte Ca(cyt) are separate and distinct ion transport phenotypes in hypertensive patients, linked through a relationship to hyperinsulinaemia that is direct with SLC activity and inverse with lymphocyte Ca(cyt).     

Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes

Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium–phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium × phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit.     

Cardiovascular remodelling and red blood cell Li+/Na+ countertransport in patients with type 1 diabetes and essential hypertension

Patients with type 1 (insulin-dependent) diabetes may develop a specific cardiac disease characterized by functional and structural abnormalities. The pathogenesis of the cardiac disease is poorly understood but cardiac and renal complications may coexist. Patients with overt diabetic nephropathy have increased red cell Li⁺/Na⁺ countertransport (CT), which reflects abnormal kinetic properties of the red cell membrane Na⁺/H⁺ exchange. Since the activation of Na⁺/H⁺ exchange has a key role in cell proliferation and cell growth, as well as in the regulation of cell sodium and cell pH and in the renal reabsorption of Na⁺ and bicarbonate, we have looked for relationships between red cell Li⁺/Na⁺ CT, Na⁺/H⁺ exchange and cardiovascular remodeling in patients with type 1 diabetes, essential hypertension and idiopathic familiar cardiomyopathy. In type 1 diabetes the maximal velocity of Li⁺/Na⁺ CT is positively correlated with interventricular septum thickness and the left ventricular wall to lumen ratio. Similar results were obtained in patients with essential hypertension. In these patients an increased Li⁺/Na⁺ CT is also associated with severe and drug-resistant hypertension and with significant vascular remodelling, estimated by the minimal post-ischaemic vascular resistance in the calf. Finally, Li⁺/Na⁺ CT is negatively correlated with diastolic relaxation of the left ventricle in familiar hypertrophic cardiomyopathy. From these data it appears that widespread abnormal kinetic properties of Na⁺/H⁺ exchange, estimated by increased red cell Li⁺/Na⁺ CT, may have epistatic effects on the pathogenesis of cardiac complications of type 1 diabetes and essential hypertension.     

Distribution of target-organ abnormalities by race and sex in children with essential hypertension

The prevalence of left ventricular hypertrophy, glomerular hyperfiltration and retinovascular abnormalities was investigated in 43 black and 45 white children with essential hypertension. Whilst 36% of subjects had left ventricular hypertrophy, 49% had glomerular hyperfiltration and 50% had retinal abnormalities, no differences were found between blacks and whites. This pattern differs from that found in adult hypertensives.