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D Cusi

Publications and source records attributed to D Cusi.

At least 55 records · Page 3Linked to original sources
PubMed1990

Predicting interindividual variations in antihypertensive therapy: the role of sodium transport systems and renin.

The efficacy of captopril at 75 mg/day, atenolol at 100 mg/day and canrenoate potassium at 200 mg/day was compared in 42 essential hypertensive patients in randomly assigned sequences. All the drugs lowered blood pressure significantly but variations were found in the individual response. Patients who were more responsive to captopril also seemed to be more responsive to atenolol and vice versa (r = 0.75; P less than 0.0001), while the relationship between mean blood pressure reached after canrenoate potassium and that reached after atenolol or captopril was much weaker. The patients who were responsive to atenolol and captopril were considered as one group (n = 22) and compared with the 12 patients more responsive to canrenoate potassium. Before treatment, the former group had higher plasma renin activity (PRA) and lower Na,K cotransport activity across the erythrocyte membrane than the latter. These two variables, considered together as a discriminant function, correctly classified 92% of cases in the canrenoate potassium responder group and 73% of cases in the atenolol-captopril responders. These results raise the problem of individual assessment to obtain the most effective antihypertensive therapy and suggest that PRA and Na,K cotransport may be useful in predicting the individual response to antihypertensive drugs.

Adolescent↗
PubMed1990

Genetic polymorphism of Na-K cotransport in essential hypertension.

Erythrocyte Na-K cotransport is high and genetically correlated to hypertension in Milan hypertensive strain (MHS) rats. In man there is a substantial overlap of individual values between essential hypertensives and controls. However, the findings in rat strains with different types of genetic hypertension suggest that Na-K cotransport studies may throw light on the different pathogenetic mechanisms of the human disease. In 28 normotensive and 22 hypertensive families the midparent-offspring correlation of Na-K cotransport values was significant only in hypertensive families (r = 0.48) and not significant in normotensive ones (r = 0.06), indicating genetic polymorphism for its phenotypic expression only in the hypertensives. In 189 essential hypertensives and 109 normotensives carefully selected from a population-based screening in order to exclude uneven sampling bias, analysis for the bimodality of the distribution of Na-K cotransport clearly showed that normotensives are distributed unimodally and hypertensives bimodally, with nadir of the distributions at about 450 mumols (1 RBC/h). Dividing the hypertensives according to Na-K cotransport value, the high Na-K cotransport subgroup has lower fractional percent excretion of uric acid and plasma renin activity. These data suggest that the high Na-K cotransport subgroup has peculiar characteristics of greater proximal tubular reabsorption (lower fractional excretion of uric acid) that may cause body volume expansion (lower plasma renin activity).

Biological Transport, Active↗
PubMed1989

Pathogenetic mechanisms in essential hypertension. Analogies between a rat model and the human disease.

Essential hypertension is a genetic disease. Its phenotypic expression depends on the interaction between genetic and environmental factors. In prehypertensive rats of the Milan hypertensive strain (MHS) a genetically inherited increase of tubular reabsorption was found, which causes the increase of blood pressure. Studies of ion transport systems in these rats have shown that the Na-K cotransport activity is increased both in erythrocytes and in tubular cells of MHS rats compared with their normotensive controls (MNS) and that this alteration is genetically linked to the transmission of high blood pressure levels. Also, in young human normotensives prone to develop essential hypertension there is an abnormal pattern of renal function which could be in agreement with a primitive increase in tubular reabsorption. Studies of erythrocyte ion transport systems in these subjects suggest that at least in a subgroup of humans predisposed to develop essential hypertension a pathogenetic mechanism similar to the one proposed for the MHS rat can be at work.

Animals↗
PubMed1989

A possible primary role for the kidney in essential hypertension.

The role of the kidney in "essential" or "genetic" types of hypertension has been evaluated both in a rat model such as the Milan hypertensive strain (MHS) or in humans. In both species, abnormalities of renal function have been demonstrated before the development of hypertension. Moreover hypertension could be "transplanted" with the kidney when kidney cross-transplantation was carried out between MHS and the Milan normotensive strain (MNS). Also in humans, the familiality for hypertension of the donor affected the requirement of antihypertensive therapy of the recipient. Further studies furnished results that were consistent with the hypothesis that a primary increase in Na transport across the tubular cell could be responsible for the pressor effect of the kidney in MHS or in humans. Because many similarities were found between the function of the tubular cell and the red blood cell in MHS, red blood cells were used to gain information about the molecular genetic mechanisms underlying these cellular changes. The results so far obtained showed that red blood cell abnormalities in MHS were genetically determined within the stem cells and genetically associated with the development of hypertension in F2 hybrids obtained by crossing the F1 (MHS X MNS). Moreover, the abnormal Na transport across the cell membrane may be due to an abnormal function of the membrane skeleton proteins. Studies are in progress to evaluate a possible cause-effect relationship between: membrane skeleton protein-ion transport across the cell membrane and the development of hypertension.

Animals↗
PubMed1988

Abnormal red-cell calcium pump in patients with idiopathic hypercalciuria.

Idiopathic hypercalciuria is a common disorder whose inheritance suggests an enzyme abnormality in calcium transport. We measured calcium-magnesium-ATPase activity in erythrocytes from 38 patients (mean age [+/- SEM], 40 +/- 2.1 years) with idiopathic hypercalciuria (24-hour urinary calcium excretion greater than or equal to 0.1 mmol per kilogram of body weight) and a history of multiple calcium oxalate kidney stones. As compared with 41 healthy controls, the patients with hypercalciuria had increased erythrocyte-membrane calcium-magnesium-ATPase activity (64.2 +/- 2.19 vs. 51.6 +/- 1.91 nmol of ATP split per milligram per minute; P less than 0.01) and increased sodium-potassium pump activity (6866 +/- 233 vs. 6096 +/- 228 mumol of sodium per liter of red cells per hour; P less than 0.05). No significant difference between the two groups was found in erythrocyte sodium-potassium cotransport, sodium-lithium countertransport, or potassium content. In 66 patients with kidney stones (38 with hypercalciuria and 28 with normal calcium excretion), 24-hour urinary calcium excretion correlated with calcium-magnesium-ATPase activity (r = 0.46, P less than 0.001). Erythrocyte calcium-magnesium-ATPase activity remained unchanged in eight subjects studied after four months on a low-calcium diet. A study of 30 healthy families found significant correlations between mean values in parents and those in offspring for calcium-magnesium-ATPase (r = 0.68, P less than 0.001) and urinary calcium excretion (r = 0.45, P less than 0.02), with no significant correlations between parents with respect to these measures (r = 0.27 and r = 0.08, respectively). We conclude that abnormalities in erythrocyte calcium-magnesium-ATPase activity may represent an inherited defect in calcium transport related to the cause of idiopathic hypercalciuria.

Adult↗
PubMed1988

Antihypertensive effect of captopril, canrenoate potassium, and atenolol. Relations with red blood cell sodium transport and renin.

We compared the antihypertensive efficacy of atenolol (100 mg/d), canrenoate potassium (200 mg/d), and captopril (75 mg/d) in 30 essential hypertensives. The three drugs were administered in a randomized change-over sequence for four-months each. The main variables associated with blood pressure regulation were measured in the basal condition and at the end of each treatment period. The erythrocyte Na transport systems were measured only in the basal condition and at the end of the first treatment period. The average blood pressure reduction was similar for each drug. Mean blood pressure levels after captopril correlated positively with those after atenolol in the individual patients (P less than 0.0001); mean blood pressure levels after canrenoate potassium, on the contrary, did not correlate with those after the other two drugs. Captopril and canrenoate potassium treatment reduced intraerythrocyte Na content (P less than 0.02), canrenoate potassium increased Na-K pump (P0.05), atenolol did not change any erythrocyte membrane Na transport parameters. The ouabain-resistant Na transport systems were not modified by any drug. The patients were divided in three groups according to their antihypertensive response: nonresponders (six patients), canrenoate potassium responders (nine patients) and captopril-atenolol responders (15 patients, equally responsive to both drugs). Nonresponders had the lowest basal Na pump (P less than 0.02). Canrenoate potassium responders had higher basal Na-K cotransport than captopril-atenolol responders (P less than 0.02). Atenolol-captopril responders had the highest basal plasma renin activity (PRA, P less than 0.02). The blood pressure reduction after atenolol correlated with the induced fall in PRA (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Erythrocyte deficiency in calpain inhibitor activity in essential hypertension.

The calpain-calpain inhibitor system was evaluated in erythrocytes of patients with essential hypertension and normotensive controls, either with or without a family history of hypertension. Calpain levels were similar in the controls and hypertensive patients, whereas the inhibitor activity level was significantly reduced in the latter (301.8 +/- 26.4 vs 220 +/- 14 U/mg hemoglobin, p less than 0.001). Borderline hypertensive patients and a few controls with a history of hypertension showed low inhibitor activity. Similar results have recently been reported in genetically hypertensive rats of the Milan strain. A significant inverse correlation (r = -0.43, p less than 0.001) was found between mean arterial pressure and calpain inhibitor. Although the pathophysiological significance of these observations is not yet clear, they suggest a new area of investigation into the molecular mechanisms underlying essential hypertension and its complications.

Adult↗
PubMed1988

Renal abnormalities at the prehypertensive stage of essential hypertension.

An approach to evaluating the genetic components of essential hypertension using an animal model, the Milan hypertensive strain (MHS) of rats, and studies in human families with positive and negative histories for high blood pressure are described and discussed. Differences at renal and cellular levels between MHS and its normotensive control strain, MNS, show many similarities to those between offspring from hyper- and normotensive families in humans. These include, with respect to the former group of each species, lower erythrocyte volume and Na content, higher Na-K cotransport across red blood cell (RBC) membranes higher Na excretion after load, and greater pressor effect in transplanted kidneys. A novel protein found in rat RBC cytoskeleton appears to have a function in Na-K cotransport and it may, eventually, be possible to demonstrate in man.

Animals↗
PubMed1988

[Sodium transport and renal hemodynamics in arterial hypertension of genetic origin: primary or secondary changes?].

Essential hypertension develops from the interaction of genetic and environmental factors. In the Milan hypertensive strain (MHS) rat before the development of hypertension, there is a genetically inherited increase of tubular reabsorption which is the cause of the following increase of blood pressure. Also in young normotensive humans, predisposed to develop essential hypertension later in life, there is an abnormal pattern of renal function that may be explained by increase of tubular reabsorption. The studies of the erythrocyte membrane transport support these data and suggest that at least a subset of essential hypertensive humans may develop a form of hypertension that has pathogenetic mechanisms similar to the ones of MHS rats.

Animals↗
PubMed1988

Role of cellular sodium and calcium metabolism in the pathogenesis of essential hypertension.

The differences observed among rat strains in both basal [Na+]i and the several cation transport systems seem to be due to the different genetic background as clearly shown in F2 populations or after bone marrow transplantation in MHS. The same may be true for humans. In spite of all the caution taken in interpreting the data, because of the great possibility of methodological errors, it is likely that the differences observed in many laboratories are due to uneven genetic or ethnic composition of the samples studied, as shown by Dagher and Canessa. One intriguing observation is that most reports of "low Na-K cotransport" values in hypertensive patients are from Mediterranean countries (Italy, France, and Spain), whereas most reports of "high," or "not low Na-K cotransport," or very high values of countertransport came from populations originating from North Europe (Denmark, USA, South African whites). We are not aware of any study on erythrocyte Na-K cotransport performed in Great Britain (the greatest source of American immigrants). Indeed the difference in cotransport values between North and South European hypertensives might be due to different environmental factors, but if this is so, the difference does not depend on the salt consumption or plasma lipids that are similar in our high and low Na-K cotransport hypertensives (Cusi D et al, submitted). The picture seems relatively less confusing for calcium. The most consistent alterations in different models of hypertension is a decreased Ca-pump in SHR, MHS, and DOCA rats, reduced calcium binding in SHR and MHS, and reduced microsomal ATP dependent calcium uptake in SHR and DOCA rats. [Ca++]i, which is increased in established hypertension in man and rats, is normal in young prehypertensive rats and humans, and returns to normal values after pharmacological treatment of hypertension. This pattern of changes suggests that genetic control of these transport systems is weaker, and probably much influenced by different environmental conditions. However, because of the pivotal role of calcium in vascular smooth muscle cell concentration, its intracellular increase may be the common pathway of the different forms of hypertension. What remains unclear is the relation, if any, between calcium and sodium. Blaustein tried to find a link between them, but his hypotheses have yet to be confirmed.

Animals↗
PubMed1986

Modes of operation and variable stoichiometry of the furosemide- sensitive Na and K fluxes in human red cells.

We report in this paper different modes of Na and K transport in human red cells, which can be inhibited by furosemide in the presence of ouabain. Experimental evidence is provided for inward and outward coupled transport of Na and K, Ki/Ko and Nai/Nao exchange, and uncoupled Na or K efflux. The outward cotransport of Na and K was defined as the furosemide-sensitive (FS) component of Na and K effluxes into choline medium and as the Cl-dependent or cis-stimulated component of the ouabain-resistant (OR) Na and K effluxes. Inward cotransport of Na and K was defined by the stimulation by external Na (Nao) of the K influx and the stimulation by external K (Ko) of the Na influx in the presence of ouabain. Both effects were FS and Cl dependent. Experimental evidence for an FS Ki/Ko exchange pathway of the Na/K cotransport was provided by (a) the stimulation by external K of FS K influx and efflux, and (b) the stimulation by internal Na or K of FS K influx in the absence of external Na. Evidence for an FS Nai/Nao exchange pathway was provided by the stimulation of FS Na influx by internal Na from a K-free medium (130 mM NaCl). This pathway was four to six times smaller than the Ki/Ko exchange. In cells containing only Na or K, incubated in media containing only Na or K, respectively, there was FS efflux of the cation without simultaneous inward transport (FS uncoupled Na and K efflux). The stoichiometric ratio of FS outward cotransport of Na and K into choline medium varied with the ratio of Nai-to-Ki concentrations, and when Nai/Ki was close to 1, the ratio of FS outward Na to K flux was also 1. In choline media, FS Na efflux was inhibited by external K (noncompetitively), whereas FS k efflux was stimulated. The stimulation of FS K efflux was due to the stimulation by Ko of the Ki/Ko exchange pathway. Thus, the stoichiometry of FS Na and K effluxes also varied in the presence of external K. A minimal model for a reaction scheme of FS Na and K transport accounts for cis stimulation, trans inhibition, and trans stimulation, and for variable stoichiometry of the FS cation fluxes.

Adult↗
PubMed1986

Furosemide-sensitive Na and K fluxes in human red cells. Net uphill Na extrusion and equilibrium properties.

This paper reports experiments designed to find the concentrations of internal and external Na and K at which inward and outward furosemide-sensitive (FS) Na and K fluxes are equal, so that there is no net FS movement of Na and K. The red cell cation content was modified by using the ionophore nystatin, varying cell Na (Nai) from 0 to 34 mM (K substitution, high-K cells) and cell K (Ki) from 0 to 30 mM (Na substitution, high-Na cells). All incubation media contained NaCl (Nao = 130 or 120 nM), and KCl (Ko = 0-30 mM). In high-K cells, incubated in the absence of Ko, there was net extrusion of Na through the FS pathway. The net FS Na extrusion increased when Nai was increased. Low concentrations of Ko (0-6 mM) slightly stimulated, whereas higher concentrations of Ko inhibited, FS Na efflux. Increasing Ko stimulated the FS Na influx (K0.5 = 4 mM). Under conditions similar to those that occur in vivo (Nai = 10, Ki = 130, Nao = 130, Ko = 4 mM, Cli/Clo = 0.7), net extrusion of Na occurs through the FS pathway (180-250 mumol/liter cell X h). The concentration of Ko at which the FS Na influx and efflux and the FS K influx and efflux become equal increased when Nai increased in high-K cells and when Ki was increased in high-Na cells. The net FS Na and K fluxes both approached zero at similar internal and external Na and K concentrations. In high-K cells, under conditions when net Na and K fluxes were near zero, the ratio of FS Na to FS K unidirectional flux was found to be 2:3. In high-K cells, the empirical expression (Nai/Nao)2(Ki/Ko)3 remained at constant value (apparent equilibrium constant, Kappeq +/- SEM = 22 +/- 2) for each set of internal and external cation concentrations at which there was no net Na flux. These results indicate that in the physiological region of concentrations of internal and external Na, K, and Cl, the stoichiometry of the FS Na and K fluxes is 2 Na:3 K. In high-Na cells under conditions when net FS Na and K fluxes were near zero, the ratio of FS Na to FS K unidirectional fluxes was 3:2 (1).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Genetic and experimental hypertension in the animal model-similarities and dissimilarities to the development of human hypertension.

In this article, we present the results we have obtained from experimental and genetic models of human essential hypertension, in order to investigate those findings relevant to understanding the time course and the mechanisms underlying the human disease. With experiments on the renal artery constriction in the conscious dog, we have shown that a kidney lesion can produce a form of hypertension not different, in the established phase, from the essential one and that the onset of this form follows a phasic pattern during which the initial stages are crucial for understanding the mechanisms leading to hypertension. We also consider a rat model (MHS) that spontaneously develops a form of hypertension very similar to the human disease. In this model, we have demonstrated by a kidney cross-transplantation experiment and functional studies that the kidney is responsible for the rise in blood pressure and that the organ dysfunction is probably due to a primary abnormality in ion handling of the cell membrane. This cellular alteration, detected both in MHS erythrocytes and in their kidney proximal tubular cells, should be the cause for the higher rate of kidney Na+ reabsorption observed in the MHS. Comparing this animal model with, at least, a subgroup of humans prone to develop hypertension or already hypertensive, it is possible to detect a series of similarities in the kidney function, hormonal pattern, and cellular function of the two species that allows us to argue that the MHS is a suitable model from which to draw conclusions relevant to the pathogenesis of essential hypertension in some humans.

Animals↗
PubMed1986

Cell membrane abnormalities and genetic hypertension.

Evidence indicates that an alteration in kidney function has a causal role in the pathogenesis of hypertension in the Milan hypertensive strain (MHS) rat. At the prehypertensive stage, these animals have increased glomerular filtration rate and 24-hour urinary output, whereas plasma renin activity and urinary kallikrein are lower. After transplantation, the MHS kidney increases the blood pressure of a normotensive recipient. Micropuncture experiments, where single nephron filtration rate, tubuloglomerular feedback, proximal tubular reabsorption, micro-pressures in tubuli, and interstitium and interstitial oncotic pressure were measured, suggest that the intrinsic ability of MHS proximal tubular epithelium to reabsorb solute and water is greater in prehypertensive MHS rats than in Milan normotensive strain (MNS) rats. Also rheogenic Na transport across the brush-border vesicles isolated from proximal tubular cells is faster. When erythrocytes and proximal tubular cells of MHS rats are compared to those of MNS rats, the former have smaller volume and Na content, whereas the Na transport is faster and the Ca ATPase at Vmax is lower. This indicates that the genetic cellular abnormality responsible for the renal functional abnormality and hypertension is also present in erythrocytes. Moreover, MHS erythrocyte abnormalities are genetically determined within the stem cells and are genetically associated with hypertension. Because a correlation was also found in human hypertension between erythrocyte Na transport abnormality and renal function, it is proposed that the erythrocyte may be used for studying the genetic molecular mechanisms of hypertension.

Animals↗
PubMed1986

Effects of captopril and of other antihypertensive drugs on cell membrane ion transport--a preliminary report.

We measured red blood cell Na+-K+ pump, Na+-Li+ countertransport and Na+-K+ cotransport activities, together with intraerythrocyte sodium content before and after 3 months therapy with captopril and two other antihypertensive drugs (atenolol and canrenoate potassium) in subjects suffering from essential hypertension. All patients discontinued any previous treatment at least 3 months before the basal evaluation of cell membrane activities. All three drugs significantly lowered blood pressure but only captopril and canrenoate potassium induced significant modifications in red blood cell parameters. After three months of captopril therapy intraerythrocyte Na+ content was significantly decreased (P less than 0.01) without any detectable change in cation transport system activity. After 3 months of canrenoate potassium therapy we also observed a significant decrease in internal Na content (P less than 0.01), together with a significant increase in Na+-K+ pump (P less than 0.02) and Na+-Li+ countertransport (P less than 0.05) activities.

Adolescent↗