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The mechanisms of cyclosporine A (Cs A) nephrotoxicity are not clear, but may be associated with high blood pressure and high serum uric acid levels even when kidney function is still normal. To evaluate proximal tubular resorption and its relationship with erythrocyte cation transport systems that are known to be abnormal in essential hypertension, we measured fractional excretion of endogenous uric acid (FE Ur%) and exogenous lithium (FE Li%), erythrocyte sodium concentration, Na-K pump, Na-K cotransport and Li-Na countertransport in two groups of kidney transplant recipients with normal kidney function (creatinine less than 1.6 mg/dL), one treated with Cs A and steroid (Cs A group) and the other with azathioprine and steroid (Aza group). Patients were matched for sex, body mass index, and age. Antihypertensive treatment was measured using arbitrary scores. Erythrocyte sodium transport systems were similar in the two groups. Despite normal kidney function, the Cs A group had higher blood pressure (mean blood pressure 108.6 +/- 3.1 mmHg vs 98.3 +/- 2.4, p less than 0.01), although taking more antihypertensive treatment, and increased proximal tubular resorption (FE Li%: 12.8 +/- 1.5 vs 20.5 +/- 1.7, p less than 0.001) and global proximal tubular resorption (FE Ur%: 5.2 +/- 0.48 vs 7.09 +/- 0.41, p less than 0.05). These findings may explain the greater prevalence of hypertension in the Cs A group. Increased urate resorption may be involved in interstitial abnormalities, which are the earliest signs of Cs A toxicity. Cs A did not modify erythrocyte ion transport systems.

This study investigated whether fractional lithium excretion (FELi), used as a marker of proximal fluid delivery, changes during different phases of essential hypertension. Forty-eight subjects were studied: 12 essential hypertensives (EH); 12 borderline hypertensives (BL); 12 normotensives with a positive family history of essential hypertension (NH) and 12 normotensives without a family history of essential hypertension (NN). Measurements were performed in the recumbent position, both in basal conditions and after a saline load (2% body weight in 1 h; 0.333 ml/min per kg body weight). In basal conditions, a moderate extracellular volume expansion was already present in the subjects. In these conditions, FELi of EH was significantly higher than that of all the other groups (P less than 0.01). After the saline load, fractional sodium excretion increased in all the groups (P less than 0.01), but to a significantly greater extent in EH (P less than 0.01). FELi rose significantly only in BL (P less than 0.05). The change in FELi of BL correlated positively (P less than 0.02) with the change in blood pressure in 10 of these subjects 3 years after this study. Moderate extracellular volume expansion may be able to either reveal or stimulate an increase of FELi in subjects with established hypertension. When a greater degree of extracellular volume expansion is induced, this increases FELi in BL and this effect may be related to the subsequent development of hypertension.

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.

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.

alpha-Latrotoxin of black widow spider venom was found to bind with high affinity (KA = 1.8 X 10(9)M-1) to specific sites present in discrete number (approximately 6300/cell, approximately 12/micron2) at the surface membrane of PC12 cells. This binding correlated with (and therefore, probably caused) the secretory response produced by the toxin. Binding was enhanced (approximately 2-fold) in the presence of mM concentrations of various divalent cations (Ca2+, Mn2+ and Co2+) while Ba2+ and Sr2+ had a smaller effect and Mg2+ was inactive. Hypertonicity, concanavalin A and trypsin pretreatment of the cells blocked the binding interaction. The alpha-latrotoxin-induced stimulation of 3H-dopamine release was massive and occurred very rapidly when cells were exposed to the toxin in a Ca2+-containing Krebs-Ringer medium, whereas it occurred at a much slower rate in a Ca2+-free, Mg2+-containing Ringer. Introduction of Ca2+ into the latter medium resulted in a shift of the release rate from slow to fast. In contrast, in divalent cation-free medium the response was abolished. The toxin-induced secretory response was unaffected by Na+ and Ca2+ channel blockers (tetrodotoxin and D600) as well as by calmodulin inhibitors (calmidazolium and trifluoperazine). The effects of Ca2+ and Mg2+ were found to be concentration-dependent, with half maximal responses occurring at approximately 0.3 and 1.5 mM for the two divalent cations, respectively. Other divalent cations could substitute for Ca2+ and Mg2+, the relative efficacy being Sr2+ greater than Ca2+ greater than Ba2+ much greater than Mn2+ greater than Mg2+ greater than Co2+. Moreover, the response occurring at suboptimal concentration of Ca2+ (0.4 mM) was potentiated by the concomitant addition of either Mg2+, Mn2+ or Co2+. The effect(s) of divalent cations in supporting the alpha-latrotoxin-induced release response seem(s) to occur primarily at step(s) beyond toxin binding because (a) the stimulatory effects of the various cations on release were not matched by parallel effects on binding, and (b) Ca2+ maintained its ability to stimulate fast release even when toxin binding had occurred in a Ca2+-free medium. Delays in the release responses were observed when cells were exposed to alpha LTx in Na+-free, glucosamine or methylamine-based media, or depolarized with high K+ (in the presence of D600) before toxin treatment. Moreover, in these two conditions the ability of Mg2+ to support the alpha LTx response was considerably decreased.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.