Coexisting independent sodium-sensitive and sodium-insensitive mechanisms of genetic hypertension in spontaneously hypertensive rats (SHR).

Some essential hypertensive patients and genetic hypertensive rat strains have less than the normal levels of Mg2+ tightly bound to the plasma membranes of their erythrocytes and other cells, i.e., the magnesium binding defect (MgBD). This binding defect appears to cause increased passive permeability of the membrane to Na+ and thereby its increased intracellular concentration, particularly if the Na+-extrusion enzyme systems of the cell are also defective. The Na+-Ca2+ exchange system in the cell membrane exports Na+ and imports Ca2+, increasing the tone of the smooth muscle cell and thus producing hypertension (HTn). This HTn is Na+-sensitive. Evidence supporting this postulate was obtained by determining the intraerythrocyte total concentrations of Na+, Ca2+, K+, and Mg2+ in two strains of spontaneously hypertensive rats (SHR and SS/Jr rats, having the MgBD together with the other requisites of the Na+-sensitive pathway) and their respective controls (WKY and SR/Jr rats, in which this complete pathway is absent). The Na+ and Ca2+ concentrations in the hypertensive rats were increased, and that of K+ was decreased. The concentrations of these cations were very similar in the two hypertensive strains. The level of membrane tightly bound Ca2+ in SHR erythrocyte membranes was significantly higher than those in the other three rat strains, which were not statistically different from each other. These results support previously reported evidence of the existence of a novel HTn-generating mechanism in the SHR rat, in which the intracellular Ca2+ concentration is increased as the result of the enhanced diffusion of this ion into the cell and the accompanying deficiency of the Ca2+ extrusion enzyme systems. This pathway is therefore Na+-insensitive, i.e., Ca2+-sensitive.

Abnormal magnesium metabolism in two rat models of genetic hypertension.

Magnesium concentrations in erythrocyte ghosts and arterial tissue of male, spontaneously hypertensive rats (SHR) were significantly less than in these tissues of male normotensive controls (Wistar-Kyoto; WKY) of the same age, which were also fed rat chow and tap water. The magnesium concentration in SHR erythrocyte ghosts was increased to the control value by incubating SHR erythrocytes with WKY blood plasma; SHR plasma did not affect the magnesium concentration in WKY erythrocyte ghosts. The magnesium concentrations in erythrocyte ghosts, aortas, and mesenteric arteries from female salt-sensitive (SS/JR) and salt-resistant (SR/JR) Dahl-derived rats, both maintained ad libitum on laboratory rat chow and either tap water or 0.9% NaCl, were not different but were significantly less than those of Sprague-Dawley rats considered as controls. While the ingestion of 0.9% NaCl had no effect on the magnesium concentrations measured in these animals, it caused the salt-sensitive rats to become severely hypertensive. It is evident from these observations that the decreased binding of magnesium to the plasma membrane of cells may be an inheritable metabolic defect that may be associated with the development of hypertension. However, in those instances of hypertension in which this defect occurs, it appears to be a contributing cause of the hypertension; by itself the defect is not a cause of hypertension.

Decreased cell membrane magnesium in some essential hypertension patients.

The concentrations of total ([T-Mg]), ultrafilterable ([UF-Mg]), and protein-bound or nonfilterable ([NF-Mg]) magnesium were measured in the plasma and in the intracellular compartment of blood from 8 essential hypertensive patients and 9 normotensive subjects. In the former, [T-Mg] was unchanged in the plasma but decreased in whole blood due to decreases of both [UF-Mg] and [NF-MG]; [UF-Mg] was increased in plasma but decreased intracellularly while [NF-Mg] was decreased in plasma and unchanged intracellularly. These concentrations correlated significantly with the average blood pressures. Decreased Mg binding to the erythrocyte membrane was also observed in 13 additional essential hypertensive patients. This decreased binding may well be responsible for the decreased intracellular [UF-Mg] in the blood of such patients. The cause of the decreased Mg binding to the erythrocyte membrane is unknown, but the binding is returned to normal by incubating erythrocytes from essential hypertensive patients with blood plasma from normotensive subjects. Decreased Mg binding to cell membranes must also occur in frankly Mg-deficient patients, some of whom, as a consequence of the primary deficiency of this mineral, are hypertensive. Normal Mg binding to erythrocyte membranes was observed in two patients with hypertension indicating that hypertension per se does not cause decreased Mg binding to cell membranes. These observations suggest that decreased Mg binding to cell membranes may be an important contributing factor in some cases of essential hypertension.

alpha-L-fucosidase variant and lipid-associated sialic acid in hereditary ovarian cancer.

In a previous study of alpha-L-fucosidase (ALF) activities in plasma samples from three ovarian cancer-prone kindreds, we observed a significant inverse correlation of cancer susceptibility and enzyme activity. Because a low level of plasma ALF activity is an inherited characteristic that has been termed the "fucosidase variant," the above demonstration has provoked great interest in the fucosidase variant relative to the genetic transmission of ovarian cancer susceptibility. We have now observed in these same plasma samples that the concentrations of lipid-associated sialic acid (LAS) are also inversely correlated with the ALF activities and, therefore, directly correlated with ovarian cancer susceptibility. In the fucosidase variant individual, the ALF is modified intracellularly, but the modified enzyme only exhibits decreased activity in the plasma. For this reason, ALF cannot be involved in tumorigenesis. Rather, the factor that modifies ALF is probably involved and is the inherited character. Therefore, we hypothesize that this modifier is responsible not only for the "fucosidase variant" but also for the elevated concentration of LAS and plays a role in hereditary ovarian cancer.

Lecithin: cholesterol acyltransferase and lysolecithin in coronary atherosclerosis.

Of 100 arteriographically examined, hospitalized, male patients, those without myocardial infarctions were divided into the following categories: zero-, one-, two-, and three-vessel disease; patients diagnosed with myocardial infarction were classified separately. The fasting plasma samples from these patients were examined for concentrations of triglycerides and total cholesterol, lipoprotein profile, lecithin: cholesterol acyltransferase (LCAT) activity, and lysolecithin (LPC) concentration. Those parameters in this group which are commonly determined were consistent with the clinical classification of these patients. Of those remaining parameters, the LCAT activity was increased as the severity of coronary atherosclerosis increased and the changes in the activity of this enzyme were appropriately reflected by increases in LPC concentration and decreases in the proportion of the plasma cholesterol unesterified. The results of this study suggest that increased, rather than decreased, plasma LCAT activity and increased LPC concentrations are characteristic of coronary atherogenesis. The plasma concentrations of LPC observed in these atherosclerotic patients are more than sufficient to qualify this substance for its previously proposed roles of mediator of transmembrane diffusion of LDL and as an inhibitor of platelet aggregation.

Hereditary ovarian carcinoma. Biomarker studies.

Three ovarian-cancer-prone kindreds were studied, two of which contained identical twin sisters concordant for ovarian carcinoma. In one kindred, both identical twin sisters had daughters with ovarian carcinoma. In another kindred, one of the identical twin sisters had an ovarian-cancer-affected daughter. Ovarian carcinoma showed vertical transmission in all three families in a pattern consonant with an autosomal dominant mode of inheritance. Medical-genetic survey of each family included detailed questionnaires with retrieval of primary medical and pathology documents on cancer of all anatomic sites. Putative biomarker determinations included: (1) in vitro hyperdiploidy in dermal monolayer cultures; and (2) lower serum levels of alpha-L-fucosidase (less than or equal to 275 IU/ml) in all cancer-affected patients and statistically significant lower levels in 50% risk individuals when compared to spouse and published controls (P = 0.04 and P = 0.0002, respectively). These findings are discussed in context with the eventual development of a risk factor profile which, given acceptable sensitivity and specificity, would enable identification of individuals who would be prime candidates for intensive surveillance/management programs.

Experimental study of chronic ambulatory peritoneal dialysis. I. Inhibition of protein and amino acid losses by single amino acids.

A successful dog model of the continuous ambulatory peritoneal dialysis patient was developed. These preparations were employed in initial studies of the effects of single amino acid-containing dialysis solutions on the losses of protein and amino acids into the dialysate. A decrease of about 40% in the loss of total amino acids into the dialysate was observed when DL-serine-containing dialysis solutions were employed. The addition of DL-serine, L-lysine, or DL-alanine to the dialysis solutions diminished protein loss into the dialysate by 27-55%. DL-Glutamic acid and DL-aspartic acid were ineffective in this regard.

Selenium concentrations in plasma of patients with arteriographically defined coronary atherosclerosis.

A prospective epidemiological study (Lancet ii: 175-179, 1982) implicates low concentrations of selenium in plasma in coronary atherogenesis. We examined this relationship more directly by fluorometry of selenium in the plasma of 91 hospitalized patients who were being examined by coronary arteriography for clinical evaluation of chest pain. We observed a significant, inverse correlation between the plasma selenium and severity of coronary atherosclerosis. These results confirm those of the epidemiological studies, but the role, if any, of selenium in atherogenesis still is unclear. Its concentration in plasma is decreased by ethanol and cigarette use; possibly this is the mechanism of its relation to hypertension and atherosclerosis.

Evidence for the involvement of beta-endorphin in the human menstrual cycle.

The possibility that beta-endorphin, an endogenous opiate, is involved in the regulation of the menstrual cycle was examined. Daily serum beta-endorphin levels, in conjunction with luteinizing hormone, progesterone, and 17 beta-estradiol were measured during 26 hormonally normal menstrual cycles. Twenty-one cycles showed a preovulatory peak and postovulatory trough of beta-endorphin, 2 cycles had a postovulatory peak, and 3 had a postovulatory peak with sustained elevation. The raw data were standardized by conversion to "Z-scores," and the composite values were computed for each of the three classes described above. Significance within these three classes was assessed using a one-way analysis of variance with an F-ratio at 95% confidence limits. The composite plot of the 26 cycles showed a statistically significant preovulatory peak occurring 2 days prior to the luteinizing hormone surge and a postovulatory trough of beta-endorphin 5 days later. These results suggest that beta-endorphins play a significant role in the neurochemical mechanisms of gonadotropin release.

Transketolase inhibition and uremic peripheral sensory neuropathy.

The relationships between predialysis and postdialysis erythrocyte transketolase activities and symptoms of uremic peripheral neuropathy were studied prospectively for 21 months in 19 chronic hemodialysis patients. In all patients the predialysis activity was observed to be sometimes greater and sometimes less than the postdialysis activity. These observations were interpreted as indicating the coexistence in uremic blood of stimulatory and inhibitory substances which influence the enzyme independently. After enzyme stimulation was assumed to be a constant feature of uremia, the expected stimulated activity in erythrocytes of predialysis blood was found to be variably inhibited up to about 55% in these patients. The occurrence of paresthesiae was closely correlated with prolonged erythrocytes transketolase inhibition which in most cases reached a level of about 40%. Our conclusion is that the magnitude of erythroycte transketolase inhibition above a certain minimum level, together with its duration, is associated with symptoms of sensory peripheral neuropathy in the uremic patient. It is therefore predicted that such measurements may be usefully applied in ascertaining the extent of hemodialysis needed to prevent the development of this pathological state.

Acetate intolerance and an inhibitor of acetate utilization in hemodialysis patients.

Diminished ability to utilize acetate (acetate intolerance) developed in a male patient on chronic hemodialysis after five years of maintenance dialysis. His ability to utilize lactate was also subnormal. We studied acetate metabolism in vitro by isolating lymphocytes from the patient's blood before dialysis and measuring their ability to convert [1-14C]acetate to 14CO2. His cells metabolized acetate only 35% as well as did lymphocytes from normal adults. The inhibition appeared when the patient's lymphocytes were cultured, and the ability of normal lymphocytes to oxidize acetate decreased after they had been incubated in the patient's plasma. We conclude that an inhibitor of acetate utilization is present in the plasma and in (or on) the cells of this acetate-intolerant patient. The diminished ability of the patient to utilize lactate and the presence of normal concentrations of pyruvate, citrate, and ketone bodies in his blood suggest that the inhibitor functions at the cell surface to impede the entrance of acetate into the cells. The inhibitor appears to be dialyzable; its nature is unknown. Its accumulation in the plasma of chronic hemodialysis patients has not been thus far associated with any deleterious effects other than prolonging the metabolic acidosis of such patients.