Digitalis-like Substance Research Articles

Clinical Analysis of Hyponatremia in Acute Craniocerebral Injury

To explore pathological mechanisms of central hyponatremia and its treatment. Synchronous assay was made for changes of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), endogenous digitalis-like substance (EDLS), antidiuretic hormone (ADH) in blood, and Na(+) concentrations in blood and urine, and plasma- and urine-osmolality in 68 patients with acute craniocerebral injury (ACI). Of the 68 patients with ACI, 27 were found to have hyponatremia, and such illness was mostly concentrated on severe cases. The central hyponatremia in patients with ACI may be related to the increase in the secretion of EDLS and ADH as the result of damaged functions of the hypothalamic-hypophysial system, and it seems that the decrease in blood ANP and BNP has no direct effect on Na(+) concentrations in blood. Inappropriate secretion of antidiuretic hormone syndrome and cerebral salt-wasting syndrome are the two main reasons for hyponatremia in patients with craniocerebral injury. The pathological mechanism, diagnostic standards, as well as treatment methods for the two, however, are not just the same. Intravenous injection of extrinsic thyrotropin-releasing hormone might inhibit dilutional hyponatremia arising from the increase in ADH secretion by patients with ACI.

Natriuretic Peptides, Antidiuretic Hormone and Hyponatraemia after Acute Craniocerebral Injury

We investigated the physiological mechanisms involved in central hyponatraemia in patients with acute craniocerebral injury (ACI). We measured blood concentrations of natriuretic peptides, antidiuretic hormone (ADH), and endogenous digitalis-like substance (EDLS), blood and urine sodium concentrations, and the plasma and urine osmolality in 68 patients with ACI and 24 healthy control subjects. A total of 27 ACI patients were hyponatraemic and the majority of these had grievous or severely grievous craniocerebral injuries. Blood concentrations of EDLS and ADH in hyponatraemic ACI patients were significantly higher compared with normonatraemic ACI patients and control subjects. Blood EDLS and sodium concentrations were negatively correlated with each other, whereas EDLS was positively correlated with urine sodium concentration and with urine osmotic pressure. Hyponatraemic ACI patients require different treatment based on the cause of their central hyponatraemia, so it is important to undertake a comprehensive analysis of each patient's physiological status.

Effect of digibind (DIG) on cardiovascular hemodynamics in rats with insulin dependent diabetes mellitus (IDDM) hypertension (HT)

We have reported that IDDM HT develops consistently in rats with 25% reduction in renal mass (25%RRM) and the injection of streptozotocin (STZ). In this model, we found that, as in other types of low renin (LR), volume expanded (VE) HT in animals and humans, increased endogenous Na+-K+ pump inhibitor (SPI), a digitalis-like substance. Increase in SPI by inhibiting cardiovascular muscle (CVM) cells Na+-K+pump (NKP) activity causes increased vascular resistance and cardiac contractility (dP/dt) resulting in the development of HT. The glycemic control, and altered diet, after HT was fully established in IDDM rats, failed to reverse the HT. The main endogenous HT agent in this model seems to be the SPI as we and others have reported in LR VE HT. Therfore, we have examined the effect of acutely administered DIG on the hemodynamics of IDDM-HT rats. DIG competitively displaces SPI from its binding site on Na+, K+-ATPase and therefore restimulates NKP and normalizes BP. Normal rats underwent 25% RRM under anesthesia. After one week, rats received a single injection of STZ, 65 mg/kg, bw. All RRM-STZ rats developed IDDM-HT. After 5 weeks of IDDM-HT, the rats were divided into experimental (E) and control (C) groups. Under anesthesia, BP, dP/dt and urine excretion were measured. At the end of the C period, the E rats received an iv infusion of DIG 30 mg/kg, bw over a 30 min period. During infusion and 60 min. post infusion, BP and dP/dt were monitored and urine collected every 10 min. The C rats underwent same procedure except, they received iv saline instead of DIG. Our preliminary results show that infusion of DIG, produced no significant effect on any of the parameters studied.

MECHANISM OF ANTIHYPERTENSIVE EFFECT OF DIETARY POTASSIUM IN EXPERIMENTAL VOLUME EXPANDED HYPERTENSION IN RATS

Dietary potassium supplementation lowers blood pressure (BP) and attenuates complications in hypertensive subjects, particularly those with the low renin volume expanded (LRVE) variety. We and others have shown that the plasma level of a digitalis like substance (DLS) is elevated in this type of hypertension. We therefore, examined the effect of increases in dietary potassium on the plasma level of endogenous DLS, myocardial and renal Na+, K+-ATPase (NKA) activities, BP, and renal excretory function in reduced renal mass (RRM)-salt hypertension in the rat, a classical model of LRVE hypertension. 70% RRM rats were divided in 4 groups, namely those consuming: 1) a sodium free and normal potassium (1.3% as KCl) diet (RRM-0 Na), 2) a normal sodium and normal potassium diet (RRM-NaK), 3) a normal sodium and high potassium (2 X normal) diet (RRM-Na2K), and 4) a normal sodium and 4 times normal potassium diet (RRM-Na4K). At the end of 4 weeks of dietary treatment, direct BP was recorded, plasma level of DLS determined by bioassay and with a radioimmunoassay for digoxin (DIF) and myocardial and renal NKA activities were measured. As expected, compared to RRM-0Na rats, RRM-NaK rats developed hypertension. BP increased significantly less in RRM-Na2K, whereas BP did not increase in RRM-Na4K rats. Hypertension in RRM-NaK rats was associated with an increase in plasma DLS and DIF and decrease in renal and myocardial NKA activities. DLS was increased (DIF was not changed) and myocardial NKA also decreased in rats consuming double potassium. However, quadrupling potassium in the diet (RRM-Na4K) normalized DLS and DIF and increased myocardial and renal NKA activities, compared to RRM-0Na rats. Also compared to RRM-0Na, water consumption, urinary volume excretion, sodium, and potassium increased in the other 3 groups, more so in RRM-Na4K rats. These data show that quadrupling the potassium in the diet prevents the BP increase in RRM rats and this is associated with diuresis/natriuresis and normalization of DLS, perhaps because the diuresis/natriuresis normalizes blood volume.

A molecular recognition hypothesis for nonpeptides: Na+ K+ ATPase and endogenous digitalis-like peptides.

The molecular recognition hypothesis for peptides is that binding sites of ligands and their receptors are encoded by short, complementary segments of DNA. A corollary hypothesis for nonpeptide ligands posited here is that peptide replicas may be encoded by the DNA segment complementary to the receptor binding sites for nonpeptides. This corollary was tested for digitalis. a family of cardiotonic and natriuretic steroids including ouabain. A hexapeptide (ouabain-like peptide, OLP) complementary to a ouabain binding site on sodium potassium dependent adenosine triphosphatase (Na+ K+ ATPase) exhibited activity in a digitalis bioassay. Antisera to the complementary peptide (OLP) stained the neurohypophysis in an immunocytochemical procedure. The complementary peptide was found to share an identical 4-amino acid region with the 39-amino acid glycopeptide moiety of the vasopressin-neurophysin precursor. This glycopeptide was isolated from pituitary extracts; it exhibited digitalis-like activity in the submicromolar range and cross-reacted with complementary peptide antibodies. Another digitalis-like substance with high activity also was detected in the extracts. These results demonstrate that the vasopressin-neurophysin glycopeptide has digitalis-like activity. Moreover, the findings are consistent with the hypothesis that peptide mimetics of nonpeptides are encoded in the genome.

Role of Digitalis-Like Substance in the Hypertension of Streptozotocin-Induced Diabetes and Simulated Weightlessness in Rats

We have examined the role of plasma Na+-K+pump inhibitor (SPI) in the hypertension of streptozotocin induced insulin dependent diabetes (IDDM) in reduced renal mass rats. The increase in blood pressure (BP) was associated with an increase in extracellular fluid volume (ECFV), and SPI and a decrease in myocardial Na+,K+ATPase (NKA) activity, suggesting that increased SPI, which inhibits cardiovascular muscle (CVM) cell NKA activity, may be involved in the mechanism of IDDM-hypertension. In a second study, using prolonged suspension resulted in a decrease in cardiac NKA activity, suggesting that cardiovascular deconditioning following space flight might in part result from insufficient SPI

Pregnanes That Bind To The Digitalis Receptor

Steroid binding domains of Na, K-ATPase and the nuclear hormone receptors share amino acid sequence homologies. In a ouabain radioligand assay, the potencies of series of planar or bent steroid moieties suggest that the domain in Na,K-ATPase can accommodate compounds with a planar configuration. The A/B -cis, C/D-cis steroid configuration in the cardenolides, in conjunction with appropriate substituents at the 3 and 17 positions, may represent a fortuitous “fit” for the exogenous compounds. It remains to be determined if the putative physiological digitalis-like substance is a member of a hormonal steroid family, an endogenous ouabain-like compound or both

Abstract

Steroid binding domains of Na, K-ATPase and the nuclear hormone receptors share amino acid sequence homologies. In a ouabain radioligand assay, the potencies of series of planar or bent steroid moieties suggest that the domain in Na,K-ATPase can accommodate compounds with a planar configuration. The A/B -cis, CD-cis steroid configuration in the cardenolides, in conjunction with appropriate substituents at the 3 and 17 positions, may represent a fortuitous fit for the exogenous compounds. It remains to be determined if the putative physiological digitalis-like substance is a member of a hormonal steroid family, an endogenous ouabain-like compound or both.

Role of dietary salt in hypertension.

Hypertension is the most common chronic disease in the United States and, untreated, results in disability or death due to stroke, heart failure or kidney failure. Fortunately the results of hypertension can be avoided to a large extent by proper treatment. One treatment which is effective in some cases is the restriction of dietary NaCl intake. This review considers the role of dietary NaCl in the genesis, therapy and prevention of hypertension. Most people can eat as much NaCl as they like; they have good kidneys which, within about 24 hours, excrete the NaCl as fast as it is taken in and nothing happens to blood pressure. A few, especially those with kidney disease, do not excrete it as fast as it is taken in and blood pressure rises. They are "salt sensitive". Once hypertension is established, the proportion who are "NaCl sensitive" is much higher. About 60% of people with hypertension respond to a high NaCl intake with a rise in pressure and to NaCl restriction with a fall in pressure and reduction in the need for antihypertensive medication. These are the same people that respond to diuretics with a fall in blood pressure. Many are black and elderly and have low plasma renin activity (low-renin hypertension) but some have normal or high plasma renin activity (normal or high-renin hypertension). Evidence suggests that very early they have a subtle kidney defect which causes them to excrete NaCl and water more slowly, e.g., even before they become hypertensive, black and elderly subjects excrete intravenously administered NaCl more slowly than white and young subjects. How does NaCl retention raise blood pressure? One possibility is that the NaCl retention causes water retention which releases a digitalis-like substance that increases the contractile activity of heart and blood vessels. Another is that the sodium itself penetrates the vascular smooth muscle cell, causing it to contract. "Salt sensitive" hypertension also responds to increased potassium and calcium intakes, perhaps in part because they increase NaCl urinary excretion.

Effect of administration of insulin on streptozotocin-induced diabetic hypertension in rat.

We have reported that streptozotocin-induced insulin-dependent diabetes mellitus in 25% reduced renal mass rats is associated with low-renin, volume-expanded hypertension and that the development of the hypertension can be prevented with insulin. In this study we examined the effect of insulin after the animals had developed sustained hypertension. Normotensive 25% reduced renal mass rats were treated with streptozotocin and, as expected, developed insulin-dependent diabetes mellitus and hypertension. After 4 weeks of sustained hypertension, neutral protamine Hagedorn insulin (6 to 8 IU/d) was administered subcutaneously for 4 weeks. As expected, insulin treatment decreased plasma glucose and increased body weight gain relative to untreated diabetic rats. On the other hand, insulin treatment did not reverse the hypertension and albuminuria. It also did not normalize extracellular fluid volume and plasma renin activity. Furthermore, insulin treatment did not reverse the increase in plasma Na+,K(+)-ATPase inhibitory activity (determined by both radioimmunoassay and bioassay) and the inhibition of myocardial microsomal Na+,K(+)-ATPase activity observed in the untreated diabetic hypertensive rats. 5'-Nucleotidase, a membrane marker, was not different between insulin-treated and untreated diabetic rats. These results show that insulin, given as here described, does not reverse the insulin-dependent diabetes mellitus hypertension in 25% reduced renal mass rats once it is established, perhaps because it does not reverse the albuminuria, volume expansion, increase in endogenous digitalis-like substance, and inhibition of cardiovascular muscle cell Na+,K(+)-ATPase activity.

Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes in reduced renal mass rats.

We have previously reported that chronic hypertension develops consistently in Wistar rats with a 25% reduction in renal mass (RRM) following the induction of insulin dependent diabetes mellitus (IDDM) with streptozotocin (STZ, 65 mg/kg body weight, intravenously). In this study, we examined the role of the endogenous digitalis-like substance in the development of hypertension. Four groups of rats were studied: 1) 25% RRM rats with STZ-induced IDDM (25-DM), 2) normal rats with STZ-induced IDDM (2K-DM), 3) 25% RRM rats with vehicle treatment (25-V), and 4) normal rats with vehicle treatment (2K-V). In 25-DM rats, blood pressure progressively increased during the 3 weeks after STZ treatment and was associated with microalbuminuria, low plasma renin activity, and extracellular volume expansion. In contrast, the 2K-DM, 25-V, and 2K-V rats remained normotensive. Furthermore, the plasma and urine levels of digoxin-like immunoreactive factor (DIF), determined by digoxin radioimmunoassay (Baxter), were significantly higher in hypertensive 25-DM rats than in their controls. The same was the case for plasma digitalis-like substance (DLS), determined by exposing canine Na+,K(+)-ATPase to plasma fractions and observing the percent inhibition. Increased DIF and DLS in hypertensive 25-DM rats was associated with a significant decrease in Na+,K(+)-ATPase activity of microsomes prepared from the left and right ventricles, when compared with microsomes from normotensive 2K-DM animals. Microsomal 5'-nucleotidase, a plasma membrane marker, was unchanged. The DIF and DLS correlated significantly with each other and with myocardial Na+,K(+)-ATPase activity and mean blood pressure. These results suggest that increased endogenous digitalis-like substance, which inhibits cardiovascular muscle cell Na(+)-K(+)-pump activity, may be involved in the mechanism of hypertension associated with IDDM in 25% RRM rats.

Oxygen administration increases plasma digoxin-like substance and renal sodium excretion in chronic hypoxic patients.

Despite the absence of cardiac or renal pathologies, edema and mild hyponatremia may often occur in patients affected by chronic obstructive pulmonary disease (COPD). Therefore, it has been suggested that hypoxia may influence the release of different hormones regulating renal sodium handling. To evaluate the effect of hyperoxia and O2 removal on plasma digitalis-like substance (DLS) levels, 9 patients affected by COPD and 7 normal subjects were studied. After 1 h in supine position, O2 was administered for 3 h by a tight-fitting face-mask. Blood samples for plasma DLS were taken at time 0, 60, 180 min and then for 3 h after O2 removal. In normal subjects, plasma DLS did not vary after O2 administration (from basal values of 162.25 +/- 8.59 to 107.75 +/- 6.65 pg/ml at 180 min; NS), and O2 removal (143.7 +/- 16.87 pg/ml after 3 h from O2 removal; NS). On the contrary, in patients affected by COPD, plasma DLS levels increased during O2 administration (from basal values of 138.98 +/- 8.31 to 202.14 +/- 8.21 pg/ml at 180 min; p < 0.05), and returned to baseline levels (142.59 +/- 8.28 pg/ml) 3 h after O2 removal. In the same patients, DLS increase was accompanied by a rise in Na+ excretion (from 0.08 +/- 0.01 at time 0 to 0.16 +/- 0.02 mEq/min after 3 h of O2 administration; p < 0.05). In conclusion, our findings showed an oxygen-related increase in plasma DLS levels and in urinary Na+ excretion in patients affected by COPD. This phenomenon could promote Na+ urinary loss during prolonged O2 therapy in these patients and should be taken into account in their management.

Role of digitalis-like substance in experimental insulin-dependent diabetes mellitus hypertension.

Hypertension is frequently associated with insulin-dependent diabetes mellitus, but the mechanism of the hypertension is unknown. An animal model of insulin-dependent diabetes mellitus hypertension could be helpful in determining the mechanism, but experimental insulin-dependent diabetes mellitus has been infrequently and irregularly associated with hypertension. In an attempt to develop a dependable model of insulin-dependent diabetes mellitus hypertension, we studied seven series of rats receiving either streptozotocin, surgical reduction of renal mass, or both. We found that superimposing streptozotocin 65 mg/kg body weight on 25% reduced renal mass regularly produced insulin-dependent diabetes mellitus and low-renin volume-expanded hypertension and that the animals remained healthy and hypertensive for as long as followed (13 weeks). Microalbuminuria correlated temporally with blood pressure. We used this dependable model to examine the role of endogenous digitalis-like substance in the development of hypertension in insulin-dependent diabetes mellitus. Plasma levels of digoxin-like immunoreactive factor (DIF), determined with a digoxin radioimmunoassay, were significantly higher in these hypertensive rats than in normotensive control rats (two-kidney diabetic rats, 25% reduced renal mass rats receiving vehicle for streptozotocin). This increase in plasma DIF was associated with a decrease in Na+, K(+)-ATPase activity in microsomes prepared from left or right ventricle. Microsomal 5'-nucleotidase, a plasma membrane marker, was unchanged. The plasma DIF level correlated inversely with myocardial Na+, K(+)-ATPase activity and positively with systolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Histological study on ouabain immunoreactivities in the mammalian hypothalamus

The endogenous degitalis-like factor (EDLF) which has recently been purified from human plasma and identified as ‘ouabain’, a cis-trans-cis steroid of plant origin, is thought to be similar to the hypothetical humoral factor, ‘endogenous digitalis-like substance (EDLS)’. In order to examine the hypothesis that EDLS is produced in the hypothalamus, we prepared an ouabian-specific antibody, and applied it to rat and macaque brains. Ouabain immunoreactivities were observed in the hypothalamus of both species. The immunopositive neurons were distributed in paraventricular and supraoptic nuclei, and some other hypothalamic regions. Their nerve fibers were seen abundantly in the hypothalamo-neurohypophysial regions. These results strongly support the possibility of existence of cis-trans-cis steroid including EDLF in mammalian brain.

Distribution of the endogenous digitalis-like substance (EDLS)-containing neurons labeled by digoxin antibody in hypothalamus and three circumventricular organs of dog and macaque

Endogenous digitalis-like substance (EDLS) is a newly discovered humoral agent which causes sodium-diuresis. EDLS is well known to have inhibitory activity to Na +, K +-ATPase and cross-immunoreactivity to digoxin antibody; however, its precise chemical structure has not yet been determined. We had previously developed a histochemical technique for EDLS, i.e., digoxin-immunohistochemistry, and demonstrated that EDLS was produced in the hypothalamic neurons. In the present study, the distribution of EDLS-containing neurons in the hypothalamus of dog and macaque was investigated using this technique, because anti-EDLS antibody cannot be obtained yet. In both species, EDLS neuronal somata were mainly localized in the paraventricular nucleus and the supraoptic nucleus and its accessory nuclei. A number of somata were also scattered in the other hypothalamic areas. The processes of these neurons ran from the area where the somata were located, through the lateral and basal area of the hypothalamus, to the infundibulum. These nerve fibers with varicosities were associated with the primary capillaries of hypophysial portal veins. A few immunopositive nerve fibers were also seen in the pituitary posterior lobe of both species. Intensive immunoreactivities were observed in the subfornical organ and organum vasculosum laminae terminalis. There were no differences between dog and macaque.

Reduction of erythrocyte (Na +-K +)ATPase activities in non-insulin-dependent diabetic patients with hyperkalemia

To elucidate the mechanism of hyperkalemia in diabetic patients without renal failure, we investigated (Na +-K +) adenosine triphosphatase (ATPase) activity in erythrocyte membrane, erythrocyte Na + and K + content, and plasma endogenous digitalis-like substance in control subjects (n = 16) and non-insulin-dependent diabetes mellitus (NIDDM) patients (n = 62). NIDDM patients were divided into normokalemic patients (NKDM, n = 48) and hyperkalemic patients (HKDM, n = 14). There was no difference in plasma glucose or hemoglobin A 1c (HbA 1c) levels, plasma renin activity (PRA), and plasma aldosterone concentrations (PAC) between NKDM and HKDM patients. (Na +-K +)ATPase activities in NIDDM patients were significantly reduced compared with those in control subjects (0.336 ± 0.016 μmol-inorganic phosphate [Pi]/mg protein/h, mean ± SEM, P < .05), and (Na +-K +)ATPase activities in HKDM patients (0.243 ± 0.015 μmol Pi/mg protein/h) were significantly reduced compared with those in NKDM patients (0.295 ± 0.008 μmol Pi/mg protein/h, P < .01). Plasma K + content had a significant negative correlation with (Na +-K +)ATPase activity in diabetic patients ( r = −.365, P < .01). Erythrocyte Na + content had a significant negative correlation with (Na +-K +)ATPase activity in control subjects ( r = −.619, P < .05). There was no difference in plasma endogenous digitalis-like substance among the three groups. (Na +-K +)ATPase activity was not significantly correlated with plasma endogenous digitalis-like substance in control subjects and diabetic patients. These findings suggest that the reduction of (Na +-K +)ATPase activity, which was not related to plasma digitalis-like substance, may be partly responsible for hyperkalemia in diabetic patients.

Mild exercise decreases plasma endogenous digitalislike substance in hypertensive individuals.

Changes in a plasma endogenous digitalislike substance were investigated in relation to the antihypertensive mechanism of mild exercise. Fifteen women with mild essential hypertension and seven normotensive female volunteers were divided into exercised hypertensive (n = 10), nonexercised hypertensive (n = 5), and nonexercised normotensive (n = 7) groups. A 4-week general clinical observation period preceded the study period of 10 weeks. The exercised hypertensive individuals were treated with a lactate threshold exercise that corresponded to approximately 50% of the maximum oxygen consumption three times a week, whereas the nonexercised groups were observed at the outpatient clinic as control groups. In the exercised group, systolic blood pressure fell by 7 mm Hg (p = 0.05), diastolic by 6 mm Hg (p less than 0.01), and mean blood pressure by 7 mm Hg (p less than 0.01) after 10 weeks. The reduction in the plasma endogenous digitalislike substance was significant after 7 (-1.02 ng/ml, p less than 0.05) and 10 (-1.04 ng/ml, p less than 0.05) weeks in this group. It positively correlated with the reduction in diastolic (r = 0.70, p less than 0.05) or mean (r = 0.66, p less than 0.05) blood pressure and with changes in plasma norepinephrine (r = 0.76, p less than 0.05). The mean corpuscular volume of erythrocytes decreased (-1.7 fl, p less than 0.01) after 10 weeks of exercise, and the plasma volume index tended to decrease (-108 ml/m2, p = 0.28). In the control groups, significant changes in blood pressure and plasma endogenous digitalislike substance were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

DIGOXIN-LIKE IMMUNOREACTIVITY INCREASES WITH INTRAVENOUS INFUSION OF SALINE IN RATS

1. The effects of sodium-loading on releases of endogenous digitalis-like substance were investigated by measuring digoxin-like immunoreactivity (DLI) during intravenous infusions of isotonic (0.15 mol/L) and hypertonic (1 mol/L) saline in anaesthetized rats. Plasma DLI was measured after death by a digoxin-radioimmunoassay. 2. The infusion of isotonic saline and hypertonic saline elevated the central venous pressure to similar levels. The plasma DLI concentration in both the infused groups rose significantly compared with that in the control rat not receiving the intravenous infusion. 3. The difference in the hypothalamic concentrations of DLI was not significant among the three groups, however, there was a significant inverse relationship between the plasma and hypothalamic concentrations of DLI. 4. Results indicate that the central venous pressure, but not sodium concentration, is essentially involved in the release of DLI, possibly from the hypothalamus.

Elevated endogenous digitalis-like substance in hypertensive diabetic patients with a family history of hypertension

Endogenous digital-like substance (DLS) is increased in patients with essential hypertension and is hypothesized to play a role in the pathogenesis of high blood pressure. Whether an increase in DLS in diabetic patients with hypertension is associated with a family history of hypertension or diabetic nephropathy was investigated. Plasma DLS was measured as Na(+)-K(+)-ATPase inhibitory activity (ATPI) in 100 Type 2 diabetic patients. Ouabain was used as a standard of Na-K-ATPase inhibition. Diabetic patients with hypertension demonstrated a greater ATPI level than normotensive diabetic patients (p less than 0.05). In patients with hypertension groups, the positive family history group had a higher ATPI level than the negative family history group (p less than 0.01). Microalbuminuria was not correlated with the ATPI level in diabetic patients. These results suggest that ATPI might play a role in the pathogenesis of hereditary hypertension associated with diabetes mellitus, but not have etiologic significance in diabetic nephropathy.

Elevated endogenous Na-K-ATPase inhibitor activity in hypertensive diabetic patients with a family history of hypertension

Digitalis-like substance (DLS) was measured by Na-K-ATPase inhibitor (ATPI) activity and digitalis-like immunoreactivity (DLI) in 100 patients with type II diabetes. Hypertensive diabetic patients with a positive family history for hypertension had high ATPI levels compared with those patients with a negative family history for the disease. DLI level did not differ between groups. There was no significant difference in ATPI and DLI levels among three groups based on level of urinary albumin excretion. These data suggest that a circulating factor (or circulating factors) determined by ATPI may be linked with genetic factors in the development of hypertension, but not to the development of diabetic nephropathy.