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F J Haddy

Publications and source records attributed to F J Haddy.

At least 19 recordsLinked to original sources
PubMed2000

Effects of a neutral endoprotease enzyme inhibitor, thiorphan, on hemodynamics and renal excretory function in four models of experimental hypertension.

Thiorphan, a neutral endoprotease (NEP) enzyme inhibitor, has been shown to enhance the effects of atrial natriuretic peptide (ANP) in vivo. In this study, we examined the effects of an intravenous (iv) infusion of thiorphan on cardiovascular hemodynamics and excretion of urine volume (UV), sodium (U(Na)V) and potassium (UKV) in four different models of experimental hypertension, namely: 1) SHR, 2) two-kidney, one clip (2K1C),3) one-kidney, 1 clip (1K1C) and. 4) 70% reduced renal mass-salt (RRM-S) hypertensive rats. SHR has normal plasma renin activity, 2K1C is renin dependent, and 1K1C and RRM-S are low renin volume dependent models of hypertension. Rats were divided into experimental and control groups. Under inactin (120 mg/kg, body weight) anesthesia, rats were instrumented to record blood pressure and dP/dt (Millar catheter) and urine was collected through a suprapubic urinary bladder catheter. Experimental animals received an iv infusion of thiorphan, 0.5 mg/kg/min for 120 minutes. Control animals received vehicle only. In some animals, vascular smooth muscle cell membrane potentials (Em) was measured in vivo. In another series of experiments, using the identical protocol, cardiac output was recorded. The thiorphan infusion produced a similar progressive decrease in blood pressure in all models of hypertension. Cardiac output did not change relative to vehicle infused control animals. Thus pressure decreased because of a decrease in total peripheral resistance. The contractility index (dP/dt/P, where P = left ventricular pressure) did not change but vascular smooth muscle cells in tail arteries hyperpolarized in all four models. In spite of a significant decrease in blood pressure, thiorphan infusion either increased or produced no change in urinary volume (UV) and sodium (U(Na)V) excretion. These data show that thiorphan, an NEP inhibitor, decreases the blood pressure of hypertensive rats due to a decrease in total peripheral resistance, perhaps by hyperpolarizing vascular smooth muscle cells. These effects are independent of the mechanism of the hypertension. Increased UV and U(Na)V in the face of decreased pressure suggests a direct renal effect.

Animals↗
PubMed2000

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.

Animals↗
PubMed1999

Sodium-potassium pump inhibitor in the mechanism of one-kidney, one wrap hypertension in dogs.

Using ouabain sensitive 86Rb uptake by the vessel wall, we previously showed that sodium-potassium pump activity is decreased in the arteries and veins, and that the sodium-potassium pump inhibitor (SPI) is increased in the plasma of dogs with one-kidney, one wrap (1-K, 1W) hypertension, a low renin model of hypertension. We also showed in rats with a similar type of hypertension that the membrane potential of vascular smooth muscle cells in arteries is decreased, and that this decrease can be reproduced in arterial cells in arteries from normal rats by applying plasma from the hypertensive animals. One endogenous SPI in human plasma has been reported to be ouabain or its isomer. In this study, we used a newly available Dupont ouabain enzyme immunoassay kit to examine plasma and kidneys for SPI in dogs with 1-K, 1W hypertension. We also examined 1) the inhibiting activity of plasma of Na+, K(+)-ATPase obtained from normal kidneys, and 2) the Na+, K(+)-ATPase activity of the kidneys from these hypertensive animals. 1-K, 1W hypertension was produced in dogs by wrapping the left kidney in a silk bag and removing the right kidney. The removed kidney was kept at -70 degrees C till assayed. After 4 weeks of hypertension, the remaining kidney was removed and stored at -70 degrees C till assayed. Blood samples were drawn before and at weeks 3 and 4 of hypertension. Plasma levels of "ouabain" and Na+, K(+)-ATPase inhibitory activity were increased at weeks 3 and 4 of hypertension, compared to pre-hypertension levels. Renal tissue "ouabain" levels were also increased at week 4 of hypertension. However, renal Na+, K(+)-ATPase activity was unchanged. These findings, using two different assays, confirm our 1980 conclusion that SPI is elevated in the plasma of dogs with 1-K, 1W hypertension. The absence of renal Na+, K(+)-ATPase inhibition, despite increased plasma and renal SPI in these animals, may have important implications for the development of this type of hypertension.

Animals↗
PubMed1996

Effects of head down tilt on hemodynamics, fluid volumes, and plasma Na-K pump inhibitor in rats.

BACKGROUND: Hindquarter suspension in rats has been used as a model of simulated weightlessness (SW) for ground based study of the effects of microgravity on the cardiovascular system (CVS). METHODS: Using this rat model of SW we tested the hypothesis that CVS deconditioning following spaceflight results, in part, from a decrease in the circulating concentration of sodium-potassium pump inhibitor (SPI). Control rats similarly prepared were not suspended. RESULTS: During the first hour of suspension, central venous pressure (CVP), blood pressure (BP), heart rate (HR), cardiac output (CO), plasma volume (PV), extracellular fluid volume (ECFV), urine output (UV), atrial natriuretic peptide (ANP), and the plasma level of SPI increased. Plasma renin activity (PRA) and myocardial Na+, K(+)-ATPase activity (NKA) decreased. By the end of 4 h of SW, the changes in CVP, BP, HR, ECFV, and UV persisted, but PV, plasma ANP and SPI, and myocardial NKA activity returned to control levels. By the end of 1 d of SW, ECFV and plasma SPI levels had decreased but the myocardial NKA had not increased. At day 4, CVP and BP were the same as in control sham treated rats. Plasma SPI levels were decreased at day 4 but the myocardial NKA was not different, whereas renal NKA was increased. At day 7, myocardial NKA and renal NKA were increased and vascular smooth muscle cell (VSMC) membrane potentials were hyperpolarized. CONCLUSIONS: These data indicate that prolonged SW causes a decrease in plasma SPI level which, by hyperpolarizing VSMC, may play a role in the CVS deconditioning seen in astronauts following spaceflight.

Animals↗
PubMed1995

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.

Age Factors↗
PubMed1994

Chronic blood pressure effects of bufalin, a sodium-potassium ATPase inhibitor, in rats.

Endogenous Na+,K(+)-ATPase inhibitors may have a role in the mechanism of low-renin hypertension. Two such compounds have been characterized: ouabain from human plasma and resibufogenin from toad plasma. Previously, we examined the acute effects of ouabain and bufalin (which has the same structure as resibufogenin except for one H+) in normal rats. Bufalin raised blood pressure, but ouabain had little effect. In contrast, given chronically, ouabain substantially increased blood pressure in normal rats and 70% reduced renal mass rats on a salt-free diet. We have now examined the chronic effects of bufalin in rats. Normal rats received 14.8 micrograms/kg per day bufalin or an equimolar dose of ouabain intraperitoneally for 6 weeks; 70% reduced renal mass rats also received 14.8 micrograms/kg per day bufalin. Another group of normal rats received 29.6 micrograms/kg per day bufalin intraperitoneally for 6 weeks. Respective control animals received vehicle. In contrast to ouabain, blood pressure did not increase in normal rats receiving the 14.8 micrograms dose of bufalin. However, normal rats receiving 29.6 micrograms bufalin and 70% reduced renal mass rats receiving 14.8 micrograms bufalin developed significant increases in blood pressure. Increases in blood pressure were associated with decreases in myocardial Na+,K(+)-ATPase activity and correlated with increased plasma Na+,K(+)-ATPase inhibitory activity. Thus, although bufalin is a more potent pressor agent than ouabain when both agents are given acutely, ouabain is at least as potent a vasopressor agent as bufalin when given chronically. Thus, both are pressor agents, more so in the presence of reduced renal mass, when given chronically in the rat.

5'-Nucleotidase↗
PubMed1994

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.

Animals↗
PubMed1993

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.

Animals↗
PubMed1993

Role of ouabain-like factors in hypertension: effects of ouabain and certain endogenous ouabain-like factors in hypertension.

Several reports suggest the presence of sodium-potassium pump inhibitor in plasma and various tissues, particularly during volume-expanded state and low-renin hypertension. It has been hypothesized that by inhibiting the cardiovascular muscle-cell Na(+)-K+ pump, this inhibitor can constrict blood vessels, enhance vasoconstriction, and increase cardiac contractility, thereby raising blood pressure. Only two such endogenous inhibitors have been chemically characterized: the bufodienolide derivative, resibufogenin, obtained from toad skin and plasma; and a factor with the same structure (based on mass spectral analysis) as ouabain, from human plasma. However, unlike bufalin (aglycone), which is almost structurally identical to resibufogenin, neither ouabain nor ouabagenin (aglycone of ouabain) caused a sustained increase in blood pressure when infused in equimolar doses during a 30-min period in rats. Because the rat is 10(4)-fold less sensitive to ouabain than the human is, we wondered whether the absence of a response to ouabain was due to the short infusion time. Therefore, in new experiments ouabain was administered chronically during a 6- to 7-week period to two-kidney normal rats and rats with 70, 60, and 25% reduced renal mass. Reduced renal mass rats were used because these rats have decreased sodium excretion capacity, and thus we hoped the action of exogenous ouabain would be potentiated in these volume-expanded rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

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)

Animals↗
PubMed1993

Long-term ouabain administration produces hypertension in rats.

Ouabain has recently been identified as an endogenous Na(+)-K+ pump inhibitor. We administered ouabain chronically to normotensive rats with varying degrees of reduced renal mass (RRM) and to normal two-kidney rats to see whether hypertension could be produced. Normal male Wistar rats and rats with 25%, 60%, and 70% RRM received ouabain (13.9 micrograms/kg per day IP) in normal saline for 4 weeks followed by ouabain (27.8 micrograms/kg per day IP) for 3 to 4 more weeks. Respective control animals received vehicle only. Blood pressure was recorded weekly by tail plethysmography. Animals received tap water and standard rat chow, except for 70% RRM rats, which received distilled water and sodium-free chow. After 6 to 8 weeks of treatment, with rats under thiobutabarbital anesthesia, direct blood pressure was determined. Plasma, tissue, and urinary ouabain levels were measured with a specific radioimmunoassay. Animals receiving ouabain developed significant increases in mean blood pressure compared with control animals (70% RRM, 147 +/- 4 vs 116 +/- 4 mm Hg; 60% RRM, 140 +/- 4 vs 107 +/- 3 mm Hg; 25% RRM, 131 +/- 5 vs 100 +/- 2 mm Hg; no RRM, 116 +/- 4 vs 98 +/- 5 mm Hg). Plasma ouabain levels measured 24 hours after the last ouabain dose were not different in animals receiving ouabain vs those receiving vehicle. However, kidney tissue ouabain levels were significantly greater (6.39 +/- 1.17 vs 2.36 +/- 0.52 micrograms/kg, P < .05) in animals receiving ouabain. In conclusion, ouabain, given chronically, is associated with the development of hypertension in RRM rats as well as in normal rats. Blood pressure was greater in animals with greater degrees of RRM for a given ouabain dose.

Animals↗
PubMed1992

A consistent model of insulin-dependent diabetes mellitus hypertension.

Hypertension is frequently seen in insulin-dependent diabetes mellitus (IDDM), but the mechanism of the hypertension is unknown. An animal model of IDDM hypertension could be helpful in determining the mechanism, but experimental IDDM has been infrequently and irregularly associated with hypertension. In an attempt to develop a consistent model of IDDM hypertension, we superimposed streptozotocin (STZ)-induced IDDM on surgical reduction of renal mass (RRM) in Wistar rats. Seven groups of rats were studied: 1) 60% RRM receiving 65 mg/kg body weight (BW) STZ; 2) 60% RRM receiving 40 mg/kg BW STZ; 3) 25% RRM receiving 65 mg/kg BW STZ; 4) two kidney normal rats receiving 65 mg/kg BW STZ; 5) 60% RRM receiving vehicle (control for group 1); 6) 60% RRM receiving vehicle (control for group 2); and 7) 25% RRM receiving vehicle. STZ produced diabetes and hypertension within 1 to 2 weeks in all three groups of RRM rats but blood pressure was unaffected by 60% or 25% RRM alone. STZ alone had no effect on blood pressure until the 5th week when the blood pressure increased slightly. Progressive weight loss resulted from 65 mg/kg BW STZ combined with 60% RRM; the animals had to be terminated after 5 weeks. In only 60% of animals with 40 mg/kg BW STZ plus 60% RRM was IDDM produced. On the other hand, 65 mg/kg BW STZ in rats with 25% RRM regularly produced IDDM and hypertension without excessive loss of body weight. In these rats, albuminuria developed in 2 weeks. Extracellular fluid volume was elevated and plasma renin activity was depressed. The animals were healthy and hypertensive when killed at the 13th week. We suggest that the 25% RRM rat receiving 65 mg/kg BW STZ is a consistent model of IDDM hypertension, which may be useful in probing the mechanism of this type of hypertension.

Albuminuria↗
PubMed1991

Effects of three sodium-potassium adenosine triphosphatase inhibitors.

Reports from several laboratories suggest the presence of an ouabainlike compound in plasma and various animal tissues, particularly during acute volume expansion and in low-renin hypertension. It has been hypothesized that this compound, through inhibition of the Na(+)-K+ pump, can constrict blood vessels, enhance vasoconstriction in response to agonists, increase cardiac contractility, raise blood pressure, and cause natriuresis/diuresis and therefore is implicated in the pathophysiology of the low-renin, volume-expanded type of hypertension. However, so far, only two steroid Na(+)-K+ pump inhibitors (namely, a bufodienolide derivative [resibufogenin], obtained from toad skin and plasma and a factor with the same carbon, oxygen, and hydrogen content as ouabain obtained from the plasma of volume-expanded humans) have been purified and structurally characterized. To determine whether such endogenous Na(+)-K+ pump inhibitors can in fact produce the above effects on the cardiovascular and renal systems, we infused commercially available bufalin (aglycone, identical to resibufogenin except for one H+), ouabain, and ouabagenin (aglycone) at equimolar doses in normotensive rats. Relative to ouabain, bufalin produced significantly greater dose-dependent increases in blood pressure, left ventricular rate of pressure change, heart rate, and excretion of urinary volume and sodium. Ouabagenin was without effect on any of these parameters. These data indicate that a Na(+)-K+ pump inhibitor can cause an increase in blood pressure despite potent diuretic and natriuretic effects and that, in rats, bufalin is much more potent in this respect than ouabain or ouabagenin.

Angiotensin II↗
PubMed1991

Roles of sodium, potassium, calcium, and natriuretic factors in hypertension.

This review first summarizes evidence from animals and humans for and against a role for dietary sodium in the genesis and treatment of hypertension. The evidence for its role is strongest in those subjects with impaired ability to excrete sodium because of organic renal disease or mineralocorticoid excess. Here, restriction of dietary sodium promptly lowers pressure. Its role in the genesis of essential hypertension is more controversial. Nevertheless, it appears that some patients with mild to moderate essential hypertension respond to moderate sodium restriction with a modest fall in pressure. This restriction also seems to reduce the amount of antihypertensive medication needed to keep pressure under control. Next, the mechanism of the pressure response to dietary sodium chloride is considered, with emphasis on potassium depletion and increased plasma levels of prohypertensive sodium pump inhibitor and antihypertensive atrial natriuretic peptide. The evidence for a primary role for dietary potassium in the genesis of hypertension then is summarized; certain subsets of subjects with a high incidence of hypertension also have a lower potassium intake. Some investigators have found that dietary potassium supplementation lowers pressure in established hypertension. This may result from natriuresis and from vasodilation subsequent to stimulation of Na+,K(+)-ATPase in vascular smooth muscle and adrenergic nerve terminals. After the role of dietary calcium is discussed, practical aspects of dietary sodium restriction and dietary potassium supplementation in the therapy for established hypertension are considered. The review concludes with comments on their possible roles in the prevention of hypertension.

Animals↗
PubMed1991

Reversal of one-kidney, one-clip hypertension in rats. Effects on myocardial Na+, K(+)-ATPase, arterial Na(+)-K+ pump, arterial membrane potential, and plasma Na(+)-K+ pump inhibitory activity.

We have previously reported that myocardial microsomal Na+,K(+)-ATPase activity, arterial wall ouabain-sensitive 86Rb uptake, and arterial smooth muscle cell membrane potentials are decreased and plasma Na(+)-K+ pump inhibitory activity is increased in rats during the fifth week of one-kidney, one-clip hypertension. We here report measurements of these four parameters and blood pressure following unclipping. A new series of rats with one-kidney, one-clip hypertension was prepared. Each animal was paired with a one-kidney, sham-clipped (nonconstricting clip) control rat. After 5 weeks, the clips were removed. In the hypertensive animals arterial pressure promptly (within 3 h) returned to normal and remained at the level for 7 observation days. On the third day following unclipping, all four parameters were not significantly different from those in the paired control animals. On the seventh day following unclipping, three of the four parameters were not significantly different from those in the paired control animals and arterial ouabain sensitive 86Rb uptake was slightly increased relative to the value in the control animals. These studies invite further inquiry into the possible role of plasma Na(+)-K+ pump inhibitory activity in the genesis and maintenance of the hypertension in this model.

Animals↗
PubMed1990

Digitalislike circulating factor in hypertension: potential messenger between salt balance and intracellular sodium.

Sodium chloride has no clearly established local direct action on blood vessels to produce constriction; on the contrary, it has an immediate local indirect action via osmolality, which produces vasodilation. Thus in order to explain salt-induced hypertension, a delayed remote indirect vasoconstrictor action must be postulated. This indirect vasoconstrictor action is apparently the result of volume expansion. Acute volume expansion imparts three physiologic properties to the plasma; these are the ability to inhibit Na,K-ATPase and the Na-K pump, to cause natriuresis, and to sensitize blood vessels to vasoconstrictor agents. Similarly, low-renin, volume-expanded hypertension endows the plasma with the capacity to inhibit the Na,K-ATPase pump, to sensitize blood vessels to vasoconstrictor agents, and to raise blood pressure. These properties apparently result from a circulating digitalislike substance(s), perhaps derived from the hypothalamus and/or adrenals. We here review the considerable effort expended in identifying the agent or agents, and conclude that both steroidal and peptidic structure must be considered. Regardless of its structure, we hypothesize that when sodium excretion does not keep pace with sodium intake, its release leads to increased contractile activity of cardiac and vascular smooth muscle and hence hypertension. Inhibition of the Na-K pump increases the intracellular sodium concentration, particularly when superimposed on genetic- or aldosterone-induced increased sodium permeability, resulting in depolarization and increased calcium influx (vascular smooth muscle) or altered Na(+)-Ca2+ exchange and decreased calcium efflux (heart muscle). The increased intracellular calcium concentration then accounts for the increased contractile activity. Depolarization may also increase the sensitivity of vascular smooth muscle to vasoconstrictor agents such as norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗