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Biomedical subjects

F J Haddy

Publications and source records attributed to F J Haddy.

At least 55 records · Page 3Linked to original sources
PubMed1987

Potassium, Na+-K+ pump inhibitor and low-renin hypertension.

A local increase in extracellular potassium concentration [K+]o, up to about 8 mEq/liter, by topical application or intra-arterial infusion of iso-osmotic solutions of K+ salts, causes arteriolar dilation and decreased resistance to blood flow in systemic vascular beds. A local decrease in [K+]o over physiologic ranges induces arteriolar constriction and increased resistance to blood flow. K+ vasodilation is accompanied by hyperpolarization of the smooth muscle cell, whereas the vasoconstriction is accompanied by depolarization. All of these responses can be blocked by ouabain, a potent Na+,K+-ATPase inhibitor. Thus it is thought that K+ vasodilation results from stimulation of the electrogenic Na+-K+ pump, and that the constriction results from its inhibition. Acute generalized inhibition of the Na+,K+-ATPase and Na+-K+ pump (hypokalemia, strophanthidin, methylguanidine, vanadate) in the anesthetized dog can raise blood pressure. In experiments in animals, myocardial Na+,K+-ATPase and vascular Na+-K+ pump activities were decreased in low-renin hypertension, and vascular Na+-K+ pump activity was decreased following acute volume expansion, changes associated with bioassay evidence of a Na+-K+ pump inhibitor in the plasma. The inhibitor appears to arise in, or to be influenced by the area of the anteroventral third ventricle of the brain. It induces electrogenic depolarization of vascular smooth muscle cells and may inhibit norepinephrine uptake by adrenergic nerve terminals. Potassium and a circulating endogenous Na+,K+-ATPase inhibitor of unknown molecular structure may partly regulate the mechanical activity of cardiovascular muscle and participate in the genesis of certain forms of hypertension. Potassium may be of value in the prevention and therapy of hypertension, partly by virtue of its vasodilator activity.

Animals↗
PubMed1986

Effects of 6-iodo-amiloride, a sodium channel blocker, on cardiovascular parameters in spontaneously hypertensive and Wistar-Kyoto rats.

6-Iodo-amiloride, an analogue of the sodium channel blocker amiloride, was infused intravenously for 10 min in anaesthetized Okamoto spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats in doses ranging from 0.08 to 0.38 mg/100 g body weight. Systemic arterial blood pressure and urine flow were measured for 120 min. In SHR, 6-iodo-amiloride produced a prompt, sustained, dose-dependent decrease in pressure. The lower doses were associated with increased urine flow and sodium excretion, while higher doses were not. Paradoxically, in WKY all doses produced a small dose-independent sustained increase in pressure and were associated with diuresis and natriuresis. 6-Iodo-amiloride had no effect on cardiac output, dP/dt or heart rate in isolated working hearts from SHR or WKY. However, addition of 6-iodo-amiloride to physiological salt solution bathing an isolated Wistar rat tail artery produced hyperpolarization of impaled vascular smooth muscle cells. These studies show that 6-iodo-amiloride is a vasodilatory antihypertensive agent in SHR, and that this can be associated with natriuresis and diuresis.

Amiloride↗
PubMed1985

The kidney in the pathogenesis of hypertension: the role of sodium.

In this review, we first summarize the evidence which indicates that the inability of the kidney to excrete salt and water normally, particularly when combined with increased salt intake, is frequently associated with hypertension. We then concentrate on the link between sodium and water retention and hypertension. The increase in blood pressure probably results from the increase in volume rather than from the increase in salt. Recent evidence suggests that an increase in volume in the lesser circulation stimulates the release of a sodium pump inhibitor, probably the putative natriuretic hormone, from the hypothalamus. This agent appears to affect cardiac and vascular smooth muscle by suppressing Na+,K+-ATPase, and hence Na+-K+ pump activity in both muscle cells and adrenergic nerve terminals. The sodium pump inhibitor is a heat stable small molecule but its chemical structure is still unknown. It is clearly different from atrial natriuretic factor. We conclude the review with speculations on the possible role of renotropin and various growth and growth inhibitory factors in the vascular structural changes.

Adenosine Triphosphatases↗
PubMed1985

Decreased myocardial Na+K+ATPase activity in rats with reduced renal mass-saline hypertension.

Inhibition of cardiovascular Na,K-pump activity has been shown to promote an increase in the contractile activity of myocardial and vascular smooth muscle and a consequent rise in blood pressure (BP). It has also been shown that vascular Na,K-pump activity and myocardial Na+K+ATPase activity [the energy source for active sodium (Na) and potassium (K) transport] are decreased in rats with various forms of low renin hypertension including rats with reduced renal mass-saline (RRM-saline) hypertension. In the present study, left ventricular Na+K+ATPase activity from rats with RRM-saline hypertension was found to be decreased in membranes prepared by two independent methods: deoxycholate, sodium iodide (Nal)-treated microsomal fractions (method 1) and membranes prepared by the hypotonic, lithium bromide (LiBr) method (method 2). Relative to RRM normotensive control rats which drank distilled water, myocardial Na+K+ATPase activity from RRM-saline drinking rats was decreased by 18.2% in membranes prepared by method 1 and 33.6% in membranes prepared by method 2. The apparent affinities of Na+K+ATPase for K and for ouabain were unaltered relative to controls in membranes prepared from these hypertensive rats by method 1, and the sialic acid content and 5'-nucleotidase activity (two putative sarcolemmal markers) were unaltered in membranes from the hypertensive rats, prepared by methods 1 and 2 respectively. The Mg2+ATPase activity of membranes prepared by method 1 was increased in the RRM-saline hypertensive rats but because it was not increased in membranes prepared by method 2 the former observation does not appear to be of any pathophysiological importance. In other experiments, hypertension was reversed in RRM-saline hypertensive rats by restricting their salt intake (substitution of distilled water for drinking).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

In vivo membrane potentials of smooth muscle cells in the caudal artery of the rat.

Membrane potentials measured in vivo may differ significantly from those measured in vitro in part due to humoral factors, innervation, and wall tension. These studies were initiated to determine whether it is feasible to record membrane potentials from vascular smooth muscle cells in vivo in the caudal artery of the pentobarbital-anesthetized male Wistar rat. Membrane potentials were measured using glass microelectrodes and correlated with systolic, diastolic, and mean blood pressures. For systolic blood pressures between 100 and 140 mmHg the average resting membrane potential was -38.4 +/- 0.48 mV. There was good correlation of systolic, diastolic, and mean blood pressures with membrane potential between 100 and 140 mmHg (r = 0.89, 0.75, and 0.89, respectively). Below 80 mmHg the arterial muscle cells became more depolarized than would be expected if the membrane potential were determined solely by transmural pressure. The depolarized membrane potential at low arterial pressures may be due to enhanced neural input. Spontaneous electrical activity was observed in some of the in vivo cells. When action potentials were present, they were generated at rates between 1-2/s and 6-7/min. These studies indicate that it is feasible to measure membrane potentials from arterial smooth muscle cells in vivo in the caudal artery of the rat.

Action Potentials↗
PubMed1985

Myocardial (Na+,K+)-ATPase activity in Dahl salt-sensitive and resistant rats.

Vascular (Na+,K+)-pump activity (ouabain-sensitive 86Rb+ uptake) and myocardial (Na+,K+)-ATPase activity are reduced in animals with various forms of low renin, experimental hypertension. On the other hand, vascular (Na+,K+)-pump activity is increased in Dahl salt-sensitive relative to resistant rats (a genetic model of hypertension), regardless of salt intake or blood pressure and it is also increased in Dahl salt-sensitive rats on high salt (8% NaCl) relative to low salt (0.4% NaCl) diets. It has been suggested that this increase in vascular (Na+,K+)-pump activity may be secondary to an increase in the vascular sarcolemmal permeability to Na+ in these salt-sensitive rats. In the present study, (Na+,K+)-ATPase activity of left ventricular microsomal fractions, was increased in Dahl salt-sensitive relative to resistant rats on low salt diets; however, this difference disappeared when these salt-sensitive and resistant rats were placed on high salt diets. In contrast, myocardial (Na+,K+)-ATPase activity was decreased in Dahl salt-sensitive rats on high relative to low salt diets. Evidence that this decrease in (Na+,K+)-ATPase activity is not secondary to myocardial hypertrophy in the hypertensive salt-sensitive rats, and mechanisms by which decreased cardiovascular (Na+,K+)-pump activity, increased sarcolemmal permeability or both, might contribute to elevated blood pressure, are discussed.

Adenosine Triphosphatases↗
PubMed1985

Evidence for a circulating sodium-potassium pump inhibitor in low renin hypertension.

In 1978, we reported that supernate of boiled plasma from acutely volume expanded dogs and rats reduces sodium-potassium pump activity when applied to the tail artery from a normal rat and then in 1980 we reported that the same is the case for plasma supernate from the dog with one-kidney, one wrapped hypertension, a model of low renin hypertension. Since then, we and a number of other investigators have described sodium-potassium pump inhibitory activity in the plasma of animals and humans with hypertension, particularly of the low renin variety. The activity results from a heat stable small molecule, probably the putative natriuretic hormone. It appears to be released from the hypothalamus in response to cardiopulmonary vascular distention subsequent to failure of the kidney to excrete the prevailing sodium and water intake. It probably acts on blood vessels both directly (electrogenic depolarization) and indirectly (inhibition of norepinephrine reuptake into adrenergic nerve terminals). While it may be sufficient by itself to raise blood pressure, it may be most effective when superimposed on vascular smooth muscle cells which are abnormally permeable to sodium. Efforts to determine its chemical structure should be intensified.

Animals↗
PubMed1985

Characteristics of hypertensive patients with increased plasma Na+-K+ pump inhibitory activity.

Recent studies in our laboratories and in the laboratories of other investigators suggest the presence of a sodium-potassium pump inhibitor in the plasma of some patients with arterial hypertension. We here review these studies in an attempt to determine what characteristics increase the likelihood of detecting the inhibitor. The review suggests but does not prove that the inhibitor is most likely to be found in males with increased sodium intake, decreased renal function, and decreased plasma renin activity. In future studies of plasma sodium-potassium pump inhibitory activity in hypertensive humans, we should pay more attention to the characteristics of the patients. These characteristics include age, sex, race, therapy, stage of hypertension, sodium intake, renal function, and renin status. We should also make an attempt to match the patients properly with normotensive control subjects.

Adult↗
PubMed1985

Evidence for a circulating endogenous Na+-K+ pump inhibitor in low-renin hypertension.

It is now more than 10 years since we suggested that an endogenous Na+,K+-ATPase inhibitor might participate in the genesis of certain forms of ren hypertension. Although the question is not yet fully resolved, there has been much activity in the area. We here review that activity. In 1980 we reported that supernatant of boiled plasma from dogs with one-kidney, one wrapped hypertension reduces Na+-K+ pump activity when applied to an artery from another animal. Since then, we and a number of other investigators have described Na+-K+ pump inhibitory activity in the plasma of animals and humans with hypertension, particularly the low-renin varieties. The activity results from a heat-stable small molecule, but the chemical structure of the molecule is unknown. It appears to be released from the hypothalamus in response to pulmonary vascular distension and to act on blood vessels via electrogenic depolarization. Although it may be sufficient by itself to raise pressure, it may be most effective when superimposed on vascular smooth muscle cells that are abnormally permeable to Na+. Efforts to determine the chemical structure of the agent or agents should be intensified.

Animals↗
PubMed1985

Vascular smooth muscle membrane potentials in rats with one-kidney, one clip and reduced renal mass-saline hypertension: the influence of a humoral sodium pump inhibitor.

Ninety to 120 min after removal of the caudal arteries, vascular smooth muscle cells from one-kidney, one clip (1-K, 1C) hypertensive animals were depolarized relative to those in appropriate control animals but cells from reduced renal mass-saline (RRM-S) hypertensive animals were not. However, supernatants of boiled plasma from both of the hypertensive models depolarized vascular smooth muscle cells in arteries taken from normotensive animals. These studies suggest that an agent in the plasma of these animals depolarizes vascular smooth muscle cells. This could help to explain the vasoconstriction in these hypertensive animals.

Animals↗
PubMed1985

Endogenous sodium-potassium pump inhibitor in low renin hypertension.

In 1978, we reported that plasma supernate from acutely volume expanded animals reduces Na+-K+ pump activity when applied to blood vessels from another animal and then in 1980 we reported that the same is the case for plasma from an animal model of low renin hypertension. Since then, we and a number of other investigators have described Na+-K+ pump inhibitory activity in the plasma of animals and humans with hypertension, particularly of the low renin variety. The activity results from a heat stable small molecule, probably the putative natriuretic hormone. We here review these and other studies.

Animals↗
PubMed1985

Response of the forelimb vasculature to vasoactive agents: effects of ouabain.

The effect of the local intra-arterial infusion of ouabain (11.8 micrograms/min.) on the response of the forelimb to vasoactive agents was examined. In seven dogs, bolus injections of CaCl2, MgSO4, KCl, norepinephrine, adenosine, acetylcholine, PGE1 and saline were made into the forelimb perfused at constant flow before and three times during ouabain infusion. Ouabain blocked potassium vasodilation and changed the response to CaCl2 from vasoconstriction to vasodilation. The response of the forelimb to the other vasoactive agents was initially unaffected by ouabain but with time the forelimb vasculature became less sensitive to all agents studied. These changes were not seen in a series of 5 saline infused control animals. In a third series of animals steady-state dose responses to CaCl2, Ca-gluconate and KCl were explored by infusing solutions intrabrachially at three dosages. Before ouabain, forelimb resistance increased as a function of Ca++ and decreased as a function of K+. Ouabain completely blocked potassium vasodilation and on the average blocked Ca++ vasoconstriction although a number of animals evidenced vasodilation to Ca++ during ouabain infusion. These data indicate that K+ vasodilation is Na+, K+-ATPase dependent and that Na+, K+-ATPase inhibition unmasks a vasodilatory action of locally applied Ca++.

Alprostadil↗
PubMed1985

Role of a humoral Na+ -K+ pump inhibitor in low renin hypertension.

In 1978 we reported that supernate of boiled plasma from acutely volume-expanded animals reduces Na+ -K+ pump activity when applied to an artery from another animal, and then in 1980 we reported that the same is the case for plasma from an animal model of low renin hypertension. Since then, we and a number of other investigators have described Na+ -K+ pump inhibitory activity in the plasma of animals and humans with hypertension, particularly of the low renin variety. The activity results from a heat-stable small molecule, probably the putative natriuretic hormone. We here review these and other studies.

Biological Transport↗
PubMed1984

Myocardial Na,K-ATPase activity in rats with steroid and spontaneous hypertension.

Vascular Na-K pump activity (ouabain-sensitive 86Rb uptake) and cardiac Na,K-ATPase activity are decreased in rats with one-kidney, one clip and reduced renal mass-saline hypertension. In the present study we measured left ventricular, microsomal Na,K-ATPase activity in rats with two steroid forms of hypertension; one-kidney, deoxycorticosterone acetate-saline (1-K, DOCA-saline) and one-kidney, dexamethasone (1-K, DEXA) hypertension and also in spontaneously hypertensive rats (SHR). Relative to one-kidney, normotensive (1-K, NT) control rats, cardiac Na,K-ATPase activity was decreased and Mg-ATPase activity was increased in rats with 1-K, DOCA-saline hypertension (systolic BP = 175 +/- 2 mmHg, sustained eight to 10 weeks, n = 11). The apparent dissociation constant of cardiac Na,K-ATPase for K was unchanged in these hypertensive rats. In rats with 1-K, DEXA hypertension (systolic BP = 171 +/- 1 mmHg, sustained eight to 10 weeks, n = 9), cardiac Na,K-ATPase activity was increased and Mg-ATPase activity was unchanged relative to 1-K, NT control rats. We observed no change in either cardiac Na,K-ATPase activity or Mg-ATPase activity in SHR (36-38 weeks of age, systolic BP = 186 +/- 7 mmHg, n = 12) relative to either age-matched normotensive Wistar-Kyoto or Wistar control rats. These studies therefore suggest that cardiac Na,K-ATPase activity is decreased in 1-K, DOCA-saline hypertensive rats, increased in 1-K, DEXA hypertensive rats and unchanged in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The vascular Na+-K+ pump in low renin hypertension.

In this article, we emphasize our studies on animals and humans and those in the literature on humans that bear on the possible role of a circulating Na+-K+ pump inhibitor in the mechanism of hypertension. An effort is made to determine the features most likely to be associated with evidence for elevated levels of this inhibitor. The data from animals indicate that these features are reduced capacity to excrete salt (functional or organic), increased salt intake, increased extracellular fluid volume, and low plasma renin activity. The data from humans suggest but do not prove that the inhibitor is most likely to be found in males with increased sodium intake, decreased renal function, and decreased plasma renin activity. In future studies on hypertensive humans we should pay more attention to the characteristics of the patients (sex, race, age, drug therapy, stage of hypertension, sodium intake, renal function, and renin status) and make a more vigorous effort to match these patients properly with normotensive control subjects.

Adenosine Triphosphatases↗
PubMed1984

The role of a humoral Na+,K+-ATPase inhibitor in regulating precapillary vessel tone.

In this review, we first present chronologically our evidence suggesting that a circulating Na+,K+-ATPase and Na+-K+ pump inhibitor in part regulates the mechanical activity of the muscle in the cardiovascular system. We then present the relevant findings from other laboratories. The evidence from our laboratories includes the observations that local hyperkalemia decreases small-vessel resistance and local hypokalemia increases small-vessel resistance and that these responses can be blocked by ouabain, a potent Na+,K+-ATPase inhibitor. Myocardial Na+,K+-ATPase and vascular Na+-K+ pump activities are decreased in animals with experimental low-renin hypertension, vascular Na+-K+ pump activity is decreased in animals following acute volume expansion, and these changes are associated with bioassay evidence for a Na+-K+ pump inhibitor in the plasma. The inhibitor appears to come from, or be influenced by, the anteroventral third ventricle (AV3V) area of the brain. It produces electrogenic depolarization of the vascular smooth-muscle cell and may inhibit norepinephrine uptake by adrenergic nerve terminals. The evidence from other laboratories includes the observations that there is (a) a pressor and vascular sensitizing agent in the plasma of animals and patients with low-renin hypertension, (b) reduced Na+-K+ pump activity in the leukocytes of some patients with essential hypertension, and (c) a Na+,K+-ATPase and Na+-K+ pump inhibitor in the plasma of some patients with essential hypertension.

Animals↗
PubMed1984

Effects of rat atrial extract on sodium transport and blood pressure in the rat.

Atrial cardiocytes contain specific atrial granules ( SAGs ) which are the storage site of atrial natriuretic factor (ANF). The purpose of the present study was to determine whether ANF produces natriuresis by inhibiting Na+-K+ pump activity and whether this factor is similar to the humoral sodium transport inhibiting factor ( HSTIF ) previously demonstrated in acutely volume expanded animals and humans as well as in experimental and human essential hypertension. Our results indicate that, in contrast to the HSTIF , ANF does not inhibit membrane Na+,K+-ATPase, vascular smooth muscle cell Na+-K+ pump activity, or sodium transport in the toad bladder. Intravenous infusion of ANF in the bilaterally nephrectomized, hexamethonium-treated rat produces only a small transient pressor response, probably due to potentiation of endogenous norepinephrine. These findings strongly suggest that the ANF is not the same as the HSTIF detected on acute volume expansion and in some forms of hypertension. They also suggest that the diuretic and natriuretic effects of ANF are due to mechanism(s) other than blood pressure elevation and inhibition of Na+-K+ pump activity.

Animals↗