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Biomedical subjects

F J Haddy

Publications and source records attributed to F J Haddy.

At least 73 records · Page 4Linked to original sources
PubMed1984

Acute volume expansion in humans releases a factor which inhibits the vascular Na+-K+ pump.

The authors previously observed increased Na+-K+ pump inhibitory activity in the plasma of low renin essential hypertensive unselected with respect to renin status. The present experiments were done to determine the effect of acute volume expansion on plasma Na+-K+ pump inhibitory activity in normotensive subjects. The data show that acute volume expansion increases vascular Na+-K+ pump inhibitory activity in plasma, suggesting that the increased level of this inhibitory activity in low essential hypertensives is probably volume dependent. The unique feature of this study is the use of vascular tissue for the bioassay.

Adult↗
PubMed1984

[The sodium-potassium pump in hypertension. Mechanisms of action of potassium].

Increasing evidence indicates that sodium ingestion in the face of an inability to excrete it normally causes hypertension by releasing a humoral pressor substance. This substance, which is probably the putative natriuretic hormone, inhibits Na+-K+-ATPase and thereby increases cardiac contractility and blood vessel tone. Potassium may be antihypertensive in part by virtue of its ability to stimulate Na+-K+-ATPase in the vascular smooth muscle cells and in adrenergic nerve endings, thereby causing vasodilation.

Animals↗
PubMed1983

Changes in dog gracilis muscle adenosine during exercise and acetate infusion.

We have previously reported that tissue acetate content increases in the canine gracilis muscle during exercise at natural flow. We here report the effects of exercise and infusion of acetate on adenosine content. Muscles were vascularly isolated, perfused naturally, and stimulated to contract isometrically at 0.5, 1.0, or 2.0 Hz for 10 min (n = 6 each). Exercising and contralateral control gracilis muscles were freeze clamped in situ in Wollenberger tongs at the temperature of liquid N2. Force development was maintained during contraction. Resistance decreased as a function of contraction frequency, and adenosine content increased. Tissue adenosine content correlated inversely with resistance (r = -0.57, P less than 0.001), suggesting a role for adenosine in exercise hyperemia. During intra-arterial infusion of sodium acetate into resting muscle, tissue acetate and adenosine contents increased (417-2,193 and 0.88-3.07 nmol/g, respectively), and vascular resistance decreased (17.5-6.01 mmHg X ml-1/min/100 g). Acetate and adenosine contents correlated negatively with resistance (r = -0.83, P less than 0.001, and r = -0.60, P less than 0.05, respectively) and positively with one another (r = 0.58, P less than 0.05). Relative to an infusion of sodium chloride, oxygen consumption, venous PO2, and venous ionized calcium were unaffected. The vasodilatory effect of acetate may be due, in part, to its ability to increase tissue adenosine.

Acetates↗
PubMed1983

Decreased myocardial Na+-K+-ATPase activity in one-kidney, one-clip hypertensive rats.

We have previously shown that Na+-K+ pump activity (ouabain-sensitive 86Rb uptake) is decreased in vascular tissue of animals with various forms of low renin hypertension. In the present study we measured Na+-K+-ATPase activity, the energy source for Na+-K+ pumping, in membrane fractions prepared from myocardial tissue of rats with chronic one-kidney, one-clip hypertension and their one-kidney normotensive controls. Membranes were prepared by two independent methods: microsomal fractions (method 1) and fractions prepared by the hypotonic LiBr method of Dhalla et al. (method 2). In membranes prepared from left ventricles of the hypertensive rats (by method 1) Na+-K+-ATPase activity was decreased, Mg2+-ATPase activity was increased, and the sialic acid content and 5'-nucleotidase activity (two putative membrane markers) were unchanged relative to the control rats. The sensitivity of cardiac Na+-K+-ATPase to inhibition by ouabain was also unchanged. Na+-K+-ATPase activity was also decreased in the right ventricles (method 1) of these hypertensive rats, suggesting that this defect is probably not pressure related. In membranes prepared from the left ventricles of the hypertensive rats by method 2, Na+-K+-ATPase activity was again reduced, whereas the Mg2+-ATPase and 5'-nucleotidase activities were unchanged relative to the controls. These studies suggest that myocardial Na+-K+-ATPase activity is suppressed in rats with this low renin form of hypertension and the possible effect of this suppression on myocardial contractile activity is discussed.

5'-Nucleotidase↗
PubMed1983

Partial isolation of an endogenous norepinephrine uptake inhibitor in canine plasma.

We have previously reported that homologous plasma inhibits the accumulation of [3H]norepinephrine ( [3H]NE) by the canine saphenous vein. The purpose of this study was to extract the inhibitory substance(s) from plasma and to examine some of its properties. The net accumulation of tritium by saphenous vein strips following incubations in [3H]NE was inhibited 34.4 +/- 6.1% by a 60% plasma in Krebs solution. An acetone extract of this plasma reconstituted to 83% of its original unextracted volume also significantly inhibited net tritium accumulation by 24.5 +/- 4.7%. After lyophilization of this extract, the inhibitor was not readily solubilized in dilute acetic acid but was soluble in dilute sodium bicarbonate solutions. This extract solution, reconstituted to 66% of the original plasma volume, significantly inhibited the accumulation of [3H]NE by 35.0 +/- 9.8%. Kinetic analysis using this preparation suggests that the inhibition may be competitive in nature. The activity was not sensitive to heat but was abolished by the neuronal uptake blocker cocaine. Further purification with gel chromatography produced a small molecular weight fraction that inhibited tritium accumulation. When this sample was reconstituted in a volume equivalent to that of the unextracted plasma, the contractile response of the isolated canine saphenous vein to electrical stimulation was significantly enhanced. Thus the inhibitory activity of plasma on the uptake of [3H]NE by the canine saphenous vein is due in part to a heat-stable small molecule that inhibits the initial rate of [3H]NE uptake.

Animals↗
PubMed1983

Sodium-potassium pump in low-renin hypertension.

Recent studies suggest that sodium-dependent low-renin hypertension in animals results at least in part from sodium-potassium pump inhibition in blood vessels and heart by a humoral agent released from or influenced by the anteroventral third ventricular area of the brain. For example, a high salt intake in a rat with reduced renal mass results in the appearance of a heat-stable sodium pump inhibitor in the plasma, decreased cardiac Na+, K+-ATPase activity, decreased arterial sodium-potassium pump activity, and hypertension. These changes are reversed by reducing the salt intake or by producing a lesion in the anteroventral third ventricular area of the brain. The course of the development of pump inhibition is similar to the course of the development of hypertension. Sodium-potassium pump inhibition by a humoral agent may also occur in humans with low-renin hypertension. A high potassium intake may stimulate pump activity.

Animals↗
PubMed1983

Potassium effects on contraction in arterial smooth muscle mediated by Na+, K+-ATPase.

A local increase in the extracellular potassium concentration [K+]o, up to about 8 meq/liter either by topical application or intra-arterial infusion of K+ salts, causes arteriolar dilation and decreased resistance to blood flow in systemic vascular beds. Isolated vascular smooth muscle responds to a similar increase in [K+] in the bathing fluid with relaxation if the preparation has some initial active tension. Reduction in [K+] over physiological ranges produces 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 these responses can be blocked by ouabain, a potent Na+, K+-ATPase inhibitor. It is therefore thought that K+ vasodilation results from stimulation of the electrogenic Na+-K+ pump whereas the vasoconstriction results from inhibition of this pump. A number of conditions that alter resistance also alter interstitial fluid [K+]. These include exercise, myocardial ischemia, epileptic convulsions, and evoked electrical activity of the somatomotor cortex. Certain findings, including those during administration of ouabain, suggest that changes in [K+] contribute significantly to some of the changes in resistance.

Animals↗
PubMed1983

The role of a humoral sodium-potassium pump inhibitor in low-renin hypertension.

We have recently concentrated our efforts on bioassay of plasma supernatant from animals with experimental low-renin hypertension (one-kidney, one-wrapped in dogs, and one-kidney, one-clip, and reduced renal mass in rats) for sodium-potassium pump inhibiting activity. We have observed changes compatible with inhibitory activity by using three different in vitro bioassays: 1) ouabain-sensitive 86Rb uptake by the normal rat tail artery, 2) short-circuit current in the toad bladder, and 3) membrane potential in the rat tail artery. We have also generated evidence suggesting that the humoral pump inhibitor(s) comes from or is influenced by the anteroventral third ventricle area of the brain and that it acts on the vascular smooth muscle cell at least in part by depolarizing the membrane. These findings are compatible with our 1976 hypothesis in which we proposed that in volume-expanded hypertension there is a circulating agent that suppresses cardiovascular membrane Na+,K+-ATPase, which results in reduced activity of the Na+-K+ pump and hence increased contractility of heart, arteries, and veins and that in blood vessels the increased contractility may be secondary to depolarization. We attempt to relate these findings to those in the literature on monovalent ion transport in blood cells of hypertensive subjects.

Animals↗
PubMed1982

Humoral factors and the sodium-potassium pump in low renin hypertension.

Recent studies suggest that sodium dependent low renin hypertension results in part from the release of a ouabain-like factor, perhaps natriuretic hormone, from the brain. This humoral factor inhibits Na+, K+-ATPase and hence the active pumping of sodium and potassium in the muscle cells of blood vessels and heart. The pump suppression causes increased contractile activity and hence increased arterial blood pressure. In the muscle cells of the blood vessels, the increased contractile activity appears to be related to membrane depolarization.

Animals↗
PubMed1982

The possible role of acetate in exercise hyperemia in dog skeletal muscle.

The possible role of acetate in the genesis of exercise hyperemia was studied in five series of dogs. Intraarterial infusion of an isomotic solution of sodium acetate at 0.76 ml/min in the dog forelimb decreased the resistance to flow through skeletal muscle by 48%, primarily by decreasing resistance to flow through small vessels. Skin lymph flow and lymph protein concentration were unaffected. The hindlimb of the conscious dog took up acetate at rest (A-V difference, + 58.3 +/- 19.6 nmoles/ml) and put out acetate during treadmill exercise (A-V difference, -105.6 +/- 20.12 nmoles/ml); femoral venous blood acetate concentration increased by 145 nmoles/ml (control 195 nmoles/ml). In the gracilis muscle of the anesthetized dog, simulated exercise at 0.5, 1.0 or 2.0 Hz increased acetate tissue content (72, 248 and 442 nmoles/g, respectively), output (18,899, and 1,830 nmoles/100 g/min, respectively) and venous concentration (82, 49 and 39 nmoles/ml, respectively) and changes in tissue acetate content correlated with changes in vascular resistance r = 0.75, P less than 0.001. Intraarterial infusion of an isosmotic solution of sodium acetate in the quiescent gracilis muscle perfused at constant flow produced a significant (6%) decrease in resistance when arterial blood acetate was increased by a calculated 96 nmoles/ml. These studies suggest that acetate might be included among those metabolites that contribute to exercise hyperemia.U

Acetates↗
PubMed1982

Relationships between adenosine and coronary resistance in conscious exercising dogs.

The relation between myocardial adenosine content, coronary sinus plasma concentration, and coronary vascular resistance was studied in conscious dogs during rest or treadmill exercise. Exercise at 5 mi/h for 7 min on a 20% slope had a significant threefold increase in cardiac work over that of dogs at rest. Exercise increased myocardial adenosine content from 1.35 +/- 0.54 to 8.18 +/- 0.60 nmol/g and decreased coronary vascular resistance from 1.07 +/- 0.13 to 0.69 +/- 0.08 mmHg.ml-1.min.100 g; the former correlated negatively with the latter (r = -0.74, P less than 0.01). The adenosine concentration in coronary sinus plasma increased from 108 +/- 16 to 184 +/- 18 nmol/l plasma and correlated negatively with coronary vascular resistance (r = -0.83, P less than 0.01). Myocardial adenosine content correlated positively with coronary sinus plasma adenosine concentration (r = 0.77, P less than 0.05). Low myocardial lactate content, continued lactate uptake, lack of change in the lactate-pyruvate ratio, and stable coronary sinus oxygen tension values indicated no myocardial hypoxia. These findings demonstrate the release of adenosine into coronary sinus blood and show significant correlations between myocardial adenosine content, coronary sinus adenosine concentration, and coronary vascular resistance during physiological exercise in the dog. The results support the hypothesis that adenosine regulates coronary blood flow during increased metabolic activity.

Adenosine↗
PubMed1982

Accumulation of [3H]norepinephrine in canine saphenous vein: influence of plasma.

This study was designed to systematically characterize the neuronal and extraneuronal uptake systems for norepinephrine (NE) in isolated nerve-rich vascular tissue and then to explore the possibility that circulating factors may alter these uptake systems. Strips from canine saphenous vein were incubated in Krebs-Ringer solution containing L-[3H]NE, and both tissue and medium were analyzed for total tritium, [3H]NE, and [3H]metabolite content. Under these conditions neuronal uptake (uptake1) played the dominant role in NE disposition. The addition of cocaine, ouabain, or potassium or the reduction of sodium decreased the activity of uptake1, and extraneuronal uptake (uptake 2) then played a major role in NE metabolism. The addition of 30, 60, and 90% plasma reduced NE accumulation and 3,4-dihydroxyphenylglycol (DOPEG) formation to 71 and 62% of control values, respectively; the formation of normetanephrine (NMN) and O-methylated deaminated compounds (OMDA) was not significantly different. In the presence of cocaine and uptake 1 inhibitor, 30% plasma did not cause a further significant decrease in neuronal accumulation of NE. The inhibitory activity of plasma on NE accumulation was not significantly affected by boiling or standing at room temperature for 45 min. These studies show that in the isolated canine saphenous vein the addition of plasma, like low sodium, cocaine, or ouabain, decreases neuronal uptake. The identity of the component in plasma responsible for inhibition of NE uptake appears to be a nonprotein, heat-stable molecule.

Animals↗
PubMed1982

Effect of norepinephrine on lymph flow and edema formation in the canine forelimb.

In the present study we sought evidence for the hypothesis that norepinephrine (NE) can cause constriction of lymph vessels in the canine forelimb perfused at constant flow. Mechanical venous compression (small-vein pressure approximately equal to 45 mmHg), intra-arterial infusion of histamine (16 micrograms base/min), and intra-arterial infusion of NE (16 micrograms base/min) caused the limbs to gain weight at similar rates due to edema formation; the first two maneuvers caused a sustained increase in skin lymph flow, but the increase in lymph flow with NE was only transient. Similar changes were seen during infusion of NE at 1 and 2 micrograms/min, and studies with radioactive microspheres indicated that NE increased capillary blood flow. When venous pressure was elevated and held constant at 45 mmHg. NE (4 micrograms base/min ia) antagonized and phentolamine (400 micrograms/min ia) potentiated the increase in skin lymph flow. Finally, NE (16 micrograms base/min ia) caused a reduction in histamine (16 micrograms base/min)-elevated skin lymph flow, despite the fact that capillary pressure was greatly increased due to active venous constriction. We conclude that intra-arterial infusion of norepinephrine in the dog forelimb perfused at constant flow causes constriction of lymphatic trunk vessels in skin, resulting in increased resistance to the flow of lymph.

Animals↗
PubMed1980

Mechanism, prevention and therapy of sodium-dependent hypertension.

This review considers the mechanism, prevention and therapy of sodium-dependent, low-renin, presumably volume-expanded, hypertension. Certain evidence suggests that in susceptible persons the basic problem is a genetic or acquired deficiency in the ability of the kidney to excrete sodium and hence water. This places them at a disadvantage in a society such as ours in which the salt intake is uniformly high, to a large extent because of the salt content in commercially processed foods. Other evidence suggests that the blood pressure level rises in part because the volume expansion evokes the release of an unknown, slowly-acting, pressor agent which operates by stimulating the contractility of cardiovascular muscle through suppression of the cellular sodium-potassium pump, much in the manner of the cardiac glycosides. Several investigators and the Select Committee on GRAS Substances suggest that the incidence of salt-dependent hypertension could be significantly decreased in a society such as ours if salt intake were reduced from the present level of approximately 10 g/day to 12 g/day. An obvious starting point is a reduction of the salt content in processed foods. The Food and Nutrition Board of the National Research Council suggest that a judicious combination of dietary sodium restriction and the use of an appropriate diuretic is the most rational approach to the treatment and management of diseases characterized by retention of sodium.

Animals↗