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Biomedical subjects

F J Haddy

Publications and source records attributed to F J Haddy.

At least 37 records · Page 2Linked to original sources
PubMed1990

Effect of increased dietary calcium on the development of reduced renal mass saline hypertension in rats.

A diet fortified with calcium carbonate has been reported to reduce blood pressure in low-renin and salt-sensitive hypertensive patients. We have therefore examined the effect of increased dietary calcium on the development of reduced renal mass-saline hypertension in rats, a classical, low-renin, volume, and sodium-dependent model of hypertension. Rats with 70-75% reduction in renal mass were divided into experimental and control groups. The experimental rats were fed a sodium-free diet supplemented with calcium carbonate (2.0% calcium) and drank 1% saline for 5 weeks. Control rats consumed the salt-free diet and drank 1% saline for the same period. In control rats, as previously observed, blood pressure progressive increased from a control value of 120.0 +/- 1.2 to 174.2 +/- 1.2 mm Hg by the fifth week. In contrast, in the calcium-supplemented rats the development of hypertension was significantly attenuated; the blood pressure only increased from 117.0 +/- 1.2 to 134.0 +/- 3.8 mm Hg by the fifth week. This was associated with a 30% decrease in saline intake by the fifth week, with proportionate decreases in urine volume and sodium excretion but not potassium excretion. Urinary magnesium excretion increased. No such changes were seen in control rats. At the end of the treatment period, plasma levels of sodium, potassium, calcium, creatinine, BUN, and protein were not different, but plasma chloride and magnesium were lower in experimental rats; vascular smooth muscle cell membrane potentials were also not different. These data show that dietary calcium carbonate can attenuate the development of reduced renal mass-saline hypertension in the rat, possibly in part by altering sodium and water intake.

Animals↗
PubMed1990

Effects of canrenone on blood pressure in rats with reduced renal mass.

Canrenone, a metabolic product of spironolactone, which competes with ouabain for binding to Na-K-ATPase at the digitalis receptor site and by itself inhibits Na-K-ATPase, was administered intramuscularly to reduced renal mass-saline drinking hypertensive and reduced renal mass-distilled water drinking normotensive rats for 8 days. Reduced renal mass-saline hypertension in the rat, is a low renin, volume expanded form of hypertension. Rats with this type of hypertension have been shown to have depressed arterial Na-K pump activity and increased Na-K pump inhibitory activity in their plasma. Canrenone treatment caused a progressive decrease in blood pressure in the hypertensive rats and this was associated with normalization of Na-K pump activity in arteries. Water and salt intake and excretion did not change. On the other hand, canrenone progressively increased blood pressure in the normotensive rats and this was associated with positive inotropy in isolated papillary muscles. These findings suggest that the depressed pump activity and the pump inhibitor play a role in reduced renal mass-saline hypertension in the rat and that the rise in blood pressure in the normotensive rats probably reflects canrenone's ability, by itself, to inhibit Na-K-ATPase.

Animals↗
PubMed1989

Humoral Na+-K+ pump inhibitory activity in essential hypertension and in normotensive subjects after acute volume expansion.

Plasma from black male patients with essential hypertension was bioassayed for vascular Na+-K+ pump inhibitory activity. Halves of the same rat tail artery were incubated for two hours in boiled plasma supernates from a hypertensive patient and a paired age-, sex-, and race-matched normotensive subject and then ouabain-sensitive 86Rb uptake was measured. Ouabain-sensitive 86Rb uptake by their leukocytes was also measured. Eighteen pairs of subjects were studied. The uptakes were not significantly different in the hypertensive patients and control subjects. However, when we selected from the eighteen hypertensive patients, nine with low plasma renin activity on the day of the study, uptakes were reduced in the hypertensive patients relative to the paired control subjects. We also assayed plasma supernates from normotensive black and white male subjects before and after acute volume expansion (2.5 L saline IV + 1.5 L distilled water orally over a three-hour period) and from paired normotensive subjects before and after sham volume expansion and obtained a positive bioassay in the expanded subjects both on intraindividual and interindividual comparisons. These studies demonstrate increased vascular Na+-K+ pump inhibitory activity in the plasma of black male patients with low renin essential hypertension and in the plasma of normotensive subjects after acute volume expansion. The findings suggest that the inhibitory activity in the hypertensive subjects' plasma is related to volume expansion, relative or absolute.

Adult↗
PubMed1989

Effects of ANP on venous pressures and microvascular protein permeability in dog forelimb.

Intravenous administration of alpha-atrial natriuretic peptide (ANP) produces a decrease in arterial blood pressure due to a decrease in cardiac output. The mechanism of the decrease in cardiac output is unknown but has been suggested to result from transcapillary fluid efflux caused by venoconstriction and/or increased permeability of the microvascular membrane to plasma proteins. We investigated these possibilities in the dog forelimb perfused at constant flow and prepared to measure 1) large and small vessel pressures in the two parallel skin and skeletal muscle vascular beds, and limb weight; or 2) skin lymph flow and skin lymph protein concentration. In both preparations, human ANP was injected and infused into the brachial artery. Bolus injections of ANP (0.1-0.4 micrograms) depressed perfusion pressure much less than acetylcholine or an isotonic solution of potassium chloride and did not raise small vein pressures. ANP infused at nine different rates ranging from 0.1 ng to 38.8 micrograms/min failed to influence skin and muscle small and large vein pressures, limb weight, skin lymph flow, and skin lymph protein concentration. It also failed to affect perfusion pressure and skin and muscle small artery pressures until the infusion was shut off, at which time they increased above control levels. These studies suggest that human alpha-ANP is neither a direct venous constrictor nor a potent arteriolar dilator and does not directly influence the permeability of the microvascular membrane to plasma proteins in the skin and skeletal muscle of the dog forelimb.

Animals↗
PubMed1988

Sustained antihypertensive effect of chronic oral administration of 6-iodo-amiloride, a sodium channel blocker, in spontaneously hypertensive rats.

We have previously shown that a 10-min intravenous infusion of 6-iodo-amiloride, an analogue of the sodium channel blocker amiloride, causes a sustained decrease in blood pressure in two genetic models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats. In contrast, the same infusion produced only a transient decrease in blood pressure in two renal models of hypertension, viz. one-kidney, one clip, and reduced renal mass-saline rats. With these findings, we suggested that 6-iodo-amiloride has potential both as a diagnostic probe and as a therapeutic agent in genetic models of hypertension. The aim of the present study was to examine the effectiveness of 6-iodo-amiloride as a long-term antihypertensive agent and determine the mechanism of its antihypertensive action. We administered 6-iodo-amiloride to SHR for 4 weeks in the drinking fluid (tap water). The treatment with 6-iodo-amiloride caused a significant decrease in blood pressure but had no effect on urine volume or urinary excretion of sodium and potassium. These data strongly suggest that 6-iodo-amiloride is an effective long-term antihypertensive agent in genetic types of hypertension.

Amiloride↗
PubMed1988

Effect of theophylline on renal vasoactivity of acetate and adenosine.

To examine the possible role of adenosine in the vasoactivity of acetate, acetate and adenosine were injected into the renal artery of the dog while measuring renal blood flow. Low (9-28 mg) doses of acetate produced vasodilation, but higher doses (28-94 mg), like adenosine, produced vasoconstriction followed by vasodilation. Theophylline, a competitive inhibitor of the vascular action of adenosine, inhibited the vasodilator action of adenosine but not that of acetate. Secondly, theophylline inhibited the vasoconstrictor effect of adenosine and acetate but the latter to a much lesser extent. These findings suggest that adenosine mediates the vasoconstriction effect of acetate in the canine kidney.

Acetates↗
PubMed1988

Effect of 6-iodoamiloride in various models of experimental hypertension.

6-Iodoamiloride, an analogue of the sodium channel blocker amiloride, is a vasodilator-depressor, diuretic-natriuretic, and antikaliuretic agent. In these experiments we intravenously infused 6-iodamiloride (0.38 mg/100 g body weight) over a 10- to 11-minute period into rats with reduced renal mass-saline hypertension or one-kidney, one clip hypertension. The infusion produced a prompt but transient fall in blood pressure. These findings are in contrast to those in spontaneously hypertensive rats (SHR), in which the same infusion of 6-iodoamiloride produced a prompt, pronounced, and sustained fall in blood pressure. Studies from a number of laboratories suggest that vascular smooth muscle cells from the SHR have increased permeability to sodium whereas vascular smooth muscle cells from the other two models do not. Thus, 6-iodoamiloride may have potential both as a diagnostic probe and a therapeutic agent for hypertension characterized by increased vascular smooth muscle cell permeability to sodium.

Amiloride↗
PubMed1988

Role of atrial natriuretic factor in regulation of blood pressure in normotensive rats having reduced renal mass.

Experiments were carried out in normotensive, saline-drinking, 60% reduced renal mass rats to determine the effect of an in vivo blockade of endogenous atrial natriuretic factor (ANF) on blood pressure. We used a 60% reduction in renal mass because blood pressure in these normotensive animals is extremely sensitive to any slight further reduction of renal excretory function. Six weeks following the reduction of renal mass and documentation of normotension, rats were injected intraperitoneally twice daily for 12 days with ANF antibody prepared against the C-terminal heptapeptide of AP III conjugated to bovine thyroglobulin. Control rats similarly prepared, received normal rabbit serum (NRS). Blood pressure progressively increased in rats receiving the antibody, and its withdrawal returned blood pressure to control levels within 4-5 days. Serum from either normal rabbits or rabbits immunized with bovine thyroglobulin or peptides unrelated to ANF had no effect on blood pressure in the control animals. These experiments show that in the normotensive saline-drinking rat with reduced renal mass, an antibody to AP III raises blood pressure. This suggests that ANF here is acting to prevent the rise in blood pressure.

Animals↗
PubMed1987

Pharmacologic agents for the in vivo detection of vascular sodium transport defects in hypertension.

Anatagonists to angiotensin, catecholamines, aldosterone, and vasopressin have long been used to help determine agonist roles in hypertension. We here call attention to a possible extension of this approach to detect, evaluate, and treat vascular sodium transport defects in hypertension. Two basic types of transport defects have been identified in the blood vessels of hypertensive animals, increased sodium permeability and decreased sodium pump activity. Intravenous injection of 6-iodo-amiloride, a sodium channel blocker and vasodilator, produces an immediate and sustained decrease in blood pressure in two genetic models of hypertension characterized by increased permeability of the vascular smooth muscle cell membrane to sodium (Okamoto spontaneously hypertensive rat, Dahl salt sensitive rat), whereas it produces only a transient fall in arterial pressure in two renal models of hypertension having normal sodium permeability in vascular smooth muscle cells (reduced renal mass-saline rat, one-kidney, one clip rat). Canrenone, a metabolic product of spironolactone which can compete with oubain for binding to Na+,K+-ATPase at the digitalis receptor site, decreases blood pressure in a low renin, volume expanded model of hypertension which has been shown to have depressed sodium pump activity in arteries and increased sodium pump inhibitor in plasma (reduced renal mass-saline rat) but has no effect on blood pressure in a genetic model of hypertension which has been shown to have increased sodium pump activity secondary to increased sodium permeability (spontaneously hypertensive rat). Thus, a sodium channel blocker and a competitor to ouabain binding can detect and determine the functional significance of sodium transport defects in the blood vessels of intact hypertensive animals. Studies in red and white blood cells suggest that similar defects may exist in the blood vessels of hypertensive humans. Thus, this approach, probing for vascular transport defects in the intact animal, may ultimately also be useful in the clinical setting.

Amiloride↗
PubMed1987

Dietary sodium and potassium in the genesis, therapy, and prevention of hypertension.

In this review, we first summarized the evidence from animals and man for and against a role for dietary sodium in the genesis and treatment of hypertension. The evidence for a role for dietary sodium in the genesis of hypertension is strongest in those subjects with impaired ability to excrete sodium due to organic renal disease or mineralocorticoid excess. Here restriction of dietary sodium promptly lowers arterial pressure. Its role in the genesis of essential hypertension is still controversial. Nevertheless, it appears that some patients with mild to moderate essential hypertension respond to moderate sodium restriction with a modest fall in blood pressure. This restriction also seems to reduce the amount of antihypertensive medication needed to keep blood pressure under control. We next considered the mechanism of the pressure response to dietary sodium chloride, concentrating upon the increase in extracellular fluid volume, potassium depletion, and increased plasma levels of prohypertensive sodium pump inhibitor and antihypertensive atrial natriuretic factor. We next summarized the evidence for a primary role for dietary potassium in the genesis of hypertension and pointed out that certain subsets of subjects with a high incidence of hypertension also have a lower dietary potassium intake. Some investigators find that dietary potassium supplementation lowers blood 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. We then considered practical aspects of dietary sodium restriction and dietary potassium supplementation in the therapy for established hypertension. The review concludes with comments on their possible roles in the prevention of hypertension.

Animals↗
PubMed1987

Effect of theophylline on adenosine production in the canine myocardium.

Adenosine is thought to participate in local regulation of coronary blood flow. However, competitive antagonists of adenosine fail to block myocardial active hyperemia. We examined the effect of locally administered theophylline on active hyperemia and myocardial adenosine production during intracoronary isoproterenol infusion in the dog heart. Isoproterenol decreased coronary resistance and increased myocardial adenosine production. Infusion of theophylline at a rate that attenuated the vasodilator response to exogenously administered adenosine failed to attenuate the increase in coronary blood flow produced by isoproterenol. However, theophylline plus isoproterenol produced greater increases in myocardial adenosine production than isoproterenol alone. The curves relating resistance and adenosine in the presence of theophylline fell to the right of those in the absence of theophylline. These findings suggest that the failure of theophylline to attenuate isoproterenol hyperemia in the dog heart results at least in part from an increase in adenosine concentration at the arteriole to a level beyond that blocked by this competitive antagonist and that adenosine may in fact play a role in isoproterenol-induced active hyperemia.

Adenosine↗
PubMed1987

Pathophysiological role of cation transport and natriuretic factors in hypertension.

This review considers in some detail the hypothetical relationships between sodium fluxes, both active and passive, across the cell membrane, and intracellular sodium concentration in vascular smooth muscle in the animal models of hypertension. It appears that two basic types of transport defects, increased cell membrane permeability to sodium and decreased active pumping of sodium at a given internal sodium concentration, can exist in vascular smooth muscle in experimental hypertension, and that sometimes the two defects coexist, further increasing internal sodium concentration. It is possible that eventually we may find similar transport defects in vascular smooth muscle in humans with arterial hypertension. Decreased active pumping at a given internal sodium concentration appears to result from a humoral sodium pump inhibitor. Future directions for research in the area are also considered. First priority should be given efforts to determine the chemical structure of the sodium pump inhibitor(s). High priority should also be given to attempts to measure passive and active sodium fluxes and intracellular sodium concentration in vascular smooth muscle cells in vivo, and to determine the role of atrial natriuretic factor in the genesis and maintenance of hypertension.

Animals↗
PubMed1987

Humoral sodium transport inhibitor in acute volume expansion and low renin hypertension.

This review summarizes our bioassay methods for determining the level of humoral sodium pump inhibiting factor after acute volume expansion in experimental animals and humans, and in low renin experimental and human essential hypertension. In brief, ouabain-sensitive 86Rb uptake and membrane potential in blood vessels from normal animals are measured after incubation in plasma supernate from experimental subjects and animals and their respective controls. The data show that humoral sodium pump inhibitor is elevated after acute volume expansion in normal animals (dogs and rats) and in normal humans. The level of inhibitor is also elevated in patients with low renin essential hypertension and in experimental animals with low renin, volume-dependent types of hypertension, namely, one-kidney, one wrapped hypertension in dogs, and one-kidney, one clip and reduced renal mass-saline hypertension in rats. Humoral sodium pump inhibiting factor inhibits the Na+-K+ pump in the cardiovascular system. Such inhibition by other means (hypokalemia, cardiac glycosides) activates the system. Therefore, we also discuss the possible role of humoral sodium pump inhibitor in low renin volume-dependent hypertension.

Animals↗
PubMed1987

Natriuretic hormones in low renin hypertension.

The possible roles of a humoral sodium pump inhibitor and atrial natriuretic peptide in low renin hypertension are considered, relying heavily on data from a classical animal model of low renin hypertension, the reduced renal mass-saline model in the rat, and on data uncovered by a new literature survey of the two agents in various normotensive and hypertensive states. Based on these data, particularly those indicating both agents are released by volume expansion, our current view is that low renin hypertension is in part generated by the sodium pump inhibitor and is in part moderated by atrial natriuretic peptide. We suggest that the atrial natriuretic peptide compensates for increased volume due to reduced renal function and/or increased salt intake and that in low renin hypertension the compensation is not sufficient to return volume and pressure to normal. In this view, the sodium pump inhibitor is prohypertensive, via actions on blood vessels and heart, and atrial natriuretic peptide is antihypertensive, via actions on kidney and the cardiovascular system.

Animals↗