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Biomedical subjects

A Hoffman

Publications and source records attributed to A Hoffman.

At least 163 records · Page 9Linked to original sources
PubMed1992

Measurement of serum [3H]tetracycline kinetics and indices of kidney function facilitate study of the activity and toxic effects of bisphosphonates in bone resorption.

The [3H]tetracycline ([3H]TC) model is based on the observation that TC is released from the bones of rats prelabeled with [3H]TC via first-order kinetics, a factor directly reflecting the kinetics of bone resorption. In the present paper we applied the [3H]TC elimination model to rats treated with antiresorptive drugs. The validity of this model was evaluated by examining the effect of the bisphosphonate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (ABP), and a novel bisphosphonate, dihydrogen disodium adipoylbisphosphonate (AdBP), on serum TC levels and the elimination rate constant. ABP and AdBP significantly inhibited the TC elimination rate. However, ABP treatment caused impairment of bone mineralization, renal dysfunction, and inhibition of somatic growth. It is concluded that antiresorptive effects of bisphosphonates could be evaluated by the [3H]TC model, but this model is limited to animals with normal kidney function. The experimental conditions provide a technically simple method which is sensitive enough to examine antiresorptive properties in a healthy animal and to detect adverse effects on the kidney. The activity of the novel bisacylphosphonate, AdBP, and lack of its adverse effects indicate the potential of this drug for clinical applications.

Alkaline Phosphatase↗
PubMed1992

Sympathoadrenal contribution to plasma dopa (3,4-dihydroxyphenylalanine) in rats.

1. To determine the sources of dopa (3,4-dihydroxyphenylalanine) in plasma, we measured regional arteriovenous differences, tissue concentrations and urinary excretion of dopa during systemic intravenous infusions of I-[3H]dopa into anaesthetized intact rats and rats pretreated with the sympathetic neurotoxin, 6-hydroxydopamine. 2. In intact rats, large arteriovenous increments in plasma dopa concentrations were noted in the femoral (47%) and adrenal (141%) beds, with a small arterial-portal venous increment (11%), whereas in the kidney there was a substantial (47%) arteriovenous decrement in plasma dopa levels. Skeletal muscle appeared to be a major source of dopa in arterial plasma. 3. Treatment with 6-hydroxydopamine abolished the afferent-efferent increment of plasma dopa concentrations in the femoral bed. The arteriovenous decrement of plasma dopa concentrations in the kidney was preserved, and the arteriovenous increment in the adrenal bed was decreased by about half. Arterial plasma dopa levels fell by 41%. 4. Regional extraction percentages of I-[3H]dopa were used to estimate the clearances and rates of appearance (spillovers) of dopa in plasma. Dopa spillover was detected in the femoral, renal, splanchnic and adrenal beds, with skeletal muscle accounting for about 44% and the kidneys accounting for about 18% of dopa in arterial plasma. Whereas chemical sympathectomy decreased the femoral and renal spillover of dopa by 90% or more, arterial dopa levels and estimated dopa spillover into arterial plasma were decreased by only about 45%. 5. The kidneys accounted for 22% of dopa clearance from arterial plasma. From the renal extraction of I-[3H]dopa and the urinary excretion of [3H]dopamine, it was estimated that 77% of dopa removed in the kidneys was excreted as dopamine in intact animals and 69% was excreted as dopamine in sympathectomized animals. Conversely, about 80% of urinary endogenous dopamine was derived from plasma dopa, regardless of 6-hydroxydopamine treatment. 6. The results indicate that endogenous dopa in arterial plasma is derived substantially but not exclusively from sympathetic nerve endings that are destroyed by 6-hydroxydopamine, especially in skeletal muscle and the kidneys. Regional dopa spillover therefore probably reflects regional catecholamine biosynthesis. In rats, urinary dopamine is derived mainly from renal decarboxylation of circulating dopa.

Adrenal Glands↗
PubMed1992

Effects of water immersion on sympathoadrenal and dopa-dopamine systems in humans.

Water immersion to the neck increases central blood volume and evokes a marked diuresis and natriuresis. The present study examined simultaneously effects of water immersion on activities of three endogenous systems thought to participate in sodium homeostasis: the sympathetic nervous system, the atrial natriuretic peptide system, and the renal dopa-dopamine system. Hourly urine collections and antecubital venous blood samples were obtained from 10 normal subjects before, during, and after sitting in a water-immersion tank for 3 h; four control subjects were studied while seated without immersion. Urine volume was increased by more than threefold after 1 h of immersion (from 1.2 +/- 0.2 ml/min at baseline to 5.9 +/- 0.7 ml/min, P less than 0.001) and peaked during the second hour. Urinary sodium excretion increased by more than twofold (from 103 +/- 17 mu eq/min at baseline to 196 +/- 36 mu eq/min at 1 h, P less than 0.001) and peaked during the third hour. Plasma levels and urinary excretion of norepinephrine (NE) and epinephrine were suppressed consistently during immersion (P less than 0.05). There was a marked, prompt, and sustained increase in plasma levels of immunoreactive atrial natriuretic factor (irANF) from 6.9 +/- 1.9 pg/ml baseline to 17.3 +/- 4.3 pg/ml at 1 h (P less than 0.001). Urinary excretion of dopa, dopamine, and 3,4-dihydroxyphenylglycol, a neuronal metabolite of NE, changed in a triphasic pattern, with decreased excretion during the first hour of immersion (P less than 0.01), small but consistent increases during the next 2 h, and decreased excretion, to below baseline, during recovery (P less than 0.01 for dopa and dopamine).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1991

Method for measuring endogenous 3-O-methyldopa in urine and plasma.

The present report describes a method using column liquid chromatography with electrochemical detection for assaying concentrations of 3-O-methyldopa in urine and plasma. The technique combines a one-step sample preparation scheme with post-column flow-through electrodes in series, allowing adequate chromatographic separation of 3-O-methyldopa from other endogenous substances in urine. The validity of the method was confirmed by markedly decreased urinary 3-O-methyldopa levels after administration of an inhibitor of catechol-O-methyltransferase to rats, radioactivity in chromatographic fractions corresponding to 3-O-methyldopa in urine of rats undergoing infusion of [3H]-L-DOPA, and correlations between excretion rates of 3-O-methyldopa and catechols in humans. In healthy humans, urinary excretion of 3-O-methyldopa averaged 974 +/- 707 (S.D.) nmol per day, and plasma levels of 3-O-methyldopa averaged 89 +/- 32 nmol/l. The method should be useful in studies about the metabolism of endogenous and exogenous DOPA.

Animals↗
PubMed1991

The relationship of nasopharyngeal carcinomas and second independent malignancies based on the Radiation Therapy Oncology Group experience.

The authors sought to learn if the incidence of second independent malignancies after the irradiation of carcinomas of the nasopharynx is similar to that observed after treatment of tumors arising in other head and neck sites. One hundred twenty-one patients who had primary carcinomas of the nasopharynx who were treated solely by ionizing radiation (according to the specifications of a Radiation Therapy Oncology Group protocol) were identified and their subsequent well-being was reviewed. Overall there was a 4.1% incidence of second malignancies (2% after 3 years, 5% after 5 years, and 8% after 8 years) with most arising in the upper aerodigestive tract. This rate is significantly less than the rate associated with other head and neck sites. It is not significantly different from the rate of first malignancies observed in an age-matched and sex-matched population. When only those patients who were free of all evidence of neoplastic disease 6 months after the completion of radiotherapy are considered, similar analysis leads to similar outcomes. The authors conclude that the risk of second malignancies after the successful irradiation of carcinomas of the nasopharynx is substantially less than after treatment of tumors at other head and neck sites.

Adolescent↗
PubMed1991

Complexes of .NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects.

Selected nucleophile/nitric oxide adducts [compounds which contain the anionic moiety, XN(O-)N = O] were studied for their ability to release nitric oxide spontaneously in aqueous solution and for possible vasoactivity. The diversity of structures chosen included those in which the nucleophile residue, X, was that of a secondary amine [Et2N, as in [Et2NN(N = O)O]Na, 1], a primary amine [iPrHN, as in [iPrHNN(N = O)O]Na, 2], a polyamine, spermine [as in the zwitterion H2N(CH2)3NH2+(CH2)4N[N(N = O)O-](CH2)3NH2, 3], oxide [as in Na[ON(N = O)O]Na, 4], and sulfite [as in NH4[O3SN(N = O)O]NH4, 5]. The rate constants (k) for decomposition in pH 7.4 phosphate buffer at 37 degrees C, as measured by following loss of chromophore at 230-260 nm, were as follows: 1, 5.4 x 10(-3) s-1; 2, 5.1 x 10(-3) s-1; 3, 0.30 x 10(-3) s-1; 4, 5.0 x 10(-3) s-1; and 5, 1.7 x 10(-3) s-1. The corresponding extents of nitric oxide release (ENO) were 1.5, 0.73, 1.9, 0.54, and 0.001 mol/mol of starting material consumed, respectively, as determined from the integrated chemiluminescence response. Vasodilatory activities expressed as the concentrations required to induce 50% relaxation in norepinephrine-constricted aortic rings bathed in pH 7.4 buffer at 37 degrees C (EC50) were as follows: 1, 0.19 microM; 2, 0.45 microM; 3, 6.2 microM; 4, 0.59 microM; and 5, 62 microM. Vasorelaxant potency (expressed as 1/EC50) was strongly correlated with the quantity of .NO calculated from the physicochemical data to be released in the interval required to achieve maximum relaxation at the EC50 doses (r = 0.995). This suggests that such nucleophile/.NO adducts might generally be useful as vehicles for the nonenzymatic generation of nitric oxide, in predictable amounts and at predictable rates, for biological purposes. The particular significance for possible drug design is underscored in the very favorable potency comparison between several of these agents and the established nitrovasodilators sodium nitroprusside and glyceryl trinitrate (EC50 values of 2.0 and greater than 10 microM, respectively) in parallel aortic ring tests.

Animals↗
PubMed1991

Increased plasma levels and blunted effects of brain natriuretic peptide in rats with congestive heart failure.

The hemodynamic and renal effects of brain natriuretic peptide (BNP) were studied in conscious rats with experimental congestive heart failure (CHF) produced by an aortocaval fistula. The peptide had potent hypotensive, diuretic, and natriuretic effects in control rats, all of which were abolished in CHF. Plasma levels of BNP increased time-dependently during the development of CHF, and were more than four-fold higher in sodium retaining rats than in control rats. The data suggest that BNP secretion from the atria is increased in CHF, and that resistance to BNP, in addition to the relative resistance to atrial natriuretic factor, may contribute to sodium retention in CHF.

Animals↗
PubMed1991

Endogenous dopa and dopamine responses to dietary salt loading in salt-sensitive rats.

We measured daily urinary excretion rates of dopamine and dopa during dietary salt loading and natriuretic responses to exogenous dopamine in Dahl salt-sensitive (DS), Dahl salt-resistant (DR) and Sprague-Dawley rats. Excretion rates of dopa increased approximately sixfold during salt loading in all rat strains. Maximal urinary dopa responses were attained within 1 day of salt loading. Daily excretion rates of dopamine also increased about five- to sixfold in DS and DR rats and about twofold in Sprague-Dawley rats, with maximal dopamine responses attained by day 5. Dopamine infusion (3 micrograms/kg per min) increased urinary sodium excretion by 406 +/- 132 % (mean +/- s.e.m.) in Sprague-Dawley rats but only 267 +/- 131% and 147 +/- 80% in DS and DR rats (P less than 0.05 for Sprague-Dawley versus Dahl rats). The results demonstrate that salt loading markedly and rapidly increases dopa excretion in rats. Considering values for dopamine excretion in other rat strains, the results suggest that Dahl rats have increased formation of dopamine for a given amount of dopa delivery to the kidney and that this abnormality is unrelated to salt-sensitive hypertension in DS rats. The results also provide in vivo support for the view that the responsiveness of renal dopamine receptors mediating natriuresis is related to production of endogenous dopamine in the kidney.

Animals↗
PubMed1991

Yohimbine increases sympathetic nerve activity and norepinephrine spillover in normal volunteers.

It has been difficult to examine clinically the physiological role of central and peripheral alpha 2-adrenoceptors in humans. We simultaneously measured directly recorded peroneal skeletal muscle sympathoneural activity (MSNA) and the rate of appearance (spillover) of norepinephrine (NE) in forearm venous and arterial plasma before and at 15 min during intravenous administration of the alpha 2-blocker yohimbine (Yoh, 125 micrograms/kg bolus, 1 microgram.kg-1.min-1 infusion) in seven normal volunteers. Yoh administration increased mean arterial pressure by 16% (P less than 0.005), heart rate by 8% (P less than 0.05), and forearm vascular resistance by 67% (P less than 0.05). MSNA was increased by 73% (P less than 0.05), NE spillover into arterial blood by 125% (P less than 0.05), and forearm NE spillover (FSO) by 337% (P less than 0.005). Ganglion blockade by trimethaphan during Yoh infusion decreased MSNA to below detection limits and reversed Yoh-induced increases in arterial concentrations of NE and epinephrine. The results demonstrate that Yoh administration increases sympathoadrenal outflow. Because the mean increase of FSO was much larger than that of MSNA, the results suggest that alpha 2-adrenoceptors on sympathetic nerve endings modulate the neuronal release of NE for a given amount of sympathetic nerve traffic in humans; this effect seems prominent in the human limb.

Adrenocorticotropic Hormone↗
PubMed1991

Tracer norepinephrine kinetics: dependence on regional blood flow and the site of infusion.

The rate of appearance of the sympathetic neurotransmitter norepinephrine (NE) in the regional venous drainage (NE spillover) can be estimated based on intravenous or intra-arterial infusions of [3H]NE. The present study examined whether forearm NE spillover (FASO) in humans depends on forearm blood flow (FBF) and on the site of infusion of the tracer. Healthy volunteers underwent infusions of [3H]NE and [3H]isoproterenol (Iso) administered intravenously (n = 21), intra-arterially (n = 32), or by both routes in the same experimental session (n = 7). FBF was manipulated by intra-arterial infusions of the vasodilator sodium nitroprusside (n = 7) or the vasoconstrictor methoxamine (n = 7). Forearm extraction percents of [3H]NE exceeded those of [3H]Iso in all subjects undergoing intravenous infusions (54 vs. 46%, P less than 0.001), whereas extraction percents of [3H]Iso exceeded those of [3H]NE when the tracers were infused intra-arterially. Regardless of the infusion site, FASO was positively correlated with FBF (r = 0.44, P less than 0.005). Nitroprusside increased FBF and FASO, and methoxamine decreased FBF and FASO. When the tracers were added to whole blood, 89% of [3H]NE and 83% of [3H]Iso remained in plasma after 1 min; although no further loss of [3H]NE occurred over time, only 60% of the added [3H]Iso remained in plasma by 20 min. The results indicate that regional NE spillover is flow dependent, complicating inferences about regional sympathoneural activity. Intra-arterial infusion of [3H]NE results in higher estimates of regional NE spillover than does intravenous infusion of the tracer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Atrial natriuretic peptide and renal cGMP in rats with experimental heart failure.

Rats with chronic aortocaval (AV) fistula, an experimental model of congestive heart failure, display high plasma levels of atrial natriuretic factor (ANF) and a blunted natriuretic response to ANF infusion. We previously reported that rats with AV fistula either develop progressive sodium retention (urinary sodium excretion, UNaV less than 100 microeq/24 h) or compensate (UNaV greater than 1,200 microeq/24 h). To gain further insight into the mechanism of renal hyporesponsiveness to ANF, we evaluated the effect of ANF on renal guanosine 3',5'-cyclic monophosphate (cGMP) production in sham-operated control rats and in the two groups of rats with AV fistula. Infusion of synthetic ANF-(99-126) (at either 10 or 50 micrograms.kg-1.h-1) resulted in a reduced fractional sodium excretion (P less than 0.05) in both compensated rats (0.7 +/- 0.2 and 7.9 +/- 1.6%) and sodium-retaining rats (0.3 +/- 0.1 and 0.5 +/- 0.1%) compared with controls (8.5 +/- 1.2 and 13.7 +/- 2.3% for low and high doses, respectively). Similarly, urinary cGMP excretion corrected by glomerular filtration rate (UcGMPV/GFR) during low-dose ANF infusion was significantly reduced (P less than 0.05) in both groups with AV fistula (compensated: 39 +/- 10 pmol/ml; sodium-retaining: 55 +/- 13 pmol/ml) compared with controls (115 +/- 16 pmol/ml). During high-dose ANF infusion, compensated rats, but not sodium-retaining rats, displayed a significant increase in UcGMPV/GFR. The differences in UcGMPV/GFR are probably not due to variations in urine flow because furosemide infusion to a separate group of rats with AV fistula increased urine flow approximately eightfold but did not increase UcGMPV/GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Glucagon and clonidine testing in the diagnosis of pheochromocytoma.

We assessed the sensitivity and specificity of glucagon stimulation and clonidine suppression tests in the diagnosis of pheochromocytoma in 113 hypertensive patients, 39 with and 74 without the tumor. In the glucagon stimulation test, blood was sampled 2 minutes after intravenous injection of 0.28 mumol (1 mg) glucagon, and in the clonidine suppression test, blood was sampled 3 hours after administration of oral clonidine, 1.30 mumol (0.3 mg)/70 kg body wt. Baseline levels of catechols in antecubital venous blood were abnormal, with norepinephrine greater than 7.10 nmol/l (1,200 pg/m), epinephrine greater than 1.51 nmol/l (276 pg/ml), norepinephrine/dihydroxyphenylglycol (DHPG) ratio greater than 1.09, or dopa greater than 35.53 nmol/l (7,000 pg/ml), in 30 of 39 patients with pheochromocytoma (sensitivity 77%) and 1 of 74 patients without pheochromocytoma (specificity 99%). Results of the glucagon test were abnormal (norepinephrine greater than 11.83 nmol/l [2,000 pg/ml] or more than threefold increase from baseline) in 25 of 31 patients with pheochromocytoma (sensitivity 81%) and 0 of 72 patients without pheochromocytoma (specificity 100%). Results of the clonidine test were abnormal (after clonidine norepinephrine greater than 2.96 nmol/l [500 pg/ml] or less than 50% decrease from baseline) in 29 of 30 patients with pheochromocytoma (sensitivity 97%) and in 7 of 30 patients without pheochromocytoma (specificity 67%). Very high baseline levels of catechols therefore indicated the presence of pheochromocytoma, but there were several false-negative results when normal levels were obtained. The glucagon test alone was highly specific but not sensitive, and the clonidine test was highly sensitive but less specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1991

Evidence for functional alpha 2-adrenoceptors on vascular sympathetic nerve endings in the human forearm.

The role of alpha 2-adrenoceptors on vascular sympathetic nerve endings in modulating release of the sympathetic neurotransmitter norepinephrine (NE) in humans was examined by measuring the regional rate of appearance of NE in forearm venous plasma (forearm NE spillover [FSO]) in 32 healthy volunteers during intra-arterial infusion of drugs acting at adrenoceptors or directly on vascular smooth muscle. Simultaneous intra-arterial infusions of tracer amounts of [3H]NE were used to calculate the extraction rate of NE in the forearm. Methoxamine or propranolol with epinephrine (PRO + EPI) was used to stimulate alpha-adrenoceptors, yohimbine was used to inhibit alpha-adrenoceptors, and sodium nitroprusside (NIP) was used to produce increases in forearm blood flow directly. Sympathetic efferent activity was manipulated by systemic intravenous infusions of NIP or trimethaphan. Yohimbine and NIP increased and PRO + EPI and methoxamine decreased NE FSO, without effects on systemic blood pressure, heart rate, or arterial levels of catechols. Changes in FSO were flow dependent; therefore, the slope of the relation between the changes in FSO and forearm blood flow was used to evaluate the effects of each drug on regional sympathoneural activity. During administration of yohimbine, the mean slope of the relation between the change in estimated FSO and the change in forearm blood flow was about four times that of the mean slope during administration of NIP (F = 6.35, p less than 0.05). The slopes of the relations between changes in FSO and forearm blood flow were unaffected by systemic trimethaphan or NIP infusion, indicating that the activity of alpha 2-adrenoceptors was not altered during inhibition or reflexive stimulation of sympathetic outflow. The results suggest that alpha 2-adrenoceptors modulate release of NE from vascular sympathetic nerve endings in humans and that the function of these receptors is unchanged during acute changes in junctional NE concentrations.

Adult↗