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Biomedical subjects

H R Keiser

Publications and source records attributed to H R Keiser.

At least 109 records · Page 6Linked to original sources
PubMed1987

Neuronal source of plasma dihydroxyphenylalanine.

The source and significance of plasma levels of dihydroxyphenylalanine (DOPA), the precursor of the endogenous catecholamines, have been unknown. We measured arterial and venous plasma DOPA concentrations in healthy subjects at rest, patients who had undergone regional sympathectomies or were undergoing general anesthesia, and subjects during procedures (tilt, oral clonidine, or iv isoproterenol, yohimbine, trimethaphan, or diazepam) known to affect plasma norepinephrine levels. We also measured plasma DOPA in laboratory animals during anesthesia, after adrenalectomy, or after administration of alpha-methyl-para-tyrosine, which competitively inhibits tyrosine hydroxylase, the intraneuronal enzyme catalyzing the rate-limiting step in catecholamine biosynthesis. In virtually all healthy subjects there was an arteriovenous increment in plasma DOPA (mean increase, 32%; P less than 0.001), whereas in sympathectomized patients there was not (mean decrease, 16%; P less than 0.001 compared with healthy subjects). Except for small decreases after clonidine treatment, none of the above procedures affected plasma DOPA levels. Plasma DOPA decreased during general anesthesia and returned to baseline upon reversal of the anesthesia. Adrenalectomy had no effect on plasma DOPA. alpha-Methyl-para-tyrosine decreased plasma DOPA by 62% (P less than 0.01). The results support the suggestion that DOPA can pass across sympathetic neuronal membranes to reach the general circulation. If so, then the regional rate of appearance of DOPA in plasma may be related to the regional rate of tyrosine hydroxylation. Conversely, DOPA taken up from the circulation may provide a source for catecholamine biosynthesis in tissues devoid of tyrosine hydroxylase.

Adolescent↗
PubMed1987

Dihydroxyphenylglycol and intraneuronal metabolism of endogenous and exogenous norepinephrine in the rat vas deferens.

To elucidate the origin and significance of dihydroxyphenylglycol (DHPG) as a metabolite of norepinephrine (NE), the isolated rat vas deferens was preloaded with tracer amounts of tritiated NE and examined for the release of radioactive and endogenous NE and DHPG before and during electrical stimulation or stimulation with excess K+. Tissues were incubated with desipramine or reserpine to determine the effects of blockade of neuronal uptake and of interference with vesicular translocation of NE. Radioactive NE appeared to distribute differently from endogenous NE into at least two pools, but for the most part endogenous NE and DHPG behaved similarly in response to pharmacological manipulations. Desipramine blocked completely the increased appearance of both radioactive and endogenous DHPG in the medium during electrical stimulation or K+ stimulation; DHPG responses to stimulation are thus dependent on recapture of NE at the synapse. Basal release of DHPG was increased by reserpine, and this increase was not affected by desipramine; therefore, reserpine-induced release of DHPG is independent of neuronal uptake consistent with formation of DHPG from NE leaking into the cytosol from vesicular stores. Reserpine enhanced the release of DHPG during stimulation, and concomitant desipramine treatment blocked this effect; thus, interference with NE translocation into storage vesicles increases the availability of recaptured NE for intraneuronal metabolism. During stimulation of NE release between 70 to 80% of the recaptured NE was estimated to be sequestered into storage vesicles for rerelease. Combined measurement of endogenous and labeled NE and DHPG provides a useful tool for examining neuronal uptake and intraneuronal disposition of NE.

Animals↗
PubMed1986

Indices of sympathetic vascular innervation in sympathectomized patients.

We measured arterial and venous plasma catecholamines and used laser-Doppler flowmetry to measure cutaneous microcirculatory flow in the sympathectomized and in the intact limbs of 3 patients who had undergone regional sympathectomies. Venous concentrations of norepinephrine, the sympathetic neurotransmitter, exceeded arterial concentrations in the intact limbs--a normal finding--but invariably were less than arterial in the sympathectomized limbs of the same patients, both during baseline conditions and during sympathetic stimulation using tilt, standing and the cold pressor test (mean arteriovenous decrement about 40%). Arterial epinephrine levels exceeded venous levels with or without sympathectomy. Skin microvascular flow rapidly decreased during the cold pressor test and the Valsalva maneuver in the intact but not in the sympathectomized limbs, and spontaneous flow oscillations occurred in the sympathectomized limbs. The results suggest that an arteriovenous increment in plasma norepinephrine reflects local release of norepinephrine from sympathetic nerve endings, whereas removal of circulating catecholamines can occur with or without sympathetic neural impulses. Laser-Doppler flowmetry can measure reflexive sympathetically mediated responses of skin microvascular flow and so can detect sympathetic denervation. Spontaneous oscillations in this flow may not depend exclusively on oscillations in the activity of the sympathetic microvascular innervation.

Adult↗
PubMed1986

Plasma catecholamine and hemodynamic responses during isoproterenol infusions in humans.

We infused isoproterenol (ISO) intravenously into 23 subjects (3.5, 7, 14, and 35 ng/kg/min for 20 minutes at each dose) and measured venous plasma concentrations of ISO and the circulatory and plasma norepinephrine (NE) and epinephrine (E) responses. At the lowest dose, venous plasma ISO averaged 48 pg/ml and was associated with increased heart rate (9%; P less than 0.001), cardiac index (20%; P less than 0.001), and stroke volume (9%; P less than 0.02) and decreased total peripheral resistance index (-21%; P less than 0.001). Linear concentration-response relationships were observed between plasma ISO and cardiac index and between plasma ISO and heart rate. Plasma NE increased as a function of plasma ISO (mean increase 81% at 35 ng/kg/min), whereas plasma E was unchanged or decreased. The results indicate that circulatory effects of ISO are detectable in humans at plasma concentrations in the range of physiologic levels of E. Since ISO increases plasma NE, ISO may act presynaptically to enhance NE release from sympathetic nerve terminals and thereby stimulate alpha-adrenoceptors indirectly. ISO does not appear to stimulate secretion from the adrenal medulla or corelease of E with NE from sympathetic nerve endings.

Adult↗
PubMed1986

Cytosolic calcium in platelets of spontaneously hypertensive rats.

To test the hypothesis that an abnormality of the intracellular concentration of ionized calcium, [Ca2+]i, is associated with high blood pressure, we measured [Ca2+]i in the platelets of spontaneously hypertensive (SHR) and Wistar-Kyoto control (WKY) rats using the Quin 2 technique after separation of the platelets in calcium-free medium, during calcium repletion, and upon exposure to agonists which increase platelet [Ca2+]i (thrombin, adenosine diphosphate, serotonin and ionomycin). Despite clear-cut changes in [Ca2+]i during these manipulations, there were no differences between the SHR and WKY rats in baseline levels of [Ca2+]i or in the kinetics of changes in [Ca2+]i. These results do not support the hypothesis that high levels of [Ca2+]i at rest or abnormal kinetics of changes in [Ca2+]i play a pathophysiological role in the hypertension of SHR.

Adenosine Diphosphate↗
PubMed1986

Clinical evaluation of impedance cardiography.

We tested the validity of thoracic impedance cardiography for measuring cardiac output in man by comparing absolute values obtained using the non-invasive impedance method with values obtained using the invasive thermodilution method. We also compared per cent changes in cardiac output using impedance cardiography and thermodilution in response to environmental manipulations including cardiac pacing and intravenous administration of ergonovine, dipyridamole, or isoproterenol. Among 19 patients, absolute values for cardiac output, using the impedance and the thermodilution techniques, agreed well (r = 0.85, P less than 0.001). The per cent change in cardiac output by impedance cardiography was positively correlated with the per cent change by thermodilution for the several manipulations (overall r = 0.87, P less than 0.001). Impedance cardiography does appear, in general, to measure cardiac output and stroke volume validly in man, even in situations where heart rate and stroke volume change in opposite directions.

Blood Pressure↗
PubMed1986

Pulse-wave model of brachial arterial pressure modulation in aging and hypertension.

We apply a pulse-wave theory to a model of the human arm arterial system that predicts the changes in the arterial pressure waveform as it traverses the vasculature (increased pulse pressure, sharper main wave, disappearance of the aortic incisura, and appearance of a diastolic dicrotic wave) and also predicts the observed modulation of the waveform during phenylephrine-induced vasoconstriction and nitroglycerin-induced vasodilation. The model considers the arm arterial system as a tapered, distensible tube that bifurcates and then ends in a loop, with sidebranch networks represented by distributed Windkessels. The model uses verifiable values for realistic parameters. We found that the vertical modulation of the dicrotic wave, in humans, decreased with advancing age and with high blood pressure. The model explained these findings in terms of increasing vascular rigidity and decreasing small vessel vasodilator responsiveness. We noted a significant negative correlation between the arterial level of plasma norepinephrine and the amount of modulation of the dicrotic wave after nitroglycerin among subjects 40 yr old or younger, suggesting a sympathetic neurogenic contribution to the vascular abnormalities observed in relatively young patients with essential hypertension.

Adult↗
PubMed1986

Estimation of intrasynaptic norepinephrine concentrations in humans.

Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.

Adult↗
PubMed1986

Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase.

This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.

Alzheimer Disease↗
PubMed1985

Decreased sympathetic neuronal uptake in idiopathic orthostatic hypotension.

The disappearance rates from plasma of intravenously administered levo-norepinephrine (l-NE), dextro-norepinephrine (d-NE), and isoproterenol (ISO) were measured in normal subjects and in patients with either multiple-system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). The two isomers, l-NE and d-NE, were removed at similar rates in all groups. In normal subjects, the d and l isomers of norepinephrine were cleared more rapidly than ISO. In patients with IOH, the initial rates of disappearance of the NE isomers from plasma were slower than normal and similar to the rate for ISO disappearance. Plasma NE levels, NE clearance, and the apparent release rate of NE into plasma from sympathetic neurons were significantly lower in patients with IOH than in normal subjects. Only the apparent NE secretion rate was related to the baseline plasma NE level. Sympathetic neuronal dysfunction in IOH is attended by a reduction in the clearance of NE. The very low plasma NE levels, in association with the striking reduction in NE clearance, suggest that in IOH there is a marked decrease in NE release. NE clearance and apparent NE secretion rate are normal in MSA, consistent with a central nervous system dysfunction in regulating the sympathetic nervous system. Neuronal uptake of NE in humans does not appear to be stereoselective.

Adult↗
PubMed1985

Evidence for the existence of atrial natriuretic factor-containing neurons in the rat brain.

Immunoreactive atrial natriuretic factor- (ANF-)positive nerve fibers and cell bodies were observed in the preoptic area, hypothalamus, mesencephalon, and pons of rats. In colchicine-treated animals a large number of immunoreactive ANF-positive cell bodies were seen in the organum vasculosum of the lamina terminalis, in several hypothalamic nuclei (e.g. periventricular, arcuate, and ventral premammillary nuclei), and in the dorsolateral tegmental nuclei of the pons. Varicose nerve fibers containing ANF were generally observed in the vicinity of the cells. These findings indicate that a widespread network of ANF-containing neurons is present in the brain.

Animals↗
PubMed1985

On the mechanism of renal vasoconstriction induced by acetylcholine in indomethacin-treated dogs.

Renal arterial infusion of acetylcholine (ACh) in control dogs produced a natriuresis and diuresis and an increase in renal plasma flow (RPF) without a change in glomerular filtration rate (GFR) or in renin secretory rate (RSR). In dogs pretreated with indomethacin (Indo), an inhibitor of prostaglandin synthetase, renal arterial infusion of ACh first produced a rise, then a decline in urine flow, sodium excretion (UNaV) and GFR that was accompanied by a progressive fall in RPF and a progressive rise in RSR. The rise in RSR was potentiated by renal arterial infusion of an alpha-adrenergic receptor blocker, phenoxybenzamine (Phenoxy), and attenuated, but not completely abolished, by beta-adrenergic receptor blockade with propranolol (Prop). Chemical denervation with reserpine alone, or in combination with chronic surgical renal denervation, failed to prevent the fall in RPF, GFR and UNaV and the rise in RSR produced by ACh in Indo-treated dogs. Renal arterial infusion of Phenoxy and intravenous infusion of Prop, alone or in combination with renal arterial infusion of an angiotensin II antagonist, saralasin, failed to maintain the vasodilatory, diuretic and natriuretic effects of ACh in Indo-treated dogs. Elimination of endogenous vasopressin by hypophysectomy also failed to prevent the vasoconstriction induced by ACh in Indo-treated dogs. The results suggest that ACh produced renal vasoconstriction in Indo-treated dogs by mechanism(s) other than an increase in renal adrenergetic activity or an increase in the activity of the renin-angiotensin system. The results also suggest that the vasoconstriction was independent of vasopresin.

Acetylcholine↗
PubMed1985

Measurement of regional neuronal removal of norepinephrine in man.

We describe here and validate an in vivo technique to measure the regional proportionate removal of norepinephrine (NE) by neuronal uptake (Uptake1) in man. The measurement is based on the steady-state arterial and venous concentrations of tritiated NE and tritiated isoproterenol (ISO) during simultaneous infusion of both. The validity of this technique depends on the removal of circulating NE, but not of ISO, by sympathetic nerve endings and on there being no other factor contributing to the net difference in the plasma disappearance of these catecholamines. To test these hypotheses, we compared the removal of NE in the arm with that of ISO in 14 people and the effects of pretreatment with the specific inhibitor of Uptake1, desipramine, in 8 people. In all the subjects a greater percent of NE than of ISO was removed during passage of blood through the forearm (54 vs. 46%, P less than 0.0001). Pretreatment with desipramine decreased significantly the removal of NE to virtually exactly that of ISO. The difference in NE and ISO clearances by arm tissues was therefore completely accounted for by Uptake1. About 15% of infused NE which is removed in the arm is removed by Uptake1. The ability to measure regional Uptake1 should contribute to better understanding of the relationship between circulating levels of plasma NE and sympathetic neural activity and may allow detection of abnormalities of neuronal norepinephrine removal in clinical disease states.

Arm↗
PubMed1985

Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men.

The present study was performed to determine the hemodynamic, hormonal, and natriuretic responses to infusions of dopamine (DA) that reflect physiological as well as pharmacological levels in blood or tissue. In six normal men, DA was infused for 2 h at three fixed dosages (0.03 or 0.1, 0.3, and 3.0 micrograms/kg X min) on three separate occasions, which resulted in increases in mean plasma DA concentrations from basal levels of less than 0.03 ng/ml to 0.69 +/- 0.12, 3.73 +/- 0.40, and 38.4 +/- 3.80 (+/- SE) ng/ml. Mean plasma PRL decreased and DA excretion increased significantly from basal levels during all three DA infusions. Plasma LH decreased and norepinephrine (NE) excretion increased during both the middle and high dose infusions, while sodium excretion, plasma NE, and heart rate increased only during the high dose DA infusion. Basal plasma aldosterone values were low and did not change with DA treatment. PRA, TSH, and FSH also did not change. GH responses were difficult to assess because of the frequency of episodic secretions. Since DA concentrations in hypophysial-portal blood may equal or exceed 1 ng/ml, these results support a role for DA in the acute regulation of PRL, and possibly LH, in normal men. As a natriuretic response occurred only at supraphysiological concentrations of circulating DA, if DA has a physiological role in modulating sodium excretion during normal sodium intake, it must be released from dopaminergic neurons or otherwise locally produced in very high concentrations in the kidney.

Adult↗