Biomedical subjects

R Zimlichman

Publications and source records attributed to R Zimlichman.

At least 91 records · Page 5Linked to original sources

PubMed1987

Angiotensin II increases cytosolic calcium and stimulates catecholamine release in cultured bovine adrenomedullary cells.

In bovine adrenomedullary cells in primary culture, angiotensin II (AII) elicited virtually immediate, dose-related increments in cytosolic calcium [( Ca++]i) measured by the Quin 2 technique and stimulated approximately proportional secretion of norepinephrine, epinephrine, and dopamine measured by liquid chromatography with electrochemical detection. Peak responses of [Ca++]i to AII were similar to peak responses to nicotine or KCl. Pre-treatment with verapamil or washing the cells in calcium-free medium attenuated the stimulatory effect of AII on [Ca++]i. Pre-treatment with nicotine, which temporarily inactivates cholinergic receptor-activated calcium channels, did not affect [Ca++]i responses to AII. The results indicate functional effects of AII on cultured chromaffin cells. The mechanism of cellular activation by AII appears to include increases in [Ca++]i due to opening of membrane calcium channels which may be unrelated to cholinergic receptor-operated calcium channels.

Adrenal Medulla↗

PubMed1987

Effects of ouabain on cytosolic calcium in lymphocytes, platelets and adrenomedullary cells.

It has been suggested that a circulating inhibitor of Na/K ATPase can stimulate natriuresis and cause vasoconstriction in essential hypertension by stimulating transmembrane Na/Ca exchange to produce increased cytosolic concentrations of ionized calcium ([Ca++]i) in renal tubular and arteriolar smooth muscle cells. If this inhibitor affected [Ca++]i in all cell types, then clinical assays for its presence could be applied to easily accessible cells such as blood cells or platelets, and the inhibitor could exert a hormonal action on Ca++-dependent adrenomedullary secretion of catecholamines. We used the Quin 2 technique for measuring [Ca++]i in lymphocytes, platelets and adrenomedullary cells in response to ouabain. Inhibition of Na/K ATPase by ouabain (10(-7) to 10(-3) mol/l enhanced transient [Ca++]i responses during Ca repletion but had no effect on steady-state [Ca++]i in any of the cell lines. Although it is possible that a Na/Ca exchange mechanism may exaggerate transient increases in [Ca++]i during Na/K ATPase inhibition, other mechanisms appear to buffer these acute perturbations of [Ca++]i in lymphocytes, platelets and adrenomedullary cells.

Adrenal Medulla↗

PubMed1987

Effect of ganglion blockade on cerebrospinal fluid norepinephrine.

The source of norepinephrine (NE) in CSF has been unclear. It has been suggested that CSF NE indicates central neural noradrenergic tone and is determined differently from plasma NE. If CSF NE depended specifically on NE release in the CNS, then interference with ganglionic neurotransmission would be expected to decrease plasma NE but not CSF NE. Hypotension caused by ganglionic blockade might be expected to increase CSF NE reflexively. We infused the ganglion blocker, trimethaphan, intravenously into anesthetized dogs and measured the effects on mean arterial blood pressure (MAP) and on cisterna magna CSF levels of NE. The results were compared with those obtained on administration of saline, clonidine (2 micrograms/kg), yohimbine (0.25 mg/kg), or nitroprusside and with those obtained when hypotension during ganglion blockade was prevented by concurrent treatment with phenylephrine. Trimethaphan decreased MAP by 40%, arterial NE by 64%, and CSF NE by 61%. Nitroprusside administered intravenously to produce the same 40% depressor response increased arterial NE by 612% and CSF NE by 155%. Prevention of ganglion blockade-induced hypotension using phenylephrine did not prevent the decrease in CSF NE caused by trimethaphan, and when phenylephrine was discontinued, the resulting hypotension was not associated with increases in CSF NE. The similar decreases in plasma NE and CSF NE during ganglionic blockade, and the abolition of reflexive increases in CSF NE during hypotension in ganglion-blocked subjects, cast doubt on the hypothesis that CSF NE indicates central noradrenergic tone and are consistent instead with at least partial derivation of CSF NE from postganglionic sympathetic nerve endings.

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

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↗

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

Clonidine suppression testing in essential hypertension.

To assess the contribution of sympathetic outflow to blood pressure in patients with essential hypertension, we measured blood pressure and plasma norepinephrine responses to clonidine, an antihypertensive agent that decreases central sympathetic outflow, in 44 patients and in 41 normotensive control subjects of similar age. Among the hypertensive patients, the resting level of plasma norepinephrine was significantly related to the decrease in mean arterial pressure 3 hours after a single oral dose of clonidine 300 micrograms (r = 0.62, p less than 0.001). The magnitude of the depressor response in the patients also was correlated significantly with the decrease in plasma norepinephrine after clonidine (r = 0.60, p less than 0.001). These results suggest that increased sympathetic outflow plays a pathophysiologic role in some patients with essential hypertension.

Adult↗

PubMed1984