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H R Keiser

Publications and source records attributed to H R Keiser.

At least 91 records · Page 5Linked to original sources
PubMed1988

Release of immunoreactive-neuropeptide by rat platelets.

Neuropeptide Y, a potent vasoconstrictor and cardiac depressant, is re-leased from sympathetic nerve endings. Its presence in megakaryocytes suggests this peptide might be stored in platelet granules and released during aggregation. Immunoreactive-neuropeptide Y was measured in platelet rich and platelet poor plasma, and was substantially greater in the former. Addition of collagen to platelets resulted in release of neuropeptide Y which paralleled, in a concentration-dependent manner, the degree of platelet aggregation. Adenosine diphosphate, at concentrations which induce only the first phase of aggregation and not the release reaction, caused only a minor release of neuropeptide Y. These results suggest that platelet release could be a major source of circulating neuropeptide Y and could contribute to hemodynamics of pathophysiological states involving platelet activation.

Adenosine Diphosphate↗
PubMed1988

Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine.

STUDY OBJECTIVE: To determine the efficacy and toxicity of combination chemotherapy in patients with advanced, malignant pheochromocytoma. DESIGN: Nonrandomized, single-arm trial. SETTING: Governmental medical referral center. PATIENTS: Fourteen patients with malignant pheochromocytoma confirmed by histologic tests. All patients had metastatic disease and elevated urinary catecholamine secretion. INTERVENTIONS: After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 body surface area on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days. MEASUREMENTS AND MAIN RESULTS: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete and partial response rate of 57% (median duration, 21 months; range, 7 to more than 34). Complete and partial biochemical responses were seen in 79% of patients (median duration, more than 22 months; range, 6 to more than 35). All responding patients had objective improvement in performance status and blood pressure. Toxicity included expected hematologic, neurologic, and gastrointestinal effects of chemotherapy without serious sequelae. There were four minor hypotensive episodes and one minor hypertensive episode. CONCLUSIONS: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine is effective for advanced malignant pheochromocytoma. Urinary catecholamines are useful to ascertain biochemical response to therapy.

Adolescent↗
PubMed1988

Sympathoadrenomedullary hyper-responsiveness to yohimbine in juvenile spontaneously hypertensive rats.

We examined responses of arterial plasma levels of the sympathetic neurotransmitter, norepinephrine (NE), of the adrenomedullary hormone, epinephrine (E), and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG), after intravenous administration of the alpha-2 adrenoceptor antagonist, yohimbine, in conscious, freely-moving juvenile (4-week old) or mature (12-week old) rats with spontaneous hypertension (SHRs) and their normotensive Wistar-Kyoto (WKY) controls. Mature SHRs and WKY rats had similar levels of plasma catechols at rest, whereas juvenile SHRs had significantly higher levels of NE (400 +/- 109 (SD) vs 233 +/- 62 pg/ml), E (371 +/- 168 vs 148 +/- 67 pg/ml), and DHPG (800 +/- 147 vs 589 +/- 54 pg/ml). After yohimbine, average responses of NE in the juvenile SHRs were more than 5 times, of E more than 7 times, and of DHPG more than 11 times those of the juvenile WKY rats. The responses of plasma catechols to yohimbine were not excessive in mature 12-week old SHRs. The results demonstrate increased sympathoadrenomedullary activity at rest and markedly enhanced sympathoadrenomedullary responsiveness to yohimbine in juvenile but not mature SHRs and are consistent with the hypothesis that early in the development of hypertension in this laboratory animal model there is an abnormal dependence on central neural alpha-2 adrenoceptors as part of an incompletely successful compensatory mechanism for limiting sympathetic outflow.

Adrenal Medulla↗
PubMed1988

Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol.

To elucidate the source and physiological significance of plasma 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as metabolites of noradrenaline (NA), unlabeled and tritium-labeled NA [( 3H]NA) were infused into conscious rats and the formation of labeled and unlabeled DHPG and MHPG examined. Animals were pretreated with clorgyline to determine the effects of inhibiting monoamine oxidase type A (MAO-A), with desipramine to determine the effects of blockade of NA neuronal uptake, or with reserpine to determine the effects of interference with vesicular translocation of NA. Inhibition of neuronal uptake prevented the formation of DHPG from exogenous NA and halved the formation of MHPG, indicating that DHPG is derived from NA metabolized intraneuronally and that MHPG is derived from NA metabolized extraneuronally and from DHPG produced intraneuronally. Blockade of vesicular translocation of NA with reserpine increased DHPG formation from exogenous NA by 300% and MHPG formation by 70%, consistent with enhanced availability of NA in the neuronal cytoplasm for metabolism by MAO-A. About 74% of NA recaptured by sympathetic nerves was estimated to be sequestered into storage vesicles. Endogenous DHPG and MHPG were derived mainly (60-70%) from leakage of NA from storage vesicles and to a smaller extent (30-40%) from NA recaptured after exocytotic release. An increased plasma DHPG to NA ratio with no change in the MHPG to NA ratio during infusions of physiologically active NA demonstrated that changes in plasma MHPG do not necessarily follow changes in DHPG. Consideration of the intra- and extraneuronal sources of plasma DHPG and MHPG, their main derivation from NA directly released into the neuronal cytoplasm and the influences of neuronal uptake and translocation of NA into storage vesicles is essential for the correct interpretation of plasma concentrations of these metabolites in the evaluation of sympathetic nervous function.

Animals↗
PubMed1988

Decreased expression of neuropeptides in malignant paragangliomas: an immunohistochemical study.

Paraffin-embedded sections of 99 human adrenal and extraadrenal paragangliomas were analyzed by the indirect immunoperoxidase technique for the presence of neuron-specific enolase (NSE) and 10 neuropeptides. Each showed diffuse staining for NSE. Most tumors were positive for [Leu5]-enkephalin (76 per cent), [Met5]-enkephalin (75 per cent), somatostatin (67 per cent), and pancreatic polypeptide (51 per cent), followed by vasoactive intestinal polypeptide (VIP) (43 per cent), substance P (31 per cent), ACTH (28 per cent), calcitonin (23 per cent), bombesin (15 per cent), and neurotensin (12 per cent). The neuropeptides paralleled to a large extent those normally found in the sympathetic nervous system. Clinically malignant paragangliomas (n = 25) with proven regional or distant metastases expressed considerably fewer neuropeptides, although the spectrum of those seen remained similar. Malignant paragangliomas contained an average of two neuropeptides per tumor, in contrast to five for the benign tumors (P less than 0.05). Logistic regression analysis of staining results revealed that the paucity of enkephalins, somatostatin, pancreatic polypeptide, and VIP along with the patient's sex was predictive of clinical malignancy. Our results show a definite relationship between expression of neuropeptides and the biologic behavior of these paragangliomas.

Adolescent↗
PubMed1988

Derivation of urinary dopamine from plasma dopa.

1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([3H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [3H]dopa delivered to the kidneys was excreted as [3H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p-aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.

Animals↗
PubMed1988

Metabolic and hemodynamic effects of antihypertensive treatment with ketanserin.

Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 hours), blood pressures measured 12 hours after dosing were not significantly different from those obtained after placebo. However, 2 hours after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (P less than 0.01) and 6 +/- 5 mm Hg (P less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. Except for a slight decline in serum prolactin levels 12 hours after dosing with ketanserin, no changes were observed in pituitary hormone levels, serum testosterone, plasma catecholamines, plasma renin activity, aldosterone, or lipoproteins. Stroke volume, measured 2 hours after dosing, increased with ketanserin therapy, but cardiac output, systemic resistance, and heart rate were unchanged. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24 hours of antihypertensive activity.

Adult↗
PubMed1988

Antihypertensive therapy with ketanserin: metabolic and hemodynamic effects.

Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 h), blood pressures measured 12 h after dosing were not significantly different from those obtained during the placebo period. However, 2 h after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (p less than 0.01) and 6 +/- 5 mm Hg (p less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. At the time of peak antihypertensive activity, plasma renin activity, aldosterone, growth hormone, and prolactin levels were unchanged. Prolactin levels decreased slightly (4.1 +/- 3.0 vs. 3.7 +/- 2.9 ng/ml, p less than 0.05) during ketanserin therapy when measured 12 h after dosing. Other pituitary hormones, serum testosterone, plasma catecholamines, and plasma lipids showed no changes. Heart rate was also unchanged. Stroke volume, measured 2 h after dosing, increased (70 +/- 22 vs. 85 +/- 31 ml, p less than 0.05) with ketanserin therapy, but cardiac output did not change significantly. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24-h antihypertensive activity.

Adult↗
PubMed1988

Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.

We examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE release, during blockade of neuronal uptake of NE (uptake-1) using desipramine, and during intravenous infusion of NE. Healthy subjects had a mean arteriovenous increment in plasma DHPG in the arm (10%, P less than 0.05), whereas sympathectomized patients had a mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P less than 0.05 compared with healthy subjects). Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE and DHPG (r = 0.94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves; (ii) increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent intraneuronal conversion to DHPG; (iii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical information about sympathetic function.

Administration, Oral↗
PubMed1988

Cellular mechanisms of hypertension and atherosclerosis: hypoxia-induced lipid accumulation in cultured vascular smooth muscle cells from the stroke-prone spontaneously hypertensive rat.

The effects of hypoxia on the lipid metabolism of cultured vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSP) were examined. The total cholesterol in smooth muscle cells cultured with hyperlipidaemic serum reached higher levels under hypoxic conditions (3.5% O2, 5.0% CO2, 91.5% N2) than under normal conditions (20% O2, 5.0% CO2, 75% N2). In normal serum, cholesterol increased slightly under hypoxic conditions. No difference was noted in cholesterol synthesis from [14C]-acetic acid. Triglyceride levels in smooth muscle cells cultured with hyperlipidaemic serum and normal serum were significantly increased compared with fetal calf serum. The increase in triglyceride levels was inhibited markedly under hypoxic conditions. Triglyceride synthesis induced by normal serum in the hypoxic cells was decreased compared with control cells. The metabolic rate of triglyceride did not differ between the two. These results indicate that hypoxic conditions accelerate the cellular uptake of cholesterol, an initial step in atherogenesis.

Animals↗
PubMed1987

Naloxone reverses the serotonin dependent hypotensive action of CGP 6085 A.

CGP 6085 A, a specific 5-hydroxytryptamine (5-HT), serotonin uptake inhibitor, is also a potent hypotensive agent. Its depressor effect in the spontaneously hypertensive (SH) rats correlates well with its ability to inhibit serotonin uptake. Here we report that the effects of CGP 6085 A on arterial blood pressure were greatly reduced in rats pretreated with p-chlorophenylalanine (pCl-Phe), a specific depletor of serotonin. Moreover, in rats pretreated with the serotonin antagonist, methysergide, CGP 6085 A did not produce significant hypotension. We also found that centrally administered naloxone reverses the hypotensive effect of CGP 6085 A. These results provide further evidence for the existence of an important serotonin-opioid interaction in the mechanisms of arterial blood regulation in the rat.

Animals↗
PubMed1987

Correlation of changes in cardiac calcium channels with hemodynamics in Syrian hamster cardiomyopathy and heart failure.

We compared hemodynamics with [3H]nitrendipine (calcium channel) binding to cardiac membranes from Bio 14.6 cardiomyopathic Syrian hamsters at 4 and 10 months with their F1B controls. A 50% increase in the number (Bmax) of nitrendipine binding sites (calcium channels) was seen only in the 4 month old myopathic vs controls (Bmax = 468 +/- 11 vs 309 +/- 10 fmol/mg prot with no change in affinity (KD) (KD = .65 +/- .12 vs .75 +/- .14 nM), while no differences in Bmax or KD were seen at 10 months (Bmax = 375 +/- 9 vs 362 +/- 7 fmol/mg prot/KD = .82 +/- .18 vs .89 +/- .17 nM) myopathic vs control respectively. Hemodynamic studies revealed no significant differences in cardiac output, cardiac index, stroke volume, heart rate, mean arterial pressure, peripheral resistance, body weight, heart weight at 4 months, but a significant decrease in peripheral resistance (1120 +/- 360 vs 2080 +/- 240) increase in body weight (118 +/- 2 vs 94 +/- 2 grams) and heart weight (97 +/- 5 vs 78 +/- 2 gms/100 gms body weight) in 10 month myopathic vs control animals. We conclude that the onset of cardiomyopathy at 4 months is associated with a selective increase in calcium channel binding sites and heart failure at 10 months is associated with a relative decrease in these sites.

Animals↗
PubMed1987

Dietary salt intake and the clonidine suppression test.

We studied the effects of one week of dietary salt restriction and one week of salt loading on hemodynamic and plasma catecholamine responses to clonidine. Among 11 outpatients with essential hypertension, urinary sodium excretion averaged 29 mEq/d during salt restriction and 322 mEq/d during salt loading. Among eight inpatient normotensive subjects, urinary sodium excretion averaged 11 mEq/d during salt restriction and 300 mEq/d during salt loading. Three hours after administration of oral clonidine 300 micrograms, the hypertensive patients had an average (+/- one standard deviation) decrease in mean arterial pressure of 20 +/- 6% while receiving the low salt diet and 19 +/- 9% while taking the high salt diet, with decreases in venous plasma norepinephrine (NE) of 61 +/- 15% and 61 +/- 16%, respectively. The normotensive subjects had a decrease in mean arterial pressure of 16 +/- 8% with the low salt diet and 15 +/- 9% with the high salt diet, with decreases in venous plasma NE of 64 +/- 10% and 66 +/- 8%. Thus, in neither group were the percent decreases in plasma NE or in mean arterial pressure after clonidine affected by diet. Short-term, large-magnitude changes in dietary intake of sodium do not affect the sympathetic contribution to blood pressure as indicated by percent responses of plasma NE or of mean arterial pressure to clonidine administration.

Adult↗
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

Alterations in systemic haemodynamics induced by atriopeptin III.

The mechanism of the hypotensive response to the intravenous administration of atriopeptin III was investigated in rats of the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) Okamoto strains. Cardiac performance and the systemic haemodynamic response to acute volume loading were evaluated before and during atriopeptin infusion. Cardiac output was measured by a thermo-dilution technique in conscious rats, and left ventricular pressures with differential (dP/dt) calculations were obtained in anaesthetized animals. Bolus injections followed by a 1-h continuous infusion of atriopeptin caused a progressive decrease in mean arterial pressure (MAP) and cardiac output with no significant change in heart rate. In addition there was a transient decrease, maximal at 5 min, and a subsequent increase in peripheral resistance. Atriopeptin did not alter the maximal cardiac output achieved following acute volume expansion. In the anaesthetized animals, bolus injection with a subsequent 15-min continuous infusion of atriopeptin III significantly reduced left ventricular pressures, dP/dt and mean arterial pressure. Volume expansion fully restored intraventricular pressures and dP/dt while increasing mean arterial pressure toward baseline. We conclude that the steady decrease in mean arterial pressure produced by atriopeptin III is due to a decrease in cardiac output secondary to a fall in stroke volume caused by a lowered filling pressure.

Animals↗
PubMed1987

Dissociation between corticotrophin and catecholamine responses to isoprenaline in humans.

1. The pituitary-adrenocortical, sympathoadrenomedullary and renin-angiotensin-aldosterone systems contribute to circulatory and metabolic homeostasis during stress. One possible site of co-ordination of these systems is the beta-adrenoceptor. 2. To determine whether circulating beta-adrenoceptor agonists can act hormonally to stimulate these systems simultaneously, plasma concentrations of corticotrophin (ACTH), noradrenaline, adrenaline and plasma renin activity were measured during graded intravenous infusions of isoprenaline in 20 people. 3. Administration of isoprenaline caused dose-related increases in noradrenaline (94% at the highest dose) and renin activity (189%), but decreases in ACTH (25%) and adrenaline (20%), findings inconsistent with simultaneous activation of these systems by circulating beta-adrenoceptor agonists.

Adrenocorticotropic Hormone↗
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↗