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Biomedical subjects

R L Zerbe

Publications and source records attributed to R L Zerbe.

At least 19 recordsLinked to original sources
PubMed1995

Antiestrogenic properties of raloxifene.

This 21-day, open-label study evaluated the effects of raloxifene and tamoxifen on estrogen-induced changes in serum levels of anterior pituitary hormones (prolactin, luteinizing hormone, and follicle-stimulating hormone), sex steroids (testosterone, estradiol), and binding globulins [thyroid binding globulin (T3 resin uptake), transcortin, sex steroid binding globulin]. Seventeen healthy male volunteers completed the study after being randomized to one of three treatments: raloxifene, tamoxifen, or placebo. Six subjects received raloxifene (200 mg daily) for 10 days, 6 subjects received tamoxifen [20 mg twice a day (b.i.d.)] for 10 days, and 5 subjects received placebo for 10 days. All subjects received ethinyl estradiol (20 micrograms b.i.d.) for 7 days starting 3 days after initiation of study drug or placebo treatment. Results of the primary analysis of this study indicate that for six of the seven analyzable parameters of estrogen action (excluding luteinizing hormone) raloxifene blunted the estrogen response; this effect was significant only for T3 resin uptake. Tamoxifen administration significantly blunted or reversed the estrogen effect in all six of these parameters. Raloxifene, an effective antiestrogen in animal models, is also antiestrogenic in humans.

Adult↗
PubMed1993

Possible monoamine oxidase inhibitor-serotonin uptake inhibitor interaction: fluoxetine clinical data and preclinical findings.

The primary objective of this article is to review information pertinent to and emphasize the seriousness of a potential adverse monoamine oxidase inhibitor (MAOI)-serotonin uptake inhibitor interaction by considering, within the context of preclinical data, clinical cases in which an MAOI and fluoxetine hydrochloride, a specific serotonin uptake inhibitor, were administered in close temporal proximity. Clinical cases were identified by a review of spontaneous adverse event reports submitted voluntarily to Eli Lilly and Company through its drug surveillance program and by a review of reports of MAOI interactions published in the scientific literature. A discussion of eight selected clinical cases of acute adverse reactions (seven with fatal outcomes; one with a favorable response after cyproheptadine therapy) reported to Eli Lilly and Company in which an MAOI was initiated concurrently or shortly after the discontinuation of fluoxetine and a review of preclinical data suggest a possible role of serotonin and/or serotonin-dopamine interactions in the hypermetabolic state that may occur when a serotonin uptake inhibitor and an MAOI are coadministered, although alternative etiologic processes are possible as well. Data reviewed reinforce the idea that the administration of an MAOI in close temporal proximity to fluoxetine is contraindicated.

Adult↗
PubMed1991

The supraoptic nuclei in vasopressin and hemodynamic responses to hemorrhage in rats.

Cardiovascular and vasopressin (AVP) responses to hemorrhage were studied in rats with lesions of the hypothalamic supraoptic nuclei (SONL). Bleeding caused hypotension and increase in heart rate (HR) and AVP. SONL rats failed to fully recover from bleeding as compared to normal rats. Plasma AVP in SONL rats was in the normal in basal conditions, but failed to increase to levels attained in normal rats throughout the post-hemorrhage period. These data suggest that the supraoptic nuclei are the primary regulatory sites for AVP release in response to hemorrhage and that lack of adequate AVP release significantly retards blood pressure recovery after bleeding.

Animals↗
PubMed1991

The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects.

The rise in plasma vasopressin produced by infusion of hypertonic saline varies widely among healthy adults. To determine if these interindividual differences are reproducible, we used linear regression to analyze the relationship of plasma vasopressin to plasma osmolality during repeat hypertonic saline infusion in seven normal subjects. The results confirmed that the slope or sensitivity of the relationship differed widely between subjects (0.12 to 1.66 pg/ml/mOsm/kg) and revealed that these differences were highly reproducible. (r = 0.94 on repeat testing). The individual values for osmotic threshold were less variable (280 to 288 mOsm/kg) as well as less clearly reproducible (r = 0.61). To determine whether these differences are genetically influenced, we compared the vasopressin osmolality relationships within seven monozygotic and six dizygotic twin pairs. We found that the threshold and sensitivity values correlated significantly within monozygotes (r = 0.95 and 0.95) but not within dizygotes (r = 0.34 and 0.21). When the osmoregulation of thirst was similarly evaluated, the individual relationships were as variable as for plasma vasopressin, but only the threshold values in monozygotes correlated significantly (r = 0.92). In 80 healthy adults, the frequency distributions of the osmotic threshold and sensitivity of the vasopressin responses were essentially normal. We conclude that the sensitivity for vasopressin secretion as well as the osmotic thresholds for thirst and vasopressin demonstrate significant polygenetic variance among healthy adults.

Adult↗
PubMed1989

Effect of morphine on the hemodynamic and neuroendocrine responses to hemorrhage in conscious rats.

We have previously reported that analgesic doses of morphine accelerate mortality of rats exposed to hemorrhage (Feuerstein and Sirén: Circ Shock 19:293-300, 1986). To study the potential mechanisms involved in this phenomenon, rats were chronically implanted with catheters in the femoral vessels and morphine (1.5 or 5 mg/kg) was administered 30 min or 24 hr after bleeding (8.5 ml/300 g over 5 min) while arterial blood pressure and heart rate were continuously monitored. Furthermore, the effect of morphine (5 mg/kg) on cardiac output (CO) response to hemorrhage was studied in rats chronically equipped with a minithermistor for CO monitoring by a thermodilution technique. In addition, plasma catecholamines (HPLC), plasma renin activity (PRA, RIA), vasopressin (RIA), pH, and blood gases were also determined. Morphine administration 30 min after hemorrhage produced a pressor response and tachycardia which were in marked contrast to its depressor effect in intact rats. Morphine elevated PRA and epinephrine but not vasopressin, while blood pH and gases showed no consistent change as compared to saline-treated hemorrhaged rats. Morphine given after the bleeding resulted in enhanced cardiac depression in response to a second bleed of 2 ml/300 g. Our data suggest that activation of pressor mechanisms by morphine during hypovolemic hypotension might enhance vasoconstriction in essential organs, depress cardiac function, and further reduce effective tissue perfusion.

Animals↗
PubMed1987

CSF neuropeptides in euthymic bipolar patients and controls.

Levels of vasopressin, somatostatin, neurotensin, vasoactive intestinal peptide, corticotrophin-releasing factor and adrenocorticotrophin in CSF were determined in lithium-treated and unmedicated euthymic bipolar patients and controls, in a search for a trait marker in affective disorder. No group differences in levels of these peptides were found. Highly significant positive correlations were found among these peptides (with the exception of neurotensin), suggesting that their presence in CSF is functionally significant, as opposed to the result of random diffusion from the interstitial space of the brain.

Adrenocorticotropic Hormone↗
PubMed1987

Kappa agonist-induced diuresis: evidence for stereoselectivity, strain differences, independence of hydration variables and a result of decreased plasma vasopressin levels.

Marked diuresis has previously been reported after administration of kappa opioid agonists. The present study shows that this effect is stereospecific; MR-2034 markedly increased urinary output over the dose range 0.08 to 1.25 mg/kg, whereas the opposite isomer, MR-2035, was markedly less potent. Bremazocine increased urinary output in Long-Evans hooded and Sprague-Dawley albino rats as well as lean and fatty Zucker rats. In the lean Zucker and the albino rats, bremazocine produced an inverted U-shaped diuretic dose-effect curve, an effect characteristic of kappa agonists with mu agonist activity. This pattern was not seen with the fatty Zucker rats or the Long-Evans hooded rats. The full kappa agonists bremazocine, ethylketazocine and U-50,488 increased urinary output under three different conditions of hydration: water loaded, normal hydration and water deprived. In contrast, the partial kappa agonists reliably only increase urinary output under the normal hydration condition. The diuretic effects of full and partial kappa agonists correlated with plasma vasopressin levels in water-deprived rats. The full kappa agonists (ethylketazocine, U-50,488, tifluadom and MR-2034) suppressed plasma vasopressin levels below the threshold of detectability of the radioimmunoassay, whereas the partial kappa agonists (nalorphine and butorphanol) suppressed vasopressin levels compared with control values but did not have the efficacy of the full kappa agonists. All these results support the hypothesis that kappa agonists produce their diuretic effect by suppression of plasma vasopressin levels.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Safety of fluoxetine in the treatment of obesity.

Observations related to the safety of fluoxetine in the treatment of obese patients are reviewed. The adverse event profile in obese patients, though differing slightly from that seen in depressed patients, was similar in that events observed were generally mild and well tolerated. Other than rash, no potentially serious adverse events believed to be related to fluoxetine were observed. Special evaluations of pharmacokinetics, psychomotor impairment, cardiac effects, phospholipidosis and addiction potential have identified no major problems in these areas. It is concluded that fluoxetine use for the treatment of obesity should carry with it minimal risk.

Drug Interactions↗
PubMed1986

The effect of hypertonic saline administration or stalk transection on histamine and histamine N-methyltransferase in the rat posterior pituitary.

There is evidence to suggest that histamine is a neurotransmitter in the CNS and functions in the regulation of arg-vasopressin (AVP) secretion. The posterior pituitary contains high levels of histamine and histamine N-methyltransferase (HNMT). Therefore, posterior pituitary histamine could also modulate the release of AVP. Paralleling the effect on AVP levels, the concentration of histamine in the rat posterior pituitary decreased from 18.8 +/- 2.7 ng/mg protein (x +/- SEM) to 12.9 +/- 1.9 ng/mg protein following 2 days of 2% (w/v) hypertonic saline administration and to 11.5 +/- 0.9 ng/mg protein with 7 days of treatment. Conversely, posterior pituitary HNMT activity was significantly elevated after hypertonic saline administration. Pituitary stalk transection did not reduce the concentration of histamine in the rat posterior pituitary although HNMT activity was reduced from 18.8 +/- 0.82 munits/gland to 9.22 +/- 1.56 munits/gland (x +/- SEM). These results indicate that histamine released from posterior pituitary mast cells could facilitate AVP release as part of the overall mechanism for osmotic stimulation of AVP secretion and support the concept that most posterior pituitary histamine is not neuronally derived from the brain. HNMT, on the other hand, may be contained in neurons disrupted by stalk section.

Animals↗
PubMed1986

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.

Animals↗
PubMed1985

Benzodiazepine receptors modulate circulating plasma vasopressin concentration.

Chlordiazepoxide pretreatment decreased basal levels of plasma arginine-vasopressin (AVP) and attenuated picrotoxin-induced increases in plasma AVP and blood pressure compared to saline-pretreated spinal animals. Prior administration of RO 15-1788 blocked the effects of chlordiazepoxide on basal plasma AVP as well as picrotoxin-evoked changes in plasma AVP and blood pressure. Thus, interactions at the benzodiazepine receptor may influence basal and evoked changes in plasma AVP concentration.

Animals↗
PubMed1985

Catecholaminergic activity of the baroreceptor areas of the brain in response to bilateral dorsolateral transection of medulla oblongata in rats.

Central catecholaminergic activity was studied by measurement of norepinephrine (NE), epinephrine (EPI), their metabolites: total 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol in brain nuclei in response to bilateral dorsomedullary knife-cut (DMK-cut) in rats. In saline-pretreated conscious rats DMK-cut caused a marked hypertension, tachycardia and increases in plasma NE, EPI and vasopressin. Chlorisondamine (CHL) prevented the rise in plasma catecholamines and the tachycardia but failed to prevent the hypertension and the increment in plasma vasopressin. DMK-cut decreased NE and EPI in the nucleus tractus solitari (NTS) and A2 area; there were no catecholamine changes in A1 area or the periventricular nucleus but an increase in the paraventricular nucleus (PVN), the latter effect reversed by CHL. CHL alone or combined with DMK-cut had no effect on catecholamine concentrations in NTS-A2 area but lowered MHPG content. It is suggested that DMK-cut decreases the activity of the catecholaminergic system originating in A1 and terminating in PVN, where it causes catecholamine accumulation and may be involved in vasopressin release and thereby contribute to hypertension. In NTS-A2 area, however, the DMK-cut appears to increase catecholaminergic activity since catecholamines are depleted. Central effects of DMK-cut differ from those of ganglionic blockade-induced inhibition of the baroflex presumably due to sectioning of other pathways in addition to the primary baroreceptor input.

Animals↗
PubMed1985

Cardiovascular effects of centrally administered vasopressin in conscious and anesthetized rats.

Intracerebroventricular (ICV) injections of arginine vasopressin (AVP) in doses of 0.015 nmoles and 0.15 nmoles produced a fall in mean actual pressure heart rate and respiration in pentobarbital anesthetized rats. The changes in mean arterial pressure and respiration after the higher dose were significantly different from saline injection. In contrast, the same doses of AVP given to conscious animals increased both blood pressure and heart rate. Following the 0.15 nmole dose, there was a marked and significant rise in plasma norepinephrine and epinephrine, indicating that activation of the sympathetic nervous system was, at least in part, responsible for the rise in blood pressure. Plasma vasopressin increased by less than 10 pg/ml following injection. Similar doses of a vasopressin pressor antagonist had no significant effect on mean arterial pressure or heart rate. These results indicate that ICV injection of vasopressin has different effects on blood pressure, depending on the presence or absence of anesthesia: depressor responses in the anesthetized animal and pressor responses in the unanesthetized animal.

Anesthesia↗
PubMed1985

Studies of the central cardiovascular effects of vasopressin.

Three approaches to the evaluation of the central cardiovascular effects of vasopressin are briefly reviewed. These include assessment of cardiovascular regulation in Brattleboro rats, cardiovascular responses to central nervous system injections of vasopressin, and changes in central nervous system vasopressin content in spontaneous and induced hypertension. The studies indicate that vasopressin could participate in baroregulation by actions within the central nervous system, but they fail to clearly define the importance of vasopressin, if any, in this capacity.

Anesthesia, General↗
PubMed1985

Hemorrhagic shock and the central vasopressin and opioid peptide system of rats.

The effect of hemorrhagic shock (40% of blood vol) on the distribution of immunoreactive dynorphin A (Dyn A-IR), [Arg8]vasopressin (AVP-IR), and [Leu5]enkephalin (LE-IR) in the pituitary and brain nuclei was studied in the conscious rat. At 24 h after hemorrhage, the neurointermediate lobe (NIL) showed a reduction in Dyn A-IR (52%) and AVP-IR (32%) and an increase in LE-IR (72%); at this time, the anterior lobe also showed decreased Dyn A-IR (50%) and increased LE-IR (210%). Dyn A-IR, but not LE-IR, was also significantly depleted in some forebrain nuclei in all experimental groups as compared with intact controls, whereas Dyn A-IR in the hypothalamic ventromedial nucleus was elevated only in the sham-control rats. AVP-IR was elevated in the supraoptic nucleus and median eminence (200 and 31%, respectively) 2 and 24 h after bleeding, although plasma AVP returned to normal levels. These data indicate that stress and hypovolemic hypotension produce site and time-dependent change in distribution of dynorphins, AVP, and LE in the central nervous system.

Animals↗
PubMed1985

Regulation of plasma vasopressin in insulin-dependent diabetes mellitus.

Patients with uncontrolled insulin-dependent diabetes mellitus have elevations in plasma vasopressin that cannot be accounted for totally by recognized osmotic or nonosmotic stimuli. To investigate the possibility that regulation of vasopressin secretion is abnormal in this disease, we characterized the vasopressin response to osmotic and hemodynamic stimuli in five uncomplicated, well-controlled insulin-dependent diabetics, and compared the results with those found in nondiabetic volunteers. During osmotic stimulation with hypertonic saline, plasma vasopressin increased in close linear correlation with plasma osmolality or sodium in both groups. However, in the diabetics, the lines describing the relationships between plasma sodium and vasopressin were shifted significantly to the left of normal, suggesting resetting of the osmostat. This shift was not due to abnormal stimulation by hyperglycemia, because increasing plasma glucose and osmolality by intravenous infusion of hypertonic dextrose produced no increase in plasma vasopressin in diabetics or normals. Tilt tests produced a slightly exaggerated increase in plasma vasopressin in diabetics, but their basal and upright pulse rate, blood pressure, plasma renin activity, norepinephrine, and hematocrit were all normal. The results indicate that in diabetic patients the osmoreceptor for osmotic regulation of vasopressin secretion is reset in such a way that higher plasma vasopressin levels are observed at comparable levels of plasma sodium. The exact cause and consequence of this abnormality remain to be determined.

Blood Pressure↗