Papers by Joseph Verbalis
PubMed, 1995
Plasma oxytocin (OT) levels are strongly correlated with inhibition of ingestion in many models o... more Plasma oxytocin (OT) levels are strongly correlated with inhibition of ingestion in many models of stimulated food and NaCl intake in rats, but peripheral administration of OT or OT antagonists has little or no effect on these behaviors. These findings led us to propose that central OT secretion from parvocellular neurons occurring in parallel with pituitary secretion from magnocellular neurons acts to inhibit ingestion of both food and salt. Multiple lines of evidence now support this hypothesis: 1) intracerebroventricular (icv) OT administration inhibits food intake in fasted rats and NaCl intake in hypovolemic rats; 2) icv administration of OT-receptor antagonists significantly blunts the effects of anorexigenic agents on food intake and the action of naloxone to inhibit hypovolemia-induced intake of NaCl, but not water; 3) most treatments that inhibit food and/or NaCl intake stimulate expression of c-fos in parvocellular as well as magnocellular OT neurons, indicating simultaneous activation of both centrally-projecting and pituitary-projecting OT neurons; 4) icv treatment with cytotoxic conjugates of ricin A and OT to disable cells bearing OT receptors leads to a disinhibition of NaCl intake similar to that produced by OT antagonists; 5) administration of ethanol, a well known inhibitor of OT secretion, produces effects on stimulated food and NaCl intake in rats analogous to those produced by OT-antagonists and ricin-OT conjugates. In conjunction with studies demonstrating natriuretic effects of circulating OT, these results therefore support the concept of coordinated central and peripheral OT secretion as a mechanism for regulating body solute homeostasis in rats. These phenomena will be used as a framework to discuss and critically evaluate the criteria that are both necessary and sufficient to firmly establish behavioral and physiological functions of centrally-secreted peptides such as OT.
Humana Press eBooks, 2008
Appetite, Jun 1, 1989
Because recent studies have shown that cholecystokinin (CCK) and gastric distention (GD) stimulat... more Because recent studies have shown that cholecystokinin (CCK) and gastric distention (GD) stimulate pituitary secretion of oxytocin (OT) in rats, we studied OT and vasopressin (AVP) secretion in response to these stimuli in 14 human subjects. Neither AVP nor OT increased in response to GD produced by ingestion of a large meal. However, a dose-related increase in plasma AVP levels occurred in response to administration of graded doses of CCK (threshold dose 0.05 pg/kg), and plasma AVP levels after CCK were correlated with the presence of visceral symptoms such as abdominal cramps, nausea, and emesis (r=O.61, p <O.OOl). These results identify central neural pathways that are activated by CCK but not by normal satiety in man, and suggest that these likely include brainstem emetic centers causing AVP secretion.
Endocrinology, Feb 1, 1996
At the end of pregnancy, the myometrium becomes extremely sensitive to oxytocin (OT) as result of... more At the end of pregnancy, the myometrium becomes extremely sensitive to oxytocin (OT) as result of a dramatic increase in the number of OT receptors (OTR), indicating an important role for OTR in the process of labor. There are no studies in sheep in which the physical properties and histological distribution of OTR are evaluated in relation to parturition. Also, no studies have been performed in any species to simultaneously examine the distribution of OTR at the messenger RNA (mRNA) as well as the protein levels in the same tissues and correlate those changes with the patterns of myometrial activity that occur at labor. In the present studies, we have used a polyclonal anti-OTR antibody and Western blot analysis to determine the apparent molecular mass of ovine OTR in late pregnant sheep myometrium and endometrium. We also examined the distribution of OTR mR.NA and protein expression in the intact myometrium and endometrium and in individual cultured cells using in situ hybridization and immunocytochemistry. The expression of OTR and its mRNA has been correlated with the patterns of activity observed in the pregnant sheep myometrium. Western blot analysis of myome
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Dec 1, 1992
In several models of salt appetite in the rat, stimulated NaCl intake can be severely blunted by ... more In several models of salt appetite in the rat, stimulated NaCl intake can be severely blunted by treatments associated with pituitary release of oxytocin (OT). Central administration of the potent dipsogen angiotensin II (ANG II) is known to elicit a limited salt appetite as well as thirst, but it has also been reported to stimulate pituitary OT secretion. These results suggest the possibility that the expression of ANG II-induced salt appetite in rats may be inhibited by a simultaneous central release of OT in response to this stimulus. To investigate this possibility, rats were given intracerebroventricular injections of OT-receptor antagonists before administration of 5 ng ANG II intracerebroventricularly in a 1-h two-bottle (water and 0.3 M NaCl) drinking test. This pretreatment resulted in a three- to fourfold potentiation of ANG II-induced saline ingestion, which was most prominent during the first 15 min of the test. OT-receptor antagonism did not, however, interfere with the dipsogenic properties of ANG II, nor did it stimulate saline ingestion alone in the absence of ANG II. Immunocytochemical studies demonstrated that central administration of ANG II at this dose caused pronounced c-fos expression in hypothalamic magnocellular OT and vasopressin neurons and also in OT neurons in parvocellular subdivisions of the paraventricular nucleus. These results therefore demonstrate that central administration of small doses of ANG II activates both magnocellular and parvocellular OT neurons in rats and indicate that some of the activated central OT pathway(s) may mediate an inhibitory effect that limits the salt ingestion induced by this treatment.
Current Opinion in Endocrinology & Diabetes, Apr 1, 1995
Neuroscience, Jun 1, 1997
IUPHAR/BPS Guide to Pharmacology CITE
Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [94]) are... more Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [94]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [69].
European Journal of Endocrinology
The articles are identical except for minor stylistic and spelling differences in keeping with ea... more The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. A citation specific to one of the journals may be used when citing this article. Abstract 'What's in a name? That which we call a rose/By any other name would smell as sweet.' (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, nephrology and pediatric societies now proposes changing the name of 'diabetes insipidus' to 'arginine vasopressin deficiency (AVP-D)' for central etiologies and 'arginine vasopressin resistance (AVP-R)' for nephrogenic etiologies. This editorial provides both the historical context and the rationale for this proposed name change. Reasons for changing a disease name Understanding of disease processes is a dynamic field, with rapidly evolving concepts of pathophysiology based on emerging molecular and genetic data. Consequently, a newer understanding of the pathophysiology is one of the major reasons for renaming diseases. In endocrinology, appreciation of hyperprolactinemia as the common pathophysiology underlying many different clinical situations causing galactorrhea and amenorrhea led to the effective abandonment of many previous eponymous names for these conditions such as Chiari-Frommel
Frontiers in Nutrition, 2021
Introduction Hyponatremia often occurs during the practice of endurance sports. We evaluated the ... more Introduction Hyponatremia often occurs during the practice of endurance sports. We evaluated the impact on hyponatremia of the hydration recommendations of the Third International Exercise-Associated Hyponatremia Consensus Development Conference 2015 (3IE-AHCD) during the 2017 Gran Trail de Peñalara marathon (GTP) and the Vitoria Gasteiz Ironman triathlon (VGI). Methods Prospective study of GTP and VGI athletes participating in four information sessions in the months prior to the events, to explain that hydration should only be according to their level of thirst, per the recommendations of the 3IE-AHCD. Consenting event finishers were included in final analysis. Pre- and post-race anthropometric and biochemical parameters were compared. Results Thirty-six GTP (33 male) and 94 VGI (88 male) finishers were evaluated. GTP race median fluid intake was 800 ml/h, with 900 ml/h in the VGI race. 83.3% GTPfin and 77.6% VGIfin remained eunatremic (blood sodium 135–145 mmol/L). Only 1/36 GTP a...
Journal of the American Society of Nephrology, 2019
The Journal of Neuroscience, 1996
Axonal injury to hypothalamic magnocellular vasopressin (AVP) and oxytocin (OT) neurons causes de... more Axonal injury to hypothalamic magnocellular vasopressin (AVP) and oxytocin (OT) neurons causes degeneration of a substantial subpopulation of these neurons. In this study, we investigated the influence of osmolality on this injury-induced cell death. Normonatremic, chronically hypernatremic, and chronically hyponatremic rats received pituitary stalk compression (SC), which causes degeneration of AVP and OT terminals in the neurohypophysis. Twenty-one days after SC, rats were perfused and hypothalami were serially sectioned and alternately stained for AVP-neurophysin and OT- neurophysin immunoreactivities. Normonatremic and hypernatremic rats exhibited a triphasic pattern of water intake after SC, with peak intakes 3 times higher than those exhibited by sham-operated normonatremic rats. In contrast, hyponatremic SC rats exhibited peak water intakes of 600 ml/24 hr, approximately 9–10 times the water intakes of sham-operated normonatremic rats. In normonatremic rats, SC caused degener...
Proceedings of the National Academy of Sciences, 1990
A monoclonal antibody (mAb L6) to a small-cell lung carcinoma surface antigen recognizes a common... more A monoclonal antibody (mAb L6) to a small-cell lung carcinoma surface antigen recognizes a common epitope of vasopressin-neurophysin and oxytocin-neurophysin in hypothalamic nuclei. We now report on the identification of a neurophysin-like precursor in human lung carcinoma (LX-1) cell membrane. mAb L6 immunoaffinity chromatography of solubilized membranes resulted in a single band of approximately 45 kDa. Western blot analysis demonstrated immunoreactivity of this band with mAb L6, anti-vasopressin, and an antibody to the vasopressin precursor, pro-pressophysin. N-terminal sequencing of this band demonstrated a 21-amino acid homology with the N terminus of human pro-pressophysin, and substitution of a Cys33 residue in the tumor antigen with Arg33. Absence of immunoreactivity with the antibodies described above in cytosolic extracts and culture medium suggests nonsecretion of processed or intact pro-pressophysin-like peptide. Northern analysis of LX-1 mRNA with a 30-mer to the C term...
Journal of the American College of Cardiology, 1985
MDL 17,043, an agent with both inotropic and vasodilator properties, was evaluated in the treatme... more MDL 17,043, an agent with both inotropic and vasodilator properties, was evaluated in the treatment of chronic severe heart failure. The early and late hemodynamic, hormonal, pharmacokinftic and clinical responses to oral MDL 17,043 were studied in 20 patients. MDL 17,043 acutely increased cardiac output from 3.6 ± 0.9 to 4.6 ± 1.0 liters/min (+28%, P < 0.001) and decreased mean pulmonary artery wedge pressure from 24 ± 8 to 13 ± 8 mm Hg (-46%, P < 0.001), mean right atrial pressure from 10 ± 5 to 4 ± 4 mm Hg (-60%, P < 0.001) and mean arterial pressure from 78 ± 9 to 70 ± 11 mm Hg (-10%, P < 0.001). Hemodynamic improvement was sustained for 8 hours. Plasma renin activity tended to increase (0.10 < P > 0.05), plasma norepinephrine tended to decrease (0.10 < P > 0.05) and arginine vasopressin did not show any directional change. Elimination halt-life for MDL 17,043 was llpproximately 20 hours. Inotropic therapy attempts to counteract directly the contractile deficit in myocardial failure. Such theoretic appeal has led to the development of several potential agents for the treatment of heart failure (1-3). One such compound is MOL 17,043 (4). This drug possesses vasodilating as well as inotropic properties (5). The exact mechanism for these actions has not been defined, although this agent is known to be a potent phosphodiesterase inhibitor (6). In previous studies from our laboratory (4,7), we have shown intravenous and oral MOL 17,043 to produce a dramatic short-From the Divisions of Cardiology and Endocrinology,
Journal of Pharmacology and Experimental Therapeutics, 2003
Synthetic agonists of the peroxisomal proliferator activated receptor, subtype γ (PPAR-γ) are hig... more Synthetic agonists of the peroxisomal proliferator activated receptor, subtype γ (PPAR-γ) are highly beneficial in the treatment of Type II diabetes. However, they are also associated with fluid retention and edema, potentially serious side effects of unknown origin. These studies were designed to test the hypothesis that rosiglitazone (RGZ, PPAR-γ agonist) may activate sodium and water reabsorptive processes in the kidney possibly in response to a drop in mean arterial blood pressure (MAP), as well as directly through PPAR-γ. Targeted proteomics of the major renal sodium and water transporters and channel proteins was used to identify potentially regulated sites of renal sodium and water reabsorption. RGZ (47 or 94 mg/kg diet) was fed to male, Sprague-Dawley rats (∼270g) for 3 days. MAP, measured by radiotelemetry, was decreased significantly in rats fed either level of RGZ, relative to control rats. Delta MAP from baseline was-3.2 ± 1.2 mm Hg in rats fed high-dose RGZ versus +3.4 ± 0.8 for rats fed control diet. RGZ did not affect feed or water intake, but rats treated with high-dose RGZ had decreased urine volume (by 22%), sodium excretion (44%), kidney weight (9%), and creatinine clearance (35%). RGZ increased whole kidney protein abundance of the α-1 subunit of Na-K-ATPase, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the sodium hydrogen exchanger, (NHE3), the aquaporins 2 and 3, and endothelial nitric oxide synthase (eNOS). We conclude that both increases in renal tubule transporter abundances and a decrease in glomerular filtration rate, likely contribute to the RGZinduced sodium retention.
Endocrinology, 1995
Partial complementary DNAs of an oxytocin (OT) receptor were cloned from rat brain and uterus. Th... more Partial complementary DNAs of an oxytocin (OT) receptor were cloned from rat brain and uterus. The complementary DNAs encoded for the same amino acid sequence, which showed a high degree of homology with the human and porcine uterine OT receptors, except for a region in the third intracellular loop. Antibodies were raised against nonoverlapping sequences of the third intracellular loop of this rat OT receptor. Using these antisera, OT receptor expression was demonstrated in the brain, pituitary, mammary gland, and uterus by immunocytochemistry. In the brain, several areas including the ventromedial hypothalamus, the bed nucleus of the stria terminalis, the ventral pallidum, the paraventricular nucleus, and the dorsal part of the supraoptic nucleus, demonstrated OT-receptor immunoreactivity. However, no immunoreactivity was detected in two areas of the brain known to contain dense OT-binding sites by receptor autoradiography studies: the ventral hippocampus and the central nucleus of the amygdala. In the pituitary, both the anterior and posterior lobes were positive for OT receptor immunoreactivity, whereas the intermediate lobe was negative. These results demonstrate that the same receptor type is expressed in both peripheral OT target tissues and the brain, and also suggest the possibility that a different OT receptor subtype may be present in some areas of the brain.
Brain Research, 1992
Degeneration of magnocellular nerve terminals in the neurohypophysis was induced by compressing t... more Degeneration of magnocellular nerve terminals in the neurohypophysis was induced by compressing the pituitary stalk of anesthetized rats for 30 s using a triangle-shaped wire. Immediately after stalk compression (SC), rats exhibited markedly increased water intake characteristic of diabetes insipidus, followed by a triphasic pattern of fluid intake. In SC rats, arginine vasopressin (AVP) and oxytocin (OT) contents of the neurointermediate lobe (NIL) of the pituitary gland were significantly reduced to ~2.5% and ~10% of sham-operated controls, respectively. In contrast, OT, but not AVP, content of the stalk-median eminence (SME) of SC rats was significantly increased. Histological examination of the pituitaries showed substantial degeneration of the neural lobe with very scarce AVP-neurophysin and OT-neurophysin immunoreactivity, while both the anterior and the intermediate lobes appeared to be intact. Plasma AVP and OT responses to infusion of hypertonic NaC1 were significantly blunted in SC rats compared to sham-operated controls. However, two days after surgery the secretory patterns of LH in SC rats were similar to those in the controls. These results indicate that controlled compression of the pituitary stalk results in selective degeneration of the neural lobe without causing permanent ischemic damage to the anterior pituitary, and produces marked sustained functional deficits in pituitary AVP and OT secretion. Consequently, SC provides an alternative means to achieve selective neurolobectomy in rats.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2004
Central injection of ANG II has been proposed to have dual effects on salt appetite including a d... more Central injection of ANG II has been proposed to have dual effects on salt appetite including a direct stimulatory effect and an indirect inhibitory effect through an activation of central oxytocinergic neurons. The inhibition was demonstrated by pretreating rats with central ornithine vasotocin (OVT; oxytocin antagonist) 30 min before a central ANG II injection. The OVT pretreatment produced a large increase in ANG II-induced saline intake. The present paper reports a failure to replicate that influential experiment. However, we also report for the first time that OVT by itself: 1) provokes drinking of both water and saline solution with a latency almost as short as that produced by ANG II; 2) produces a mild pressor response; and 3) increases c-Fos expression in the organum vasculosum laminae terminalis (OVLT) and the median preoptic nucleus (MnPO). Oxytocin activity may provide an inhibitory control of drinking responses as has been suggested, but the inhibition is tonic and includes both water and saline drinking. Inhibition of this tonic activity may stimulate drinking by increasing neural activity in the OVLT and MnPO.
Kidney International, 2004
Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 con... more Acute endotoxemia in rats induces down-regulation of V2 vasopressin receptors and aquaporin-2 content in the kidney medulla. Background. Endotoxemia can lead to fluid metabolism alterations despite unchanged or elevated plasma vasopressin (VP) levels, suggesting a refractoriness of the kidney to the effect of the peptide. To test this hypothesis, we examined the effect of lipopolysaccharide (LPS) injection on the expression of V2 receptors and aquaporin-2 in the kidney. Methods. Plasma VP and urine osmolality, and binding of [ 3 H]VP to kidney membranes, Western blot, and immunohistochemical analysis of aquaporin-2, in situ hybridization for V2 VP receptors and cytokines mRNAs were measured in the kidney 3 to 24 hours after LPS injection, 250 lg/100 g, intraperitoneally. Results. LPS injection caused prolonged decreases in urine osmolality (up to 24 hours) without significant changes in plasma levels of sodium or VP. This was associated with marked decreases in V2 VP receptor mRNA and VP receptor number in the kidney, which were evident for up to 12 hours after LPS injection. Aquaporin-2 in kidney inner medulla was also reduced by about 50%. LPS induced interleukin (IL)-1b in the kidney medulla by 3 hours, reached maximum at 6 hours, and started to decline by 12 hours, while it increased IL-6 mRNA significantly only at 3 hours. Interleukin mRNA expression was absent in kidneys of control rats. In vitro incubation of kidney medulla slices with IL-1b reduced VP binding. Conclusion. The inflammatory response to acute endotoxemia down regulates V2 VP receptors and aquaporin-2 of the kidney inner medulla resulting in prolonged impairment of the renal capacity to concentrate urine.
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Papers by Joseph Verbalis