A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: changes in emotion- and stress-related eating, food cravings and appetite.

Anti-obesity medication may help people maintain diet-induced reductions in appetite. The present exploratory analysis assessed the effects of lorcaserin on changes at 24 weeks post-randomization in emotion- and stress-related eating, food cravings and other measures of appetite (i.e. binge eating, cognitive restraint, disinhibition, hunger, preoccupation with eating and fullness). The parent study investigated the efficacy of combined lorcaserin and behavioural treatment in facilitating weight loss maintenance (WLM) in 137 adults (mean age = 46.1 years, 86.1% female, 68.6% black) who had lost ≥5% of initial weight during a 14-week, low-calorie diet (LCD) run-in. Participants were randomly assigned to lorcaserin or placebo and were provided with group WLM counselling sessions. Emotion- and stress-related eating, food cravings and appetite were measured at the start of the LCD (week -14), randomization (0) and week 24. From randomization, lorcaserin-treated participants had significantly greater improvements in emotion- and stress-related eating compared to placebo-treated participants (P = 0.04). However, groups did not differ significantly after randomization in changes in the frequency of food cravings, binge eating or other measures of appetite (Ps > 0.05). Compared to placebo, lorcaserin may improve emotion- and stress-related eating.

Excitotoxin paraventricular nucleus lesions: stress and endocrine reactivity and oxytocin mRNA levels.

Electrolytic lesion of the paraventricular nucleus (PVN) of the hypothalamus blocks the tachycardia response to stress. The current study examined the effects of chemical lesion of PVN parvocellular neurons on the cardiovascular and endocrine responses to stress and on the content of hypothalamic oxytocin (OT) mRNA levels. Acute footshock stress increased heart rate in both ibotenic acid lesion and control groups of animals; however, the tachycardia was significantly lower in animals with a PVN lesion than the controls. Lesion of the PVN also attenuated the increase in plasma OT induced by stress, 4-fold in the lesion group versus 20-fold for the controls. There was not a generalized decrease in hormonal responsiveness since the OT response to an osmotic challenge was exaggerated in the lesion group. There was no difference between the groups in the arterial pressure and vasopressin responses to acute stress. Neurotoxin lesions of the PVN also resulted in significant depletions of VP and OT in all levels of the spinal cord and decreased OT levels in the dorsal brainstem. Ibotenic acid lesions of the PVN resulted in no significant changes in OT mRNA in the PVN, SON and PP. In addition, the 48-h dehydration resulted in a significant increase in plasma OT and OT mRNA in the PVN. These data indicate that the parvocellular neurons of the PVN play a role in integration of cardiovascular and endocrine responses to both stressful and osmotic stimuli and provide further evidence that parvocellular OT and VP neurons project to the brainstem and spinal cord.

Central administration of angiotensin II receptor antagonists and arterial pressure regulation: a note of caution.

The blunting of arterial pressure increases to a variety of pressor agents or the lowering of arterial pressure in some models of hypertension following intracerebroventricular administration of an angiotensin II (AII) antagonist, has been interpreted as prima facie evidence for the involvement of the central AII system in these situations. Central administration of vasopressin or carbachol (a cholinergic agonist) produces pressor effects which have been reported to be due to an increase in the activity of the sympathetic nervous system. We now report that central administration of AII antagonists [either (Sar-1, Ile-8) AII or (Sar-1, Ala-8) AII] in rats prevents the majority (greater than 70%) of the pressor effects of intraventricular vasopressin or carbachol. These results can be interpreted in two ways. The first is that all of these pressor agents use a central angiotensinergic mechanism(s) to increase sympathetic nervous system activity. An alternative hypothesis is that centrally administered AII antagonists non-specifically inhibit sympathetic nervous system function.

ACTH-(4-10) through gamma-MSH: evidence for a new class of central autonomic nervous system-regulating peptides.

Examination of the cardiovascular effects produced by peripheral administration of peptide sequences derived from adrenocorticotropic hormone (ACTH) led to the discovery of the pressor, cardioaccelerator, and natriuretic actions of intravenous (iv) ACTH-(4-10). Based on pharmacological studies in rats with alpha- and beta-adrenergic receptor antagonists, the cardiovascular effects of this peptide appeared to be mediated by the release of catecholamines. A peptide sequence analogous to ACTH-(4-10), gamma-melanocyte-stimulating hormone (gamma-MSH), possesses greater than 100-fold more cardiovascular activity and 1,000-fold more natriuretic activity than ACTH-(4-10). The pressor effect of iv gamma-MSH peptides appears to be dependent on the maintenance of preganglionic sympathetic drive, with no significant contribution of circulating vasopressin or angiotensin II. However, the presence of central vasopressinergic, and perhaps angiotensinergic, pathways appears to be crucial for expression of the full pressor effect of circulating gamma-MSH. Further evidence for the potential importance of the central nervous system (CNS) in these cardiovascular effects was obtained from central lesion experiments and a comparison of intracarotid vs. intrajugular infusions. Structure-activity studies suggested that the cardiovascular effects of ACTH-(4-10) or gamma-MSH are dependent on an Arg-hydrophobic amino acid sequence, located at or near their COOH-terminal. A similar requirement for biological activity is found in molluscan cardioexcitatory peptides, and the molluscan peptides have cardiovascular effects in rats, which resemble ACTH-(4-10) or gamma-MSH. This suggests that peptides of the gamma-MSH family are the pharmacological analogues, and perhaps the physiological homologues, of a cardioexcitatory family of peptides found in molluscs and birds. Elevated circulating levels of peptides derived from the NH2-terminal of pro-opiomelanocortin (POMC) have been found in psychological stress, cardiovascular distress, and hemorrhage. Increases in central sympathetic drive are common to all of these states. gamma-MSH peptides have been localized to POMC neurons in the arcuate nucleus and nucleus commissuralis of the rat. Projections from the latter nucleus innervate hindbrain vasomotor centers. Intraventricular administration of gamma-MSH produces prolonged elevation of mean arterial pressure. gamma-MSH peptides may provide a link between humoral and neurogenic mechanisms in cardiovascular regulation and could potentially be important neurotransmitters for central control of the cardiovascular system.

ACTH-induced hypertension in rats: fact or artifact?

Evidence from numerous laboratories has shown that administration of adrenocorticotropic hormone (ACTH) to rats produces hypertension within 5 days. However, the analysis of blood pressure in these studies was by the tail-cuff technique, an acute and indirect approach. We have now administered ACTH, via a subcutaneous depot injection (5 or 10 U/day for 9 days), to chronically instrumented rats maintained in metabolic cages. Although tail-cuff measurements of arterial pressure indicated that the ACTH treatment produced hypertension, this was not confirmed by direct 24-h measurements of mean arterial pressure. There was no effect of ACTH on 24-h heart rate throughout the treatment period compared with saline-injected controls. We also examined coefficient of variation of all our measurements. None of the factors was altered by ACTH administration. However, ACTH treatment did produce a diuretic effect, further confirming previous work and providing renal, in addition to cardiovascular, evidence for the bioavailability of the ACTH depot. These results demonstrate that chronic ACTH treatment does not produce a true hypertensive state in rats but rather may enhance the cardiovascular response to the stress of the indirect arterial pressure measurement technique.

Central oxytocin systems may mediate a cardiovascular response to acute stress in rats.

The role of central nervous system arginine vasopressin (AVP) and oxytocin (OXY) in the cardiovascular response to acute stress was examined using three experimental models: pharmacological antagonism of central AVP-OXY receptors; lesions of the paraventricular nucleus (PVN); and rats genetically lacking in AVP synthesis, i.e., the Brattleboro strain. Central administration of an AVP-OXY antagonist abolished the increase in heart rate (HR) seen following acute footshock stress. The group receiving centrally administered antagonist increased HR 15 +/- 17 (SE) beats/min, whereas, in contrast, the group receiving intravenous administration of the antagonist showed a 66 +/- 17 beats/min increase, and the group receiving intraventricular antagonist vehicle showed a 101 +/- 14 beats/min increase in response to stress. In a second study, electrolytic lesions of the PVN also blocked the increase in HR seen following stress, 20 +/- 12 beats/min for PVN-lesioned rats, 74 +/- 25 beats/min for sham lesion rats, and 93 +/- 7 beats/min for rats with a lesion not destroying the PVN. In the final study, the responses of Brattleboro rats, i.e., rats genetically deficient in vasopressin synthesis, were equivalent to their Long-Evans controls (131 +/- 13 and 147 +/- 12 beats/min, respectively). In each of these studies, the blood pressure responses to the stressor were equivalent for control and experimental groups. The results of these studies suggest that a neuropeptide system originating in or passing through the PVN may play an important role in the cardiovascular responses to stress and further suggest that the central OXY system may be one pathway mediating this response.

Activation of supraoptic magnocellular neurons by gamma 2-melanocyte stimulating hormone (gamma 2-MSH).

The effects of intracarotid infusions of the peptide gamma 2-melanocyte stimulating hormone (gamma 2-MSH) on electrophysiologically and immunohistochemically identified supraoptic nucleus (SON) units were investigated. Over a wide dose range this agent always excited SON units, while control infusions of vehicle had no effect. Because neural responses invariably preceded blood pressure elevation, it appears that gamma 2-MSH excitation of the magnocellular system was due to a direct effect on the central nervous system and was not a result of systemic cardiovascular responses. These results suggest a forebrain gamma 2-MSH sensitive site in the activation of SON magnocellular neurons.

Sympathetic terminal mediation of the acute cardiovascular response of gamma 2-MSH.

Peptides of the ACTH4-10/gamma 2-MSH3-9 class produce pressor and cardioaccelerator effects upon i.v. administration. These actions appear to be mediated by peripheral catecholamines. To ascertain the role of sympathetic nerve terminals in the cardiovascular effects of these peptides, we used bretylium tosylate to prevent nerve terminal release of norepinephrine. Pretreatment with bretylium significantly attenuated the pressor and cardioaccelerator responses of gamma 2-MSH, and shifted the peak of the remaining responses to a later time point. It appears that the acute cardiovascular response to gamma-MSH administration depends primarily on the release of sympathetic terminal norepinephrine, though some contribution from other pressor systems such as adrenal catecholamines is possible.

Dehydration natriuresis in Dahl S rats: no evidence for renal excretory deficit.

There is conflicting evidence for the existence of a renal sodium excretory deficit in the salt-sensitive hypertensive Dahl S (DS) rat strain. While presentation of acute sodium loads, in vivo or in vitro, suggests that DS kidneys cannot excrete sodium as efficiently as kidneys from the salt insensitive genetic control Dahl R (DR) rat strain, metabolic studies of Dahl rats on a high-sodium diet are unable to differentiate between DS and DR rats. The natriuretic response to acute sodium loads is dependent on the integrity of structures in or near the anteroventral 3rd ventricle (AV3V) region. Therefore, it was thought that an AV3V-dependent chronic sodium challenge might also uncover an excretory defect in DS rats. We have investigated the renal response of inbred Dahl S (SS/Jr) and Dahl R (SR/Jr), and Sprague-Dawley rats to 48 h of dehydration; a manoeuvre which produces hyperosmolality and hypernatremia, with its renal response dependent on the integrity of the AV3V. Inbred Dahl S, Dahl R and Sprague-Dawley rats showed identical renal electrolyte excretory responses to both dehydration and rehydration. These results are discussed in terms of the mechanism of salt-induced hypertension and dehydration natriuresis.

Role of the anteroventral third ventricle (AV3V) region of the rat brain in the pressor response to gamma 2-melanocyte-stimulating hormone (gamma 2-MSH).

We have examined the role of the anteroventral third ventricle (AV3V) region of the forebrain on the pressor responses to intravenous injections of the pituitary pressor agent, gamma 2-melanocyte-stimulating hormone (gamma 2-MSH) and the direct acting alpha 1-adrenergic agonist, phenylephrine in unanesthetized rats. Lesions of the AV3V region produce a parallel shift to the right in the dose response curve to gamma 2-MSH, with no effect on the pressor response to phenylephrine. The lesion had no effect on the heart rate response to either agent. These experiments indicate that the forebrain region surrounding the anterior third ventricle area is important to some of the cardiovascular actions of gamma 2-MSH.

The natriuretic response to hydromineral imbalance.

Many recent investigations of the mechanism of volume-expansion natriuresis fail to appreciate that the observed renal sodium excretion may not be dependent on an increase in intravascular volume, but rather on the infused sodium load or extracellular fluid volume expansion. With this in mind, the natriuresis of isotonic volume expansion, hypertonic saline infusion, and dehydration have a common basis: they present a relative or absolute sodium load. Lesions of forebrain periventricular tissue prevent the natriuretic response to these three states of body fluid imbalance. In this review we discuss the evidence for a common central nervous system-mediated natriuretic mechanism in response to disturbances of fluid and electrolyte balance. We also propose a role for pars intermedia-derived, proopiomelanocortin-derived peptides as humoral mediators of renal sodium excretion. Evidence from our laboratory, as well as others, provides data for a testable hypothesis to explain central nervous system-mediated natriuresis, as well as an explanation of how central nervous system lesions or neurochemical perturbations affect the renal response to body fluid imbalance.

Activation of the central vasopressin system: a potential factor in the etiology of hypertension.

Peptides containing the ACTH4-10 or gamma MSH3-9 sequence have varying degrees of natriuretic activity. Several of these peptides also possess pressor activity. The basis for the cardiovascular effect appears to be increased central sympathetic drive. The mechanism by which circulating gamma MSH affects central cardiovascular regulation is via an interaction with structures in the anteroventral third ventricle (AV3V) region, resulting in stimulation of the central vasopressin system. This pathway projects from the forebrain to hindbrain and spinal cord centers which regulate autonomic drive. We have extended these initial findings to other central sympathoexcitatory pressor factors, including hypertonic saline (HS) and angiotensin II (A-II). In both of these cases, the central vasopressin system mediates their autonomic effects. Since HS and A-II also work through the AV3V, the central vasopressin system may be partially responsible for the increased sympathetic drive noted in forms of hypertension which are AV3V-dependent.

Activation of the central vasopressin system: a common pathway for several centrally acting pressor agents.

Hypertonic saline (HS) and angiotensin II (ANG II) administered centrally or peripherally produce a forebrain-mediated central nervous system-(CNS) dependent pressor action. Although the majority of these effects are due to increased central sympathetic drive and inhibition of the cardiac baroreceptor reflex, evidence from peripheral infusions of vasopressin (Vp) receptor antagonists have suggested that part of the blood pressure increase may be due to circulating Vp. We now report that blockade of CNS Vp receptors in rats, via a fourth ventricle infusion of a Vp receptor antagonist, attenuated greater than 70% of the pressor response to lateral ventricle infusion of HS, ANG II, or hypertonic glucose (HG). Intravenous administration of the Vp antagonist could block only 40% of the HS response. When lateral ventricle infusion of HS was performed in rats with a hereditary lack of Vp (diabetes insipidic rats) no pressor response was obtained. Because centrally administered Vp has autonomic nervous system effects that are similar to those induced by HS or ANG II, our results suggest that CNS Vp may provide a link between forebrain acting pressor agents and autonomic nervous system regulation. Finally, HG produced a pressor effect that had an equivalent peak response to HS. However, unlike the HS response, the pressor effect to HG returned to base line within approximately 5 min during a 10-min infusion. Thus there appears to be a quantitative difference in the pressor responses produced by activation of sodium vs. osmoreceptors.

Neurohypophyseal hormone release and biosynthesis in rats with lesions of the anteroventral third ventricle (AV3V) region.

Lesions of the periventricular tissue surrounding the anteroventral third ventricle (AV3V) have been shown to disrupt body fluid homeostasis. The acute post-lesion phase in rats is characterized by adipsia, the lack of an appropriate antidiuretic response, and plasma vasopressin levels which do not rise. Electron micrographs of the supraoptic nucleus and neural lobe of lesioned adipsic rats suggest no stimulation of biosynthetic activity, and large stores of neurosecretory material in the axon terminals. To directly investigate the status of these neurons, we determined neural lobe vasopressin and oxytocin content and the incorporation of [35S]cysteine into hypothalamic proteins in rats with sham-lesions or lesions of the AV3V after 3 days of adipsia or water deprivation, and in water replete sham-lesioned rats. The results demonstrate that adipsic rats with AV3V lesions have neural lobe vasopressin and oxytocin content equivalent to water-replete sham-lesioned rats. Neural lobe vasopressin and oxytocin levels of water-deprived sham-lesioned rats were significantly below those of all other groups. In addition, this group had a radioactivity incorporation rate into hypothalamic proteins which was two-fold greater than either of the other groups. The results indicate that 3-day adipsic AV3V-lesioned rats do not increase neurohypophyseal hormone release or biosynthesis as do 3-day water-deprived sham-lesioned rats. The periventricular tissue of the AV3V would therefore appear to be crucial in providing information to the hypothalamo-neurohypophyseal neurons on body fluid homeostasis.

Central vasopressin system mediation of acute pressor effect of gamma-MSH.

Intravenous (iv) administration of gamma-melanocyte-stimulating hormone (gamma-MSH) produces central sympathetically mediated pressor and cardioaccelerator effects and increases the activity of hypothalamic vasopressinergic neurons. The autonomic actions are similar to infusion of vasopressin (Vp) into the hindbrain of 4th ventricle (Ven). To ascertain whether activation of the central Vp system is the proximate cause of the pressor effects of gamma-MSH, we investigated the effects of gamma-MSH in rats pre- and postblockade of central nervous system Vp receptors and in rats with a hereditary lack of vasopressin (Brattleboro strain). Central Vp receptor blockade significantly reduced (80%) the pressor effects of iv gamma-MSH. As a control, iv administration of the antagonist, while effective in blocking the pressor effect of iv Vp, had no effect on the gamma-MSH pressor response. When compared with their genetic controls (Long-Evans strain), Brattleboro rats also had greater than 80% reduction in their pressor response to iv gamma-MSH. The results indicate that circulating gamma-MSH activates the central Vp system to produce its sympathoexcitatory pressor effects.

Changes in magnocellular-neurohypophyseal vasopressin following anteroventral third-ventricle (AV3V) lesions.

Lesions of the brain region surrounding the anteroventral third ventricle (AV3V) have been shown to result in adipsia without a corresponding antidiuretic response or rise in plasma vasopressin levels. Electron microscopic examination of the supraoptic nucleus and neural lobe of the pituitary has shown that large stores of neurosecretory material build up in the neurohypophysis. In the present study, the increased neurosecretory material was characterized by immunocytochemistry. Vasopressin immunoreactivity was examined and compared between adipsic rats with AV3V lesions, water-deprived rats, and normal rats. Two days after surgery, sham-lesioned, water-deprived rats displayed decreased vasopressin immunostaining density compared to normal controls, and adipsic AV3V-lesioned rats displayed increased vasopressin immunoreactivity throughout the magnocellular-hypophyseal system. These results indicate that AV3V lesions interrupt neural inputs that stimulate the magnocellular system to release vasopressin in response to normal humoral stimuli.

Cardiovascular investigations of an endogenous digoxin-like factor.

A circulating factor with digoxin immunoreactivity has been demonstrated. Elevated levels of this substance appear to be present after volume expansion and salt loading, and in some forms of hypertension. The potentially causative role for this factor in hypertension can be demonstrated by the normalization of blood pressure after antidigoxin antibody infusions in low-renin and sodium-dependent hypertension. The possibility that renal excretory defects may be the initiating event to elevate endogenous digoxin is suggested by studies with normotensive humans and monkeys with renal disease. In the latter case cardiovascular deficits were noted that were analogous to those detected in renal hypertensive monkeys with elevated endogenous digoxin. Considered together, these results suggest the existence of a natriuretic and hypertensive substance that plays a role in body fluid homeostasis and blood pressure regulation.

Sympathetic nervous system mediation of acute cardiovascular actions of gamma 2-melanocyte-stimulating hormone.

Peptides of the pro-opiocortin class produce pronounced cardiovascular and natriuretic actions. We have investigated the acute cardiovascular effects of one of the most potent members of this class, gamma 2-melanocyte stimulating hormone (gamma 2-MSH), in rats. Pressor actions of gamma 2-MSH administered systemically were eliminated by ganglionic blockade with chlorisondamine. Peripheral cholinergic blockade failed to affect either the pressor or cardioaccelerator responses to gamma 2-MSH. Administration of gamma 2-MSH (2.0-10.0 micrograms) produced vasoconstriction primarily in the mesenteric and hindlimb vascular beds, while the renal bed showed little response. Infusions of phenylephrine produced pressor responses similar to those found with gamma 2-MSH, which were accompanied by a decrease in heart rate and vasoconstriction in the mesenteric and renal vascular beds. Hemodynamic changes produced by gamma 2-MSH and phenylephrine were blocked or attenuated by alpha 1-adrenergic receptor blockade with prazosin. Direct injection of gamma 2-MSH into the renal artery produced an acute renal vasoconstriction that was not attenuated by alpha 1-adrenergic or ganglionic blockade. These findings and the results of previous publications are consistent with the hypothesis that gamma 2-MSH may produce a centrally mediated activation of the sympathetic nervous system, have direct vasoconstriction actions on the renal vasculature, and inhibit baroreceptor function to produce an increase in blood pressure without an accompanying bradycardia.