High-Salt Exposure During Perinatal Development Enhances Stress Sensitivity.

Excess consumption of dietary sodium during pregnancy has been shown to impair offspring cardiovascular function and enhance salt preference in adulthood, but little is known regarding the long-term impact of this nutritional surplus on offspring brain morphology and behavior. Using a combination of cellular and behavioral approaches, we examined the impact of maternal salt intake during the perinatal period on structural plasticity in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in weanling and adult offspring as well as reward- and stress-driven behaviors in adult offspring. We found that weanling rats born to 4% NaCl-fed dams exhibited an increase and decrease in thin spine density in the infralimbic PFC (IL-PFC) and prelimbic PFC (PL-PFC), respectively, as well as an increase in mushroom spine density in the NAc shell, compared to 1% NaCl-fed controls. Structural changes in the IL-PFC and NAc shell persisted into adulthood, the latter of which is a phenotype that has been observed in rats exposed to early life stress. There was no effect of maternal salt intake on reward-driven behaviors, including sucrose preference, conditioned place preference (CPP) for cocaine, and forced swim stress (FSS)-induced reinstatement of cocaine-induced CPP. However, rats born to high-salt fed dams spent less time swimming in the FSS and displayed heightened plasma CORT levels in response to the FSS compared to controls, suggesting that early salt exposure increases stress sensitivity. Overall, our results suggest that perinatal salt exposure evokes lasting impacts on offspring physiology and behavior.

Does salt have a permissive role in the induction of puberty?

Puberty is starting earlier than ever before and there are serious physiological and sociological implications as a result of this development. Current research has focused on the potential role of high caloric, and commensurate high adiposity, contributions to early puberty. However, girls with normal BMI also appear to be initiating puberty earlier. Westernized diets, in addition to being high in fat and sugar, are also high in salt. To date, no research has investigated a link between elevated salt and the reproductive axis. We hypothesize that a high salt diet can result in an earlier onset of puberty through three mechanisms that are not mutually exclusive. (1) High salt activates neurokinin B, a hormone that is involved in both the reproductive axis and salt regulation, and this induces kisspeptin release and ultimate activation of the reproductive axis. (2) Vasopressin released in response to high salt acts on vasopressin receptors expressed on kisspeptin neurons in the anteroventral periventricular nucleus, thereby stimulating gonadotropin releasing hormone and subsequently luteinizing hormone secretion. (3) Salt induces metabolic changes that affect the reproductive axis. Specifically, salt acts indirectly to modulate adiposity, ties in with the obesity epidemic, and further compounds the pathologic effects of obesity. Our overall hypothesis offers an additional cause behind the induction of puberty and provides testable postulates to determine the mechanism of potential salt-mediated affects on puberty.

Activation of the neurokinin 3 receptor promotes filopodia growth and sprouting in rat embryonic hypothalamic cells.

Members of the tachykinin family have trophic effects on developing neurons. The tachykinin neurokinin 3 receptor (NK3R) appears early in embryonic development; during the peak birthdates of hypothalamic neurons, but its involvement in neural development has not been examined. To address its possible role, immortalized embryonic hypothalamic neurons (CLU209) were treated with CellMask, a plasma membrane stain, or the membranes were imaged in CLU209 cells that were transfected with a pEGFP-NK3R expression vector. Nontransfected cells and transfected cells were then treated with senktide, a NK3R agonist, or Dulbecco's Modified Eagle's Medium (DMEM) and time-lapse confocal images were captured for the following 30 min. Compared to DMEM, senktide treatment led to filopodia initiation from the soma of both nontransfected and transfected CLU209 cells. These filopodia had diameters and lengths of approximately 200 nm and 3 µm, respectively. Pretreatment with an IP3 receptor blocker, 2-aminoethoxydiphenyl borate (2-APB), prevented the senktide-induced growth in filopodia; demonstrating that NK3R-induced outgrowth of filopodia likely involves the release of intracellular calcium. Exposure of transfected CLU209 cells to senktide for 24 h led to further growth of filopodia and processes that extended 10-20 µm. A mathematical model, composed of a linear and population model was developed to account for the dynamics of filopodia growth during a timescale of minutes. The results suggest that the ligand-induced activation of NK3R affects early developmental processes by initiating filopodia formation that are a prerequisite for neuritogenesis.

Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus.

Central neuronal circuits that relay stress information include vasopressin- (AVP) and oxytocin- (OC) containing neurons of the paraventricular nucleus of the hypothalamus (PVN). These neurons are potentially modulated by neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides. NK3Rs have been localized in PVN neurons and have showed nuclear translocation following an osmotic challenge in rodents. However, their subcellular distribution in AVP or OC neurons of the PVN and plasticity following restraint stress in rats are unknown. In the present study, densities of NK3Rs in PVN AVP- or OC-labeled somatodendritic profiles were measured by quantitative immunoelectron microscopy in control or stressed rats. In resting conditions, NK3Rs were predominantly located in AVP neurons, however sparsely distributed in OC neurons of the PVN. All NK3-labeled somata of the PVN in control rats showed cytoplasmic but no nuclear immunolabeling. An acute restraint stress session of 30 min significantly increased nuclear NK3R density in AVP-labeled somata but not in OC-labeled somata. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK3R densities in AVP-labeled but not in OC-labeled dendrites. The results of this study suggest that in the rat PVN 1) NK3R distribution is conducive to modulation of systemic and/or central AVP release through PVN inputs to the posterior pituitary and/or the amygdala and 2) acute restraint stress activates (internalizes) NK3Rs on surface and evokes nuclear NK3R translocation exclusively in AVP neurons. This trafficking might contribute to neurochemical imbalances observed in neuronal circuits involved in stress-related disorders such as anxiety.

Activation of tachykinin, neurokinin 3 receptors affects chromatin structure and gene expression by means of histone acetylation.

The tachykinin, neurokinin 3 receptor (NK3R) is a g-protein coupled receptor that is broadly distributed in the nervous system and exerts its diverse physiological actions through multiple signaling pathways. Despite the role of the receptor system in a range of biological functions, the effects of NK3R activation on chromatin dynamics and gene expression have received limited attention. The present work determined the effects of senktide, a selective NK3R agonist, on chromatin organization, acetylation, and gene expression, using qRT-PCR, in a hypothalamic cell line (CLU 209) that expresses the NK3R. Senktide (1 nM, 10nM) caused a relaxation of chromatin, an increase in global acetylation of histone H3 and H4, and an increase in the expression of a common set of genes involved in cell signaling, cell growth, and synaptic plasticity. Pretreatment with histone acetyltransferase (HAT) inhibitor (garcinol and 2-methylene y-butylactone), that inhibits p300, p300/CREB binding protein (CBP) associated factor (PCAF), and GCN 5, prevented the senktide-induced increase in expression of most, but not all, of the genes upregulated in response to 1 nM and 10nM senktide. Treatment with 100 nM had the opposite effect: a reduction in chromatin relaxation and decreased acetylation. The expression of four genes was significantly decreased and the HAT inhibitor had a limited effect in blocking the upregulation of genes in response to 100 nM senktide. Activation of the NK3R appears to recruit multiple pathways, including acetylation, and possibly histone deactylases, histone methylases, or DNA methylases to affect chromatin structure and gene expression.

Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge.

The neurokinin 3 receptor (NK3R) is a G protein-coupled receptor that is expressed in brain and is highly expressed by magnocellular vasopressinergic neurons in both the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus. Hyperosmolarity causes a ligand-mediated internalization of NK3Rs to the cytoplasm and to the nuclei of vasopressinergic PVN neurons. This receptor activation-dependent pathway is presumed to be a means to directly transmit synaptic signals from the cell membrane to the nucleus. The present study evaluated in vivo the subnuclear domains that associate with NK3R. Rats were administered 2 M NaCl (intragastric) or no intragastric load, and 40 min later, the PVN was dissected and nuclei were isolated. Using double-immuno-transmission electron microscopy (TEM), we show that, compared with controls, hyperosmolarity causes a significant increase in NK3R Immunogold beads in the nucleus of PVN neurons. Furthermore, NK3R spatially colocalized with histone H4 and with highly acetylated H4 in nuclei isolated from the PVN of rats administered 2 M NaCl, but not in nuclei from control rats. Next, coimmunoprecipitation experiments showed that acetylated H4, as well as acetylated H3, were pulled down with NK3R in the PVN nuclear enriched fraction from rats treated with 2 M NaCl, but not from control rats. In response to hyperosmolarity, NK3R is transported to the nucleus of PVN neurons and associates with transcriptionally active chromatin, where it may influence the transcription of genes.

Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetamines.

This study examined critical periods in development to determine when offspring were most susceptible to dietary sodium manipulation leading to amphetamine sensitization. Wistar dams (n = 6-8/group) were fed chow containing low (0.12% NaCl; LN), normal (1% NaCl; NN), or high sodium (4% NaCl; HN) during the prenatal or early postnatal period (birth to 5 wk). Offspring were fed normal chow thereafter until testing at 6 mo. Body weight (BW), blood pressure (BP), fluid intake, salt preference, response to amphetamine, open field behavior, plasma adrenocorticotropin hormone (ACTH), plasma corticosterone (Cort), and adrenal gland weight were measured. BW was similar for all offspring. Offspring from the prenatal and postnatal HN group had increased BP, NaCl intake, and salt preference and decreased water intake relative to NN offspring. Prenatal HN offspring had greater BP than postnatal HN offspring. In response to amphetamine, both prenatal and postnatal LN and HN offspring had increased locomotor behavior compared with NN offspring. In a novel open field environment, locomotion was also increased in prenatal and postnatal LN and HN offspring compared with NN offspring. ACTH and Cort levels 30 min after restraint stress and adrenal gland weight measurement were greater in LN and HN offspring compared with NN offspring. These results indicate that early life experience with low- and high-sodium diets, during the prenatal or early postnatal period, is a stress that produces long-term changes in responsiveness to amphetamines and to subsequent stressors.

Blockade of NK3R signaling in the PVN decreases vasopressin and oxytocin release and c-Fos expression in the magnocellular neurons in response to hypotension.

Tachykinin neurokinin 3 receptor (NK3R) signaling has a broad role in vasopressin (VP) and oxytocin (OT) release. Hydralazine (HDZ)-induced hypotension activates NK3R expressed by magnocellular neurons, increases plasma VP and OT levels, and induces c-Fos expression in VP and OT neurons. Intraventricular pretreatment with the specific NK3R antagonist, SB-222200, eliminates the HDZ-stimulated VP and OT release. NK3R are distributed in the central pathways conveying hypotension information to the magnocellular neurons, and the NK3R antagonist could act anywhere in the pathways. Alternatively, the antagonist could act at the NK3R expressed by the magnocellular neurons. To determine whether blockade of NK3R on magnocellular neurons impairs VP and OT release to HDZ, rats were pretreated with a unilateral PVN injection of 0.15 M NaCl or SB-222200 prior to an intravenous injection of 0.15 M NaCl or HDZ. Blood samples were taken, and brains were processed for VP/c-Fos and OT/c-Fos immunohistochemistry. Intravenous injection of 0.15 M NaCl did not alter plasma hormone levels, and little c-Fos immunoreactivity was present in the PVN. Conversely, intravenous injection of HDZ increased plasma VP and OT levels and c-Fos expression in VP and OT magnocellular neurons. Intra-PVN injection of SB-222200 prior to an intravenous injection of HDZ significantly decreased c-Fos expression in both VP and OT neurons by approximately 70% and attenuated plasma VP and OT levels by 33% and 35%, respectively. Therefore, NK3R signaling in magnocellular neurons has a critical role for the release of VP and OT in response to hypotension.

Tachykinin neurokinin 3 receptor signaling in cholecystokinin-elicited release of oxytocin and vasopressin.

Neurokinin 3 receptor (NK3R) signaling has an integral role in the stimulated oxytocin (OT) and vasopressin (VP) release in response to hyperosmolarity and hypotension. Peripheral injections of cholecystokinin (CCK) receptor agonists for the CCK-A (sulfated CCK-8) and CCK-B (nonsulfated CCK-8) receptors elicit an OT release in rat. It is unknown whether NK3R contributes to this endocrine response. Freely behaving male rats were administered an intraventricular pretreatment of 250 or 500 pmol of SB-222200, a specific NK3R antagonist, or 0.15 M NaCl before an intraperitoneal or intravenous injection of CCK-8 (nonsulfated or sulfated) or 0.15 M NaCl. Blood samples were taken before intraventricular treatment and 15 min after intraperitoneal or intravenous injection, and plasma samples were assayed for OT and VP concentration. Intraperitoneal injection of both nonsulfated and sulfated CCK-8 significantly increased plasma OT levels and had no effect on plasma VP levels. Intravenous injection of sulfated CCK-8 stimulated an increase in plasma OT levels and did not alter plasma VP levels. However, intravenous injection of nonsulfated CCK-8 stimulated a significant increase in plasma levels of both OT and VP. No other studies have demonstrated CCK-8-stimulated release of VP in rat. NK3R antagonist did not alter baseline levels of either hormone. However, pretreatment of NK3R antagonist significantly blocked the CCK-stimulated release of OT in all CCK treatment groups and blocked VP release in response to intravenous injection of nonsulfated CCK-8. Therefore, central NK3R signaling is required for OT and VP release in response to CCK administration.

Centrally administered vasopressin cross-sensitizes rats to amphetamine and drinking hypertonic NaCl.

Prior sodium restriction cross-sensitizes rats to the psychomotor effects of amphetamines and vice versa. Repeated central injections of vasopressin (VP) induce a psychomotor sensitization similar to amphetamine sensitization and repeated sodium deficiency. Thus brain VP signaling may be a common mechanism involved in mediating these two motivational systems. In experiment 1, we tested the hypothesis that rats previously sensitized to central VP would show enhanced psychomotor responses to amphetamine. Rats were administered saline, VP (50 ng), or amphetamine (1 mg/kg or 3 mg/kg) on days 1 and 2, and given saline or amphetamine on day 3. Amphetamine produced psychomotor arousal in all groups. However, amphetamine on day 3 elicited a significantly greater psychomotor response in rats that had prior injections of amphetamine or VP than in rats previously treated with saline. In experiment 2, the hypothesis that prior experience with central VP would cross-sensitize rats to drinking hypertonic sodium (NaCl) solutions was tested. Rats were administered VP (50 ng) or saline for 3 days. On the fourth day, nondeprived rats were given access to 0.3 M NaCl and water for 1 h. Control and saline-treated rats only drank 1 ml of 0.3 M NaCl, but rats previously exposed to central VP drank significantly more hypertonic saline (4 ml). These results show that prior experience with central VP cross-sensitizes rats to the psychomotor stimulant effects of amphetamine and the ingestion of concentrated NaCl solutions. This pattern of cross-sensitization links central VP signaling, amphetamine, and sodium deficiency, and therefore it may play a role in the cross-sensitization between sodium appetite and amphetamines.

Tachykinin NK3 receptor contribution to systemic release of vasopressin and oxytocin in response to osmotic and hypotensive challenge.

Activation of the neurokinin 3 receptor (NK3R) by a receptor agonist, hypotension, and hyperosmolarity results in the internalization of NK3R expressed by magnocellular neurons and the release of vasopressin (VP) and oxytocin (OT) into the circulation. The contribution of NK3R activation to the release of VP and OT in response to hyperosmolarity and hypotension was evaluated by measuring the release of both hormones following pretreatment with a selective NK3R antagonist, SB-222200. Freely behaving male rats were given an intraventricular injection of either 0.15 M NaCl or 250, 500, or 1,000 pmol SB-222200, and then were administered an intravenous infusion of 2 M NaCl or 0.15 M NaCl (experiment 1), or a bolus intra injection of 0.15 M NaCl or hydralazine (HDZ), a hypotension-inducing drug (experiment 2). Blood samples were taken from indwelling arterial catheters at various time points for 1-2 h, both before and after treatments. Plasma VP and OT levels were determined by ELISA. Blockade of NK3R did not affect the baseline levels of either hormone. In contrast, pretreatment with SB-222200 significantly reduced ( approximately 60%) or abolished the release of VP and OT, respectively, to 2 M NaCl infusion. HDZ-induced VP and OT release was eliminated by pretreatment with 500 pmol SB-222200. Therefore, NK3R activation contributes significantly to the systemic release of both VP and OT in response to osmotic and hypotensive challenges.

Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines.

Acute sodium deficiency sensitizes adult rats to psychomotor effects of amphetamine. This study determined whether prenatal and early life manipulation of dietary sodium sensitized adult offspring to psychomotor effects of amphetamine (1 or 3 mg/kg ip) in two strains of rats. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) dams were fed chow containing low NaCl (0.12%; LN), normal NaCl (1%; NN), or high NaCl (4%; HN) throughout breeding, gestation, and lactation. Male offspring were maintained on the test diet for an additional 3 wk postweaning and then fed standard chow thereafter until testing began. Overall, blood pressure (BP), total fluid intake, salt preference, and adrenal gland weight were greater in SHR than in WKY. WKY LN offspring had greater water intake and adrenal gland weight than did WKY NN and HN offspring, whereas WKY HN offspring had increased BP, salt intake, and salt preference compared with other WKY offspring. SHR HN offspring also had increased BP compared with other SHR offspring; all other measures were similar for SHR offspring. The low-dose amphetamine increased locomotor and stereotypical behavior compared with baseline and saline injection in both WKY and SHR offspring. Dietary sodium history affected the rats' psychomotor response to the higher dose of amphetamine. Injections of 3 mg/kg amphetamine in both strains produced significantly more behavioral activity in the LN offspring than in NN and HN offspring. These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine.

Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamus.

To better understand the involvement of hindbrain catecholamine neurons in hypovolemia-induced secretion of AVP, we injected antidopamine beta-hydroxylase saporin (DSAP) or unconjugated saporin (SAP) control solution into the hypothalamic paraventricular nucleus (PVH) of anesthetized rats to retrogradely lesion catecholamine neurons innervating magnocellular areas of the hypothalamus. Subsequently, hypotensive hypovolemia was induced by remote blood withdrawal (4.5 ml, 1 ml/min) using an intra-atrial catheter. Blood was sampled at 2, 5, 20, and 50 min after onset of blood withdrawal. The AVP response was severely impaired by DSAP. Peak responses at 50 min were 51 pg/ml in SAP control and 17 pg/ml in DSAP-lesioned rats, indicating the importance of catecholamine neurons for this response. We also measured AVP responses to osmotic challenge induced by administration of hypertonic saline (1 M, 15 ml/kg, sc) and to insulin-induced hypoglycemia. Osmotic challenge increased AVP levels, but the response was not impaired by DSAP, indicating that AVP neurons were not damaged by the DSAP injection. Insulin-induced hypoglycemia did not increase AVP levels in either DSAP- or SAP-treated rats. However, the same dose of insulin increased food intake and corticosterone secretion in SAP controls, and these responses were profoundly impaired by DSAP. Thus catecholamine neurons are required for both the AVP response to hypotensive hypovolemia and for feeding and corticosterone responses to hypoglycemia. Lack of an AVP response to insulin-induced hypoglycemia in intact rats therefore indicates that responses to hypovolemia and hypoglycemia are mediated by different catecholamine neurons under distinct sensory controls.

Intraventricular injections of tachykinin NK3 receptor agonists suppress the intake of "salty" tastes by sodium deficient rats.

Intraventricular injections of the tachykinin NK3 receptor (NK3-R) agonist, senktide, suppress the ingestion of hypertonic (0.5 M) NaCl by decreasing the initial lick rate and accelerating the decay in lick rate in sodium deficient rats. The present experiment examined whether the effects of intraventricular injections of senktide on lick rate were selective for NaCl solution, or if the ability of NK3-R agonists to inhibit intake generalizes other sodium-containing solutions. The effects of lateral ventricular injections of isotonic saline or senktide (200 ng) on intake and lick rate of 0.5 M solutions of sodium chloride (NaCl), sodium acetate (Na acetate), sodium bicarbonate (Na bicarbonate), and monosodium glutamate (MSG) were measured in sodium deficient rats. Compared to saline injection, senktide injection had no effect on the lick rate or intake of Na bicarbonate. In contrast, intraventricular injection of senktide suppressed the intake of NaCl, Na acetate, and MSG compared to saline injection. Senktide injection accelerated the decay in lick rate for NaCl, Na acetate and MSG, but only suppressed the initial lick rate for NaCl and Na acetate. The results show that activation of NK3-R in sodium deficient rats suppresses the intake of tastes that are classified as "salty" tasting and that the decrease in intake reflects effects on the initial lick rate, the decay in lick rate, or both.

Agonist and hypertonic saline-induced trafficking of the NK3-receptors on vasopressin neurons within the paraventricular nucleus of the hypothalamus.

The neurokinin 3 receptor (NK3R) is colocalized with vasopressinergic neurons within the hypothalamic paraventricular nucleus (PVN) and intraventricular injections of NK3R agonists stimulate vasopressin (VP) release. Our objectives were to test the hypotheses that intraventricular injections of the selective NK3R agonist, succinyl-[Asp6, N-Me-Phe8] substance P (senktide), activate NK3R expressed by vasopressinergic neurons within the PVN, and see whether NK3R expressed by vasopressinergic neurons in the PVN are activated by hyperosmolarity. NK3R internalization was used as a marker of receptor activation. Immunohistochemistry revealed that NK3Rs were membrane-bound on VP immunoreactive neurons in control rats. Following senktide injection, there was a significant increase in the appearance of NK3R immunoreactivity within the cytoplasm and a morphological rearrangement of the dendrites, indicating receptor internalization, which was reversible. Furthermore, pretreatment with a selective NK3R antagonist, SB-222200, blocked the senktide-induced VP release and internalization of the NK3R in the PVN. These results show that the trafficking of the NK3R is due to ligand binding the NK3R. In a subsequent experiment, rats were administered intragastric loads of 2 or 0.15 M NaCl, and NK3R immunohistochemistry was used to track activation of the receptor. In contrast to control rats, 2 M NaCl significantly increased plasma VP levels and caused the internalization of the NK3R on VP neurons. Also, NK3R immunoreactivity was located in the nuclei of vasopressinergic neurons after senktide and 2 M NaCl treatment. These results show that hyperosmolarity stimulates the local release of an endogenous ligand in the PVN to bind to and activate NK3R on vasopressinergic neurons.

Intraventricular injections of tachykinin NK3 receptor agonist reduce the gain of the baroreflex in unrestrained rats.

The tachykinin neuropeptides acting at NK3 receptors affect mean arterial pressure (MAP) through both neuroendocrine and neural mechanisms. NK3 receptors are found in brainstem nuclei that mediate the baroreflex, but the effects of NK3 receptor stimulation on baroreflex function are unknown. The present study tests the effects of intraventricular injections of senktide, a selective NK3 receptor agonist, on the sensitivity of the baroreflex in three stains of rats: Charles River Laboratory, Long-Evans, and Brattleboro rats, which lack the ability to synthesize vasopressin. Rats with lateral ventricle cannulas were administered injections of isotonic saline, 100 ng, or 200 ng senktide, and 5 min later arterial baroreceptor-heart rate (HR) function was examined by constructing full-range blood pressure-HR curves using alternating doses (5-20 microg kg min) of phenylephrine and nitroprusside to raise and decrease blood pressure approximately 50 mm Hg over a period of 1 min, respectively. Intraventricular injections of 200 ng senktide had no significant effect on baseline MAP, but significantly decreased the gain of the baroreflex in all three rat strains whereas the 100 ng dose had no effect on the baroreflex. These results show that NK3 receptor stimulation modulates the baroreflex that is independent of any action of vasopressin.

delta2 opioid receptor agonist facilitates mean arterial pressure recovery after hemorrhage in conscious rats.

delta opioid receptor agonists exert potent hemodynamic effects under ischemic conditions. This study was designed to assess the cardiovascular effects of Deltorphin-D(variant) (Delt-D(var)), a selective delta(2) opioid receptor agonist, in conscious, freely moving male rats during the posthemorrhage, recompensatory phase of a hemorrhagic trauma. Rats were fitted with femoral arterial and venous catheters for measurements of mean arterial pressure (MAP), heart rate (HR), and intravenous (i.v.) injections of isotonic saline, 1 mg/kg Delt-D(var), or 2 mg/kg Delt-D(var). During hemorrhaging, 30% (approximately 5 mL) of total blood volume was collected from the arterial catheter. MAP-HR was fitted to a logistic equation to determine baroreceptor reflex properties. Hemorrhaged rats progressed through three distinct phases: compensation, decompensation, and recompensation. Saline and 1 mg/kg Delt-D(var) rats treated posthemorrhage had similar MAP and HR after hemorrhage. In contrast, 2 mg/kg Delt-D(var) administered after hemorrhaging led to a faster and more complete recovery of MAP than compared with the other groups. In hemorrhaged rats, the average HR gain (bpm/mmHg) after 2 mg/kg Delt-D(var) treatment was greater and the BP(50) (BP at one-half the HR range) was significantly lower than after saline treatment. The results show that after hemorrhage, during the recompensatory period, stimulation of delta(2) opioid receptors leads to improved MAP, and this recovery may involve a change in baroreflex sensitivity.

Cardiovascular alteration and treatment of hypertension: do men and women differ?

Cardiovascular disease is one of the most common causes of mortality affecting both men and women in industrialized nations. Sex-related differences have been well established with regard to heart and vascular function as well as cardiovascular disease processes. Nevertheless, the precise mechanisms of action behind these gender-related differences are poorly understood. Premenopausal women have a relatively lower arterial blood pressure compared to age-matched men and post-menopausal women, suggesting a role of ovarian hormones in blood pressure regulation. Sex-related differences in vasculature and neuroendocrine systems are also present that can affect hemostasis, vascular reactivity, and vascular tone. Treatment for cardiovascular disease and hypertension has been challenging and unsatisfactory. Men and women may require different antihypertensive regimens due to differences in the progression and presentation of hypertension. Additionally, hormone replacement therapy in postmenopausal women has been controversial, producing both beneficial and detrimental effects. Therefore, this review will focus on sex-related differences in the heart and vasculature, and treatments for cardiovascular disease, such as hypertension.

Hypovolemia stimulates intraoral intake of water and NaCl solution in intact rats but not in chronic decerebrate rats.

This experiment tested the hypothesis that afferent signals from cardiac baroreceptors to the caudal brain stem are integrated by hindbrain systems to control ingestive behavior in response to plasma volume deficits in rats. A supracollicular transection was made which should not interfere with the neural signal of volume depletion to the hindbrain. Decerebrate (n=5) and control rats (n=7) were given subcutaneous injections of 30% polyethylene glycol (PEG) to induce hypovolemia or of isotonic saline as a control. Four hours after the injection, either water or 0.1 M NaCl was administered through an intraoral cannula, and intakes were measured. Decerebrate rats did not ingest significantly more water or saline after PEG treatment than after the control treatment, whereas control rats ingested both fluids in significantly larger volumes after PEG treatment. In another test using the same animals, heart rate was monitored after intravenous injections of phenylephrine (to raise blood pressure) and nitroprusside (to lower it). Similar reflexive changes in heart rate were observed in control and decerebrate rats, showing that baroreflex function was not impaired by decerebration. These results indicate that baroafferent signals are processed at multiple levels of the neuraxis, with hindbrain systems mediating autonomic cardiovascular reflexes in response to changes in blood pressure, and midbrain or forebrain systems mediating behavioral responses associated with thirst.

Salt intake by normotensive and spontaneously hypertensive rats: two-bottle and lick rate analyses.

Spontaneously hypertensive rats (SHR) overconsume NaCl compared to the normotensive Wistar Kyoto rat (WKY) rat. In the present experiment, two-bottle preference for NaCl (0.01, 0.03, 0.1, 0.3, 0.5, 1.0, 3.0 M) and lick rate analyses were used to identify the possible mechanisms that underlie the intake of NaCl by male SHR. Two-bottle preference and absolute NaCl intake by SHR were greater than that of WKY rats. When NaCl intake was calculated on the basis of body weight, SHR consumed more NaCl per 100 g body weight than did WKY. Also, during the one-bottle test, SHR consumed more 0.1 and 0.3 M NaCl per 100 g body weight than did WKY. The increased intake of NaCl by SHR was most evident for 0.3 M NaCl. Intake is determined by the initial rate of licking and the decline in lick rate over time. Nonlinear regression analysis of lick rate showed that the initial lick rates (licks/min) were similar for male WKY and SHR. Lick rate declined more rapidly when WKY rats drank 0.3 M than when they drank 0.1 M NaCl, a result consistent with the role of negative feedback in controlling the decay in lick rate. This concentration-dependent change in lick rate was not seen in SHR. Also, SHR lick rate for 0.1 and 0.3 M NaCl decelerated more slowly than that of WKY rats. The increased intake of hypertonic NaCl by SHR was due to a decrease in the decline in lick rate, suggesting that SHR are less responsive to ingestion-contingent negative feedback.