Cardiovascular actions of central neuropeptide W in conscious rats

Neuropeptide W (NPW) is a novel hypothalamic peptide that activates the orphan G protein-coupled receptors, GPR7 and GPR8. Two endogenous molecular forms of NPW that consist of 23- and 30-amino acid residues were identified. Intracerebroventricular (i.c.v.) administration of NPW is known to suppress spontaneous-feeding at dark-phase and fasting-induced food intake and to decrease body weight and plasma growth hormone and to increase prolactin and corticosterone; however, little is known about its effect on other physiological functions. We examined the effects of i.c.v. administration of NPW30 (0.3 and 3 nmol) on the mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine and epinephrine in conscious rats. NPW30 (3 nmol) provoked increases in MAP (85.12+/-3.16 to 106.26+/-2.66 mm Hg) and HR (305.75+/-13.76 to 428.45+/-26.82 beats/min) and plasma norepinephrine (138.1+/-18.1 to 297.2+/-25.9 pg/ml) and epinephrine (194.6+/-21.4 to 274.6+/-22.7 pg/ml). Intravenously administered NPW30 (3 nmol) had no significant effects on MAP and HR. These results indicate that central NPW30 increases sympathetic nervous outflow and affects cardiovascular function.     

Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin

Intracerebroventricular (ICV) administration of Neuromedin U (NMU), a hypothalamic neuropeptide, or leptin, an adipostat hormone released from adipose tissue, reduces food intake and increases energy expenditure. Leptin stimulates the release of NMU in vitro, and NMU expression is reduced in models of low or absent leptin. We investigated the role of NMU in mediating leptin-induced satiety. ICV administration of anti-NMU immunoglobulin G (IgG) (5 nmol) to satiated rats significantly increased food intake 4 h after injection, an effect seen for 相似文献   

Neuromedin U suppresses prolactin secretion via dopamine neurons of the arcuate nucleus

Neuromedin U (NMU) has a precursor that contains one additional peptide consisting of 33 or 36 amino acid residues. Recently, we identified this second peptide from rat brain and designated it neuromedin U precursor-related peptide (NURP), showing it to stimulate prolactin release from the pituitary when injected via the intracerebroventricular (icv) route. Here, we examined whether NMU, like NURP, also stimulates prolactin release. Unlike NURP, icv injection of NMU significantly decreased the secretion of prolactin from the pituitary. This suppression of prolactin release by NMU was observed in hyper-prolactin states such as lactation, stress, pseudopregnancy, domperidone (dopamine antagonist) administration, and icv injection of NURP. Immunohistochemical analysis revealed that icv injection of NMU induced cFos expression in dopaminergic neurons of the arcuate nucleus, but not the substantia nigra. Mice with double knockout of NMU and neuromedin S (NMS), the latter also binding to NMU receptors, showed a significant increase of the plasma prolactin level after domperidone treatment relative to wild-type mice. These results suggest that NMU and NURP may play important reciprocal roles in physiological prolactin secretion.     

Central stresscopin modulates cardiovascular function through the adrenal medulla in conscious rats

Stresscopin (SCP or urocortin III), a member of the corticotropin-releasing factor (CRF) neuropeptide family, is a high-affinity ligand for the type 2 CRF receptor (CRF(2)). When administered peripherally, SCP suppresses food intake, delays gastric emptying and decreases heat-induced edema. Central administration of CRF produces marked hypertension and increased plasma catecholamine. However, the effects of SCP on the cardiovascular system are unknown. Thus, the present study compared the effects of intracerebroventricular (i.c.v.) administration of CRF and SCP on cardiovascular function. Central administration of SCP (0.05 or 0.5 nmol) elicited transient increases in mean arterial blood pressure (MABP) and heart rate (HR), and the higher dose of SCP (0.5 nmol) resulted in increased plasma epinephrine. In contrast, central administration of CRF provoked long-lasting increases in MABP, HR and plasma catecholamine levels (norepinephrine and epinephrine). Intravenously administered CRF and SCP (0.5 nmol) did not elicit significant changes in MABP and HR. Therefore, these data suggest that centrally administered SCP modulates cardiovascular function, likely through the sympatho-adrenal-medullary (SAM) system.     

PEGylated neuromedin U-8 shows long-lasting anorectic activity and anti-obesity effect in mice by peripheral administration

Neuromedin U (NMU) is a neuropeptide found in the brain and gastrointestinal tract. The NMU system has been shown to regulate energy homeostasis by both a central and a peripheral mechanism. Peripheral administration of human NMU-25 was recently shown to inhibit food intake in mice. We examined the possibility that other NMU-related peptides exert an anorectic activity by intraperitoneal (i.p.) administration. We found that rat NMU-23 and its structurally-related peptide rat neuromedin S (NMS) significantly reduced food intake in lean mice, whereas NMU-8, an active fragment of the octapeptide sequence conserved in porcine, human and mouse NMU, had no effect. When rat NMU-23, NMU-8, and rat NMS were covalently conjugated to polyethylene glycol (PEG) (PEGylation) at the N-terminus of these peptides, PEGylated NMU-8 showed the most long-lasting and robust anorectic activity. The exploration of the linker between NMU-8 and PEG using hetero-bifunctional chemical cross-linkers led to an identification of PEGylated NMU-8 analogs with higher affinity for NMU receptors and with more potent anorectic activity in lean mice. The PEGylated NMU-8 showed potent and robust anorectic activity and anti-obesity effect in diet-induced obesity (DIO) mice by once-daily subcutaneous (s.c.) administration. These results suggest that PEGylated NMU-8 has the therapeutic potential for treatment of obesity.     

Neuromedin U acts in the central nervous system to inhibit gastric acid secretion via CRH system

Neuromedin U (NMU) is a hypothalamic peptide involved in energy homeostasis and stress responses. NMU, when administered intracerebroventricularly, decreases food intake and body weight while increasing body temperature and heat production. In addition, NMU, acting via the corticotropin-releasing hormone (CRH) system, induces gross locomotor activity and stress responses. We studied the effect of intracerebroventricularly administered NMU (0.5-4 nmol) in the regulation of gastric functions in conscious rats. Intracerebroventricular administration of NMU significantly decreased gastric acid output to 30-60% and gastric emptying to 35-70% in a dose-dependent manner. Vagotomy did not abolish the inhibitory effect of NMU on pentagastrin-induced gastric acid secretion. Pretreatment with indomethacin (10 mg/kg), an inhibitor of prostaglandin synthesis, also did not affect NMU-induced acid inhibition. Pretreatment with anti-CRH IgG (1 microg/rat), however, completely blocked NMU-induced acid inhibition (P < 0.01). Administration of yohimbine (4 mg/kg), an alpha(2)-adrenergic receptor antagonist, also abolished NMU-induced acid inhibition (P < 0.01). These findings suggest that NMU is critical in the central regulation of gastric acid secretion via CRH.     

Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway

Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.     

Nphe1]nociceptin(1-13)-NH2 antagonizes nociceptin-induced hypotension, bradycardia, and hindquarters vasodilation in the anesthetized rat

The purpose of this study was to investigate the effects of [Nphe1]nociceptin(1-13)-NH2 on nociceptin-induced decreases in mean arterial pressure (MAP), heart rate (HR), and hindquarters vascular bed resistance (HVBR) of the anesthetized rat. The results showed that i.c.v. or i.v. [Nphe1]nociceptin(1-13)-NH2 (1.5-12 nmol/kg and 5-120 nmol/kg, respectively) could antagonize the depressor effects of i.c.v. or i.v. nociceptin (3 and 30 nmol/kg, respectively) on MAP and HR. Furthermore, [Nphe1]nociceptin(1-13)-NH2 (5-120 nmol/kg) could reverse nociceptin (30 nmol/kg)-induced decrease of HVBR. However, [Nphe1]nociceptin(1-13)-NH2 had no significant effects on similar effects induced by morphine. Our results suggest that [Nphe1]nociceptin(1-13)-NH2 acts as a selective antagonist of the nociceptin receptor in the cardiovascular system of the rat.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for neuromedin U in stress response.

Neuromedin U (NMU) is a hypothalamic peptide that has been recently found to reduce food intake, but few is known about its other functions in the central nervous system. We here studied behavioral activities induced by an intracerebroventricular (ICV) administration of NMU in rats and mice. NMU increased gross locomotor activity, face washing behavior, and grooming. NMU-induced stress response was significantly abolished by pretreatment with an antagonist of corticotropin-releasing hormone (CRH), alpha-helical CRH (9-41) (alpha-hCRH), or anti-CRH IgG. NMU did not induce locomotor activity in CRH knockout mice. NMU that interacts anatomically and/or functionally with the CRH system is a novel physiological regulator of stress response.     

Influences of exogenous insulin on arterial blood pressure measurements of the rat

Studies were undertaken with adult male rats to test the hypothesis that euglycemic hyperinsulinemia would alter mean arterial blood pressure (MAP) and heart rate (HR) relationships by activation of the sympathetic nervous system. Conscious rats were infused either with insulin or control vehicle (0, 0.47, 1.5, 4.7, 15.0 mU.kg-1.min-1) for 75 min before injection of hexamethonium. Compared with the control period, insulin infusion significantly increased MAP by 7.1 +/- 0.1, 12.7 +/- 2.0, and 19.7 +/- 0.3 (SE) mmHg and HR by 44 +/- 8.4, 66 +/- 10.3, and 95 +/- 6.3 beats/min, respectively, during the three highest rates of infusion. The dose-dependent increases in MAP and HR were due to increases in the activity of hexamethonium-sensitive pathways. In chemically sympathectomized rats, insulin infusion did not produce a significant increase in either MAP or HR. The influence of exogenous norepinephrine on MAP and HR was also studied after insulin infusion. Compared with the insulin-vehicle infusion, insulin infusion significantly depressed (P less than 0.05) the norepinephrine dose-response increase in MAP. In addition, isolated smooth muscle strips were studied to determine the influence of insulin on their in vitro responses to increasing doses of norepinephrine. Although insulin did not alter contractility, it significantly (P less than 0.05) decreased the sensitivity of the vascular strips to norepinephrine. Collectively, the data from these euglycemic experiments indicated that infusions of insulin caused increases in HR and MAP because of activation of the sympathetic nervous system, even though the responsiveness of the vascular smooth muscle was depressed.     

Geomagnetic field effect on cardiovascular regulation

The goal of the present research was try to explain the physiological mechanism for the influence of the geomagnetic field (GMF) disturbance, reflected by the indices of the geomagnetic activity (K, K(p), A(k), and A(p) indices), on cardiovascular regulation. One hundred forty three experimental runs (one daily) comprising 50 min hemodynamic monitoring sequences were carried out in rabbits sedated by pentobarbital infusion (5 mg/kg/h). We examined the arterial baroreflex effects on the short term blood pressure and heart rate (HR) variabilities reflected by the standard deviation (SD) of the average values of the mean femoral arterial blood pressure (MAP) and the HR. Baroreflex sensitivity (BRS) was estimated from blood pressure/HR response to intravenous (i.v.) bolus injections of vasoconstrictor (phenylephrine) and vasodilator (nitroprusside) drugs. We found a significant negative correlation of increasing GMF disturbance (K(p)) with BRS (P = 0.008), HR SD (P =0.022), and MAP SD (P = 0.002) signifying the involvement of the arterial baroreflex mechanism. The abrupt change in geomagnetic disturbance from low (K = 0) to high (K = 4-5) values was associated with a significant increase in MAP (83 +/- 5 vs. 99 +/- 5 mm Hg, P = 0.045) and myocardial oxygen consumption, measured by MAP and HR product (24100 +/- 1800 vs. 31000 +/- 2500 mm Hg. bpm, P = 0.034), comprising an additional cardiovascular risk. Most likely, GMF affects brainstem and higher neural cardiovascular regulatory centers modulating blood pressure and HR variabilities associated with the arterial baroreflex.     

The effect of CNS opioid on autonomic nervous and cardiovascular responses in diet-induced obese rats

The intracerebroventricular (i.c.v.) infusion of beta-endorphin can cause either a decrease in blood pressure in normal rats or an increase in obese rats. Diet-induced obesity is associated with an increase of hypothalamic mu opioid receptors. Since beta-endorphins act by opioid receptors, we investigated the effect of CNS mu as well as kappa opioid receptor agonist and antagonist on mean blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male Wistar rats fed either a high fat (HF) (40% fat by weight) or a regular low fat (control) (4% fat by weight) diet. After a 12-week-feeding period the animals were implanted with i.c.v. cannulas and 3-5 days later they were anesthetized and instrumented to record MAP, HR and RSNA. HF rats have higher MAP and the i.c.v. injection of a mu opioid agonist (DAMGO) initially decreased the MAP and then increased MAP, HR and RSNA in the normal animals. The increase was greater in HF animals. The i.c.v. injection of the mu antagonist (beta-FNA) resulted in a significantly greater decrease in MAP in HF animals. beta-FNA increased the RSNA in the HF rats but decreased it in the normal rats. The kappa agonist (dynorphin) decreased MAP in normal rats followed by a return to baseline, but not in HF rats. The kappa antagonist, nor-binaltorphimine (N-BP), increased MAP and RSNA in normal rats and to a lesser extent in HF rats. These findings suggest that rats given a high fat diet have higher blood pressures and a greater mu opioid-mediated responsiveness with a greater mu opioid-mediated autonomic tone. Additionally there is a decreased kappa responsiveness and tone in the HF rats. Both these changes, increased mu and decreased kappa responsiveness could strongly contribute to the increased blood pressure in obese animals.     

Differential cardiovascular effects of central clonidine and B-HT 920 in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of the alpha 2-adrenoceptor agonists clonidine and B-HT 920 on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of noradrenaline and adrenaline was examined in conscious unrestrained rats. The injection of 1.0 microgram clonidine significantly decreased MAP and slightly decreased HR. Plasma noradrenaline and adrenaline levels were slightly but not significantly decreased after the injection of 1 microgram clonidine. In contrast, the injection of 0.1-10.0 micrograms B-HT 920 increased MAP and decreased HR. Plasma noradrenaline and adrenaline levels were slightly increased after the injection of the 1- and 10-micrograms doses. The i.c.v. injection of the alpha 2-antagonist rauwolscine slightly but not significantly increased MAP and plasma noradrenaline and adrenaline levels. The responses to i.c.v. injection of clonidine and B-HT 920 were not changed by prior administration of rauwolscine. Neither the pressor response to B-HT 920 nor the depressor response to clonidine was abolished by rauwolscine, suggesting that neither response was mediated by alpha 2-adrenoceptors.     

The cardiovascular actions of centrally administered neuropeptide Y

The cardiovascular actions of intracerebroventricular (i.c.v.) administration of neuropeptide Y (NPY) were examined in conscious, unrestrained rats. A prolonged decrease in heart rate (HR) and a fall in mean arterial pressure (MAP) were obtained following i.c.v. administration of NPY (1 and 10 micrograms). Passive immunization with an antiserum directed against NPY confirmed that the slowing of HR following i.c.v. administration of NPY was mediated via a central nervous mechanism and not from leakage of NPY out of the brain. Administration of NPY into different brain parenchymal regions identified a putative site of action in the rostral region of the solitary tract. The mechanism of the decrease in HR caused by centrally administered NPY was investigated by i.c.v. administration of NPY to animals that were pretreated with agents that altered autonomic tone. Administration of NPY to atropine-treated animals produced a reversal of the atropine-induced tachycardia, suggesting that the NPY-induced decrease in HR was not due to augmented vagal tone. However, administration of NPY to animals pretreated with propranolol did not significantly lower HR below that obtained with propranolol alone. These data suggest that i.c.v. administration of NPY may cause a decrease in cardiac sympathetic outflow. The effects of centrally administered NPY on baroreflex function were studied. The changes in HR caused by NPY did not significantly alter baroreflex set-point or gain. These studies provide evidence that NPY acted within a brainstem region to decrease sympathetic nervous outflow, resulting in a decrease in HR and MAP.     

Hemodynamics of anesthetized ventilated mouse models: aspects of anesthetics,fluid support,and strain

This study evaluates the effects of anesthesia and fluid support on hemodynamic parameters of the mechanically ventilated mouse of four different strains. All experiments were performed at a similar surgical level of anesthesia, as indicated by the probing of the pedal withdrawal reflex. Three anesthetic regimens [fentanyl-fluanisone-midazolam (FFM), ketamine-medetomidine-atropine (KMA), and isoflurane (ISO)], four commonly used mouse strains (Swiss, CD-1, BalbC, and C57Bl6), and three different fluid support strategies (no fluid, 0.2 ml x h(-1) x 10 g(-1) of 6% polystarch solution, and 0.5 ml x h(-1) x 10 g(-1) saline) were studied. Mean arterial pressure (MAP) or heart rate (HR) was similar among the four strains of mice except a trend toward lower HR for the BalbC mice. In terms of MAP, KMA is the preferred anesthetic for the Swiss and CD-1 mice, whereas KMA or ISO are recommended for BalbC or C57Bl6 mice. In terms of HR, ISO is the preferred anesthetic for the Swiss, CD-1, and C57Bl6 strains. No differences in HR for the three anesthetics were observed for the BalbC strain. Compared with administration of no fluid, both saline and polystarch administration similarly increased MAP by 7 +/- 2, 10 +/- 2, and 11 +/- 2 mmHg at t = 1, 2, and 3 h, respectively, whereas fluid administration was without effect on HR. Saline supplementation resulted in an increased dry-to-wet ratio of the heart and both fluid regimens decreased total hemoglobin in the blood from 12.6 +/- 0.5 to 10.4 +/- 0.5 g/100 ml. Saline administration was associated with blood acidosis (pH 7.20 +/- 0.03) compared with the Haes (pH 7.29 +/- 0.02) or no-fluid group (pH 7.34 +/- 0.03), whereas PCO(2) was approximately 30 mmHg for all groups. We conclude that at similar surgical levels of anesthesia, the preferable type of anesthesia (ISO or KMA, but never FFM) depends on the strain used and whether MAP or HR is the focus of study. Additional fluid support is beneficial in terms of raising arterial blood pressure, although this is at the cost of changes in organ water content and increased anemia.     

Perfusion pressure manipulation in porcine sepsis: effects on intestinal hemodynamics

Limited information is available about selection of the threshold for arterial blood pressure in critically ill patients, particularly in sepsis when normal organ blood flow autoregulation may be altered. The present experimental study investigated whether increasing perfusion pressure using norepinephrine in normotensive hyperdynamic porcine bacteremia affects intestinal macro- and microcirculation. Nine pigs received continuous i.v. administration of Pseudomonas aeruginosa (PSAE) to develop hyperdynamic, normotensive (mean arterial pressure [MAP] 65 mm Hg) sepsis. Norepinephrine was used to achieve 10-15 % increase in MAP. Mesenteric arterial blood flow (Q(gut)), ileal mucosal microvascular perfusion (LDF(gut)) and ileal-end-tidal PCO(2) gap (PCO(2) gap) were measured before norepinephrine, after 60 min of norepinephrine infusion and 60 min after norepinephrine infusion had been discontinued. During a 12 h period of PSAE infusion all pigs developed hyperdynamic circulation with significantly decreased MAP. Although the mesenteric blood flow remained unchanged, infusion of PSAE resulted in a gradual fall of ileal microvascular perfusion, which was associated with progressively rising PCO(2) gap. Norepinephrine which induced a 10-15 % increase in perfusion pressure (i.e. titrated to attain near baseline values of MAP) affected neither Q(gut) nor the intestinal blood flow distribution (Q(gut)/CO). Similarly, norepinephrine did not change either LDF(gut) or PCO(2) gap. In this hyperdynamic, normotensive porcine bacteremia, norepinephrine-induced increase in perfusion pressure exhibited neither beneficial nor deleterious effects on intestinal macrocirculatory blood flow and ileal mucosal microcirculation. The lack of changes suggests that the gut perfusion was within its autoregulatory range.     

Participation of the inducible nitric oxide synthase on atrial natriuretic peptide plasma concentration during endotoxemic shock

Atrial natriuretic peptide (ANP) is a hormone secreted in response to atrial or ventricular volume expansion and pressure overload, respectively. However, it has been found in studies with animals and patients an increase in ANP plasma concentration, during advanced septic shock, despite the fall in mean arterial pressure (MAP).

Several studies support the hypothesis that NO may be involved in the regulation of ANP release. Since NO may have an effect on ANP release, we hypothesized that NO pathway may participate in the control of the ANP release induced by the endotoxemic shock. Thus, the purpose of the present study was to assess the effect of the intravenous (i.v.) and intracereboventricular (i.c.v.) administration of aminoguanidine, an iNOS blocker, on plasma ANP levels and MAP during experimental endotoxemic shock.

Experiments were performed on adult male Wistar rats weighing 180–240 g. Rats were injected i.v. by bolus injection with 1.5 mg/kg of Lipopolysaccharide (LPS) or saline (0.5 mL) and were decapitated 2, 4 and 6 h after LPS injection for ANP determination by radioimmunoassay. In a separate set of experiments, rats received intravenous (i.v.) (100 mg/kg) or intracerebroventricular (i.c.v.) (250 μg in a final volume of 2 μL) injection of aminoguanidine (AG). Thirty minutes after the i.c.v. or i.v. injections, animals received LPS and were decapitated 2, 4 and 6 h later to determine plasma ANP concentration. In the two set of experiments MAP and heart rate (HR) were measured each 15 min for a period of 6 h using a polygraph.

When animals were injected with LPS, a reduction (p < 0.01) in MPA and an increase in HR occurred. A significant increase in plasma ANP concentration occurred, coinciding with the period of drop in blood pressure.

We found a significant increase in plasma ANP concentration after AG plus LPS injection, when compared to the rats treated with LPS plus saline. Further, the administration of AG plus LPS attenuated the decrease in the MAP after LPS and attenuated the increase in the HR when compared to the rats treated with LPS plus saline.

Our study suggests that inducible NOS pathway may activate an inhibitory control mechanism that attenuates ANP secretion, which is not regulated by the changes in blood pressure.     

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 microg) and angiotensin II (Ang II, 150 ng) were measured. Concentration-response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88+/-2 mm Hg to 83+/-2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86+/-1 mm Hg to 89+/-1 mm Hg), increased HR (350+/-3 beats/min to 371+/-3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.