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1.
Br J Pharmacol ; 173(4): 752-65, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26103560

ABSTRACT

BACKGROUND AND PURPOSE: Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1ß and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1ß and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH: Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS: 1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1ß, as well as protein levels of active caspase-1 and mature IL-1ß. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS: Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1ß pathway as a potential therapeutic target in hypertension.


Subject(s)
Hypertension/metabolism , Inflammasomes/metabolism , Kidney Diseases/metabolism , Animals , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/metabolism , CARD Signaling Adaptor Proteins , Desoxycorticosterone/administration & dosage , Hypertension/chemically induced , Inflammasomes/antagonists & inhibitors , Kidney Diseases/chemically induced , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Salts/administration & dosage
2.
Spinal Cord ; 49(10): 1036-41, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21625243

ABSTRACT

STUDY DESIGN: Animal proof of principle study. OBJECTIVES: To determine whether capromorelin, a compound that causes defecation by stimulating ghrelin receptors within the lumbosacral defecation centers, is effective after spinal cord injury (SCI), and whether SCI significantly alters sensitivity to the compound. SETTING: University of Melbourne and Austin Hospital, Melbourne, Australia. METHODS: Rats were subjected to spinal cord contusion injury or were sham-operated. At 6 weeks after surgery, effects of capromorelin on blood pressure, heart rate and propulsive contractions of the colorectum were investigated. RESULTS: Capromorelin caused robust propulsive activity in the colorectum soon after its application. The compound was similarly effective in naïve, sham-operated and spinal cord-injured rats. Blood pressure increases caused by capromorelin were not exaggerated after SCI, and there was no evidence of phasic blood pressure increases when the colon was contracted by the compound. CONCLUSION: Capromorelin is a therapeutic compound that could potentially be used to relieve constipation by triggering defecation in spinal cord-injured patients.


Subject(s)
Constipation/drug therapy , Constipation/physiopathology , Defecation/drug effects , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptors, Ghrelin/agonists , Spinal Cord Injuries/physiopathology , Animals , Constipation/etiology , Defecation/physiology , Disease Models, Animal , Growth Hormone/metabolism , Male , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/physiology , Spinal Cord Injuries/complications
3.
Neuroscience ; 166(2): 671-9, 2010 Mar 17.
Article in English | MEDLINE | ID: mdl-20060438

ABSTRACT

Agonists of ghrelin receptors can lower or elevate blood pressure, and it has been suggested that the increases in blood pressure are caused by actions at receptors in the spinal cord. However, this has not been adequately investigated, and the locations of neurons in the spinal cord that express ghrelin receptors, through which blood pressure increases may be exerted, are not known. We investigated the effects within the spinal cord of two non-peptide ghrelin receptor agonists, GSK894490 and CP464709, and two peptide receptor agonists, ghrelin and des-acyl ghrelin, and we used polymerase chain reaction (PCR) and in situ hybridization to examine ghrelin receptor expression. I.v. application of the non-peptide ghrelin receptor agonists caused biphasic changes in blood pressure, a brief drop followed by a blood pressure increase that lasted several minutes. The blood pressure rise, but not the fall, was antagonized by i.v. hexamethonium. Application of these agonists or ghrelin peptide directly to the spinal cord caused only a blood pressure increase. Des-acyl ghrelin had no significant action. The maximum pressor effects of agonists occurred with application at spinal cord levels T9 to T12. Neither i.v. nor spinal cord application of the agonists had significant effect on heart rate or the electrocardiogram. Ghrelin receptor gene expression was detected by PCR and in situ hybridization. In situ hybridization localized expression to neurons, including autonomic preganglionic neurons of the intermediolateral cell columns at all levels from T3 to S2. The numbers of ghrelin receptor expressing neurons in the intermediolateral cell columns were similar to the numbers of nitric oxide synthase positive neurons, but there was little overlap between these two populations. We conclude that activation of excitatory ghrelin receptors on sympathetic preganglionic neurons increases blood pressure, and that decreases in blood pressure caused by ghrelin agonists are mediated through receptors on blood vessels.


Subject(s)
Adrenergic Fibers/metabolism , Autonomic Fibers, Preganglionic/metabolism , Neurons/metabolism , Receptors, Ghrelin/metabolism , Spinal Cord/metabolism , Animals , Blood Pressure/drug effects , Ghrelin/metabolism , Ghrelin/pharmacology , Heart Rate/drug effects , In Situ Hybridization , Male , Piperazines/pharmacology , Pyridines/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/agonists , Receptors, Ghrelin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Serine/analogs & derivatives , Serine/pharmacology , Spinal Cord/drug effects , Sulfonamides/pharmacology
4.
Neurogastroenterol Motil ; 19(5): 383-9, 2007 May.
Article in English | MEDLINE | ID: mdl-17509020

ABSTRACT

The movements of the intestine shift between different motor patterns, including between propulsion and mixing, but there is little information concerning mechanisms that may lead to changes in the patterns of motility. We have investigated the influence on intestinal motility of drugs that affect the after-hyperpolarization potential (AHP) of intrinsic primary afferent neurons (IPANs). The current of the AHP is carried by the intermediate conductance, calcium-activated, potassium (IK) channel. In anaesthetized rats, the IK channel blocker, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (0.05-1 mg kg(-1), i.v.) disrupted the regular propulsive pressure waves that occur in the small intestine and reduced propulsion of the contents (after 1 mg kg(-1), the fluid propelled was <25% of control). If the propulsion in the intestine was regular, the IK channel opener, 5,6-dichloro-1-ethyl-2-benzimidazolinone (DC-EBIO, 0.1 mg kg(-1) h(-1)) had no effect. DC-EBIO (0.1 mg kg(-1) h(-1)) restored propulsive activity after the nitric oxide synthase inhibitor, Nomega-nitro-l-arginine had changed motility to a mixing pattern. We suggest that the AHP determines the synchrony of action potential firing in synaptically coupled IPANs, and that this synchrony influences the patterns of firing of muscle motor neurons, and hence the pattern of contraction of the muscle and whether the pattern is predominantly propulsive or predominantly mixing.


Subject(s)
Gastrointestinal Motility/physiology , Intestine, Small/metabolism , Potassium Channels, Calcium-Activated/metabolism , Animals , Benzimidazoles/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Humans , Intestine, Small/drug effects , Male , Membrane Potentials/physiology , Neurons, Afferent/cytology , Neurons, Afferent/metabolism , Nitroarginine/pharmacology , Potassium Channel Blockers/metabolism , Potassium Channel Blockers/pharmacology , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley
5.
Neurogastroenterol Motil ; 17(5): 714-20, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16185310

ABSTRACT

We have used spatio-temporal maps derived from video images to investigate propagated contractions of the rat small intestine in vivo. The abdomen, including an exteriorized segment of jejunum, was housed in a humid chamber with a viewing window. Video records were converted to spatio-temporal maps of jejunal diameter changes. Intraluminal pressure and fluid outflow were measured. Contractions occupied 3.8 +/- 0.2 cm of intestine and propagated anally at 3.1 +/- 0.2 mm s(-1) when baseline pressure was 4 mmHg. Contractions at any one point lasted 8.7 +/- 0.6 s. Contractions often occurred in clusters; within cluster frequencies were 2.28 +/- 0.04 min(-1). Pressure waves, with amplitudes greater than about 9 mmHg, expelled fluid when the baseline pressure was 4 mmHg. In the presence of L-NAME, circular muscle contractions occurred at a high frequency, but they were not propagated. We conclude that video recording methods give good spatio-temporal resolution of intestinal movement when applied in vivo. They reveal neurally-mediated propulsive contractions, similar to those previously recorded from intestinal segments in vitro. The propagated contractions had speeds of propagation that were slower and frequencies of occurrence that were less than speeds and frequencies of slow waves in the rat small intestine.


Subject(s)
Jejunum/physiology , Muscle Contraction/physiology , Muscle, Smooth/physiology , Anal Canal/physiology , Animals , In Vitro Techniques , Male , Microscopy, Video , Motor Activity , Rats , Rats, Sprague-Dawley
6.
Neurogastroenterol Motil ; 17(2): 262-72, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15787946

ABSTRACT

We have developed methods that allow correlation of propulsive reflexes of the intestine with measurements of intraluminal pressure, fluid movement and spatio-temporal maps of intestinal wall movements for the first time in vivo. A segment of jejunum was cannulated and set up in a Trendelenburg recording system while remaining connected to the vascular and nerve supply of the anaesthetized rat. The resting intraluminal pressure in intact intestine was 2-4 mmHg. Hydrostatic pressures of 2, 4, 8 and 16 mmHg were imposed. At a baseline pressure of 4 mmHg, propulsive waves generated pressures of 9 +/- 1 mmHg, that progressed oral to anal at 2-5 mm s(-1). Individual propulsive waves propelled 0.8 +/- 0.4 mL of fluid. The frequency of propulsive waves increased with pressure, but peristaltic efficiency (mL per contraction) decreased with pressure increase between 4 and 16 mmHg. Atropine, as a bolus, transiently blocked peristalsis, but caused maintained block when infused. Hexamethonium blocked propulsive contractions. Inhibition of nitrergic transmission converted regular peristalsis to non-propulsive contractions. These studies demonstrate the utility of an adapted Trendelenburg method for quantitative investigation of motility and pharmacology of enteric reflexes in vivo.


Subject(s)
Intestine, Small/physiology , Peristalsis/physiology , Animals , Atropine/pharmacology , Enzyme Inhibitors/pharmacology , Ganglionic Blockers/pharmacology , Hexamethonium/pharmacology , Intestinal Mucosa/drug effects , Intestinal Mucosa/physiology , Male , Muscarinic Antagonists/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/metabolism , Peristalsis/drug effects , Pressure , Rats , Videotape Recording
7.
Arch Dis Child ; 89(1): 22-5, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14709496

ABSTRACT

BACKGROUND: Currently, there is no consistent evidence that breast feeding reduces the risk for sudden infant death syndrome (SIDS). Arousal from sleep is believed to be an important survival mechanism that may be impaired in victims of SIDS. Previously it has been shown that arousability is impaired by the major risk factors for SIDS such as prone sleeping and maternal smoking. AIMS: To establish whether arousability was altered by method of feeding, and whether breast fed infants would have lower arousal thresholds. METHODS: Forty three healthy term infants were studied using daytime polysomnography on three occasions: 2-4 weeks post-term, 2-3 months post-term, and 5-6 months post-term. Multiple measurements of arousal threshold (cm H(2)O) in response to nasal air jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS) while infants slept supine. Arousal thresholds and sleep period lengths were compared between formula fed and breast fed infants at each age. RESULTS: Arousal thresholds were not different between breast fed and formula fed infants in QS. However, in AS breast fed infants were significantly more arousable than formula fed infants at 2-3 months of age. There was no difference between groups of infants when sleep period length was compared at any study. CONCLUSIONS: Breast fed infants are more easily aroused from AS at 2-3 months of age than formula fed infants. This age coincides with the peak incidence of SIDS.


Subject(s)
Arousal/physiology , Bottle Feeding/adverse effects , Breast Feeding , Infant Formula , Sleep/physiology , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Sudden Infant Death/epidemiology , Time Factors
8.
Arch Dis Child Fetal Neonatal Ed ; 87(2): F100-5, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12193515

ABSTRACT

OBJECTIVES: To investigate whether a history of maternal tobacco smoking affected the maturation of arousal responses and whether sleeping position and infant age alters these relations. DESIGN: Healthy term infants (13 born to mothers who did not smoke and 11 to mothers who smoked during pregnancy) were studied using daytime polysomnography on three occasions: (a) two to three weeks after birth, (b) two to three months after birth, and (c) five to six months after birth. Multiple measurements of arousal threshold in response to air jet stimulation were made in both active sleep (AS) and quiet sleep (QS) when infants slept both prone and supine. RESULTS: Maternal smoking significantly elevated arousal threshold in QS when infants slept supine at 2-3 months of age (p<0.05). Infants of smoking mothers also had fewer spontaneous arousals from QS at 2-3 months in both prone (p<0.05) and supine (p<0.001) sleeping positions. In infants of non-smoking mothers, arousal thresholds were elevated in the prone position in AS at 2-3 months (p<0.01) and QS at 2-3 weeks (p<0.05) and 2-3 months (p<0.001). CONCLUSIONS: Maternal tobacco smoking significantly impairs both stimulus induced and spontaneous arousal from QS when infants sleep in the supine position, at the age when the incidence of sudden infant death syndrome is highest.


Subject(s)
Arousal/physiology , Prenatal Exposure Delayed Effects , Sleep/physiology , Smoking/adverse effects , Cotinine/urine , Female , Humans , Infant , Longitudinal Studies , Male , Mothers , Pregnancy , Prone Position , Smoking/urine
9.
J Pediatr ; 138(6): 811-6, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11391321

ABSTRACT

OBJECTIVE: To investigate whether the prone sleeping position impaired arousal from sleep in healthy infants and whether this impairment was related to cardiorespiratory variables, temperature, or age. STUDY DESIGN: Healthy term infants (n = 24) were studied with daytime polysomnography on 3 occasions: 2 to 3 weeks after birth, 2 to 3 months after birth, and 5 to 6 months after birth. Multiple measurements of arousal threshold (cm H(2)O) in response to air-jet stimulation applied alternately to the nares were made in both active sleep and quiet sleep when infants slept both prone and supine. RESULTS: Arousal thresholds were significantly higher in both active sleep and quiet sleep when infants slept prone at 2 to 3 weeks and 2 to 3 months, but not at 5 to 6 months. These increases were independent of any sleep position-related change in either rectal or abdominal skin temperature, respiratory rate, oxygen saturation, or heart rate. CONCLUSIONS: The prone position significantly impairs arousal from both active sleep and quiet sleep in healthy term infants. This impairment in arousability occurred with no clinically significant changes in cardiorespiratory variables or body temperature. Decreased arousability from sleep in the prone position provides an important insight into its role as a risk factor for sudden infant death syndrome.


Subject(s)
Arousal/physiology , Prone Position , Sleep/physiology , Female , Heart Rate , Humans , Infant , Infant, Newborn , Male , Oxygen/analysis , Respiratory Physiological Phenomena , Skin Temperature , Sudden Infant Death/etiology , Supine Position
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