ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri have a long history of use in the traditional treatment of various ailments including hypertension. Literature reports have indicated that it is a potent antihypertensive herbal medication used traditionally. AIM OF THE STUDY: This study was carried out to investigate the antihypertensive and vasodilatory activity of four solvents extracts of P. niruri namely; petroleum ether (PEPN), chloroform (CLPN), methanol (MEPN) and water (WEPN), with the aim of elucidating the mechanism of action and identifying the phytochemical constituents. MATERIALS AND METHODS: Male Spontaneous Hypertensive Rats (SHRs) were given oral gavage of P. niruri extract daily for two weeks and the blood pressure was recorded in vivo. We also determine the vasodilation effect of the extracts on rings of isolated thoracic aorta pre-contracted with phenylephrine (PE, 1 µM). Endothelium-intact or endothelium-denuded aorta rings were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM) and Methylene blue (MB 10 µM), sGC inhibitors; Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 µM) a nitric oxide synthase (NOS) inhibitor; atropine (10 µM), a cholinergic receptor blocker; indomethacin (10 µM), a cyclooxygenase inhibitor and various K+ channel blockers such as glibenclamide (10 µM) and tetraethyl ammonium (TEA 10 µM) for mechanism study. RESULTS: SHRs receiving P. niruri extracts showed a significant decrease in their blood pressure (BP) when compared to the baseline value, with PEPN being more potent. The extracts (0.125-4 mg/mL) also induced vasorelaxation on endothelium-intact aorta rings. PEPN elicited the most potent maximum relaxation effect (Rmax). Mechanism assessment of PEPN showed that its relaxation effect is significantly suppressed in endothelium-denuded aorta rings. Pre-incubation of aorta rings with atropine, L-NAME, ODQ, indomethacin, and propranolol also significantly attenuated its relaxation effect. Conversely, incubation with TEA and glibenclamide did not show a significant effect on PEPN-induced relaxation. CONCLUSION: This study indicates that the antihypertensive activity of P. niruri extract is mediated by vasoactive phytoconstituents that dilate the arterial wall via endothelium-dependent pathways and ß-adrenoceptor activity which, in turn, cause vasorelaxation and reduce blood pressure.
Subject(s)
Antihypertensive Agents/pharmacology , Phyllanthus , Plant Extracts/pharmacology , Vasodilator Agents/pharmacology , Animals , Antihypertensive Agents/chemistry , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Blood Pressure/drug effects , Cyclic GMP/physiology , Heart Rate/drug effects , Hypertension/drug therapy , Hypertension/physiopathology , In Vitro Techniques , Nitric Oxide/physiology , Phytochemicals/analysis , Phytochemicals/pharmacology , Plant Extracts/chemistry , Rats, Inbred SHR , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/physiology , Signal Transduction/drug effects , Vasodilation/drug effects , Vasodilator Agents/chemistryABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Citrus reticulatae Pericarpium (Chen pi) was widely used as an important ingredient in the prescription of TCM to treat phlegm fluid retention type hypertension. Since Chen pi is involved in treatment as antihypertensive TCM formula, we have reasonable expectation in believing that it might possess vasorelaxant activity. AIM OF THE STUDY: This study is designed to investigate the vasorelaxant effect of Chen pi and to study its pharmacology effects. MATERIALS AND METHODS: The vasorelaxant effect of water extract of Chen pi (CRW) were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. The fingerprint of Chen pi and the extracts were developed with quantification of hesperidin content by HPTLC. RESULTS: CRW exhibited the strongest vasorelaxant activity. CRW caused the relaxation of the phenylephrine pre-contracted aortic rings in the presence and absence of endothelium as well as in potassium chloride pre-contracted endothelium-intact aortic ring. The incubation of propranolol (ß-adrenergic receptor blocker), atropine (muscarinic receptor blocker), Nω-nitro-L-arginine methyl ester (NO synthase inhibitor), ODQ (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV blocker), barium chloride (Kir blocker), and glibenclamide (KATP blocker) significantly reduced the vasorelaxant effects of CRW. CRW was also found to be active in reducing Ca2+ releases from the sarcoplasmic reticulum and suppressing the voltage-operated calcium channels. CONCLUSION: The vasorelaxant effect of CRW on rat aorta involves NO/sGC, calcium and potassium channels, muscarinic and ß-adrenergic receptors.
Subject(s)
Aorta, Thoracic/drug effects , Citrus , Plant Extracts/pharmacology , Vasodilator Agents/pharmacology , Animals , Aorta, Thoracic/physiology , Calcium Channels/physiology , Citrus/chemistry , In Vitro Techniques , Male , Phytochemicals/analysis , Phytochemicals/pharmacology , Plant Extracts/chemistry , Potassium Channels/physiology , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/physiology , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/physiology , Vasodilator Agents/chemistryABSTRACT
The sympathetic nervous system, via epinephrine and norepinephrine, regulates ß-adrenergic receptor (ß-AR) expression, and renal sympathetic activation causes sustained increases in blood pressure by enhanced renin release. In this study, we aim to investigate the effect and underlying mechanism of acupuncture at Taichong (LR3) on renal sympathetic activity in spontaneously hypertensive rats. Unanesthetized rats were subject to daily acupuncture for 2 weeks. Mean blood pressure (MBP) and heart rate variability (HRV) were monitored at days 0, 7, and 14 by radiotelemetry. After euthanasia on the 14th day, blood and the kidneys were collected and subject to the following analyses. Epinephrine and norepinephrine were detected by ELISA. The expression of ß-ARs was studied by western blotting and PCR. The renin content was analyzed by radioimmunoassay. 14-day acupuncture significantly attenuates the increase of MBP. The HRV indices, the standard deviation of all normal NN intervals (SDNN), and the ratio of the low-frequency component to the high-frequency component (LF/HF) were improved following acupuncture. Renal sympathetic activation induced upregulation of epinephrine, norepinephrine, and renin content were attenuated by acupuncture. In addition, acupuncture decreased ß1-AR expression and improved ß2-AR expression. These results indicated that acupuncture relieves the increased MBP via the regulation of renal sympathetic activity and ß-ARs.
Subject(s)
Acupuncture Therapy , Blood Pressure , Heart Rate , Receptors, Adrenergic, beta/physiology , Sympathetic Nervous System/physiology , Animals , Epinephrine/metabolism , Male , Norepinephrine/metabolism , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Renin/metabolismABSTRACT
AIMS: Our previous studies demonstrated that remote electro-stimulation (RES) increased myocardial GSK3 phosphorylation and attenuated ischemia/ reperfusion (I/R) injury in rat hearts. However, the role of various opioid receptors (OR) subtypes in preconditioned RES-induced myocardial protection remains unknown. We investigated the role of OR subtype signaling in RES-induced cardioprotection against I/R injury of the rat heart. METHODS & RESULTS: Male Spraque-Dawley rats were used. RES was performed on median nerves area with/without pretreatment with various receptors antagonists such as opioid receptor (OR) subtype receptors (KOR, DOR, and MOR). The expressions of Akt, GSK3, and PKCε expression were analyzed by Western blotting. When RES was preconditioned before the I/R model, the rat's hemodynamic index, infarction size, mortality and serum CK-MB were evaluated. Our results showed that Akt, GSK3 and PKCε expression levels were significantly increased in the RES group compared to the sham group, which were blocked by pretreatment with specific antagonists targeting KOR and DOR, but not MOR subtype. Using the I/R model, the duration of arrhythmia and infarct size were both significantly attenuated in RES group. The mortality rates of the sham RES group, the RES group, RES group + KOR antagonist, RES group + DOR/MOR antagonists (KOR left), RES group + DOR antagonist, and RES group + KOR/MOR antagonists (DOR left) were 50%, 20%, 67%, 13%, 50% and 55%, respectively. CONCLUSION: The mechanism of RES-induced myocardial protection against I/R injury seems to involve multiple target pathways such as Akt, KOR and/or DOR signaling.
Subject(s)
Electric Stimulation , Myocardial Reperfusion Injury/prevention & control , Receptors, Opioid/metabolism , Signal Transduction , Animals , Ischemic Preconditioning , Male , Myocardium/enzymology , Myocardium/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha/physiology , Receptors, Adrenergic, beta/physiology , Receptors, Muscarinic/physiologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Pistacia integerrima J.L. Stewart ex Brandis (Family: Anacardiaceae) galls are used in Indian ethnomedicine for its anti-asthmatic, sedative and spasmolytic properties, however, there are no scientific studies demonstrating its spasmolytic activity. The present investigation deals with the evaluation of relaxant and spasmolytic activities of the essential oil isolated from the galls of Pistacia integerrima J.L. Stewart ex Brandis (EOPI). MATERIALS AND METHODS: In vitro pharmacological assays were carried out on rabbit jejunum spontaneous contractions, guinea pig ileum. The present investigation studied the relaxation of basal tone of isolated guinea pig ileum by possible involvement of NO, prostaglandins, membrane Na(+) channels, potassium channel, enteric nervous system, adrenoceptors, Ca(2+) channels. Additional studies were conducted for comparison of the relaxant effects of EOPI on CaCl2 induced contraction in calcium free tyrode solution, effect on nifedipine insensitive component of ACh-induced contraction and on the contractile machinery to intracellular [Ca(2+)] on isolated guinea pig ileum. RESULTS: EOPI at non-relaxing dose potentiated the isoprenaline induced relaxation of rabbit jejunum. EOPI (50 µg/mL) exhibited 28% relaxation of basal tone of 60 mM K(+) induced contraction which is unaltered by preincubation with 0.5 mM hexamethonium, 0.5 µM Tetrodotoxin, 1 µM indomethacin, and 100 µM L-NG-Nitroarginine Methyl Ester (L-NAME). EOPI inhibited Ca(2+) induced contraction of isolated guinea pig ileum in Ca(2+) free medium. EOPI (10 µg/ml) potentiated the reversal of a KCl-induced tonic contraction has been observed in Ca(2+) free medium. CONCLUSION: The present investigation reinforces the use of Pistacia integerrima Stewart ex Brandis as antispasmodic in folk medicine. Moreover, it is demonstrated the involvement of ß- adrenoceptors and calcium channels in this activity, but not the participation of nicotinic receptors, Na(+) channels, prostaglandins or nitric oxide.
Subject(s)
Oils, Volatile/pharmacology , Parasympatholytics/pharmacology , Pistacia , Acetylcholine/pharmacology , Animals , Calcium Channels/physiology , Calcium Chloride/pharmacology , Epinephrine/pharmacology , Guinea Pigs , Hexamethonium/pharmacology , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Indomethacin/pharmacology , Jejunum/drug effects , Jejunum/physiology , Male , Mice , Muscle Contraction/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Nifedipine/pharmacology , Oils, Volatile/toxicity , Parasympatholytics/toxicity , Potassium/pharmacology , Rabbits , Receptors, Adrenergic, beta/physiology , Tetrodotoxin/pharmacologyABSTRACT
This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Electroacupuncture , Neuralgia/chemically induced , Paclitaxel/adverse effects , Receptors, Adrenergic, alpha-2/physiology , Receptors, Adrenergic, beta/physiology , Receptors, Opioid/physiology , Acupuncture Points , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Mice, Inbred ICR , Neuralgia/therapy , Paclitaxel/administration & dosage , Peptide Fragments/metabolism , Phosphorylation , Receptors, N-Methyl-D-Aspartate/metabolism , Spinal CordABSTRACT
Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/physiology , Anti-Obesity Agents/therapeutic use , Energy Metabolism/drug effects , Hypoglycemic Agents/therapeutic use , Obesity/prevention & control , 1-Deoxynojirimycin/pharmacology , Acarbose/pharmacology , Adipocytes, Brown/metabolism , Animals , Cell Line , Diet, High-Fat , Dietary Carbohydrates/administration & dosage , Dietary Carbohydrates/metabolism , Digestion/drug effects , Eating/drug effects , Glycoside Hydrolase Inhibitors , Male , Mice , Mice, Inbred C57BL , Oxygen Consumption/drug effects , Receptors, Adrenergic, beta/physiology , Signal Transduction/drug effectsABSTRACT
AIMS: Arrhythmogenic Ca(2+) waves result from uncontrolled Ca(2+) release from the sarcoplasmic reticulum (SR) that occurs with increased Ca(2+) sensitivity of the ryanodine receptor (RyR) or excessive Ca(2+) accumulation during ß-adrenergic stimulation. We hypothesized that inhibition of the L-type Ca(2+) current (I(CaL)) could prevent such Ca(2+) waves in both situations. METHODS AND RESULTS: Ca(2+) waves were induced in mouse left ventricular cardiomyocytes by isoproterenol combined with caffeine to increase RyR Ca(2+) sensitivity. I(CaL) inhibition by verapamil (0.5 µM) reduced Ca(2+) wave probability in cardiomyocytes during electrostimulation, and during a 10 s rest period after ceasing stimulation. A separate type of Ca(2+) release events occurred during the decay phase of the Ca(2+) transient and was not prevented by verapamil. Verapamil decreased Ca(2+) spark frequency, but not in permeabilized cells, indicating that this was not due to direct effects on RyR. The antiarrhythmic effect of verapamil was due to reduced SR Ca(2+) content following I(CaL) inhibition. Computational modelling supported that the level of I(CaL) inhibition obtained experimentally was sufficient to reduce the SR Ca(2+) content. Ca(2+) wave prevention through reduced SR Ca(2+) content was also effective in heterozygous ankyrin B knockout mice with excessive SR Ca(2+) accumulation during ß-adrenergic stimulation. CONCLUSION: I(CaL) inhibition prevents diastolic Ca(2+) waves caused by increased Ca(2+) sensitivity of RyR or excessive SR Ca(2+) accumulation during ß-adrenergic stimulation. In contrast, unstimulated early Ca(2+) release during the decay of the Ca(2+) transient is not prevented, and merits further study to understand the full antiarrhythmic potential of I(CaL) inhibition.
Subject(s)
Arrhythmias, Cardiac/prevention & control , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/physiology , Calcium Signaling , Calcium/metabolism , Ryanodine Receptor Calcium Release Channel/physiology , Sarcoplasmic Reticulum/metabolism , Animals , Male , Mice , Mice, Inbred C57BL , Receptors, Adrenergic, beta/physiology , Sarcolemma/physiology , Verapamil/pharmacologyABSTRACT
This study was designed to investigate whether alpha- and beta-adrenergic systems mediate the analgesic effect of electroacupucture (EA) on inflammatory pain in a rat model of collagen-induced arthritis (CIA). To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant, followed by a booster injection 14 days later. After induction of arthritis, the inflammatory pain threshold by the tail flick latency decreased as time passed and reached the minimum value at 4th week. Four weeks after the first immunization, low-frequency EA stimulation (2 Hz, 0.07 mA, 0.3 ms) delivered to Zusanli (ST(36)) for 30 min showed the analgesic effect. And also, the analgesic effect of EA was blocked by pretreatment with yohimbine (alpha2-adrenoceptor antagonist, 2 mg/kg, i.p.), but not by pretreatment with prazosin (alpha1-adrenoceptor antagonist, 1 mg/kg, i.p.) and propranolol (non-selective beta-adrenoceptor antagonist, 10 mg/kg, i.p.). These results suggest that the low-frequency EA can relieve the inflammatory pain in CIA, and the analgesic effect of EA can be mediated by alpha2- and beta-adrenoceptor, but not by alpha1-adrenoceptor.
Subject(s)
Acupuncture Analgesia , Arthritis, Experimental/therapy , Electroacupuncture , Receptors, Adrenergic, alpha-2/physiology , Receptors, Adrenergic, beta/physiology , Acupuncture Points , Animals , Male , Prazosin/pharmacology , Rats , Rats, Sprague-Dawley , Yohimbine/pharmacologyABSTRACT
The use of global gene expression profiling, also known as transcriptomics or genomics, provides a means to identify key pathways affected in ageing skin that can be improved with appropriate cosmetic compounds. Aspects of skin ageing that can be addressed include matrix production, barrier, lipid synthesis, antioxidant capacity and hyperpigmentation. Gene expression profiling together with in vitro human skin cell cultures for compound screening and verification have led to the identification of cosmetic compounds and an understanding of the biological effects of compounds such as niacinamide, Pal-KTTKS, hexamidine, retinyl propionate and sodium dehydroacetate. In addition, understanding of the decreased antioxidant capacity of aged skin has led to the identification of new antiageing ingredients, olive-derived fatty acid ethoxylates, which have been shown to restore antioxidant enzymes in skin keratinocytes and fibroblasts. Gene expression profiling of age spots has also provided an understanding of the role of undecylenoyl phenylalanine in reducing melanin production by an adrenergic receptor mechanism in melanocytes. The use of these compounds in cosmetic formulations for skin care can aid improvements in the appearance of aged skin, including the improved appearance of fine lines, wrinkles and age spots.
Subject(s)
Cosmetics/pharmacology , Genomics/methods , Pigmentation Disorders/drug therapy , Skin Aging/genetics , Antioxidants/pharmacology , Cosmetics/chemistry , Fatty Acids/pharmacology , Humans , Olive Oil , Plant Oils/pharmacology , Receptors, Adrenergic, beta/physiology , Skin Aging/drug effects , Skin Pigmentation/drug effects , Skin Pigmentation/genetics , Transcription, Genetic/genetics , Up-RegulationABSTRACT
The use of left ventricular assist devices to induce substantial myocardial recovery with explantation of the device, bridge to recovery (BTR), is an exciting but currently grossly underused application. Recently acquired knowledge relating to BTR and its mechanisms offers unprecedented opportunities to streamline its use and unravel some of the secrets of heart failure with much wider implications. This article reviews the status, challenges, and future of cardiac recovery.
Subject(s)
Heart Failure/therapy , Heart-Assist Devices/trends , Apoptosis/physiology , Combined Modality Therapy , Cytoskeletal Proteins/metabolism , Device Removal , Electrophysiologic Techniques, Cardiac , Extracellular Matrix/physiology , Heart Failure/pathology , Heart Failure/rehabilitation , Humans , Immunity, Innate/physiology , Membrane Proteins/metabolism , Myocardial Contraction , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Patient Selection , Postoperative Care/methods , Prosthesis Design , Prosthesis Implantation/methods , Receptors, Adrenergic, beta/physiology , Recovery of Function/physiology , Time FactorsABSTRACT
Although the mechanism is unknown, Calculus Bovis and its active components, cholic acid analogs (CAAs), have been used in China to treat a wide range of diseases. Based on the previous finding that the potency of CAA is strongly dependent on the intrinsic surface activity, this paper aimed to investigate the role of the plasma membrane in the pharmacological activity of CAAs. First, CAAs (0.1 mM) caused a surface activity-dependent depression on ATPase activity in the cell membrane extract, but it had no effects on other cellular extracts, suggesting an indispensable role of the membrane environment for pharmacological activity. Second, CAAs lowered the membrane fluidity of cultured Caco-2 cells with the same rank-order of potency sequence. Third, the hypothesis that any functional protein located on the membrane is influenced by changes in cellular membrane fluidity was supported by: ileal contraction that was induced by acetylcholine and mediated by the muscarinic receptor (M-receptor) or the relaxation induced by adrenaline and mediated by the ß-adrenergic receptor (ß-receptor) was inhibited by CAAs. They also had similar rank-order of potency and the effects on the plasma membrane. Collectively, the plasma membrane may be a target for the CAAs to exert the multiple pharmacological effects which are mediated by the alteration of the membrane mobility and the function of integral membrane proteins.
Subject(s)
Cell Membrane/metabolism , Cholic Acids/pharmacology , Molecular Targeted Therapy , Adenosine Triphosphatases/analysis , Adenosine Triphosphatases/physiology , Adrenergic beta-Agonists/pharmacology , Animals , Caco-2 Cells , Carrier Proteins/physiology , Cholic Acids/chemistry , Drugs, Chinese Herbal/metabolism , Epinephrine/pharmacology , Humans , Ileum/drug effects , Male , Membrane Fluidity/drug effects , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats , Receptors, Adrenergic, beta/physiology , Receptors, Muscarinic/physiologyABSTRACT
The last decade has witnessed a profound resurgence in brown adipose tissue (BAT) research. The need for such a dramatic increase stems from the ever-growing trend toward global obesity. Indeed, it is currently estimated that rates of obesity in developed countries such as the United States exceed 35% of the population (1). The higher incidence of obesity is associated with increased prevalence of the metabolic syndrome including diabetes, hypertension, and coronary heart disease, among others (1, 2). BAT holds great promise in combating obesity given its unprecedented metabolic capacity. Leading the way has been recent studies, which conclusively demonstrate significant quantities of functional BAT in adult humans (3-7). These findings have been complimented by elegant studies elucidating the developmental origin of the brown adipocyte and the transcriptional regulation involved in its differentiation. This review will attempt to meld the wealth of new information regarding BAT development with established literature to provide an up to date synopsis of what is known and thus a framework for future research directions.
Subject(s)
Adipose Tissue, Brown/physiology , Body Temperature Regulation/physiology , Adipocytes, Brown/cytology , Adipocytes, Brown/drug effects , Adipocytes, Brown/physiology , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/growth & development , Adult , Aged , Animals , Animals, Newborn , Arginine/administration & dosage , Body Temperature Regulation/drug effects , Bone Morphogenetic Proteins/physiology , Catecholamines/physiology , Cell Differentiation/drug effects , Cell Lineage , DNA-Binding Proteins/physiology , Diet/adverse effects , Dietary Supplements , Gene Expression Regulation , Heat-Shock Proteins/physiology , Humans , Infant, Newborn , Ion Channels/physiology , Lipolysis/drug effects , Middle Aged , Mitochondrial Proteins/physiology , Obesity/etiology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Receptors, Adrenergic, beta/physiology , Sheep , Thyroid Hormones/physiology , Transcription Factors/physiology , Uncoupling Protein 1ABSTRACT
BACKGROUND: KCNH2 gene mutations disrupting rapid component of I(K) (I(Kr)) underlie type 2 congenital long QT syndrome (LQT2). Startled auditory stimuli are specific symptomatic triggers in LQT2, thus suggesting fast arrhythmogenic mechanism. OBJECTIVE: We investigated acute alpha(1A)- and cyclic adenosine monophosphate (cAMP)-related beta-adrenergic modulation of I(Kr) in HL-1 cardiomyocytes, wild type (WT)- and 2 LQT2-associated mutant Kv11.1 channels (Y43D- and K595E-Kv11.1) reconstituted in Chinese hamster ovary (CHO) cells. METHODS: I(Kr) and Kv11.1 currents were recorded using the whole-cell patch-clamp technique and confocal microscopy of HL-1 cardiomyocytes transfected with green fluorescent protein (GFP)-tagged pleckstrin homology domain of phospholipase C-delta(1) visualized fluctuations of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) content. RESULTS: In HL-1 cardiomyocytes expressing human alpha(1A)-adrenoceptor, superfusion with phenylephrine significantly reduced I(Kr) amplitude, shifted current activation to more positive potentials, and accelerated kinetics of deactivation. Confocal images showed a decline of membrane PIP(2) content during phenylephrine exposure. Simultaneous application of adenylyl cyclase activator forskolin and phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) shifted I(Kr) activation to more negative potentials and decreased tail current amplitudes after depolarizations between +10 and +50 mV. In CHO cells, alpha(1A)-adrenoceptor activation downregulated WT-Kv11.1 channels and forskolin/IBMX produced a dual effect. Expressed alone, the Y43D-Kv11.1 or K595E-Kv11.1 channel had no measurable function. However, co-expression of WT-Kv11.1 and each mutant protein evoked currents with loss-of-function alterations but identical to WT-Kv11.1 alpha(1A)- and forskolin/IBMX-induced regulation. CONCLUSION: Acute adrenergic regulation of at least 2 Kv11.1 mutant channels is preserved as in WT-Kv11.1 and native I(Kr). Suppression of alpha(1A)-adrenoceptor-related transduction might have therapeutic implications in some cases of LQT2.
Subject(s)
Long QT Syndrome/physiopathology , Myocytes, Cardiac/physiology , Potassium Channels, Voltage-Gated/physiology , Receptors, Adrenergic, alpha/physiology , Receptors, Adrenergic, beta/physiology , Adult , Animals , Cells, Cultured , Cricetinae , Disease Models, Animal , Electrophysiologic Techniques, Cardiac , Female , Humans , Long QT Syndrome/congenital , Long QT Syndrome/genetics , Microscopy, Confocal , Patch-Clamp Techniques , Potassium Channels, Voltage-Gated/geneticsABSTRACT
Recent work from our laboratory and others has shown that certain stressors increase expression of the pro-inflammatory cytokine interleukin-1beta (IL-1) in the hypothalamus. The first goal of the following studies was to assess the impact of acute stress on other key inflammatory factors, including both cytokines and cell surface markers for immune-derived cells resident to the CNS in adult male Sprague Dawley rats exposed to intermittent footshock (80 shocks, 90 s variable ITI, 5 s each). While scattered changes in IL-6 and GFAP were observed in the hippocampus and cortex, we found the hypothalamus to be exquisitely sensitive to the effects of footshock. At the level of the hypothalamus, mRNA for IL-1 and CD14 were significantly increased, while at the same time CD200R mRNA was significantly decreased. A subsequent experiment demonstrated that propranolol (20mg/kg i.p.) blocked the increase in IL-1 and CD14 mRNA observed in the hypothalamus, while the decrease in CD200R was unaffected by propranolol. Interestingly, inhibition of glucocorticoid synthesis via injection of metyrapone (50mg/kg s.c.) plus aminoglutethimide (100mg/kg s.c.) increased basal IL-1 mRNA and augmented IL-1 and CD14 expression provoked by footshock. Injection of minocycline, a putative microglial inhibitor, blocked the IL-1 response to footshock, while CD14 and CD200R were unaffected. Together, these gene expression changes (i) provide compelling evidence that stress may provoke neuroinflammatory changes that extend well beyond isolated changes in a single cytokine; (ii) suggest opposing roles for classic stress-responsive factors (norepinephrine and corticosterone) in the modulation of stress-related neuroinflammation; (iii) indicate microglia within the hypothalamus may be key players in stress-related neuroinflammation; and (iv) provide a potential mechanism (increased CD14) by which acute stress primes reactivity to later immune challenge.
Subject(s)
Hypothalamus/physiology , Interleukin-1/genetics , Lipopolysaccharide Receptors/genetics , Microglia/physiology , Neurons/physiology , Stress, Physiological/genetics , Adrenergic beta-Antagonists/pharmacology , Analysis of Variance , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/physiology , Corticosterone/blood , Electroshock , Enzyme Inhibitors/pharmacology , Gene Expression , Hippocampus/drug effects , Hippocampus/physiology , Hypothalamus/drug effects , Interleukin-1/immunology , Lipopolysaccharide Receptors/immunology , Male , Metyrapone/pharmacology , Microglia/drug effects , Minocycline/pharmacology , Propranolol/pharmacology , RNA, Messenger/physiology , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/physiology , Reverse Transcriptase Polymerase Chain Reaction , Stress, Physiological/immunologyABSTRACT
OBJECTIVE: To observe the inhibitory effects of acupuncture pretreatment on arrhythmia and intracellular calcium ([Ca2+]i) oscillation in single cardiocyte in rats subjected to myocardial ischemia-reperfusion (MIR). METHODS: Male SD rats were evenly randomized into normal control (NC), MIR and electroacupuncture (EA) groups. MIR was performed by ligation (30 min) and reperfusion (10 min) of the left anterior descending coronary artery in vivo in rats or in the isolated and perfused rat heart subjected to a 40 min global ischemia followed by a 10 min reperfusion. EA pretreatment was applied to bilateral "Neiguan" (PC 6) for 30 min once a day in 3 consecutive days. Arrhythmic score was calculated according to Curtis's and Walker's method, and the count of [Ca2+]i oscillation was measured by using InCytPm 2 intracellular ion detecting system. RESULTS: Both the arrhythmic score and the count of [Ca2+]i oscillation in MIR group were considerably higher than those in NC group (P<0.05). While compared with MIR group, the arrhythmia score and the count of [Ca2+]i oscillation in EA group were decreased significantly (P<0.05). CONCLUSION: Pretreatment of EA can effectively resist MIR-induced arrhythmia and intracellular calcium oscillation in the rat.
Subject(s)
Arrhythmias, Cardiac/therapy , Calcium Signaling , Electroacupuncture , Myocardial Ischemia/complications , Myocardial Reperfusion , Myocytes, Cardiac/metabolism , Animals , Male , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/physiologyABSTRACT
Aging associated changes in cardiac contraction, Ca(2+) homeostasis and their neurohumoral regulations have been studied using rodents. The changes can be understood not only to reduce energy consumption but also to be susceptible to Ca(2+) overload, possibly leading arrhythmia and cell death. N-3 polyunsaturated fatty acid is reported to prevent cardiac Ca(2+) overload. Its content in the cellular membrane is reduced in aged cardiomyocytes, suggesting that the aging-associated change in n-3 fatty acid content is related to the changes in cardiac function. Ingestion balance between n-3 and n-6 fatty acids may affect on the risk of cardiovascular diseases associated with aging.
Subject(s)
Aging/physiology , Calcium/metabolism , Myocardial Contraction , Adenylyl Cyclases/physiology , Animals , Arrhythmias, Cardiac/etiology , Cardiovascular Diseases/etiology , Endothelins/physiology , Energy Metabolism , Fatty Acids, Omega-3/metabolism , Fatty Acids, Omega-3/physiology , Fatty Acids, Omega-6 , Humans , Myocardium/metabolism , Receptors, Adrenergic, beta/physiologyABSTRACT
The discovery that leptin regulates bone mass through a central relay generated a lot of interest and raised the question about the identity of the neural mediator linking the brain to the skeleton. In this review we discuss the genetic, neuroanatomical and physiological evidence identifying the sympathetic tone as one of the mediator of leptin regulation of bone mass. We also discussed the antagonistic role played by two beta adrenergic receptors in this regulation and the relevance of these results obtained through studies of model organisms to human physiology and pathology.
Subject(s)
Bone Density/physiology , Leptin/physiology , Sympathetic Nervous System/physiology , Animals , Bone Remodeling/physiology , Humans , Hypothalamus/physiology , Models, Biological , Receptors, Adrenergic, beta/physiologyABSTRACT
With the aim to study if selenium (Se) deficiency affects the basal frequency and cardiac response to isoproterenol (ISO), mice were fed a Se-deficient diet (Se-) or the same diet supplemented with 0.2 ppm Se as sodium selenite (Se+) for 4 wk. Atria frequency, cyclic AMP (cAMP) accumulation, nitric oxide synthase (NOS) activity, and beta-adrenoceptor-binding assay were then examined. Results showed that Se-mice have both a reduction in atria frequency as well as in cAMP content but higher NOS activity levels either at basal or after ISO stimulation. These differences were suppressed by feeding Se-mice with a Se-supplemented diet for 1 wk or by inhibition of inducible nitric oxide synthase (iNOS). Alterations observed after ISO stimulation in atria of Se-mice were not related to a beta-adrenoceptor expression modification because specific radioligand-binding parameters in cardiac membranes from Se-mice and Se+ mice were similar. The reduced response on rate and cAMP in atria from Se-mice to direct adenylate cyclase (AC) stimulation by forskolin and the shifted upward levels present in 2-amino-4-methylpyridine-treated Se-mice is in agreement with a negative crosstalk between iNOS activity and AC activity in Se-mice.
Subject(s)
Cyclic AMP/antagonists & inhibitors , Down-Regulation/physiology , Myocardial Contraction/physiology , Nitric Oxide Synthase Type II/physiology , Receptors, Adrenergic, beta/metabolism , Selenium/deficiency , Adrenergic beta-Agonists/pharmacology , Animals , Cyclic AMP/metabolism , Female , Heart Atria/metabolism , Heart Atria/physiopathology , Isoproterenol/pharmacology , Male , Mice , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/metabolism , Random Allocation , Receptors, Adrenergic, beta/physiology , Up-Regulation/physiologyABSTRACT
Previous studies have shown that the gating kinetics of the slow component of the delayed rectifier K(+) current (I(Ks)) contribute to postrepolarization refractoriness in isolated cardiomyocytes. However, the impact of such kinetics on arrhythmogenesis remains unknown. We surmised that expression of I(Ks) in rat cardiomyocyte monolayers contributes to wavebreak formation and facilitates fibrillatory conduction by promoting postrepolarization refractoriness. Optical mapping was performed in 44 rat ventricular myocyte monolayers infected with an adenovirus carrying the genomic sequences of KvLQT1 and minK (molecular correlates of I(Ks)) and 41 littermate controls infected with a GFP adenovirus. Repetitive bipolar stimulation was applied at increasing frequencies, starting at 1 Hz until loss of 1:1 capture or initiation of reentry. Action potential duration (APD) was significantly shorter in I(Ks)-infected monolayers than in controls at 1 to 3 Hz (P<0.05), whereas differences at higher pacing frequencies did not reach statistical significance. Stable rotors occurred in both groups, with significantly higher rotation frequencies, lower conduction velocities, and shorter action potentials in the I(Ks) group. Wavelengths in the latter were significantly shorter than in controls at all rotation frequencies. Wavebreaks leading to fibrillatory conduction occurred in 45% of the I(Ks) reentry episodes but in none of the controls. Moreover, the density of wavebreaks increased with time as long as a stable source sustained the fibrillatory activity. These results provide the first demonstration that I(Ks)-mediated postrepolarization refractoriness can promote wavebreak formation and fibrillatory conduction during pacing and sustained reentry and may have important implications in tachyarrhythmias.