Effects of Ruscus extract on muscarinic receptors: Is there a role for endothelium derived relaxing factors on macromolecular permeability protection and microvascular diameter changes?

2021 ◽  
pp. 1-17
Author(s):  
Maria das Graças C. de Souza ◽  
Fatima Z. G. A. Cyrino ◽  
Fernando L. Sicuro ◽  
Eliete Bouskela
Keyword(s):  
Muscarinic Receptors ◽  
Cheek Pouch ◽  
Protective Effects ◽  
Cox Inhibitors ◽  
Nos Inhibitors ◽  
Dose Dependent Fashion ◽  
Oxide Synthase ◽  
Macromolecular Permeability ◽  
Dose Dependent ◽  
Higher Doses

BACKGROUND: Protective effects of Ruscus extract on macromolecular permeability depend on its capacity to stimulate muscarinic receptors on endothelial cells and induce the release of endothelium derived relaxing factors (EDRFs). OBJECTIVE: To investigate if these effects depend only on activation of muscarinic receptors or EDRFs release are also necessary. We have also investigated the participation of Ruscus extract on muscarinic-induced release of EDRFs on microvascular diameters. METHODS: Hamsters were treated daily during two weeks with Ruscus extract (50, 150 and 450 mg/kg/day) and then macromolecular permeability induced by histamine and arteriolar and venular diameters after cyclooxygenase (COX) and nitric oxide synthase (NOS) inhibitors: indomethacin and Nω-Nitro-L-arginine (LNA), respectively applied topically at 10–8M, 10–6M and 10–4M were observed on the cheek pouch preparation. RESULTS: Ruscus extract decreased macromolecular permeability in a dose-dependent fashion and did not affect microvascular diameters. NOS and COX inhibitors enhanced this effect. NOS inhibition reduced arteriolar diameter and COX blocking decreased arteriolar and venular diameters at the lowest dose and increased them at higher doses of Ruscus extract. CONCLUSION: The protective effect of Ruscus extract on macromolecular permeability seems to be mediated only via muscarinic receptors. Muscarinic activation attenuated vasoconstrictive tone through cyclooxygenase-independent endothelium derived relaxing factors.

Pirenzepine-sensitive muscarinic receptors regulate gastric somatostatin and gastrin

1985 ◽  
Vol 248 (2) ◽  
pp. G184-G187 ◽  
Author(s):  
R. Sue ◽  
M. L. Toomey ◽  
A. Todisco ◽  
A. H. Soll ◽  
T. Yamada
Keyword(s):  
Acid Secretion ◽  
Muscarinic Receptors ◽  
Potent Inhibitor ◽  
Competitive Inhibition ◽  
Hormone Regulation ◽  
Rat Stomach ◽  
Response Curves ◽  
Gastrin Secretion ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Pirenzepine, a newly described antagonist of selective muscarinic receptors (M1), has been shown to be a potent inhibitor of acid secretion. To determine whether this property of pirenzepine can be explained in part by its actions on hormones regulating acid secretion, we examined pirenzepine's effects on gastrin and somatostatinlike immunoreactivity (SLI) secretion from the isolated, perfused rat stomach. Carbachol at a dose of 10(-6) M inhibited SLI and stimulated gastrin secretion. Both atropine and pirenzepine reversed these effects in a dose-dependent fashion with D50 values of 1 X 10(-9) and 1 X 10(-7) M, respectively, against gastrin stimulation and 1 X 10(-8) and 1 X 10(-7) M, respectively, against SLI inhibition. Pirenzepine caused a progressive parallel rightward shift in the dose-response curves for SLI inhibition and gastrin stimulation by carbachol, suggesting competitive inhibition. The apparent inhibitory constant (ki) was calculated to be approximately 2 X 10(-9) M. These results indicate that gastrin and SLI release from the stomach is governed by high-affinity muscarinic receptors that are sensitive to pirenzepine. Pirenzepine's action as an acid secretory inhibitor, and possibly as an ulcer therapy drug, may be explained in part by these effects on gastric hormone regulation.

In vivo pharmacological evaluation off two novel type II (inducible) nitric oxide synthase inhibitors

1995 ◽  
Vol 73 (5) ◽  
pp. 665-669 ◽  
Author(s):  
W. Ross Tracey ◽  
Masaki Nakane ◽  
Fatima Basha ◽  
George Carter
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
No Production ◽  
Type Ii ◽  
Nos Inhibitors ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Inducible Nitric Oxide

Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and >95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.Key words: nitric oxide, nitrite, nitrate, sepsis, lipopolysaccharide.

Arteriolar oxygen reactivity is inhibited by leukotriene antagonists

1989 ◽  
Vol 257 (5) ◽  
pp. H1565-H1572 ◽  
Author(s):  
W. F. Jackson
Keyword(s):  
Related Compound ◽  
Cheek Pouch ◽  
Hamster Cheek Pouch ◽  
Leukotriene Antagonists ◽  
Lipoxygenase Inhibitors ◽  
Dose Dependent Fashion ◽  
Leukotriene Receptor ◽  
Oxygen Tensions ◽  
Oxygen Reactivity ◽  
Dose Dependent

Experiments were performed to test the hypothesis that the arteriolar constriction produced by elevated oxygen tensions in the hamster cheek pouch is mediated by a leukotriene. To test this hypothesis, the diameter response of arterioles in superfused hamster cheek pouch preparations to stepwise increases in superfusion solution oxygen content was measured by video microscopy in the absence and 30 min after superfusion with solutions containing inhibitors of the synthesis or actions of leukotrienes. Oxygen-induced constrictions were inhibited in a dose-dependent fashion by two structurally distinct 5-lipoxygenase inhibitors (U 60257 and SC 43251) and two different leukotriene receptor antagonists (SKF 102922 and FPL 55712). Also, all four inhibitors tended to dilate the arterioles under low PO2 conditions. The inhibition of oxygen reactivity appeared to be selective in that arteriolar constrictions induced by topical application of phenylephrine were unaffected (SC 43251, SKF 102922, FPL 55717, and 30 microM U 60257) or only modestly reduced (100 microM U 60257) by the inhibitors. These data are consistent with the hypothesis that a leukotriene, or related compound, mediates arteriolar oxygen reactivity in the hamster cheek pouch.

Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever

1996 ◽  
Vol 271 (2) ◽  
pp. R333-R338 ◽  
Author(s):  
T. E. Scammell ◽  
J. K. Elmquist ◽  
C. B. Saper
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Dependent Manner ◽  
Febrile Response ◽  
Bolus Intravenous Injection ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Higher Doses

The labile gas nitric oxide (NO) mediates a wide variety of thermoregulatory processes including vasomotor control, brown fat thermogenesis, and neuroendocrine regulation. Additionally, during endotoxemia, NO modulates the release of cytokines and hypothalamic peptides. To determine the role of NO in thermoregulation and fever, we intravenously injected the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and measured its effects on body temperature during normal thermoregulation and endotoxemia in awake, unrestrained rats. L-NAME produced a stereoselective, dose-dependent hypothermia that lasted up to 4 h after bolus intravenous injection. Intravenous lipopolysaccharide (LPS) produced fever in a dose-dependent manner, which was preceded by hypothermia at higher doses alpha-LPS. NOS inhibition reduced the febrile response to LPS and produced marked hypothermia with a low dose of LPS. These findings indicate that NO may play an important role in thermoregulation and suggest that NO is required for the production of fever.

Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages

2000 ◽  
Vol 278 (5) ◽  
pp. L1025-L1031 ◽  
Author(s):  
Sha Zhu ◽  
Khaled F. Basiouny ◽  
John P. Crow ◽  
Sadis Matalon
Keyword(s):  
Nitric Oxide ◽  
Alveolar Macrophages ◽  
Protein A ◽  
Surfactant Protein ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Dose Dependent Fashion ◽  
Carbonyl Formation ◽  
Oxide Synthase ◽  
Dose Dependent

We assessed whether reactive oxygen-nitrogen intermediates generated by alveolar macrophages (AMs) oxidized and nitrated human surfactant protein (SP) A. SP-A was exposed to lipopolysaccharide (100 ng/ml)-activated AMs in 15 mM HEPES (pH 7.4) for 30 min in the presence and absence of 1.2 mM CO2. In the presence of CO2, lipopolysaccharide-stimulated AMs had significantly higher nitric oxide synthase (NOS) activity (as quantified by the conversion ofl-[U-14C]arginine tol-[U-14C]citrulline) and secreted threefold higher levels of nitrate plus nitrite in the medium [28 ± 3 vs. 6 ± 1 (SE) nmol ⋅ 6.5 h−1 ⋅ 106AMs−1]. Western blotting studies of immunoprecipitated SP-A indicated that CO2 enhanced SP-A nitration by AMs and decreased carbonyl formation. CO2(0–1.2 mM) also augmented peroxynitrite (0.5 mM)-induced SP-A nitration in a dose-dependent fashion. Peroxynitrite decreased the ability of SP-A to aggregate lipids, and this inhibition was augmented by 1.2 mM CO2. Mass spectrometry analysis of chymotryptic fragments of peroxynitrite-exposed SP-A showed nitration of two tyrosines (Tyr164 and Tyr166) in the absence of CO2 and three tyrosines (Tyr164, Tyr166, and Tyr161) in the presence of 1.2 mM CO2. These findings indicate that physiological levels of peroxynitrite, produced by activated AMs, nitrate SP-A and that CO2 increased nitration, at least partially, by enhancing enzymatic nitric oxide production.

Dose-dependent inhibition of cold air-induced bronchoconstriction by atropine

1982 ◽  
Vol 53 (1) ◽  
pp. 169-174 ◽  
Author(s):  
D. Sheppard ◽  
J. Epstein ◽  
M. J. Holtzman ◽  
J. A. Nadel ◽  
H. A. Boushey
Keyword(s):  
Base Line ◽  
Muscarinic Agonist ◽  
Cold Air ◽  
Dependent Inhibition ◽  
Dose Dependent Fashion ◽  
Dose Dependent Inhibition ◽  
Airway Tone ◽  
Maximal Reduction ◽  
Dose Dependent ◽  
Higher Doses

We undertook a study to demonstrate whether inhalation of atropine could inhibit cold air-induced bronchoconstriction in a dose-dependent fashion. In seven subjects with asthma we assessed the effects of placebo and of various doses of inhaled atropine (0.1313;2.08 mg) on a base-line specific airway resistance (sRaw) and on the increase in sRaw produced by 5 min of voluntary eucapnic hyperventilation with subfreezing air at -17 degrees C. We also assessed the effect of the lowest doses of atropine on the increase in sRaw produced by five breaths of 1.0% metacholine. Atropine in doses of 0.13 or 0.26 mg caused a maximal reduction in base-line sRaw and completely inhibited the effect of 1.0% methacholine on sRaw, but it did not inhibit the bronchomotor response to cold air. Higher doses of atropine did inhibit the effect of cold air on sRaw in a dose-dependent fashion. The dose of atropine required to inhibit this effect of cold air varied with the increase in sRaw produced by cold air after placebo. These results suggest that cold air causes bronchoconstriction through vagal pathways and that higher doses of antimuscarinic agents are required to inhibit vagally mediated bronchoconstriction than those required to reduce base-line airway tone or to inhibit the effects of a large dose of an inhaled muscarinic agonist.

scholarly journals Dual orexin receptor antagonists increase sleep and cataplexy in wild type mice

SLEEP ◽  
2019 ◽  
Vol 43 (6) ◽  
Author(s):  
Carrie E Mahoney ◽  
Takatoshi Mochizuki ◽  
Thomas E Scammell
Keyword(s):  
Rem Sleep ◽  
Positive Emotions ◽  
Dark Period ◽  
Nrem Sleep ◽  
Wild Type ◽  
Receptor Antagonists ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Higher Doses ◽  
Desirable Effect

Abstract Orexin receptor antagonists are clinically useful for treating insomnia, but thorough blockade of orexin signaling could cause narcolepsy-like symptoms. Specifically, while sleepiness is a desirable effect, an orexin antagonist could also produce cataplexy, sudden episodes of muscle weakness often triggered by strong, positive emotions. In this study, we examined the effects of dual orexin receptor antagonists (DORAs), lemborexant (E2006) and almorexant, on sleep–wake behavior and cataplexy during the dark period in wild-type (WT) mice and prepro-orexin knockout (OXKO) mice. In WT mice, lemborexant at 10 and 30 mg/kg quickly induced NREM sleep in a dose-dependent fashion. In contrast, lemborexant did not alter sleep–wake behavior in OXKO mice. Under the baseline condition, cataplexy was rare in lemborexant-treated WT mice, but when mice were given chocolate as a rewarding stimulus, lemborexant dose-dependently increased cataplexy. Almorexant produced similar results. Collectively, these results demonstrate that DORAs potently increase NREM and REM sleep in mice via blockade of orexin signaling, and higher doses can cause cataplexy when co-administered with a likely rewarding stimulus.

Microcirculatory responses to exogenous endothelial cell-derived relaxing factor

1990 ◽  
Vol 258 (2) ◽  
pp. H606-H609 ◽  
Author(s):  
R. J. Rivers ◽  
A. L. Loeb ◽  
N. J. Izzo ◽  
M. J. Peach ◽  
B. R. Duling
Keyword(s):  
Endothelial Cells ◽  
Active Role ◽  
Direct Application ◽  
Cheek Pouch ◽  
Aortic Endothelial Cells ◽  
Relaxing Factor ◽  
First Pass ◽  
Dose Dependent Fashion ◽  
Pass Through ◽  
Dose Dependent

Endothelium-derived relaxing factor (EDRF) plays an important role in the vasodilatory responses of large blood vessels. However, such a role has yet to be conclusively shown for the microvasculature. In this study we tested the sensitivity of arterioles in the cheek pouch of pentobarbital-anesthetized hamsters to the EDRF-dependent agonists bradykinin and A23187, as well as to exogenous EDRF from cultured bovine aortic endothelial cells. The pouch superfusion fluid was arranged to first pass through a column containing endothelial cells and then on to the tissue. Bradykinin (10–30 nM) or A23187 (0.3 microM) was introduced either upstream or downstream to the endothelial cells, and the resultant responses were measured with video microscopy. Bradykinin and A23187 both caused a dose-dependent release of a microvessel dilator from cultured endothelial cells. We take this dilator to be EDRF based on the characteristics of the responses to the stimuli. Indomethacin (7.7 microM) was present in the superfusate to eliminate the production of cyclooxygenase products from the endothelial cells, and the magnitude of the response was diminished if the superfusate was first passed through a 3-min delay coil before arrival at the pouch. The arterioles dilated to the direct application of bradykinin in a dose-dependent fashion. They did not respond however to the direct application of A23187. These studies demonstrate that arteriolar smooth muscle is able to respond to exogenous EDRF and support the premise that EDRF may play an active role in the regulation of blood flow in the microcirculation.

scholarly journals The Protective Effects of Lactoferrin Feeding against Endotoxin Lethal Shock in Germfree Piglets

1998 ◽  
Vol 66 (4) ◽  
pp. 1421-1426 ◽  
Author(s):  
Wang J. Lee ◽  
Jeffrey L. Farmer ◽  
Milo Hilty ◽  
Yoon B. Kim
Keyword(s):  
Clinical Symptoms ◽  
Protective Effects ◽  
Lps Challenge ◽  
Flow Cytometric ◽  
Dose Dependent Fashion ◽  
Lethal Shock ◽  
Dose Dependent ◽  
Lps Binding

ABSTRACT The unique germfree, colostrum-deprived, immunologically “virgin” piglet model was used to evaluate the ability of lactoferrin (LF) to protect against lethal shock induced by intravenously administered endotoxin. Piglets were fed LF or bovine serum albumin (BSA) prior to challenge with intravenousEscherichia coli lipopolysaccharide (LPS), and temperature, clinical symptoms, and mortality were tracked for 48 h following LPS administration. Prefeeding with LF resulted in a significant decrease in piglet mortality compared to feeding with BSA (16.7 versus 73.7% mortality, P < 0.001). Protection against the LPS challenge by LF was also correlated with both resistance to induction of hypothermia by endotoxin and an overall increase in wellness, as quantified by a toxicity score developed for these studies. In vitro studies using a flow cytometric assay system demonstrated that LPS binding to porcine monocytes was inhibited by LF in a dose-dependent fashion, suggesting that the mechanism of LF action in vivo may be inhibition of LPS binding to monocytes/macrophages and, in turn, prevention of induction of monocyte/macrophage-derived inflammatory-toxic cytokines.

scholarly journals Synergistic Protective Effects of Antioxidant and Nitric Oxide Synthase Inhibitor in Transient Focal Ischemia

1999 ◽  
Vol 19 (2) ◽  
pp. 139-143 ◽  
Author(s):  
Brigitte Spinnewyn ◽  
Sylvie Cornet ◽  
Michel Auguet ◽  
Pierre-Etienne Chabrier
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Free Radical Scavengers ◽  
Protective Effects ◽  
Nos Inhibitors ◽  
Oxide Synthase

Both nitric oxide synthase (NOS) inhibitors and free radical scavengers have been shown to protect brain tissue in ischemia-reperfusion injury. Nitric oxide and superoxide anion act via distinct mechanisms and react together to form the highly deleterious peroxynitrite. Therefore the authors examined the effects and the interaction between the NOS inhibitor, NG nitro-L-arginine (LNA) and the antioxidant/superoxide scavenger, di-tert-butyl-hydroxybenzoic acid (DtBHB) in the rat submitted to 2 hours of middle cerebral artery occlusion. Posttreatment was initiated 4 hours after the onset of ischemia and infarct volume was measured at 48 hours. The dose-related effect of LNA resulted in a bell-shaped curve: 15, 56, 65, and 33% reduction of total infarct for 0.03, 0.1, 0.3, and 1 mg/kg (intravenously [IV]) respectively and 11% increase in infarct volume for 3 mg/kg (IV). Whereas DtBHB (20 mg/kg; intraperitoneally [IP]) was ineffective, the dose of 60 mg/kg produced 65% protection in infarct volume. The combination of a subthreshold dose of LNA (0.03 mg/kg; IV) and DtBHB (20 mg/kg; IP) resulted in significant reduction (49%) in infarct volume. These results show that LNA and DtBHB act synergistically to provide a consistent neuroprotection against ischemic injury when administered 4 hours after ischemia. This suggests that nitric oxide and free radicals are involved and interact in synergy in ischemia-reperfusion injury.

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