Characterization of the vasorelaxation to methanandamide in rat gastric arteries

2006 ◽  
Vol 84 (11) ◽  
pp. 1121-1132 ◽  
Author(s):  
Joke Breyne ◽  
Johan Van de Voorde ◽  
Bert Vanheel
Keyword(s):  
Smooth Muscle ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Relaxant Effect ◽  
High K ◽  
Calcitonin Gene ◽  
Perivascular Nerves ◽  
High Concentrations ◽  
Stimulation Of

In the present study, the relaxant effect of the cannabinoid methanandamide was explored in rat gastric arteries. Since in some vessels cannabinoids have been shown to release calcitonin gene-related peptide (CGRP) from perivascular nerves, the influence of methanandamide was compared with that of exogenous CGRP. Methanandamide and CGRP elicited concentration-dependent, endothelium-independent relaxations. Methanandamide-induced relaxations were unaffected by the CB1 receptor antagonist AM251, the CB2 receptor antagonists AM630 and SR144528, and combined pre-exposure to AM251 and SR144528. Pre-exposure to O-1918, an antagonist of a novel nonCB1/nonCB2 cannabinoid receptor, did not influence the relaxations to methanandamide. Capsaicin or capsazepine treatment slightly inhibited methanandamide-induced relaxations. Preincubation with 30 mmol/L extracellular K+ or 3 mmol/L TEA had no significant effect on the responses elicited by methanandamide, but reduced CGRP-induced relaxations. Relaxation to 10−5 mol/L methanandamide was significantly blunted by Bay K8644 and by preincubation with nifedipine. Furthermore, 10−5 mol/L methanandamide significantly inhibited CaCl2-induced contractions in norepinephrine-stimulated vessels previously depleted of intra- and extracellular Ca2+. Finally, preincubation with 10−5 mol/L methanandamide almost completely abolished high K+-induced contractions. These findings suggest that the vasorelaxant action of methanandamide in rat gastric arteries is not mediated by stimulation of known cannabinoid receptors and only partly related to stimulation of TRPV1 receptors on perivascular nerves. At high concentrations, methanandamide might induce relaxation by reducing calcium entry into the smooth muscle cells.

scholarly journals Pharmacological characterization of the relaxant effect induced by adrenomedullin in rat cavernosal smooth muscle

2014 ◽  
Vol 47 (10) ◽  
pp. 876-885
Author(s):  
L.N. Leite ◽  
N.A. Gonzaga ◽  
D.P.C. Tirapelli ◽  
L.F. Tirapelli ◽  
C.R. Tirapelli
Keyword(s):  
Smooth Muscle ◽  
Pharmacological Characterization ◽  
Relaxant Effect

scholarly journals CB1 Receptor-Dependent and Independent Induction of Lipolysis in Primary Rat Adipocytes by the Inverse Agonist Rimonabant (SR141716A)

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 896 ◽  
Author(s):  
Günter A. Müller ◽  
Andreas W. Herling ◽  
Susanne Wied ◽  
Timo D. Müller
Keyword(s):  
Cannabinoid Receptor ◽  
Inverse Agonist ◽  
Hormone Sensitive Lipase ◽  
Acute Administration ◽  
Free System ◽  
Peripheral Tissues ◽  
Rat Adipocytes ◽  
A Cell ◽  
High Concentrations ◽  
Stimulation Of

(1) Background: Acute administration of the cannabinoid receptor 1 (CB1R) inverse agonist Rimonabant (SR141716A) to fed Wistar rats was shown to elicit a rapid and short-lasting elevation of serum free fatty acids. (2) Methods: The effect of Rimonabant on lipolysis in isolated primary rat adipocytes was studied to raise the possibility for direct mechanisms not involving the (hypothalamic) CB1R. (3) Results: Incubation of these cells with Rimonabant-stimulated lipolysis to up to 25% of the maximal isoproterenol effect, which was based on both CB1R-dependent and independent mechanisms. The CB1R-dependent one was already effective at Rimonabant concentrations of less than 1 µM and after short-term incubation, partially additive to β-adrenergic agonists and blocked by insulin and, in part, by adenosine deaminase, but not by propranolol. It was accompanied by protein kinase A (PKA)-mediated association of hormone-sensitive lipase (HSL) with lipid droplets (LD) and dissociation of perilipin-1 from LD. The CB1R-independent stimulation of lipolysis was observed only at Rimonabant concentrations above 1 µM and after long-term incubation and was not affected by insulin. It was recapitulated by a cell-free system reconstituted with rat adipocyte LD and HSL. Rimonabant-induced cell-free lipolysis was not affected by PKA-mediated phosphorylation of LD and HSL, but abrogated by phospholipase digestion or emulsification of the LD. Furthermore, LD isolated from adipocytes and then treated with Rimonabant (>1 µM) were more efficient substrates for exogenously added HSL compared to control LD. The CB1R-independent lipolysis was also demonstrated in primary adipocytes from fed rats which had been treated with a single dose of Rimonabant (30 mg/kg). (4) Conclusions: These data argue for interaction of Rimonabant (at high concentrations) with both the LD surface and the CB1R of primary rat adipocytes, each leading to increased access of HSL to LD in phosphorylation-independent and dependent fashion, respectively. Both mechanisms may lead to direct and acute stimulation of lipolysis at peripheral tissues upon Rimonabant administration and represent targets for future obesity therapy which do not encompass the hypothalamic CB1R.

scholarly journals Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation

2008 ◽  
Vol 100 (5) ◽  
pp. 2794-2806 ◽  
Author(s):  
Carl Potenzieri ◽  
Thaddeus S. Brink ◽  
Cholawat Pacharinsak ◽  
Donald A. Simone
Keyword(s):  
Receptor Antagonist ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Evoked Responses ◽  
Intraplantar Injection ◽  
Withdrawal Threshold ◽  
Antinociceptive Effects ◽  
Electrophysiological Studies ◽  
Stimulation Of

Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2′-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Aδ nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Aδ nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Aδ nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB1 receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Aδ nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inflammation.

Myoplasmic Ca2+-force relationship studied with fura-2 during stimulation of rat aortic smooth muscle

1988 ◽  
Vol 254 (5) ◽  
pp. H840-H854 ◽  
Author(s):  
G. Bruschi ◽  
M. E. Bruschi ◽  
G. Regolisti ◽  
A. Borghetti
Keyword(s):  
Smooth Muscle ◽  
Adherent Cell ◽  
Aortic Smooth Muscle ◽  
Fura 2 ◽  
Parallel Increase ◽  
High K ◽  
Intracellular Ca ◽  
Cell Layers ◽  
Force Relationship ◽  
Stimulation Of

The intracellular Ca indicator fura-2 was used for simultaneous measurements of intracellular free Ca (Ca2+i) and force in arterial smooth muscle. Rat aortic medial rings were submitted to fluorometry in a geometrical arrangement resembling that of adherent cell layers. A rigid force-transducing system served to immobilize the tissue and record the developed force quasi-isometrically. Stimulation was performed with norepinephrine (NE), KCl depolarization (high K), and a nonfluorescent Ca ionophore (ionomycin) at varying extracellular Ca concentrations. The following facts were observed. NE, high K, and ionomycin increased tension along with fura-2-reported Ca2+i; under any circumstances tension was Ca2+i dependent and could be varied by manipulating Ca2+i. However, NE and high K determined a parallel increase in the effectiveness of Ca2+i in comparison with the simple ionophore, i.e., they increased the force-to-Ca2+i ratio. NE and high K produced half-maximal tension at fura-2 estimated Ca2+i of 0.10 and 0.13 microM, whereas ionomycin required 0.6 microM to achieve the same amount of force. It is inferred that Ca2+i is a determinant of vascular contraction, but some results suggest the existence of factors that sensitize the contractile machinery to Ca.

Stimulation of nitric oxide from muscle cells by VIP: prejunctional enhancement of VIP release

1992 ◽  
Vol 262 (4) ◽  
pp. G774-G778 ◽  
Author(s):  
J. R. Grider ◽  
K. S. Murthy ◽  
J. G. Jin ◽  
G. M. Makhlouf
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Muscle Cells ◽  
No Synthase ◽  
No Production ◽  
Field Stimulation ◽  
Relaxant Effect ◽  
Gastric Muscle ◽  
Synthase Inhibitor ◽  
Stimulation Of

The source of nitric oxide (NO) and its role in neurally induced relaxation was examined in smooth muscle of the stomach and tenia coli. Field stimulation of gastric muscle strips was accompanied by frequency-dependent relaxation, vasoactive intestinal peptide (VIP) release, and NO production: the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA) completely inhibited NO production and partly inhibited VIP release (52-54%) and relaxation (58-88%); inhibition of all three functions was reversed by L-arginine but not by D-arginine. In isolated gastric muscle cells, VIP caused relaxation and stimulated NO production: L-NNA completely inhibited NO production and partly inhibited relaxation; the inhibition was reversed by L-arginine but not by D-arginine. Abolition of NO production with only partial inhibition of relaxation implied that NO production from muscle cells induced by the action of VIP was partly responsible for relaxation. By contrast, field stimulation of tenia coli was accompanied by relaxation and VIP release but not by NO production. Neither VIP release nor relaxation was affected by L-NNA. In isolated muscle cells of tenia coli, VIP caused relaxation but did not stimulate NO production; relaxation in these cells was not affected by L-NNA. We conclude that 1) VIP is the primary relaxant transmitter in both gastric muscle and tenia coli, 2) the release of VIP in gastric muscle but not in tenia coli stimulates NO production from target muscle cells, and 3) NO amplifies the relaxant effect of VIP in muscle cells and acts presynaptically to enhance the release of VIP.

The uptake and efflux of α-aminoisobutyric acid by the smooth muscle of the guinea pig's taenia coli

1979 ◽  
Vol 57 (10) ◽  
pp. 1114-1121
Author(s):  
J. H. Widdicombe ◽  
D. M. Paton
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Effective Treatment ◽  
Taenia Coli ◽  
Free Medium ◽  
Efflux Rate ◽  
Aminoisobutyric Acid ◽  
High K ◽  
Treatment Changes ◽  
High Concentrations

The uptake of α-aminoisobutyric acid (AIB) by guinea pig taenia coli was linear with time over a 5-h period. There was a saturable component with Km of 0.7 mM and a maximal value of 4.75 mmol/kg tissue per hour. A second nonsaturable component of uptake became important at high concentrations of AIB (> 5 mM). Preincubation in K+-free or Na+-free (high-K+) media greatly reduced uptake. The dependence of AIB uptake on outside [Na+] ([Na+]0) was approximately linear over the range 0–140 mM. With [Na+]0 equal to 25 mM the uptakes with various substitutes were in the order sucrose > Mg2+ > choline+ > Li+ > Cs+ > Rb+ = K+. Addition of ouabain or removal of K+ during efflux of AIB led to marked increases in the efflux rate, ouabain being the more effective treatment. Changes in tissue Na+ and K+ levels were found to be slightly greater with ouabain than with K+-free medium. Lanthanum (5 mM) prevented the uptake of Na+ seen in K+-free medium and also abolished the increase in the rate of loss of AIB. It also reduced the rise in tissue Na+ produced by ouabain; there was a corresponding reduction in the ouabain-induced increase in the rate of loss of AIB. It is concluded that both the influx and efflux of AIB in this tissue are Na+ dependent, and that the accumulation of AIB relies on the transmembrane Na+ gradient.

Effect of cannabinoids on neural transmission in rat gastric fundus

2002 ◽  
Vol 80 (1) ◽  
pp. 67-76 ◽  
Author(s):  
M Storr ◽  
E Gaffal ◽  
D Saur ◽  
V Schusdziarra ◽  
H D Allescher
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Physiological Role ◽  
Gastric Fundus ◽  
Dependent Manner ◽  
Receptor Agonists ◽  
Relaxant Response ◽  
Rat Gastric Fundus

The purpose of this study was to examine the possible role of cannabinoids on the neuromuscular function of rat gastric fundus. In addition to possible direct effects on smooth muscle, the influence of cannabinoids on contractile (cholinergic) and relaxant (non-adrenergic, non-cholinergic (NANC)) neural innervation of the rat gastric fundus was investigated in vitro. Neither anandamide (an endogenous cannabinoid receptor agonist) nor Win 55,212-2 and methanandamide (synthetic cannabinoid receptor agonists) nor AM 630 (a cannabinoid receptor antagonist) showed any effect on smooth muscle activity at baseline or after precontraction with 5-hydroxytryptamine (5-HT; 10–7 M). Electrical field stimulation (EFS) of the smooth muscle preparation (40 V; 5 Hz) caused cholinergically mediated twitch contractions that were abolished by atropine (10–6 M) or tetrodotoxin (TTX; 10–6 M). Anandamide and Win 55,212-2 reduced these twitch contractions in a concentration-dependent manner, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When NANC relaxant neural responses (presence of atropine (10–6 M) and guanethidine (10–6 M)) were induced by EFS, the cannabinoid receptor agonists anandamide and Win 55,212-2 reduced the relaxant response, an effect that could be reversed by the cannabinoid receptor antagonist AM 630 for anandamide, but not for Win 55,212-2. When given alone AM 630 caused an increase in the EFS-induced relaxant response. The presence of CB1 and CB2 cannabinoid receptor mRNA within the rat stomach was demonstrated by reverse transcription polymerase chain reaction (RT-PCR). The results of this study indicate that cannabinoids modulate excitatory cholinergic and inhibitory NANC neurotransmission in the rat gastric fundus. Endogenous cannabinoids may play a physiological role only in NANC inhibitory transmission, as AM 630 did not modify the electrically induced cholinergic contraction. The involved cannabinoid receptors are most likely located on neuronal structures. The present study also provides evidence that more than one receptor type is involved.Key words: cannabinoid, anandamide, rat gastric fundus relaxation, NANC, AM 630.

Selectlve desensitization of 5-hydroxytryptamine 2A receptor mediated contraction in guinea pig trachea

1994 ◽  
Vol 72 (5) ◽  
pp. 463-470 ◽  
Author(s):  
Stephanie W. Watts ◽  
Kathryn W. Schenck ◽  
Marlene L. Cohen
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Jugular Vein ◽  
Rat Aorta ◽  
Receptor Desensitization ◽  
Maximal Contraction ◽  
High Concentrations ◽  
Over Time ◽  
Stimulation Of

5-Hydroxytryptamine (serotonin, 5-HT) contracts the guinea pig trachea through stimulation of 5-HT2A receptors, an effect previously reported to rapidly desensitize. The present studies were designed to examine further the putative desensitization to serotonin. In vitro studies investigating functional desensitization of the guinea pig tracheal 5-HT2A receptor documented that 5-HT (3 × 10−7 M) significantly (50%) but incompletely reduced subsequent tracheal maximal contraction to 5-HT. In contrast, an equieffective concentration of carbamylcholine (3 × 10−8 M) did not reduce guinea pig tracheal contraction to 5-HT. Furthermore, 5-HT (3 × 10−7 M) did not diminish tracheal contraction to carbamylcholine. These data indicate that 5-HT can selectively desensitize guinea pig tracheal contraction to 5-HT. In addition, 5-HT-induced contraction but not carbamylcholine-induced contraction in guinea pig trachea declined over time, an effect that was more pronounced at high concentrations of 5-HT (1 × 10−6 and 1 × 10−5 M). Inhibitors of mechanisms that oppose contractility to 5-HT (5-HT-induced relaxation, uptake of 5-HT, or metabolism of 5-HT) did not reverse the decline in contraction to 5-HT (1 × 10−5 M). The decline in 5-HT-induced contraction was most rapid in the guinea pig trachea and less so in the rat jugular vein and rat aorta, two preparations in which 5-HT induced contraction also occurred via activation of 5-HT2A receptors. These studies suggest that 5-HT can functionally and selectively desensitize the 5-HT2A receptor in guinea pig trachea, an effect not likely to be related to opposing actions of 5-HT or reduction in concentration of 5-HT.Key words: phosphatidylinositol hydrolysis, receptor desensitization, smooth muscle.

Dual effects of carbachol on cytosolic Ca2+ and contraction in intestinal smooth muscle

1990 ◽  
Vol 258 (5) ◽  
pp. C787-C793 ◽  
Author(s):  
M. Mitsui ◽  
H. Karaki
Keyword(s):  
Smooth Muscle ◽  
Channel Blocker ◽  
Muscle Tension ◽  
Inhibitory Effect ◽  
Intestinal Smooth Muscle ◽  
Inhibitory Effects ◽  
High K ◽  
High Concentrations ◽  
Channel Activator ◽  
Sustained Increase

The effects of carbachol on muscle tension and cytosolic Ca2+ concentrations ([Ca2+]cyt), measured with fura-2, were examined in the guinea pig intestinal smooth muscle. Carbachol induced an initial transient increase followed by a sustained increase in [Ca2+]cyt and muscle tension. Higher concentrations of carbachol induced larger transient changes and smaller sustained changes. In the presence of carbachol, application of Ca2+ to a Ca2(+)-depleted muscle induced a contraction that was smaller in the presence of higher concentrations of carbachol. High concentrations of carbachol inhibited the high-K(+)-stimulated muscle tension and [Ca2+]cyt. Contractile and inhibitory effects of carbachol were inhibited by a muscarinic M2 antagonist. Increase in the external Ca2+ concentration or addition of BAY K 8644, a Ca2(+)-channel activator, antagonized the inhibitory effect. There was a linear correlation between log [Ca2+]cyt and muscle tension under the conditions employed in the present experiments (r = 0.949). These results suggest that lower concentrations of carbachol increase [Ca2+]cyt and induce contraction, whereas high concentrations of carbachol have an additional effect to decrease [Ca2+]cyt and inhibit contraction by a Ca2(+)-channel blocker-like action.

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