Modulation of phorbol ester-induced contraction by endogenously released cyclooxygenase products in rat aorta

1994 ◽  
Vol 267 (5) ◽  
pp. H1654-H1662 ◽  
Author(s):  
S. P. Williams ◽  
A. K. Campbell ◽  
N. Roszell ◽  
L. Myatt ◽  
G. D. Leikauf ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Phorbol Ester ◽  
Phorbol Esters ◽  
Smooth Muscle Contraction ◽  
Receptor Activation ◽  
Rat Aorta ◽  
Cyclooxygenase Inhibitor ◽  
Relaxant Effect

This study tests the hypothesis that prostaglandins (PGs) released in response to phorbol esters act as modulators of the phorbol ester-induced smooth muscle contraction. The rate and magnitude of the phorbol 12-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin. The thromboxane (Tx) A2/PGH2 receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition was greater than that due to indomethacin. PMA induced the release of PGI2, PGE2, PGF2 alpha, and arachidonic acid, but not TxA2. The amount of PGI2 released was greater than that of PGE2 and PGF2 alpha. Indomethacin blocked the PMA-induced release of PG, but not of arachidonic acid. In PMA-contracted tissues, PGF2 alpha, PGE2, and the stable PGI2 and PGH2 analogues, carbacyclin and U-46619, respectively, induced further contraction. Pretreatment of PMA-contracted tissues with SQ-29548 partially inhibited the PGF2 alpha- and PGE2-induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These results demonstrate that, in rat aorta, PMA induces the release of PGs that exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-induced increase in PMA contraction is mediated, in large part, through TxA2/PGH2 receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA2/PGH2 receptor suggests that one or more of these PGs, in addition to, presumably, PGH2, may be responsible for the increase in PMA contraction. PGI2 is the only endogenously released PG that can account for the relaxant effect.

scholarly journals NTPDase1 Modulates Smooth Muscle Contraction in Mice Bladder by Regulating Nucleotide Receptor Activation Distinctly in Male and Female

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 147
Author(s):  
Romuald Brice Babou Kammoe ◽  
Gilles Kauffenstein ◽  
Julie Pelletier ◽  
Bernard Robaye ◽  
Jean Sévigny
Keyword(s):  
Smooth Muscle ◽  
Ex Vivo ◽  
Smooth Muscle Contraction ◽  
Receptor Activation ◽  
Nucleoside Triphosphate ◽  
Nucleotide Receptors ◽  
Nerve Terminals ◽  
Wild Type ◽  
Nucleoside Triphosphate Diphosphohydrolase ◽  
Bladder Contraction

Nucleotides released by smooth muscle cells (SMCs) and by innervating nerve terminals activate specific P2 receptors and modulate bladder contraction. We hypothesized that cell surface enzymes regulate SMC contraction in mice bladder by controlling the concentration of nucleotides. We showed by immunohistochemistry, enzymatic histochemistry, and biochemical activities that nucleoside triphosphate diphosphohydrolase-1 (NTPDase1) and ecto-5′-nucleotidase were the major ectonucleotidases expressed by SMCs in the bladder. RT-qPCR revealed that, among the nucleotide receptors, there was higher expression of P2X1, P2Y1, and P2Y6 receptors. Ex vivo, nucleotides induced a more potent contraction of bladder strips isolated from NTPDase1 deficient (Entpd1−/−) mice compared to wild type controls. The strongest responses were obtained with uridine 5′-triphosphate (UTP) and uridine 5′-diphosphate (UDP), suggesting the involvement of P2Y6 receptors, which was confirmed with P2ry6−/− bladder strips. Interestingly, this response was reduced in female bladders. Our results also suggest the participation of P2X1, P2Y2 and/or P2Y4, and P2Y12 in these contractions. A reduced response to the thromboxane analogue U46619 was also observed in wild type, Entpd1−/−, and P2ry6−/− female bladders showing another difference due to sex. In summary, NTPDase1 modulates the activation of nucleotide receptors in mouse bladder SMCs, and contractions induced by P2Y6 receptor activation were weaker in female bladders.

Dependence of stress on cross-bridge phosphorylation in vascular smooth muscle

1989 ◽  
Vol 256 (1) ◽  
pp. C96-C100 ◽  
Author(s):  
P. H. Ratz ◽  
C. M. Hai ◽  
R. A. Murphy
Keyword(s):  
Smooth Muscle ◽  
Steady State ◽  
Vascular Smooth Muscle ◽  
Light Chain ◽  
Phorbol Esters ◽  
Receptor Activation ◽  
Bay K 8644 ◽  
Cross Bridge ◽  
Cross Bridges ◽  
State Stress

Cross-bridge phosphorylation associated with agonist-stimulated contraction of vascular smooth muscle is often transiently elevated. Such observations led to the concept that phosphorylation of the 20-kDa myosin regulatory light chain (Mp) was required for initial activation and cross-bridge cycling but might not be necessary for steady-state maintenance of stress in the latch state. The possibility that stress maintenance is not regulated by phosphorylation has received some experimental support in contractions induced by phorbol esters and the calcium channel activator BAY K 8644 in which significant increases in Mp were not detected. Our aim was to test the hypothesis that phosphorylation is both necessary and sufficient for activation and for maintenance of steady-state stress. Activation of swine carotid media using agents that bypass receptor activation and elevate Ca2+ influx without mobilizing intracellular Ca2+ stores (BAY K 8644 and ionomycin) produced monotonic increases in both stress and Mp. Transient initial peaks in Mp were absent. Steady-state stress induced by both receptor- and nonreceptor-mediated activation was dependent on small increases in Mp. Increases in Mp greater than 0.3 mol Pi/mol myosin light chain had small effects on stress but produced large increases in the maximum rate of cross-bridge cycling at zero load (Vo). The experimentally determined dependence of stress on Mp was quantitatively predicted by our working hypothesis. This model proposes that Ca2+-stimulated cross-bridge phosphorylation is obligatory for cross-bridge attachment. However, dephosphorylation of attached cross bridges to form noncycling "latch bridges" allows stress maintenance with reduced Mp and cycling.

scholarly journals The Vasorelaxant Effect ofp-Cymene in Rat Aorta Involves Potassium Channels

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Martapolyana T. M. Silva ◽  
Fernanda P. R. A. Ribeiro ◽  
Maria Alice M. B. Medeiros ◽  
Pedrita A. Sampaio ◽  
Yonara M. S. Silva ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Potassium Channels ◽  
Vascular Smooth Muscle ◽  
Channel Blocker ◽  
Antimicrobial Activities ◽  
Rat Aorta ◽  
Relaxant Effect ◽  
Vasorelaxant Effect ◽  
Dose Dependent ◽  
Relaxing Effect

The monoterpenes are the main constituents of most essential oils andp-cymene is a monoterpene commonly found in various species of aromatic herbs, which has been reported for anti-inflammatory, antinociceptive, and antimicrobial activities. However, there is no report concerning its pharmacological activity on the vascular smooth muscle. The aim of current work was to investigate the effects ofp-cymene in isolated rat aorta and also study its mechanism of action. In this work, we show thatp-cymene has a relaxant effect, in a dose-dependent way, on the vascular smooth muscle, regardless of the presence of the endothelium. Using a nonselective potassium channel blocker, the CsCl, the relaxant effect ofp-cymene was attenuated. In the presence of more selective potassium channels blockers, such as TEA or 4-AP, no change in the relaxant effect ofp-cymene was evidenced, indicating thatBKCaandKVchannels are not involved in that relaxant effect. However, in the presence of glibenclamide or BaCl2,KATPandKirblockers, respectively, the relaxant effect ofp-cymene was attenuated. The data presented indicate thatp-cymene has a relaxing effect on rat aorta, regardless of the endothelium, but with the participation of theKATPandKirchannels.

Cyclooxygenase-2 induction by bradykinin in aortic vascular smooth muscle cells

2006 ◽  
Vol 290 (1) ◽  
pp. H30-H36 ◽  
Author(s):  
Jorge A. Rodriguez ◽  
Paula De la Cerda ◽  
Eileen Collyer ◽  
Valerie Decap ◽  
Carlos P. Vio ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Receptor Antagonist ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Receptor Activation ◽  
Atheromatous Plaque ◽  
Protein Levels ◽  
Cox 2

Vascular smooth muscle cell proliferation and migration play an important role in the pathophysiology of several vascular diseases, including atherosclerosis. Prostaglandins that have been implicated in this process are synthesized by two isoforms of cyclooxygenase (COX), with the expression of the regulated COX-2 isoform increased in atherosclerotic plaques. Bradykinin (BK), a vasoactive peptide increased in inflammation, induces the formation of prostaglandins through specific receptor activation. We hypothesized that BK plays an important role in the regulation of COX-2, contributing to the increase in production of prostaglandins in vascular smooth muscle cells. Herein we examined the signaling pathways that participate in the BK regulation of COX-2 protein levels in primary cultured aortic vascular smooth muscle cells. We observed an increase in COX-2 protein levels induced by BK that was maximal at 24 h. This increase was blocked by a B2 kinin receptor antagonist but not a B1 receptor antagonist, suggesting that the B2 receptor is involved in this pathway. In addition, we conclude that the activation of mitogen-activated protein kinases p42/p44, protein kinase C, and nitric oxide synthase is necessary for the increase in COX-2 levels induced by BK because either of the specific inhibitors for these enzymes blocked the effect of BK. Using a similar approach, we further demonstrated that reactive oxygen species and cAMP were not mediators on this pathway. These results suggest that BK activates several intracellular pathways that act in combination to increase COX-2 protein levels. This study suggests a role for BK on the evolution of the atheromatous plaque by virtue of controlling the levels of COX-2.

Effect of Desmodium adscendens fractions on antigen- and arachidonic acid-induced contractions of guinea pig airways

1988 ◽  
Vol 66 (6) ◽  
pp. 820-825 ◽  
Author(s):  
Marian E. Addy ◽  
John F. Burka
Keyword(s):  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Guinea Pig ◽  
Muscle Contraction ◽  
Aqueous Extract ◽  
Contractile Response ◽  
Late Phase ◽  
Smooth Muscle Contraction ◽  
Pharmacologically Active ◽  
Active Substances

Three fractions (n-butanol, F2, and L5), isolated from an aqueous extract of Desmodium adscendens, a plant used in Ghana for the management of asthma, were evaluated for their pharmacological activity using ovalbumin and arachidonic acid-induced contractions of guinea pig airways. All three fractions inhibited the ovalbumin-induced contractions of indomethacin-pretreated tracheal spirals from sensitized animals dose dependently, but only L5 and n-butanol inhibited such contractions in the absence of indomethacin. The concentrations required to inhibit ovalbumin-induced contractions of lung parenchymal strips were threefold higher than with trachea. The contractile response over a 60-min period was divided into three phases. F2 and n-butanol inhibited all phases, whereas L5 inhibited only the late phase. n-Butanol and L5 inhibited arachidonic acid-induced contractions on indomethacin-pretreated tracheal spirals, a leukotriene-dependent reaction. There was no inhibition of arachidonic acid-induced contractions of lung parenchymal strips, which is largely a thromboxane-dependent reaction. The results suggest that D. adscendens contains several pharmacologically active substances that can inhibit allergic airway smooth muscle contraction at multiple sites, including the synthesis and (or) activity of the bronchoconstrictor leukotrienes.

scholarly journals Effects Of F-18 On KCL And Phenylephrine - Induced Contractions Of Rat Aorta

2021 ◽  
Vol 03 (06) ◽  
pp. 100-108
Author(s):  
Abdisalim Zaripov ◽  
◽  
Adilbay Esimbetov ◽  
Pulat Usmanov ◽  
Durdona Shokirova ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Mechanism Of Action ◽  
Isometric Contraction ◽  
Functional Activity ◽  
Rat Aorta ◽  
Relaxant Effect ◽  
Voltage Dependent ◽  
Ca2 Channels

The mechanism of action of the alkaloid 1-(2´-bromine-4´,5´-dimethoxyphenyl) - 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (F-18) on the functional activity of smooth muscle cells of the rat aorta was studied. Isometric contraction activity was recorded using a Grass FT – 03 (Grass Instrument, USA) mechanotron. The relaxant effect of the F-18 alkaloid was found to be associated with blockade of Ca2 + (IP3R) channels in the SR, along with voltage- dependent and receptor-operated Ca2+channels in the aorta smooth muscle cell plasmalemma.

Contractile regulation of the Na+-K+-2Cl− cotransporter in vascular smooth muscle

2001 ◽  
Vol 281 (2) ◽  
pp. C579-C584 ◽  
Author(s):  
Fatma Akar ◽  
Gengru Jiang ◽  
Richard J. Paul ◽  
W. Charles O'Neill
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Isometric Force ◽  
Specific Inhibitor ◽  
Smooth Muscle Contraction ◽  
Rat Aorta ◽  
Direct Result ◽  
Aortic Smooth Muscle ◽  
Butanedione Monoxime ◽  
Stimulation Of

Vasoconstrictors activate the Na+-K+-2Cl− cotransporter NKCC1 in rat aortic smooth muscle, but the mechanism is unknown. Efflux of86Rb+ from rat aorta in response to phenylephrine (PE) was measured in the absence and presence of bumetanide, a specific inhibitor of NKCC1. Removal of extracellular Ca2+ completely abolished the activation of NKCC1 by PE. This was not due to inhibition of Ca2+-dependent K+ channels since blocking these channels with Ba2+ in Ca2+-replete solution did not prevent activation of NKCC1 by PE. Stimulation of NKCC1 by PE was inhibited 70% by 75 μM ML-9, 97% by 2 μM wortmannin, and 70% by 2 mM 2,3-butanedione monoxime, each of which inhibited isometric force generation in aortic rings. Bumetanide-insensitive Rb+efflux, an indication of Ca2+-dependent K+channel activity, was reduced by ML-9 but not by the other inhibitors. Stretching of aortic rings on tubing to increase lumen diameter to 120% of normal almost completely blocked the stimulation of NKCC1 by PE without inhibiting the stimulation by hypertonic shrinkage. We conclude that activation of the Na+-K+-2Cl− cotransporter by PE is the direct result of smooth muscle contraction through Ca2+-dependent activation of myosin light chain kinase. This indicates that the Na+-K+-2Cl− cotransporter is regulated by the contractile state of vascular smooth muscle.

Role of muscarinic M2 receptors in regulating beta-adrenergic responsiveness in maturing rabbit airway smooth muscle

1995 ◽  
Vol 269 (6) ◽  
pp. L783-L790 ◽  
Author(s):  
C. M. Schramm ◽  
N. C. Arjona ◽  
M. M. Grunstein
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Airway Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Receptor Subtypes ◽  
Response Curves ◽  
Beta Adrenergic ◽  
Gi Protein ◽  
Functional Antagonism

Muscarinic M2 and M3 receptor subtypes have been pharmacologically distinguished in airway smooth muscle. Whereas M3 receptors have been associated with smooth muscle contraction, M2 receptors have been implicated in Gi protein-coupled inhibition of adenylyl cyclase. To determine whether the role of M2 receptors varies with age in tracheal smooth muscle (TSM), dose-dependent relaxation responses to isoproterenol were compared in TSM isolated from 3-day-old and adult rabbits precontracted with acetylcholine (ACh) in the absence (control) and presence of an M2 receptor antagonist (gallamine or methoctramine). From sustained half-maximal ACh contractions, adult TSM were 5.6-fold less sensitive than 3-day-old tissues to isoproterenol-induced relaxation. Furthermore, the magnitude of muscarinic functional antagonism of isoproterenol-mediated TSM relaxation, assessed by varying the initial degree of ACh-induced contraction, significantly increased with age. In gallamine- and methoctramine-treated tissues, the relaxation-response curves to isoproterenol were shifted to the left in both 3-day-old and adult TSM. In contrast, pretreatment with either M2 receptor antagonist had no significant effect on the magnitude of muscarinic functional antagonism at either age. Moreover, Western blot analysis of G alpha i common and specific subunit expression in TSM membranes demonstrated qualitatively similar levels in 3-day-old and adult TSM. Collectively, these findings provide new evidence that 1) there exist inherent age-dependent differences in both the airway relaxant responsiveness to beta-adrenoceptor stimulation and muscarinic functional antagonism of beta-adrenergic relaxation, and 2) the latter are attributed to mechanisms other than ontogenetic alteration in M2 receptor function or Gi protein expression in maturing rabbit TSM.

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