cGMP and cAMP inhibit tension development in skinned coronary arteries

Pfitzer, Gabriele; Hofmann, Franz; DiSalvo, Joseph; Rüegg, J. C.

doi:10.1007/bf00582596

Cited by 79 publications

(32 citation statements)

References 21 publications

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“…These findings are similar to those described by Pfitzer et al (1984) who used cyclic GMP in porcine Triton-skinned coronary arteries. Since cyclic GMP is thought to exert its effects via activation of a cyclic GMP-dependent protein kinase it would have been interesting to test the purified catalytic subunit of this enzyme.…”

Section: Discussionsupporting

confidence: 91%

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Bryson¹,

Rodger²

1987

British J Pharmacology

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1 The effects of three phosphodiesterase inhibitors (papaverine, igobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2 The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation of histamine-induced contractions of the trachealis. 3 Papaverine-induced relaxation was associated with concentration-related increases in the levels of both cyclic nucleotides. 4 IBMX at low concentrations (1 gmol 1-') produced significant relaxation (36%) of histaminecontracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX-induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels.Only at the highest concentration tested (100 gmol I-) did IBMX increase cyclic AMP levels significantly.5 SKF 94120(1 pmol 1-') elicited a 23% relaxation of the contracted trachealis without altering the tissue content ofeither cyclic nucleotide. At the two higher concentrations tested (10 and 100 pmol 1 -'), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6 In the skinned trachealis Ca2" (10 and 20 gmol I ')-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 gtmol 1I-') and by cyclic AMP (10 pmol 1 1'), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 pmol I') and cyclic GMP (10 pmol l'). 7 Papaverine (1O00Imoll-') significantly inhibited (31 ± 6%) the Ca2t-induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. 8 It is concluded that cyclic nucleotide-dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase-inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.

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Section: Discussionsupporting

confidence: 91%

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Bryson¹,

Rodger²

1987

British J Pharmacology

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“…The free Ca2+ concentration was varied by changing the ratio of EGTA to Ca-EGTA, assuming the apparent dissociation constant of 1.6 PM [6]. Except for the measurement of protein phosphatase activity, the solution also contained 0.2pM calmodulin.…”

Section: Methodsmentioning

confidence: 99%

Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin

Takai¹,

Bialojan²,

Troschka³

et al. 1987

FEBS Letters

268

130

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“…Ca 2ϩ sensitization due to inhibition of MLCP activity is mediated by an agonist G protein-coupled, Ca 2ϩ -independent process that activates RhoA͞Rho-kinase, phosphorylates the myosin regulatory subunit of MLCP (MYPT1), and leads to increased force (1). On the other hand, cyclic nucleotideactivated kinases, in addition to decreasing cytosolic Ca 2ϩ , make a significant contribution to dephosphorylation of RLC 20 and relaxation through Ca 2ϩ -desensitization processes (2)(3)(4)(5) and can reverse G protein-coupled Ca 2ϩ sensitization (2,3). Interaction between the leucine zipper motifs of protein kinase G and MYPT1 leads to direct stimulation of MLCP (6).…”

mentioning

confidence: 99%

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

Khromov¹,

Wang²,

Choudhury³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic nucleotides can relax smooth muscle without a change in [Ca 2؉ ]i, a phenomenon termed Ca 2؉ desensitization, contributing to vasodilation, gastrointestinal motility, and airway resistance. The physiological importance of telokin, a 17-kDa smooth musclespecific protein and target for cyclic nucleotide-induced Ca 2؉ desensitization, was determined in telokin null mice bred to a congenic background. Telokin null ileal smooth muscle homogenates compared to wild type exhibited an Ϸ30% decrease in myosin light-chain phosphatase (MLCP) activity, which was reflected in a significant leftward shift (up to 2-fold at pCa 6.3) of the Ca 2؉ force relationship accompanied by an increase in myosin light-chain phosphorylation. No difference in the Ca 2؉ force relationship occurred in telokin WT and knockout (KO) aortas, presumably reflecting the normally Ϸ5-fold lower telokin content in aorta vs. ileum smooth muscle. Ca 2؉ desensitization of contractile force by 8-Br-cGMP was attenuated by 50% in telokin KO intestinal smooth muscle. The rate of force relaxation reflecting MLCP activity, in the presence of 50 M 8-Br-cGMP, was also significantly slowed in telokin KO vs. WT ileum and was rescued by recombinant telokin. Normal thick filaments in telokin KO smooth muscles indicate that telokin is not required for filament formation or stability. Results indicate that a primary role of telokin is to modulate force through increasing MLCP activity and that this effect is further potentiated through phosphorylation by cGMP in telokin-rich smooth tissues. S mooth muscle (SM) myosin II ATPase activity and associated contraction is activated by actin only when Ser-19 of the myosin regulatory light chain (RLC 20 ) is phosphorylated. The extent of RLC 20 phosphorylation is a reflection of the balance between Ca 2ϩ calmodulin-dependent myosin light-chain kinase (MLCK) and myosin light-chain phosphatase (MLCP) activities. Although the major mechanism for initiating contraction is the rise in [Ca 2ϩ ] i , force can be further increased or decreased through signaling pathways that modulate MLCK and͞or MLCP activities giving rise to processes termed Ca 2ϩ sensitization or -desensitization (reviewed in ref. 1). Ca 2ϩ sensitization due to inhibition of MLCP activity is mediated by an agonist G protein-coupled, Ca 2ϩ -independent process that activates RhoA͞Rho-kinase, phosphorylates the myosin regulatory subunit of MLCP (MYPT1), and leads to increased force (1). On the other hand, cyclic nucleotideactivated kinases, in addition to decreasing cytosolic Ca 2ϩ , make a significant contribution to dephosphorylation of RLC 20 and relaxation through Ca 2ϩ -desensitization processes (2-5) and can reverse G protein-coupled Ca 2ϩ sensitization (2, 3). Interaction between the leucine zipper motifs of protein kinase G and MYPT1 leads to direct stimulation of MLCP (6). A role for this interaction in Ca 2ϩ desensitization is supported by the observation that chicken gizzard MYPT1 lacking the leucine zipper motifs is resistant to 8-BrcGMP-induced depho...

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cGMP and cAMP inhibit tension development in skinned coronary arteries

Cited by 79 publications

References 21 publications

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation

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cGMP and cAMP inhibit tension development in skinned coronary arteries

Cited by 79 publications

References 21 publications

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Effects of phosphodiesterase inhibitors on normal and chemically‐skinned isolated airway smooth muscle

Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin

Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca 2+ and decreased cGMP-induced relaxation

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Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca ²⁺ and decreased cGMP-induced relaxation