Contribution of nitric oxide, prostanoids and Ca 2+ -activated K + channels to the relaxant response of bradykinin in the guinea pig bronchus in vitro

Mazzuco, Tânia Longo; André, Eunice; Calixto, João B.

doi:10.1007/s002109900201

Cited by 9 publications

(7 citation statements)

References 35 publications

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“…That K Ca channels are at the root of the cGMP-independent relaxing action of NO is intriguing and is consistent with the cGMP-independent actions of NO described thus far (Ahern et al, 1999;Mazzuco et al, 2000;Yu et al, 2002). The notion that myometrial K Ca are regulated directly by NO is supported by evidence in vascular (Bolotina et al, 1994) and gastrointestinal smooth muscle cells (Lang et al, 2000) that these channels can be modulated by S-nitrosylation.…”

Section: K Ca -Channelssupporting

confidence: 72%

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Buxton

2004

Molecular Pharmacology

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Premature birth accounts for the majority of fetal morbidity and mortality in the developed world and is disproportionately represented in some populations, such as African Americans in the United States. The costs associated with prematurity are staggering in both monetary and human terms. Present therapeutic approaches for the treatment of labor leading to preterm delivery are inadequate and our understanding of the regulation of myometrial smooth muscle contraction-relaxation is incomplete. The ability of nitric oxide to relax smooth muscle has led to an interest in employing nitric oxide-donors in the treatment of preterm labor. Fundamental differences exist, however, in the regulation of uterine smooth muscle relaxation and that of other smooth muscles and constitute a conundrum in our understanding. We review the evidence that nitric oxide-mediated relaxation of myometrial smooth muscle, unlike vascular or gastrointestinal smooth muscle, is independent of global elevation of cyclic guanosine 5Ј-monophosphate. Applying our current understanding of microdomain signaling and taking clues from genomic studies of pregnancy, we offer a framework in which to view the apparent conundrum and suggest testable hypotheses of uterine relaxation signaling that can explain the mechanistic distinctions. We propose that understanding these mechanistic distinctions in myometrium will reveal molecular targets that are unique and thus may be explored as therapeutic targets in the development of new uterine smooth musclespecific tocolytics.

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Section: K Ca -Channelssupporting

confidence: 72%

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Buxton

2004

Molecular Pharmacology

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“…Due to the similar regional effects of l-NAME and iberiotoxin and because the PKG I inhibitor Rp-G lacked any SC-modulatory effect, NO possibly activates BK channels directly in the epididymal contractile cells. A cGMP-independent activation of Ca 2ϩ -dependent K ϩ channels (K Ca ) by NO in (vascular) smooth muscle is amply verified (33)(34)(35)(36). By contrast, the mechanism(s) underlying the l-NAME-induced transient SC suppression in the corpus remain(s) to be elucidated.…”

Section: Epididymal Basal No Productionmentioning

confidence: 93%

Regulation of Spontaneous Contractile Activity in the Bovine Epididymal Duct by Cyclic Guanosine 5′-Monophosphate-Dependent Pathways

Mewe¹,

Bauer²,

Müller³

et al. 2006

Endocrinology

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Passage of spermatozoa through the epididymis is obligatory for sperm maturation processes and is based on spontaneous phasic contractions (SC) of the epididymal duct. Here, the functional role of cyclic GMP (cGMP) signaling in modulating SC in the bovine epididymal caput and corpus region was examined by muscle tension recording and immunological and autoradiographic techniques. The cGMP-analog 8-bromo (Br)-cGMP, as well as the nitric oxide (NO) donor sodium nitroprusside and the natriuretic peptides (NPs) atrial NP and C-type NP, displayed distally increasing SC-relaxant effects. In agreement, a distally increasing epididymal expression of the cGMP-dependent protein kinase I (PKG I), endothelial NO synthase (eNOS), and the atrial NP receptor was found. Immunoreactivity for PKG, soluble guanylate cyclase, and eNOS could be localized to the epididymal muscle cells as well as to the epithelial basal cells only at the corpus level. The SC-relevant action of NO and the NPs was cGMP dependent, and the action of 8-Br-cGMP, in turn, was modified by epithelial and luminal factors. The NOS inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) caused an increase in SC frequency, indicating basal activity of NO generating enzymes. The SC-inhibitory effect of 8-Br-cGMP was clearly reduced by the PKG inhibitor Rp-8-Br-cGMPS as well as by iberiotoxin, thapsigargin, and indomethacin, pointing to PKG as main SC-relevant target of cGMP, and to large-conductance calcium-activated K(+) channels, the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase and cyclooxygenase-1 as possible targets of PKG. These data support an essential role of cGMP signaling in the control of epididymal peristalsis, thereby enabling fine tuning of sperm transport and maturation.

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“…In the airways, there is accumulating evidence to indicate that kinins play an important role in the control of bronchoalveolar function (Barnes et al ., 1988; Farmer, 1992). Pharmacological and molecular studies now indicate that most BK actions in the guinea‐pig airways are mediated by the activation of B 2 receptors (Proud et al ., 1993; Schlemper & Calixto, 1994) and the subsequent release of prostanoids and nitric oxide (NO) (Bramley et al ., 1989; Schlemper & Calixto, 1994, 1995; Figini et al ., 1996; Van Heuven‐Nolsen et al ., 1997; Mazzuco et al ., 2000). On the other hand, BK‐induced contraction in denuded guinea‐pig trachea (GPT−E) is dependent on prostanoid production and on the release of calcium from intracellular sources, an effect that is largely sensitive to ryanodine, and it seems to be associated with the activation of protein kinase C (PKC) (Calixto, 1995; Schlemper & Calixto, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the relaxation response induced by bradykinin in the epithelium‐intact guinea‐pig trachea in vitro

Schlemper¹,

Medeiros²,

Ferreira³

et al. 2005

British J Pharmacology

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1 In this study, we investigated some of the signalling pathways involved in bradykinin (BK)-induced relaxation in epithelium-intact strips of the guinea-pig trachea (GPT þ E). BK induced timeand concentration-dependent relaxation of GPT þ E. Similar responses were observed for prostaglandin E 2 (PGE 2 ) or the combination of subthreshold concentrations of BK plus PGE 2 . 2 The nonselective cyclooxygenase (COX) inhibitors indomethacin or pyroxicam, or the selective COX-2 inhibitors DFU, NS 398 or rofecoxib, but not the selective COX-1 inhibitor SC 560, all abolished BK-induced relaxation. 3 The tyrosine kinase inhibitors herbimycin A and AG 490 also abolished BK-induced relaxation in GPT þ E. 4 The nonselective nitric oxide synthase (NOS) inhibitor 7-NINA concentration-dependently inhibited BK effects. 5 BK-induced relaxation was prevented by the selective antagonists for EP 3 (L 826266), but not by EP 1 (SC 19221), EP 1 /EP 2 (AH 6809) or EP 4 (L 161982) receptor antagonists. 6 Otherwise, the selective inhibitors of protein kinases A, G and C, mitogen-activated protein kinases, phospholipases C and A 2 , nuclear factor-kB or potassium channels all failed to significantly interfere with BK-mediated relaxation. 7 BK caused a marked increase in PGE 2 levels, an effect that was prevented by NS 398, HOE 140 or AG 490. 8 COX-2 expression did not differ in preparations with or without epithelium, and it was not changed by BK stimulation. However, incubation with BK significantly increased the endothelial NOS (eNOS) and neuronal NOS (nNOS) expression, independent of the epithelium integrity. 9 Our results indicate that BK-induced relaxation in GPT þ E depends on prostanoids (probably PGE 2 acting via EP 3 receptors) and NO release and seems to involve complex interactions between kinin B 2 receptors, COX-2, nNOS, eNOS and tyrosine kinases.

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Contribution of nitric oxide, prostanoids and Ca 2+ -activated K + channels to the relaxant response of bradykinin in the guinea pig bronchus in vitro

Cited by 9 publications

References 35 publications

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Regulation of Uterine Function: a Biochemical Conundrum in the Regulation of Smooth Muscle Relaxation

Regulation of Spontaneous Contractile Activity in the Bovine Epididymal Duct by Cyclic Guanosine 5′-Monophosphate-Dependent Pathways

Mechanisms underlying the relaxation response induced by bradykinin in the epithelium‐intact guinea‐pig trachea in vitro

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