Cyclic GMP‐independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor

Homer, Kerry L.; Wanstall, Janet C.

doi:10.1038/sj.bjp.0703613

Cited by 51 publications

(40 citation statements)

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“…The lack of effect of 8-bromo-cGMP on 86 Rb uptake is consistent with its poor dilator response in ovine pulmonary artery. Although cGMPindependent stimulation of Na ϩ -K ϩ -ATPase by NO/NO donors has been demonstrated in several arterial smooth muscles (rabbit aorta, Gupta et al, 1994; rat pulmonary artery, Homer and Wanstall, 2000; and ovine pulmonary artery, Sathishkumar et al, 2005), the mechanism by which BAY Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

“…Sarcolemmal Na ϩ -K ϩ -ATPase has been implicated in both cGMP-dependent (rat aorta, Rapoport et al, 1985; canine pulmonary artery, Tamaoki et al, 1997) and -independent vasodilation (rabbit aorta, Gupta et al, 1994; rat pulmonary artery, Homer and Wanstall, 2000). Taking into consideration that BAY 41-2272 also increases cGMP level through the activation of sGC, we examined the hypothesis whether dilation of the pulmonary artery by this compound involves activation of sodium pump.…”

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confidence: 99%

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BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump

Bawankule

Sathishkumar

Sardar

et al. 2005

J Pharmacol Exp Ther

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The mechanisms of relaxation to nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) activator BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]pyrimidin-4-ylamine] were investigated in isolated ovine pulmonary artery. BAY 41-2272 (1 nM-10 M) produced concentration-dependent relaxation of endothelium-denuded pulmonary artery rings (pD 2 ϭ 6.82 Ϯ 0.16; E max ϭ 92.30 Ϯ 2.31%; n ϭ 8), precontracted with 1 M 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 M), an inhibitor of sGC, partially inhibited (E max ϭ 57.10 Ϯ 3.10%; n ϭ 6) the relaxation response of BAY 41-2272. In comparison with ODQ, sodium pump inhibitor ouabain (1 M) produced a greater decrease in the vasodilator response of BAY 41-2272 (E max ϭ 20.17 Ϯ 4.55%; n ϭ 6). K ϩ -free solution also attenuated (E max ϭ 39.97 Ϯ 3.52%; n ϭ 6) BAY 41-2272-induced relaxation. ODQ (10 M) plus 1 M ouabain abolished the relaxant response of BAY 41-2272 (E max ϭ 12.09 Ϯ 3.76%, n ϭ 6 versus vehicle control dimethyl sulfoxide; E max ϭ 15.83 Ϯ 1.72%, n ϭ 6). 2,2Ј,pyrrolo [3,4-I] [1,6]benzodiazocine-10-carboxylic acid methyl ester (2 M), a specific inhibitor of protein kinase G had no effect on 10 M ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 M) inhibited Ca 2ϩ -induced contractions in K ϩ -depolarized preparations. BAY 41-2272 (10 M) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 M ODQ. BAY 41-2272 (0.1, 1.0, and 10 M) significantly (P Ͻ 0.05) increased ouabain-sensitive 86 Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 M) also stimulated sarcolemmal Na ϩ -K ϩ -ATPase activity. However, 10 M ODQ had no significant effect on either basal or BAY 41-2272-stimulated 86 Rb uptake/Na ϩ -K ϩ -ATPase activities. In conclusion, this study provides the first evidence of sodium pump stimulation by BAY 41-2272 independent of cGMP as an additional mechanism to sGC activation in relaxation of ovine pulmonary artery.Endogenous nitric oxide (NO), derived from vascular endothelium is an important regulator of vascular functions. Thus, endothelial dysfunction is associated with several vascular disorders, such as atherosclerosis, systemic and pulmonary hypertension, and angina pectoris (Ignarro et al., 1999). Nitrovasodilators have been clinically used for the therapeutic management of NO deficiency-related conditions, such as angina pectoris and pulmonary hypertension (Sperling and Creager, 1999). However, there are certain disadvantages with NO donor-based therapy, which include development of tolerance after prolonged use (Parker, 1989), peroxinitrite formation that may lead to protein S-nitrosylation (Stamler, 1994), tyrosine nitration (Beckman et al., 1994), and the absence of clinically significant antiplatelet activity as with organic nitrates (Parker, 1989). Therefore, there has been search in the recent past for NO-independent sGC activators that could be used clinically for the treatment ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump

Bawankule

Sathishkumar

Sardar

et al. 2005

J Pharmacol Exp Ther

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“…The second limitation of the classical diffusion model of NO to guanylate cyclase is that oxodiazole quinoaxlin (ODQ), a potent guanylate cyclase inhibitor, does not entirely inhibit NO-mediated vasorelaxation. This indicates that there may be other biochemical pathways for NO (9). Perhaps the most convincing evidence of the complexity of NO biology is its multiplicity of function: NO is active in every major organ system and possesses over 36 different functions, many of which seem to operate independently of guanylate cyclase (10).…”

Section: Biochemical History Of Nitric Oxidementioning

confidence: 99%

The Biological Chemistry of Nitric Oxide as It Pertains to the Extrapulmonary Effects of Inhaled Nitric Oxide

Gow¹

2006

Proceedings of the American Thoracic Society

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The chemical properties of nitric oxide (NO) have been studied for over 200 years. However, it is only within the last 20 years that the biological implications of this chemistry have been considered. The classical model of NO action within the vasculature centers on production in the endothelium, diffusion to the smooth muscle, and subsequent activation of guanylate cyclase via binding to its heme iron. In the context of this model, it is difficult to conceptualize extrapulmonary effects of inhaled NO. However, NO possesses complex redox chemistry and is capable of forming a range of nitrogen oxide species and is therefore capable of interacting with a variety of biomolecules. Of particular interest is its reaction with reduced cysteine to form an S-nitrosothiol (SNO). SNOs are formed throughout NO biology and are a post-translational modification that has been shown to regulate many proteins under physiologic conditions. Hemoglobin, which was considered to be solely a consumer of NO, can form SNO in a conformationally dependent manner, which allows for the transport of inhaled NO beyond the realm of the lung. Higher oxides of nitrogen are capable of modifying proteins via nitration of tyrosines, which has been shown to occur under pathologic conditions. By virtue of its redox reactivity, one can appreciate that inhaled NO has a variety of routes by which it can act and that these routes may lead to extrapulmonary effects. Keywords: lung; nitric oxide; nitrotyrosine; S-nitrosothiol BIOCHEMICAL HISTORY OF NITRIC OXIDEThe history of chemical experimentation with nitrogen oxides traces back to Priestley's original experiments with the "gaseous oxide of azote" (1). Subsequently, Sir Humphry Davy performed the first biological experiments with NO, termed "nitrous air," while examining the effects of various gases on respiration and the circulatory system (2). Davy noticed that inhaling nitric oxide (NO)-containing gases caused animals "to die infinitely sooner than in common air or oxygen: but not nearly so short a time as in gases incapable of effecting positive changes in the venous blood." Davy noted that tissues from these animals were "purple red" in color, consistent with the formation of nitrosylheme within the periphery. It is fair to say that Humphry Davy, among his many other great achievements, was the first to discover an extrapulmonary effect of NO.Nearly 200 years later, the Nobel Prize in Physiology or Medicine was awarded for the discovery of the endothelium-derived relaxing factor and its identification as NO (3). The award recognized three seminal experiments: (1 ) the discovery that NO activated guanylate cyclase to induce smooth muscle cell relaxation (4), (2 ) the observation that the endothelium released a diffusible factor that was responsible for acetylcholine-mediated relaxation of blood vessels (5), and (3 ) the identification of the released factor as NO by spectroscopic examination of reaction products with hemoglobin (6). Along with the identification of NO synthase (NOS), these experime...

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“…This finding suggests that the relaxant activity of S-NONOate is mainly due to stimulation of soluble guanylate cyclase in the cavernous smooth muscle cells. Although there are some studies that suggest that S-NONOate can produce cyclic GMP-independent relaxation in some tissues such as rat pulmonary and femoral arteries (19,20), it appears that most of the effects of S-NONOate are due to direct nitric oxide-dependent interaction of S-NONOate with soluble guanylate cyclase, which enhances cGMP synthesis in this tissue. The results are presented as the percentage of the maximal response to phenylephrine-induced contraction at the end of each experiment (mean ± SE, n = 6).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological profile of a nitric oxide donor spermine NONOate in the mouse corpus cavernosum

Ertuğ

Şingirik²,

Buyuknacar³

et al. 2014

Turk J Med Sci

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Cyclic GMP‐independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor

Cited by 51 publications

References 25 publications

BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump

BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump

The Biological Chemistry of Nitric Oxide as It Pertains to the Extrapulmonary Effects of Inhaled Nitric Oxide

Pharmacological profile of a nitric oxide donor spermine NONOate in the mouse corpus cavernosum

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