Lack of effect of zaprinast on methacholine‐induced contraction and inositol 1,4,5‐trisphosphate accumulation in bovine tracheal smooth muscle

Chilvers, Edwin R.; Giembycz, Mark A.; Challiss, R. A. John; Barnes, Peter J.; Nahorski, Stefan R.

doi:10.1111/j.1476-5381.1991.tb12310.x

Cited by 28 publications

(12 citation statements)

References 37 publications

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“…42 In brief, 4 aortic rings (derived from the abdominal aorta from the portion enclosed by the diaphragm to 3 cm just above the orifice of the right renal artery; wet weight each, 30Ϯ1 mg) were incubated in test tubes containing Krebs-Henseleit buffer saturated with 95% O 2 /5% CO 2 for 30 minutes to exclude the hypoxic effect induced during sacrifice of the rabbits. The rings were promptly frozen in LN 2 and stored at Ϫ80°C.…”

Section: Measurement Of Cgmpmentioning

confidence: 99%

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Hayashi

Esaki

Muto

et al. 2000

ATVB

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Abstract-Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), a specific aromatase inhibitor; group 4, an HCD plus 17␤-estradiol (20 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by Ϸ60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that Ϸ50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17␤-estradiol. have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEA-S serves as a reservoir for DHEA, since various tissues have been shown to contain steroid sulfatases. 1 The peak plasma levels of DHEA and DHEA-S occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95% around the age of 85 years. Epidemiological evidence has shown that adult men with high plasma DHEA-S levels are less likely to die of cardiovascular disease. 2 A study indicated that administration of DHEA reduced aortic fatty streak formation and cholesterol accumulation by Ϸ30% to 40% in cholesterol-fed rabbits. 3 Another report has shown a 50% reduction...

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Section: Measurement Of Cgmpmentioning

confidence: 99%

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Hayashi

Esaki

Muto

et al. 2000

ATVB

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“…23 In brief, 4 aortic rings from the segment of abdominal aorta from 2 cm distal to the portion enclosed by the diaphragm (11 cm distal to the aortic valve) to 2 cm distal to the bifurcation of the internal iliac arteries (wet weight each was 10Ϯ1 mg) were incubated for 30 minutes in test tubes containing Krebs-Henseleit buffer saturated with 95% O 2 /5% CO 2 . The rings were frozen in LN 2 and stored at Ϫ80°C.…”

Section: Determination Of Cgmpmentioning

confidence: 99%

“…Samples were assayed by a radioimmunoassay for cGMP. 23 Solids left from the initial homogenization step were digested in 1 mL of 0.1N NaOH overnight, after which total protein was determined.…”

Section: Determination Of Cgmpmentioning

confidence: 99%

Physiological Concentration of 17β-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury

Hayashi

Jayachandran

Sumi

et al. 2000

ATVB

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Abstract-The molecular mechanisms of the antiatherosclerotic effects of estrogen are not yet known. We evaluated the effects of 17␤-estradiol (E 2 ) on high cholesterol diet-(HCD; standard diet and 1% cholesterol) and balloon injury-induced atherosclerosis in female New Zealand White rabbits. The abdominal aortas of 40 oophorectomized (Groups 1 through 5) and 8 nonoophorectomized (Group 6) rabbits were injured by balloon catheter, and the animals were then divided into the following groups and treated for 10 weeks: Group 1, standard diet; Group 2, standard diet plus a moderate dose of E 2 (100 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); Group 3, HCD; Group 4, HCD plus a moderate dose of E 2 ; Group 5, HCD plus a low dose of E 2 (20 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ); and Group 6, HCD in nonoophorectomized rabbits. After the treatment phase, plasma E 2 was increased up to 282.2Ϯ45.5 pg/mL in Group 2, 263.0Ϯ41.5 pg/mL in Group 4, 87.9Ϯ18.8 pg/mL in Group 5, and 45.6Ϯ7.3 pg/mL in Group 6. HCD-mediated increases in plasma lipid levels were not changed by E 2 treatment, whereas E 2 decreased the aortic intimal thickening in Group 2 animals compared with those in Group 1 and reduced atherosclerosis in the thoracic and abdominal aortas of Group 4, 5, and 6 rabbits compared with those in Group 3. E 2 restored the impaired abdominal aortic endothelium-dependent relaxation of balloon-injured and HCDsupplemented rabbits, and E 2 increased basal nitric oxide (NO) release. The basal NO-releasing effect showed a significant, inverse relation with the severity of atherosclerosis. Plasma E 2 concentration also showed a significant, inverse relation with atherosclerotic area. In conclusion, physiological concentrations of E 2 can retard the progression of severe atherosclerosis and stabilize atheromas induced by HCD and balloon injury. Key Words: nitric oxide Ⅲ estradiol Ⅲ arteriosclerosis Ⅲ balloon injury Ⅲ endothelium I t is well known that estrogen retards the development of atherosclerosis, 1 but the mechanisms of action are not clearly established. Estrogen replacement therapy suppresses the incidence of cardiovascular disease in postmenopausal women, 2 and it reduces plasma LDL cholesterol and increases HDL cholesterol levels. 3 However, the alterations in lipid profiles reportedly account for only a limited portion of the protective effects of estrogen against cardiovascular disease. 4 Estrogen exerts a direct action on the vessel wall via incompletely understood mechanisms. 5 Recently, estradiol was found to inhibit leukocyte adhesion and transendothelial migration in rabbits, which suggests one of the mechanisms of a direct antiatherosclerotic effect by estrogen on the vessel wall. 6 Nitric oxide (NO), released from endothelial nitric oxide synthase (endothelial NOS), has been demonstrated to offer protection against the development of atherosclerosis by producing vascular dilatation, inhibiting monocyte adhesion to the endothelium, and other modes of action. [7][8][9] We have found that estrogen acts via an NO-mediated system in vivo and in vitro. The aortas...

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“…Accordingly, the inhibition by ibudilast of PDE 5 seems to contribute to the enhancement of SNP-and ANPinduced relaxation. In support of this idea, zaprinast, a PDE 5 selective inhibitor (IC 50 <~1 µM; Silver et al 1988;Chilvers et al 1991;Shahid et al 1991), also enhanced both relaxation and cGMP accumulation in response to SNP or ANP.…”

Section: Discussionmentioning

confidence: 52%

“…Ibudilast is approximately 10-30 times less potent than zaprinast in inhibiting the PDE 5 isoenzyme (Silver et al 1988;Chilvers et al 1991;Shahid et al 1991;Souness et al 1994). However, unlike ibudilast, zaprinast at concentrations up to 100 µM failed to relax bovine tracheal smooth muscle.…”

Section: Discussionmentioning

confidence: 97%

Relaxation and potentiation of cGMP-mediated response by ibudilast in bovine tracheal smooth muscle

Nakahara

Yunoki

Moriuchi

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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The effects of ibudilast, an inhibitor of phosphodiesterases (PDEs), on tension, levels of guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) were investigated in bovine tracheal smooth muscle. We especially examined the combined effect of ibudilast with the cGMP-elevating agents on these parameters. Ibudilast was equipotent to attenuate the precontractions induced by both 0.3 microM methacholine and 40 mM K(+). By contrast, the relaxant effects of sodium nitroprusside and salbutamol on 40 mM K(+)-contracted preparations were smaller than those on 0.3 microM methacholine-contracted ones. Neither N(omega)-nitro-L-arginine (100 microM), an inhibitor of nitric oxide synthase, nor ODQ (1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 5 microM), an inhibitor of soluble guanylyl cyclase, affected the ibudilast-induced relaxation. The relaxations induced by ibudilast and diltiazem on 40 mM K(+)-contracted preparations were significantly attenuated when extracellular CaCl(2) was increased from 2.54 mM to 10 mM. Ibudilast (10 microM), which caused only minor effect by itself, significantly ( P<0.05) shifted the concentration-response curves for the relaxant responses to sodium nitroprusside (SNP), atrial natriuretic peptide (ANP) and salbutamol to the left. On the other hand, ibudilast did not change the relaxant responses to diltiazem. Unlike ibudilast, diltiazem (3 microM) failed to affect the SNP- and salbutamol-induced relaxations. Ibudilast significantly ( P<0.05) increased basal levels of cGMP and cAMP. Furthermore, ibudilast enhanced SNP (0.3 microM)- and ANP (0.3 microM)-induced cGMP accumulation and salbutamol (10 nM)-induced cAMP accumulation. Zaprinast (10 microM), a type 5 PDE inhibitor, enhanced both relaxation and cGMP accumulation induced by SNP and ANP without changing salbutamol-induced responses. These findings suggest that blockade of voltage-gated Ca(2+) channels is involved in the relaxing action of ibudilast in bovine tracheal smooth muscle. However, ibudilast potentiates relaxation responses to ANP and SNP by inhibition of PDE 5, not by blockade of Ca(2+) channels. The enhancement of cGMP-mediated response may contribute to the therapeutic effects of ibudilast.

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Lack of effect of zaprinast on methacholine‐induced contraction and inositol 1,4,5‐trisphosphate accumulation in bovine tracheal smooth muscle

Cited by 28 publications

References 37 publications

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Dehydroepiandrosterone Retards Atherosclerosis Formation Through Its Conversion to Estrogen

Physiological Concentration of 17β-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury

Relaxation and potentiation of cGMP-mediated response by ibudilast in bovine tracheal smooth muscle

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