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Kanji Nakatsu – One of the best experts on this subject based on the ideXlab platform.

  • superoxide does not inhibit glyceryl trinitrate rabbit Aortic Strip mediated relaxation of rabbit taenia coli evidence against a role for nitric oxide itself as the smooth muscle active drug metabolite
    Drug Metabolism and Disposition, 1996
    Co-Authors: Aman S Hussain, James F Brien, Gerald S Marks, Kanji Nakatsu

    Abstract:

    This study was designed to test the hypothesis that nitric oxide (NO) is the relaxant metabolite produced by metabolic activation of glyceryl trinitrate (GTN) in rabbit Aortic Strip (RAS). Superoxide anion, an inactivator of NO, was included in a two-tissue bioassay in which rabbit Taenia coli Strip (RTCS) relaxed to GTN in the presence of RAS. Superoxide as generated by xanthine (10 microM)/ xanthine oxidase (20 mU/ml) failed to attenuate relaxations of RTCS to GTN (0.1 nM-10 microM) and RAS, compared with the untreated control. In contrast, superoxide attenuated the relaxation of RTCS to both authentic NO gas and to SIN-1 (0.1 nM-10 microM), a known spontaneous releaser of NO; the attenuation of RTCS relaxation to NO gas was reversed by superoxide dismutase (100 units/ml). In addition, another drug that has been reported to scavenge NO, hydroquinone, did not attenuate the RTCS relaxation to GTN. These results suggest that biotransformation of GTN in vascular smooth muscle that leads to relaxation is caused by a NO-containing species (i.e. a S-nitrosothiol). Such a molecule would be less susceptible to inactivation by superoxide anion and hydroquinone.

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  • nitric oxide formation from glyceryl trinitrate by rabbit Aortic Strip detection by rabbit taenia coli concurrent with vasorelaxation
    British Journal of Pharmacology, 1994
    Co-Authors: Aman S Hussain, James F Brien, Gerald S Marks, Margo Poklewskakoziell, Kanji Nakatsu

    Abstract:

    : 1. The purpose of the present study was to assay NO formation from GTN biotransformation by the rabbit Aortic Strip (RAS) at times concurrent with its vasorelaxation. Such an assay is an important test of the prodrug hypothesis where it is postulated that glyceryl trinitrate (GTN) is biotransformed to nitric oxide (NO), the active species that initiates vascular smooth muscle relaxation. To test such a hypothesis, we propose that a sample of smooth muscle, poorly responsive to GTN, yet sensitive to the effects of NO could be used to detect RAS production of NO from GTN. 2. Muscle Strips of rabbit taenia coli (RTCS) and RAS in close apposition, were mounted in tissue baths, and muscle relaxation was recorded with isometric force transducers. Tissues were submaximally precontracted with 30-35 mM K+ depolarizing solution and exposed to increasing concentrations of GTN (0.1 nM-10 microM). 3. EC25 for GTN-induced relaxation of RTCS in the presence of RAS was significantly decreased to that for RTCS in the absence of RAS (5.9 +/- 3.0 x 10(-8) M and 5.5 +/- 3.7 x 10(-6) M, respectively). Mean maximal levels of GTN-induced relaxation of similarly precontracted RTCS also differed in the presence and absence of RAS, viz., 80.8 +/- 2.1% and 29.8 +/- 8.3% respectively. 4. RTCS was found to relax upon administration of NO gas bubbled through the incubation medium. Analysis of tissue bath medium revealed that the NO concentration to which RTCS was exposed attained a maximum of 33 nM. Relaxation of RTCS by NO gas was inhibited by 1 microM reduced haemoglobin. 5. For GTN-incubation with intestinal and vascular smooth muscle preparations, NO formation was greater with RAS compared to RTCS. Thus, in the two-issue bioassay, the RAS was the predominant source of NO formation from GTN. 6. Reduced deoxyhaemoglobin (1 microM), a potent extracellular NO scavenger, was found to decrease the augmented GTN-induced relaxation in the RTCS-RAS sandwich preparation from 17.3 +/- 1.8% to 8.0 +/- 0.8%. The augmented RTCS response was restored upon washout and subsequent addition of GTN, in the absence of reduced Hb.7 These data indicate that nitric oxide or a closely related NO-donor is produced by vascular biotransformation of GTN as seen by the increased sensitivity of RTCS to GTN when in the presence of RAS. The results of this bioassay thus support the GTN-NO prodrug hypothesis.

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  • nitric oxide formation fromglyceryl trinitrate byrabbit Aortic Strip detection byrabbit taenia coli concurrentwith vasorelaxation
    , 1994
    Co-Authors: Kanji Nakatsu

    Abstract:

    bythe rabbit Aortic Strip (RAS)attimes concurrent withitsvasorelaxation. Suchan assay isan important test oftheprodrug hypothesis whereitispostulated thatglyceryl trinitrate (GTN)isbiotransformed to nitric oxide (NO),theactive species thatinitiates vascular smoothmusclerelaxation. To testsucha hypothesis, we proposethat a sample ofsmoothmuscle, poorly responsive toGTN, yetsensitive tothe effects ofNO couldbeusedtodetect RAS production ofNO fromGTN. 2 Muscle Strips ofrabbit taenia coli(RTCS)andRAS inclose apposition, were mountedintissue baths, andmuscle relaxation was recorded withisometric force transducers. Tissues were submaximally precontracted with30-35mMK+ depolarizing solution andexposed toincreasing concentrations of GTN (0.1nM-l0IM). 3 EC25forGTN-induced relaxation ofRTCSinthepresenceofRAS was significantly decreased to thatforRTCSintheabsence ofRAS(5.9 ± 3.0X 10-8 M and5.5 ± 3.7X 10-6 M, respectively). Mean maximal levels ofGTN-induced relaxation ofsimilarly precontracted RTCSalsodiffered inthepresence andabsence ofRAS,viz., 80.8 ± 2.1%and29.8 ± 8.3%respectively. 4 RTCSwas found torelax upon administration ofNO gasbubbled through theincubation medium. Analysis oftissue bathmediumrevealed thattheNO concentration towhichRTCS was exposed attained a maximumof33nM. Relaxation ofRTCS byNO gas was inhibited by 1 gM reduced haemoglobin. 5 ForGTN-incubation withintestinal andvascular smooth muscle preparations, NO formation was greater withRAScompared toRTCS.Thus, inthetwo-issue bioassay, theRAS was thepredominant sourceofNO formation fromGTN. 6 Reduced deoxyhaemoglobin (1pM), a potentextracellular NO scavenger,was found todecrease the augmented GTN-induced relaxation intheRTCS-RASsandwich preparation from17.3 ± 1.8%to 8.0 ± 0.8%.Theaugmented RTCS responsewas restored upon washout andsubsequent addition of GTN,intheabsence ofreduced Hb. 7 Thesedataindicate thatnitric oxide or a closely related NO-donorisproduced byvascular biotransformation

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Aman S Hussain – One of the best experts on this subject based on the ideXlab platform.

  • superoxide does not inhibit glyceryl trinitrate rabbit Aortic Strip mediated relaxation of rabbit taenia coli evidence against a role for nitric oxide itself as the smooth muscle active drug metabolite
    Drug Metabolism and Disposition, 1996
    Co-Authors: Aman S Hussain, James F Brien, Gerald S Marks, Kanji Nakatsu

    Abstract:

    This study was designed to test the hypothesis that nitric oxide (NO) is the relaxant metabolite produced by metabolic activation of glyceryl trinitrate (GTN) in rabbit Aortic Strip (RAS). Superoxide anion, an inactivator of NO, was included in a two-tissue bioassay in which rabbit Taenia coli Strip (RTCS) relaxed to GTN in the presence of RAS. Superoxide as generated by xanthine (10 microM)/ xanthine oxidase (20 mU/ml) failed to attenuate relaxations of RTCS to GTN (0.1 nM-10 microM) and RAS, compared with the untreated control. In contrast, superoxide attenuated the relaxation of RTCS to both authentic NO gas and to SIN-1 (0.1 nM-10 microM), a known spontaneous releaser of NO; the attenuation of RTCS relaxation to NO gas was reversed by superoxide dismutase (100 units/ml). In addition, another drug that has been reported to scavenge NO, hydroquinone, did not attenuate the RTCS relaxation to GTN. These results suggest that biotransformation of GTN in vascular smooth muscle that leads to relaxation is caused by a NO-containing species (i.e. a S-nitrosothiol). Such a molecule would be less susceptible to inactivation by superoxide anion and hydroquinone.

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  • nitric oxide formation from glyceryl trinitrate by rabbit Aortic Strip detection by rabbit taenia coli concurrent with vasorelaxation
    British Journal of Pharmacology, 1994
    Co-Authors: Aman S Hussain, James F Brien, Gerald S Marks, Margo Poklewskakoziell, Kanji Nakatsu

    Abstract:

    : 1. The purpose of the present study was to assay NO formation from GTN biotransformation by the rabbit Aortic Strip (RAS) at times concurrent with its vasorelaxation. Such an assay is an important test of the prodrug hypothesis where it is postulated that glyceryl trinitrate (GTN) is biotransformed to nitric oxide (NO), the active species that initiates vascular smooth muscle relaxation. To test such a hypothesis, we propose that a sample of smooth muscle, poorly responsive to GTN, yet sensitive to the effects of NO could be used to detect RAS production of NO from GTN. 2. Muscle Strips of rabbit taenia coli (RTCS) and RAS in close apposition, were mounted in tissue baths, and muscle relaxation was recorded with isometric force transducers. Tissues were submaximally precontracted with 30-35 mM K+ depolarizing solution and exposed to increasing concentrations of GTN (0.1 nM-10 microM). 3. EC25 for GTN-induced relaxation of RTCS in the presence of RAS was significantly decreased to that for RTCS in the absence of RAS (5.9 +/- 3.0 x 10(-8) M and 5.5 +/- 3.7 x 10(-6) M, respectively). Mean maximal levels of GTN-induced relaxation of similarly precontracted RTCS also differed in the presence and absence of RAS, viz., 80.8 +/- 2.1% and 29.8 +/- 8.3% respectively. 4. RTCS was found to relax upon administration of NO gas bubbled through the incubation medium. Analysis of tissue bath medium revealed that the NO concentration to which RTCS was exposed attained a maximum of 33 nM. Relaxation of RTCS by NO gas was inhibited by 1 microM reduced haemoglobin. 5. For GTN-incubation with intestinal and vascular smooth muscle preparations, NO formation was greater with RAS compared to RTCS. Thus, in the two-issue bioassay, the RAS was the predominant source of NO formation from GTN. 6. Reduced deoxyhaemoglobin (1 microM), a potent extracellular NO scavenger, was found to decrease the augmented GTN-induced relaxation in the RTCS-RAS sandwich preparation from 17.3 +/- 1.8% to 8.0 +/- 0.8%. The augmented RTCS response was restored upon washout and subsequent addition of GTN, in the absence of reduced Hb.7 These data indicate that nitric oxide or a closely related NO-donor is produced by vascular biotransformation of GTN as seen by the increased sensitivity of RTCS to GTN when in the presence of RAS. The results of this bioassay thus support the GTN-NO prodrug hypothesis.

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Shiqi Peng – One of the best experts on this subject based on the ideXlab platform.

  • a new class of analgesic agents toward prostacyclin receptor inhibition synthesis biological studies and qsar analysis of 1 hydroxyl 2 substituted phenyl 4 4 5 5 tetramethylimidazolines
    European Journal of Medicinal Chemistry, 2008
    Co-Authors: Ming Zhao, Li Peng, Yurong Tang, Chao Wang, Ziding Zhang, Shiqi Peng

    Abstract:

    Abstract By studying the structural similarity of analgesic imidazolines and 2-phenylnitronyl nitroxides, 20 1-hydroxyl-2-substituted phenyl-4,4,5,5-tetramethylimidazolines (2a–t) were newly synthesized as selective antagonists of prostacyclin receptor (IP receptor). In the in vivo tail-flick assay, 2a–t (dose, 0.13 mmol/kg) receiving mice showed increased pain thresholds ranging from 20.52 ± 7.25% to 90.94 ± 11.97%, which were significantly higher than that ranged from 12.27 ± 9.56% to 17.71 ± 7.00% shown by normal saline (NS) receiving mice. In the in vivo tail bleeding assay, 2a–t (dose, 1.30 mmol/kg) receiving mice gave a bleeding time ranging from 116.3 ± 8.0 s to 119.6 ± 7.1 s, and NS receiving mice gave a bleeding time ranging from 116.7 ± 7.5 s to 119.1 ± 8.7 s, which were at a substantially equal level. These observations imply that no bleeding risk occurred even when 10-fold dose of analgesic assay was used. In the in vitro vasorelaxation assay, it was found that when the Aortic Strip contracted by noradrenaline (NE, final concentration, 10−7 M) was treated with the solution of 2a–t in NS (final concentration, 5 × 10−3 M) only lower percentage inhibitions ranged from 6.63 ± 2.72% to 46.28 ± 2.63% were recorded. Relatively higher concentration of 2a–t (5 × 10−3 M) and relatively lower percentage inhibitions (13 of 20 less than 23.27 ± 3.47%) suggest that 2a–t exhibit few vasodilation activity. To shed some light on the potential analgesic mechanisms of 2a–t, moreover, a QSAR analysis was carried out by using the multiple linear regression method. Taken altogether, the current study confirms that as selective antagonist of IP receptor 1-hydroxyl-2-substituted phenyl-4,4,5,5-tetramethylimidazoline may be a promising lead compound of analgesic agent without cardiovascular and bleeding side effects.

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