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OtherCARDIOVASCULAR PHARMACOLOGY

Coronary Vasorelaxation by Nitroglycerin: Involvement of Plasmalemmal Calcium-Activated K+ Channels and Intracellular Ca++ Stores

Sajida A. Khan, Nicole R. Higdon and Kaushik D. Meisheri
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 838-846;
Sajida A. Khan
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Nicole R. Higdon
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Kaushik D. Meisheri
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Abstract

This study investigated nitroglygerin (NTG) relaxations in isolated dog coronary artery in comparison with other vascular preparations. Under maximal PNU-46619 precontraction, the coronary artery was significantly more sensitive to NTG than mesenteric artery, mesenteric vein and saphenous vein. In the coronary artery, NTG (1–100 nM) produced relaxations with EC50 = 9.4 nM. In KCl-contracted arteries (20–80 mM KCl), relaxation by NTG was progressively reduced. Relaxation responses to NTG also were inhibited significantly by potent calcium-activated K+ (BK) channel blockers, charybdotoxin (100 nM) and iberiotoxin (200 nM), but not by KATP blockers such as PNU-37883A (10 μM) or PNU-99963 (100 nM). Nitric oxide (0.1–30 nM) and acetylcholine (3–300 nM) also produced relaxations which were significantly attenuated by the BK blockers. In further experiments, NTG (1–100 nM) produced inhibition of PNU-46619-induced SR [Ca++]i release, with an IC50of 8.5 nM, which was not affected by charybdotoxin. Furthermore, P1075 (50 nM), a KATP opener, did not inhibit agonist-stimulated SR [Ca++]i release. Ryanodine (10 μM), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 μM), a selective inhibitor of SR Ca++-ATPase pump, produced pronounced inhibition of NTG relaxations. These results suggest that NTG, in the therapeutic concentration range, produces coronary relaxation primarilyvia two cellular mechanisms: plasmalemmal BK channel activation and stimulation of SR Ca++-ATPase to produce increased SR Ca++ accumulation. These two mechanisms apparently are equally important and act together to produce a unique vasorelaxation profile demonstrated by NTG-type coronary vasodilators.

Footnotes

  • Send reprint requests to: Sajida A. Khan, Pharmacology, 7250–209-315, Pharmacia & Upjohn Inc., Kalamazoo, MI 49001. e-mail:sakhan{at}am.pnu.com

  • Abbreviations:
    BK
    calcium-activated K+ channels or Maxi K channels
    KATP
    ATP-sensitive K+channel
    CRC
    concentration response curve
    PSS
    physiological salt solution
    ACh
    acetylcholine
    NTG
    nitroglycerin
    RY
    ryanodine
    TG
    thapsigargin
    SR
    sarcoplasmic reticulum
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    NO
    nitric oxide
    MeB
    methylene blue
    ChTX
    charybdotoxin
    IbTX
    iberiotoxin
    EGTA
    ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
    • Received August 28, 1997.
    • Accepted November 14, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Coronary Vasorelaxation by Nitroglycerin: Involvement of Plasmalemmal Calcium-Activated K+ Channels and Intracellular Ca++ Stores

Sajida A. Khan, Nicole R. Higdon and Kaushik D. Meisheri
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 838-846;

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OtherCARDIOVASCULAR PHARMACOLOGY

Coronary Vasorelaxation by Nitroglycerin: Involvement of Plasmalemmal Calcium-Activated K+ Channels and Intracellular Ca++ Stores

Sajida A. Khan, Nicole R. Higdon and Kaushik D. Meisheri
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 838-846;
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