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OtherAUTONOMIC PHARMACOLOGY

Differentiation of Muscarinic Receptors Mediating Negative Chronotropic and Vasoconstrictor Responses to Acetylcholine in Isolated Rat Hearts

Donald B. Hoover and David A. Neely
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1337-1344;
Donald B. Hoover
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David A. Neely
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Abstract

The primary goal of this study was to determine the extent that selective muscarinic receptor antagonists could discriminate between the chronotropic and coronary vasoconstrictor responses to acetylcholine in isolated rat hearts perfused at constant flow rate. Bolus injections of acetylcholine caused dose-dependent decreases in heart rate and increases in perfusion pressure. The ED50(95% confidence) of acetylcholine for decreasing rate was 0.463 (0.336–0.640) nmol and the dose that increased perfusion pressure by 30 mm Hg (ED30 mmHg↑) was 3.19 (2.00–5.08) nmol. The M2 selective antagonist methoctramine (3.16 μM) produced a 307-fold increase in the ED50 for bradycardia but had no significant effect on the pressor response to acetylcholine. In marked contrast, the M3 antagonist hexahydrosiladifenidol displayed a distinct preference for inhibiting coronary vasoconstrictor responses to acetylcholine. When present at 316 nM, this drug produced a 66-fold increase in the ED30 mmHg↑ but only a 6-fold increase in the ED50for bradycardia. The M1 selective antagonist pirenzepine (316 nM) produced a 5- to 7-fold increase in both parameters. Pretreatment with pertussis toxin (25 μg/kg, i.p.) essentially eliminated acetylcholine-evoked bradycardia although pressor responses persisted with some reduction. These observations demonstrate that cardiac and coronary vascular effects of acetylcholine can be clearly discriminated with specific muscarinic antagonists. Furthermore, they provide evidence that the M3 receptor subtype mediates the vasoconstrictor effect of acetylcholine on resistance vessels in rat heart.

Footnotes

  • Send reprint requests to: Dr. Donald B. Hoover, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614.

  • ↵1 This study was supported by a Grant-in-Aid from the American Heart Association, Tennessee Affiliate, Inc.

  • Abbreviations:
    ACh
    acetylcholine
    HHSiD
    hexahydrosiladifenidol
    PTX
    pertussis toxin
    ANOVA
    analysis of variance
    • Received January 8, 1997.
    • Accepted May 9, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherAUTONOMIC PHARMACOLOGY

Differentiation of Muscarinic Receptors Mediating Negative Chronotropic and Vasoconstrictor Responses to Acetylcholine in Isolated Rat Hearts

Donald B. Hoover and David A. Neely
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1337-1344;

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OtherAUTONOMIC PHARMACOLOGY

Differentiation of Muscarinic Receptors Mediating Negative Chronotropic and Vasoconstrictor Responses to Acetylcholine in Isolated Rat Hearts

Donald B. Hoover and David A. Neely
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1337-1344;
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