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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Distribution of Angiotensin AT2Receptors in the Normal and Failing Human Heart

John Wharton, Kevin Morgan, Richard A. D. Rutherford, John D. Catravas, Adrian Chester, Bruce F. Whitehead, Marc R. De Leval, Magdi H. Yacoub and Julia M. Polak
Journal of Pharmacology and Experimental Therapeutics January 1998, 284 (1) 323-336;
John Wharton
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Kevin Morgan
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Richard A. D. Rutherford
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John D. Catravas
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Adrian Chester
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Bruce F. Whitehead
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Marc R. De Leval
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Magdi H. Yacoub
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Julia M. Polak
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Abstract

Cardiac expression of angiotensin II (Ang II) AT1 and AT2 receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using125I-(Sar1,Ile8)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT2 receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT2 binding sites (Kd = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT2 binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT1 binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial125I-(Sar1,Ile8)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT2 receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of125I-351A. Specific myocardial AT2 receptor mRNA transcripts (≈3 kb) were identified and exhibited alternative splicing of untranslated 5′ exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT2 sites in the diseased heart suggest that cells bearing the AT2 receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.

Footnotes

  • Send reprint requests to: Dr. John Wharton, Department of Histochemistry, Imperial College School of Medicine, The Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail:jwharton{at}rpms.ac.uk

  • ↵1 This work was supported by a grant from the British Heart Foundation (PG/95017).

  • Abbreviations:
    ACE
    angiotensin-converting enzyme
    Ang II
    angiotensin II
    Ang IV
    hexapeptide fragment 3–8 of angiotensin II
    DTT
    dithiothreitol
    PECAM
    platelet-endothelial cell adhesion molecule
    CI
    confidence interval
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    • Received March 13, 1997.
    • Accepted September 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 1
1 Jan 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Distribution of Angiotensin AT2Receptors in the Normal and Failing Human Heart

John Wharton, Kevin Morgan, Richard A. D. Rutherford, John D. Catravas, Adrian Chester, Bruce F. Whitehead, Marc R. De Leval, Magdi H. Yacoub and Julia M. Polak
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 323-336;

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OtherCARDIOVASCULAR PHARMACOLOGY

Differential Distribution of Angiotensin AT2Receptors in the Normal and Failing Human Heart

John Wharton, Kevin Morgan, Richard A. D. Rutherford, John D. Catravas, Adrian Chester, Bruce F. Whitehead, Marc R. De Leval, Magdi H. Yacoub and Julia M. Polak
Journal of Pharmacology and Experimental Therapeutics January 1, 1998, 284 (1) 323-336;
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