Vol. 303, Issue 2, 581-591, November 2002

Induction of Hypertrophic Responsiveness of Cardiomyocytes to Neuropeptide Y in Response to Pressure Overload

David Bell, Adrian R. Allen, Elizabeth J. Kelso, Ambikaipakan Balasubramaniam and Barbara J. McDermott

Department of Therapeutics and Pharmacology, Centre for Cardiovascular and Genetics Research, School of Medicine, The Queen's University of Belfast, United Kingdom (D.B., A.R.A., E.J.K., B.J.McD.); and Division of Gastrointestinal Hormones, Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio (A.B.)

To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [¹⁴C]Phe, 0.1 µCi ml¹) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10⁸ M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 ± 2.1% (n = 8, P < 0.05). De novo protein synthesis was increased maximally in SHRs at 12, 16, and 20 weeks (P < 0.05, n = 8) in response to NPY by 12.6 ± 2.1% (10⁶ M), 20.1 ± 4.2% (10⁸ M), and 9.4 ± 1.8% (10⁷ M), respectively. Peptide YY_3-36, (PYY_3-36), which displays selectivity for NPY Y₂ and NPY Y₅ receptors, and the NPY Y₅-selective agonist [D-Trp³⁴]-NPY increased de novo protein synthesis maximally by 16.2 ± 5.1% (10⁷ M; n = 4, P < 0.05) and 17.8 ± 5.2% (10⁶ M; n = 7, P < 0.05), respectively, in SHRs at 16 weeks, whereas [Leu³¹Pro³⁴]-NPY (10⁶ M), which displays some activity at NPY Y₁ and NPY Y₄ receptors, did not. The NPY Y₁-selective antagonist BVD-42 (2 × 10⁷ M) and the NPY Y₂-selective antagonist BIIE0246 (2 × 10⁷ M) did not attenuate responses to NPY (10⁷ M) and PPY_3-36 (10⁷ M). These data indicate that hypertrophic responsiveness to NPY, mediated via NPY Y₅ receptors, is induced transiently in SHR cardiomyocytes subsequent to onset of cardiomyocyte hypertrophy in response to pressure overload.