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CARDIOVASCULAR

Modulation of Contractile Function through Neuropeptide Y Receptors during Development of Cardiomyocyte Hypertrophy

Cardiovascular Research Group, School of Medicine and Dentistry, Queen's University Belfast, Belfast, United Kingdom

Severity of left ventricular hypertrophy (LVH) correlates with elevated plasma levels of neuropeptide Y (NPY) in hypertension. NPY elicits positive and negative contractile effects in cardiomyocytes through Y₁ and Y₂ receptors, respectively. This study tested the hypothesis that NPY receptor-mediated contraction is altered during progression of LVH. Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks), and at established LVH (20 weeks) and age-matched normotensive Wistar Kyoto (WKY) rats. Electrically stimulated (60 V, 0.5 Hz) cell shortening was measured using edge detection and receptor expression determined at mRNA and protein level. The NPY and Y₁ receptor-selective agonist, Leu³¹Pro³⁴NPY, stimulated increases in contractile amplitude, which were abolished by the Y₁ receptor-selective antagonist, BIBP3226 [R-N²-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y₁ receptor involvement. Potencies of both agonists were enhanced in SHR cardiomyocytes at 20 weeks (2300- and 380-fold versus controls). Maximal responses were not attenuated. BIBP3226 unmasked a negative contraction effect of NPY, elicited over the concentration range (10^–12 to 3 x 10^–9 M) in which NPY and PYY_3–36 attenuated the positive contraction effects of isoproterenol, the potencies of which were increased in cardiomyocytes from SHRs at 20 weeks (175- and 145-fold versus controls); maximal responses were not altered. Expression of NPY-Y₁ and NPY-Y₂ receptor mRNAs was decreased (55 and 69%) in left ventricular cardiomyocytes from 20-week-old SHRs versus age-matched WKY rats; parallel decreases (32 and 80%) were observed at protein level. Enhancement of NPY potency, producing (opposing) contractile effects on cardiomyocytes together with unchanged maximal response despite reduced receptor number, enables NPY to contribute to regulating cardiac performance during compensatory LVH.

Address correspondence to: Dr. David Bell, Division of Medicine and Therapeutics, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK. E-mail: d.bell{at}qub.ac.uk