Modulation of contractile function through neuropeptide Y receptors during development of cardiomyocyte hypertrophy.
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 Y(1) and Y(2) 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 Y(1) receptor-selective agonist, Leu(31)Pro(34)NPY, stimulated increases in contractile amplitude, which were abolished by the Y(1) receptor-selective antagonist, BIBP3226 [R-N(2)-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y(1) 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-Y(1) and NPY-Y(2) 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.
Allen
Adrian R
AR
Cardiovascular Research Group, School of Medicine and Dentistry, Queen's University Belfast, Belfast, United Kingdom.
Kelso
Elizabeth J
EJ
Bell
David
D
Zhao
Youyou
Y
Dickson
Paula
P
McDermott
Barbara J
BJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D048429:Cell Size / Q000187:drug effects; D004558:Electric Stimulation; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000473:pathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010446:Peptide Fragments; D019894:Peptide YY / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C092926:BIBP 3226; D002316:Cardiotonic Agents; D008565:Membrane Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; C061785:peptide YY (3-36); D001120:Arginine; D007545:Isoproterenol; D002118:Calcium