title: Inotropic action of the puberty hormone kisspeptin in rat, mouse and human: cardiovascular distribution and characteristics of the kisspeptin receptor.
abstract: Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [(125)I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (K(D) = 0.12 nM, human; K(D) = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.
authors: Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom. jjm1003@medschl.cam.ac.uk
authors: Janet J
authors: JJ
authors: Maguire
authors: Helen R
authors: HR
authors: Kirby
authors: Emma J
authors: EJ
authors: Mead
authors: Rhoda E
authors: RE
authors: Kuc
authors: Xavier
authors: X
authors: d'Anglemont de Tassigny
authors: William H
authors: WH
authors: Colledge
authors: Anthony P
authors: AP
authors: Davenport
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D059648:Kisspeptins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011627:Puberty / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D055815:Young Adult
chemical_list: D002316:Cardiotonic Agents; D059648:Kisspeptins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface