Relevance of the C-terminal Arg-Phe sequence in gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) for inducing cardiovascular effects in conscious rats.
1. The cardiovascular effects by gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) are probably not due to any of the well-known melanocortin subtype receptors. We hypothesize that the receptor for Phe-Met-Arg-Phe-amide (FMRFa) or Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide (neuropeptide FF; NPFFa), other Arg-Phe containing peptides, is the candidate receptor. Therefore, we studied various Arg-Phe containing peptides to compare their haemodynamic profile with that of gamma(2)-MSH(6 - 12), the most potent fragment of gamma(2)-MSH. 2. Mean arterial pressure (MAP) and heart rate (HR) changes were measured in conscious rats after intravenous administration of gamma(2)-MSH related peptides. 3. Phe-Arg-Trp-Asp-Arg-Phe-Gly (gamma(2)-MSH(6 - 12)), FMRFa, NPFFa, Met-enkephalin-Arg-Phe-amide (MERFa), Arg-Phe-amide (RFa), acetyl-Phe-norLeu-Arg-Phe-amide (acFnLRFa) and desamino-Tyr-Phe-norLeu-Arg-Phe-amide (daYFnLRFa) caused a dose-dependent increase in MAP and HR. gamma(2)-MSH(6 - 12) showed the most potent cardiovascular effects (ED(50)=12 nmol kg(-1) for delta MAP; 7 nmol kg(-1) for delta HR), as compared to the other Arg-Phe containing peptides (ED(50)=177 - 292 nmol kg(-1) for delta MAP; 130 - 260 nmol kg(-1) for delta HR). 4. Peptides, which lack the C-terminal Arg-Phe sequence (Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Pro-Gly (gamma(2)-pro(11)-MSH), desamino-Tyr-Phe-norLeu-Arg-[L-1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid]-amide (daYFnLR[TIC]a) and Met-enkephalin (ME)), were devoid of cardiovascular actions. 5. The results indicate that the baroreceptor reflex-mediated reduction of tonic sympathetic activity due to pressor effects is inhibited by gamma(2)-MSH(6 - 12) and that its cardiovascular effects are dependent on the presence of a C-terminal Arg-Phe sequence. 6. It is suggested that the FMRFa/NPFFa receptor is the likely candidate receptor, involved in these cardiovascular effects.
Nijsen
M J
MJ
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Nijsen@med.uu.nl
de Ruiter
G J
GJ
Kasbergen
C M
CM
Hoogerhout
P
P
de Wildt
D J
DJ
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019825:gamma-MSH / Q000737:chemistry / Q000494:pharmacology*
D000596:Amino Acids; D009842:Oligopeptides; D019825:gamma-MSH