Cardiovascular effects of gamma-MSH/ACTH-like peptides: structure-activity relationship.
Intravenous administration of gamma2-melanocyte-stimulating hormone (gamma2-MSH) to conscious rats causes a dose-dependent increase in blood pressure and heart rate, while the structurally related peptide adrenocorticotropic hormone-(4-10) (ACTH-(4-10)) is 5-10 times less potent in this respect. This prompted us to investigate which amino acid sequence is determinant for the cardiovascular selectivity of peptides of the gamma-MSH family. Lys-gamma2-MSH, most likely the endogenously occurring gamma-MSH analog, was as potent as gamma2-MSH in inducing increases in blood pressure and heart rate. Removal of C-terminal amino acids resulted in gamma-MSH-fragments which were devoid of cardiovascular activities. Removal of amino acids from the N-terminal side of gamma2-MSH resulted in fragments which were less potent, but had an intrinsic activity not different from that of gamma-MSH. Surprisingly, gamma-MSH-(6-12) was more potent than gamma2-MSH. The shortest fragment which displayed pressor and tachycardiac responses was the MSH 'core', His-Phe-Arg-Trp (= gamma-MSH-(5-8)), which is identical to ACTH-(6-9). This was corroborated by testing fragments of ACTH-(4-10). We conclude that the message essential for cardiovascular effects resides in the gamma-MSH-(5-8)/ACTH-(6-9) sequence. Proper C-terminal elongation is required for full expression of cardiovascular activity of gamma2-MSH, as the sequence of Asp9-Arg10-Phe11 appears to play an important role in establishing intrinsic activity. The amino acids N-terminal to the MSH 'core' sequence appear to be essential for the potency of the peptides.
Van Bergen
P
P
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht, Netherlands.
Janssen
P M
PM
Hoogerhout
P
P
De Wildt
D J
DJ
Versteeg
D H
DH
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018043:Receptors, Corticotropin / Q000187:drug effects; D044101:Receptors, Melanocortin; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones; C011394:ACTH (4-10)