CARDIOVASCULAR EFFECTS OF GAMMA-MSH ACTH-LIKE PEPTIDES - STRUCTURE-ACTIVITY RELATIONSHIP

Intravenous administration of gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) to conscious rats causes a dose-dependent increase in b lood pressure and heart rate, while the structurally related peptide a drenocorticotropic hormone-(4-10) (ACTH-(4-10)) is 5-10 times less pot ent 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-gamma(2)-MSH, most likely the endogenous ly occurring y-MSH analog, was as potent as gamma(2)-MSH in inducing i ncreases in blood pressure and heart rate. Removal of C-terminal amino acids resulted in gamma-MSH-fragments which were devoid of cardiovasc ular activities. Removal of amino acids from the N-terminal side of ga mma(2)-MSH resulted in fragments which were less potent, but had an in trinsic activity not different from that of gamma-MSH. Surprisingly, g amma-MSH-(6-12) was more potent than gamma(2)-MSH. The shortest fragme nt which displayed presser and tachycardiac responses was the MSH 'cor e', 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 conc lude 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 gamma(2) -MSH, as the sequence of Asp(9)-Arg(10)-Phe(11) appears to play an imp ortant role in establishing intrinsic activity. The amino acids N-term inal to the MSH 'core' sequence appear to be essential for the potency of the peptides.