S. Moisan et al., STRUCTURAL REQUIREMENTS AND MECHANISM OF THE PRESSOR ACTIVITY OF LEU-VAL-VAL-HEMORPHIN-7, A FRAGMENT OF HEMOGLOBIN BETA-CHAIN IN RATS, Peptides, 19(1), 1998, pp. 119-131
A rat blood pressure assay was used to perform a structure-activity re
lationship study (SAR) of Leu-Val-Val-hemorphin-7 (LVV-H7), a fragment
of hemoglobin (Hb) P-chain, elucidate the mechanisms of its cardiovas
cular effects, and test its potential involvement in the presser activ
ity of diaspirin crosslinked Hb (DCLHb), a recently developed Hb-based
oxygen carrier. The SAR study revealed that the C-terminal-Arg-Phe-am
ino acid sequence of LVV-H7 contained the main determinants of the pre
sser activity of this peptide. Drug interaction studies using various
inhibitory drugs (e.g., phentolamine, clonidine, etc.) and LVV-H7 show
ed that the presser effect and tachycardia elicited by LVV-H7 involved
the activation of the sympathetic nervous system (SNS). Additional st
udies using phenytoin (sodium channel blocker), [Tic(7)]H7(5-7)-NH2 (p
utative antagonist of receptors for LVV-H7) and H7(5-7)-NH2, an amidat
ed C-terminal fragment of LVV-H7, suggested that LVV-H7 activated the
SNS by interacting with specific receptors functionally coupled with p
henytoin-sensitive sodium channels. The presser effect and tachycardia
caused by LVV-H7 were potentiated by captopril, suggesting that the a
ngiotensin converting enzyme may contribute to the inactivation of LVV
-H7 in rats. The presser activity of DCLHb, in contrast to that elicit
ed by LVV-H7, was not affected by animal pretreatment with LVV-H7 frag
ments shown to inhibit the presser effect of LVV-H7. We conclude that:
1) LVV-H7 is unlikely to mediate the presser activity of DCLHb in rat
s; 2) the presser and tachycardic activities of LVV-H7 are mediated by
the SNS; 3) the C-terminal-Arg-Phe-amino acid sequence of LVV-H7 cont
ains the chemical groups responsible for the presser effect of this pe
ptide in rats; 4) LVV-H7 and FMRF amide-related peptides may share the
same mechanism of presser activity in rats. (C) 1998 Elsevier Science
Inc.