Structural requirements and mechanism of the pressor activity of Leu-Val-Val-hemorphin-7, a fragment of hemoglobin beta-chain in rats.
A rat blood pressure assay was used to perform a structure-activity relationship study (SAR) of Leu-Val-Val-hemorphin-7 (LVV-H7), a fragment of hemoglobin (Hb) beta-chain, elucidate the mechanisms of its cardiovascular effects, and test its potential involvement in the pressor activity of diaspirin crosslinked Hb (DCLHb), a recently developed Hb-based oxygen carrier. The SAR study revealed that the C-terminal-Arg-Phe-amino acid sequence of LVV-H7 contained the main determinants of the pressor activity of this peptide. Drug interaction studies using various inhibitory drugs (e.g., phentolamine, clonidine, etc.) and LVV-H7 showed that the pressor effect and tachycardia elicited by LVV-H7 involved the activation of the sympathetic nervous system (SNS). Additional studies using phenytoin (sodium channel blocker), [Tic7]H7(5-7)-NH2 (putative antagonist of receptors for LVV-H7) and H7(5-7)-NH2, an amidated C-terminal fragment of LVV-H7, suggested that LVV-H7 activated the SNS by interacting with specific receptors functionally coupled with phenytoin-sensitive sodium channels. The pressor effect and tachycardia caused by LVV-H7 were potentiated by captopril, suggesting that the angiotensin converting enzyme may contribute to the inactivation of LVV-H7 in rats. The pressor activity of DCLHb, in contrast to that elicited by LVV-H7, was not affected by animal pretreatment with LVV-H7 fragments shown to inhibit the pressor effect of LVV-H7. We conclude that: 1) LVV-H7 is unlikely to mediate the pressor activity of DCLHb in rats; 2) the pressor and tachycardic activities of LVV-H7 are mediated by the SNS; 3) the C-terminal-Arg-Phe-amino acid sequence of LVV-H7 contains the chemical groups responsible for the pressor effect of this peptide in rats; 4) LVV-H7 and FMRF amide-related peptides may share the same mechanism of pressor activity in rats.
Moisan
S
S
Research Center (Laval University), Hôtel-Dieu de Québec, Canada.
Harvey
N
N
Beaudry
G
G
Forzani
P
P
Burhop
K E
KE
Drapeau
G
G
Rioux
F
F
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D014628:Vagotomy
D006454:Hemoglobins; D010446:Peptide Fragments; C074309:LVV-hemorphin-7; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin