Structural requirements and mechanism of the pressor activity of Leu-Val-Val-hemorphin-7, a fragment of hemoglobin beta-chain in rats.

Abstract

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.

• Authors: S Moisan, N Harvey, G Beaudry, P Forzani, K E Burhop, G Drapeau, F Rioux
• Journal: Peptides (Peptides) Vol. 19 Issue 1 Pg. 119-31 ( 1998) ISSN: 0196-9781 [Print] United States
• PMID: 9437744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hemoglobins
• Peptide Fragments
• LVV-hemorphin-7
• diaspirin-cross-linked hemoglobin
• Aspirin

Topics

• Animals
• Aspirin (analogs & derivatives, pharmacology)
• Blood Pressure (drug effects)
• Heart Rate (drug effects)
• Hemoglobins (chemistry, pharmacology)
• Male
• Peptide Fragments (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Sympathetic Nervous System (drug effects, physiopathology)
• Vagotomy