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Venous endothelin receptor function in patients with chronic heart failure
M P Love1, W G Haynes, D J Webb
1Department of Cardiology, Western General Hospital, Edinburgh EH4 2XU, Scotland, U.K. MLove39495@aol.com
Insights
Endothelin-1 causes less venoconstriction in patients with chronic heart failure than in healthy individuals. This suggests a potential need for dual ET(A) and ET(B) receptor antagonists to treat heart failure effectively.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Medical Research
Background:
- Cardiac preload reduction via venodilation benefits chronic heart failure (CHF).
- Endothelin receptor antagonists are a potential CHF therapy, necessitating understanding of endothelin-1's venoconstrictor role in CHF.
- Human blood vessels possess two main endothelin receptor subtypes: ET(A) and ET(B).
Purpose of the Study:
- To investigate the in vivo venoconstrictor effects of endothelin-1 and sarafotoxin S6c in patients with CHF and healthy controls.
- To determine the roles of ET(A) and ET(B) receptors in mediating venoconstriction in CHF.
Main Methods:
- Locally active doses of endothelin-1 (non-selective ET(A)/ET(B) agonist) or sarafotoxin S6c (selective ET(B) agonist) were infused into a dorsal hand vein for 1 hour.
- Venous internal diameter was measured using a displacement technique in patients with CHF and age-matched healthy controls.
- Comparisons were made between the groups regarding the peak reduction in vein calibre.
Main Results:
- Venoconstriction to endothelin-1 was significantly blunted in CHF patients (26+/-7% reduction) compared to controls (51+/-6% reduction).
- Venoconstriction to sarafotoxin S6c was similar in both CHF patients (17+/-5% reduction) and controls (17+/-4% reduction).
- Both ET(A) and ET(B) receptors mediate venoconstriction in both healthy subjects and CHF patients.
Conclusions:
- Chronic heart failure may involve a selective decrease in venous ET(A) receptor sensitivity.
- Optimal inhibition of endothelin-1's venoconstrictor effects in CHF might require an antagonist blocking both ET(A) and ET(B) receptors.
- Further research is needed to clarify the functional significance of altered venous ET(A) receptor sensitivity in CHF.
Abstract:
Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17+/-5% and 17+/-4% peak reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET(A)- and ET(B)-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET(A) receptor sensitivity, but further studies are required to clarify the functional significance of this observation.