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Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia
V Mathew1, V M Miller, D Hasdai
1Department of Internal Medicine, Mayo Foundation, Rochester, Minnesota, USA. mathew.verghese@mayo.edu
Insights
In hypercholesterolemia, endothelin-B receptor stimulation accentuates coronary vasoconstriction, particularly in microvasculature. This may involve reduced endothelin-derived relaxing factor activity, highlighting endothelin-B receptor
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Endocrinology
Background:
- Endothelin-1 primarily mediates vasoconstriction via endothelin-A receptors.
- Experimental hypercholesterolemia increases coronary vasoconstriction to endothelin-1.
- The role of endothelin receptor subtypes in hypercholesterolemia-induced vasoconstriction is unclear.
Purpose of the Study:
- To investigate if endothelin-B receptor stimulation increases coronary vasoconstriction in hypercholesterolemia.
- To determine if this is linked to reduced endothelin-derived relaxing factor activity.
Main Methods:
- Infusion of sarafotoxin (endothelin-B receptor agonist) or NG-monomethyl-L-arginine (L-NMMA, nitric oxide synthase inhibitor) into coronary arteries of pigs.
- Measurements taken before and after a 10-week cholesterol-rich diet.
- Assessment of coronary blood flow (CBF) and coronary artery diameter.
Main Results:
- Hypercholesterolemia significantly increased serum cholesterol levels.
- Sarafotoxin infusion caused a greater decrease in CBF post-diet (60%) compared to baseline (34%).
- L-NMMA's effect on CBF was attenuated post-diet, suggesting reduced nitric oxide synthase activity.
Conclusions:
- Selective endothelin-B receptor stimulation enhances coronary vasoconstriction in experimental hypercholesterolemia, mainly in the microvasculature.
- This effect may be associated with diminished endothelin-derived relaxing factor activity.
- Endothelin-B receptors play a role in regulating coronary vascular tone during pathophysiological conditions.
Background:
Vasoconstriction in response to endothelin-1 has been shown to be primarily related to its effects on the endothelin-A receptor. Experimental hypercholesterolemia is associated with an increase in coronary vasoconstrictor response to endothelin-1 in vivo, although the relative contributions of subtypes of endothelin receptor in this model remain unknown.
Objective:
To test the hypothesis that there is an increase in coronary vasoconstriction in response to stimulation of endothelin-B receptor in hypercholesterolemia, which might be related to attenuation of activity of endothelin-derived relaxing factor.
Methods:
We infused 5 ng/kg/min sarafotoxin, a specific endothelin-B receptor agonist, or 50 micrograms/kg/min NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase, into the left anterior descending coronary arteries of pigs before and after feeding them a cholesterol-rich diet for 10 weeks.
Results:
There was a significant increase in serum level of cholesterol. After 10 weeks, infusion of sarafotoxin resulted in an accentuated decrease in coronary blood flow (CBF) compared with baseline (decreases by 60 +/- 7 versus 34 +/- 6%, P < 0.05). There was no significant difference between the effects on diameter of coronary arteries for the two time periods. The effect of L-NMMA on CBF was attenuated after 10 weeks (by 5 +/- 10.1 versus 45.6 +/- 4.7%, P < 0.05). Endothelin-receptor status of epicardial coronary arteries remained unchanged. Sarafotoxin and L-NMMA were co-infused at the above-mentioned doses into normolipidemic animals; the decrease in CBF in response to this co-infusion was comparable to the decrease observed with sarafotoxin alone in hypercholesterolemic animals (decreases of 67 +/- 5 versus 60 +/- 7, NS).
Conclusions:
The present results demonstrate that selective stimulation of the endothelin-B receptor increases coronary vasoconstriction in experimental hypercholesterolemia, primarily at the level of the microvasculature. These findings may be related to the attenuation of activity of endothelin-derived relaxing factor in this model, and support the hypothesis that endothelin-B receptor plays a role in the regulation of coronary vascular tone in pathophysiologic states.
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