Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia

Verghese Mathew, Virginia M Miller, David Hasdai, Dustan A. Barber, David Holmes, Amir Lerman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 μg/kg/min N(G)-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. (C) 2000 Lippincott Williams and Wilkins.

Original languageEnglish (US)
Pages (from-to)585-592
Number of pages8
JournalCoronary Artery Disease
Volume11
Issue number8
DOIs
StatePublished - 2000

Fingerprint

Endothelin B Receptors
Hypercholesterolemia
omega-N-Methylarginine
Vasoconstriction
Endothelin Receptors
Coronary Vessels
Endothelins
Endothelin-1
Cholesterol
Endothelin A Receptors
Vasoconstrictor Agents
Microvessels
Nitric Oxide Synthase
Blood Vessels
Arginine
Swine
Diet
Serum

Keywords

  • Coronary circulation
  • Endothelin
  • Endothelin receptor
  • Endothelin-derived relaxing factor
  • Hypercholesterolemia
  • Sarafotoxin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia. / Mathew, Verghese; Miller, Virginia M; Hasdai, David; Barber, Dustan A.; Holmes, David; Lerman, Amir.

In: Coronary Artery Disease, Vol. 11, No. 8, 2000, p. 585-592.

Research output: Contribution to journalArticle

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abstract = "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 μg/kg/min N(G)-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. (C) 2000 Lippincott Williams and Wilkins.",
keywords = "Coronary circulation, Endothelin, Endothelin receptor, Endothelin-derived relaxing factor, Hypercholesterolemia, Sarafotoxin",
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T1 - Increased coronary effects of stimulation of endothelin-B receptor in experimental hypercholesterolemia

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AU - Miller, Virginia M

AU - Hasdai, David

AU - Barber, Dustan A.

AU - Holmes, David

AU - Lerman, Amir

PY - 2000

Y1 - 2000

N2 - 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 μg/kg/min N(G)-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. (C) 2000 Lippincott Williams and Wilkins.

AB - 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 μg/kg/min N(G)-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. (C) 2000 Lippincott Williams and Wilkins.

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KW - Endothelin-derived relaxing factor

KW - Hypercholesterolemia

KW - Sarafotoxin

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