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Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental
V Mathew1, C R Cannan, V M Miller
1Division of Cardiovascular Diseases and Internal Medicine, Mayo Foundation, Rochester, Minn 55905, USA.
Insights
Experimental hypercholesterolemia alters coronary vasomotor responses. Endothelin-1 caused increased vasoconstriction, while nitric oxide synthase inhibition effects were reduced, indicating impaired coronary vascular reactivity.
Area of Science:
- Cardiovascular Physiology
- Endothelial Function
- Metabolic Disorders
Background:
- Experimental hypercholesterolemia is linked to coronary vasomotor dysfunction.
- This study investigated changes in coronary vasomotor responses to endothelin and nitric oxide pathways in hypercholesterolemia.
Purpose of the Study:
- To test the hypothesis that experimental hypercholesterolemia alters coronary vasomotor responses to endothelin and endogenous nitric oxide (NO) pathway inhibition.
Main Methods:
- Infusion of Endothelin-1 (ET-1) and N(G)-monomethyl-L-arginine (L-NMMA) into the coronary arteries of pigs before and after a 10-week cholesterol diet.
- Measurement of coronary blood flow (CBF), coronary artery diameter (CAD), and coronary vascular resistance (CVR).
- Assessment of ET receptor density and immunohistochemical staining for constitutive nitric oxide synthase (NOS).
Main Results:
- Hypercholesterolemic pigs showed significantly accentuated decreases in CBF and CAD, and increased CVR in response to ET-1.
- The effects of L-NMMA on CBF, CAD, and CVR were attenuated in hypercholesterolemic pigs.
- A decrease in constitutive NOS immunoreactivity was observed in the coronary arteries of hypercholesterolemic pigs.
Conclusions:
- Experimental hypercholesterolemia enhances coronary vasoconstriction to endothelin.
- There is an attenuated response to the inhibition of endogenous NO activity in hypercholesterolemia.
- These findings suggest an alteration in coronary vascular reactivity in experimental hypercholesterolemia.
Background:
Experimental hypercholesterolemia is associated with coronary vasomotor dysfunction. This study was designed to test the hypothesis that experimental hypercholesterolemia is characterized by altered coronary vasomotor responses to endothelin and inhibition of the endogenous NO pathway.
Methods And Results:
Endothelin-1 (ET-1) at 5 ng x kg(-1) x min(-1) or N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase (NOS), at 50 microg x kg(-1) x min(-1) was infused into the left anterior descending coronary artery in pigs before and after 10 weeks of cholesterol diet. There was a significant increase in serum cholesterol. At 10 weeks, ET-1 resulted in an accentuated decrease in coronary blood flow (CBF) and coronary artery diameter (CAD) compared with baseline (-88+/-6% versus -45+/-9%, P<.05, and -77+/-14% versus -18+/-8%, P<.05, respectively) and an increase in coronary vascular resistance (CVR) (242+/-18% versus 110+/-17%, P<.05); ET receptor density and binding affinity in epicardial coronary arteries were unchanged. The effect of L-NMMA on CBF, CAD, and CVR was attenuated at 10 weeks (-7+/-8% versus -48+/-4%, -2+/-3% versus -17+/-5%, and 16+/-10% versus 125+/-32%; each P<.05). Immunohistochemistry staining for constitutive NOS revealed a decrease in immunoreactivity in the coronary arteries of hypercholesterolemic pigs.
Conclusions:
The present study demonstrates an enhanced coronary vasoconstrictive response to pathophysiological doses of endothelin and an attenuated response to the inhibition of endogenous NO activity, suggesting an alteration in coronary vascular reactivity in experimental hypercholesterolemia.