Altered effects of potassium channel modulation in the coronary circulation in experimental hypercholesterolemia.
OBJECTIVE
To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia.


BACKGROUND
Potassium (K(+)) channels play an important role in coronary vasoregulation. It has previously been demonstrated that experimental hypercholesterolemia is associated with altered coronary vasomotion; however, the role of K(+) channels in modulating coronary blood flow in this pathophysiologic state has not been evaluated.


RESULTS
Pinacidil (group 1, n=5) at 2 microg/kg per min, glibenclamide (group 2, n=5), or N-monomethyl-L-arginine (LNMMA) (group 3, n=4) at 50 microg/kg per min were infused into the left anterior descending artery of pigs prior to and following 10 weeks of 2% cholesterol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil resulted in a significant increase in coronary blood flow (CBF) and coronary artery diameter (CAD) compared to the normolipidemic state (111+/-10 versus 59+/-12%, and 6+/-1.1 versus 2.7+/-1.0%, respectively, P<0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a significant decrease in CBF and CAD compared to the normolipidemic state (-17+/-5 versus 5+/-6%, and -0.8+/-1.4 versus 3.6+/-1.6%, respectively, P<0.05 for both comparisons). The effect of intracoronary LNMMA on CBF and CAD was significantly attenuated after 10 weeks of cholesterol feeding as compared to the normolipidemic state (-47+/-5.4 versus -0.8+/-6.8%, and -19.4+/-5.7 versus -2.3+/-3.3%, respectively, P<0.05 for both comparisons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n=4) (57.4+/-19 versus 59+/-12%, P=NS).


CONCLUSIONS
The current study demonstrates an enhanced effect of coronary K(+) channel modulation and confirms the attenuated basal NO activity previously reported in experimental hypercholesterolemia. Acute withdrawal of basal NO activity alone, however, does not explain the enhanced effect of coronary K(+) channel modulation. These findings underscore the importance of the K(+) channel pathway in the regulation of coronary vasomotor tone in pathophysiologic states.
Mathew
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Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. mathew.verghese@mayo.edu
Lerman
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A
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000097:blood; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D027682:Cation Transport Proteins; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000633:toxicity; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005905:Glyburide / Q000008:administration & dosage; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007269:Injections, Intra-Arterial; D020110:Pinacidil / Q000008:administration & dosage; D015221:Potassium Channels / Q000097:blood* / Q000187:drug effects; D013552:Swine; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D027682:Cation Transport Proteins; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D020110:Pinacidil; D002784:Cholesterol; D000251:Adenosine Triphosphatases; C022761:potassium transporting ATPase; D005905:Glyburide