Decreased expression of voltage- and Ca(2+)-activated K(+) channels in coronary smooth muscle during aging.
Aging is the main risk factor for coronary artery disease. One characteristic of aging coronary arteries is their enhanced contractile responses to endothelial vasoconstricting factors, which increase the risk of coronary vasospasm in older people. Because large-conductance voltage- and Ca(2+)-activated K(+) channels (MaxiK) are key regulators of vascular tone, we explored the possibility that this class of channels is diminished with increasing age. Using site-directed antibodies recognizing the pore-forming alpha subunit and electrophysiological methods, we demonstrate that the number of MaxiK channels is dramatically diminished in aged coronary arteries from old F344 rats. Channel density was reduced from 52+/-9 channels/pF (3 months old) to 18+/-5 channels/pF (25 to 30 months old), which represents a 65% reduction in the older population. Pixel intensity of Western blots was also diminished by approximately 50%. Moreover, the age-related decrease in the channel protein expression was also evident in humans, which showed approximately 80% reduction in 61- to 70-year-old subjects compared with 3- to 18-year-old youngsters and approximately 45% reduction compared with 19- to 56-year-old adults. In agreement with a reduction of MaxiK channel numbers in aging coronary arteries, old coronary arteries from F344 rats contract less effectively ( approximately 70% reduction) than young coronary arteries when exposed to the MaxiK channel blocker iberiotoxin. The contraction studies indicate that under physiological conditions, MaxiK channels are tonically active, serving as a hyperpolarizing force that opposes contraction. Thus, reduced expression of MaxiK channels in aged coronary arteries would lead to a decreased vasodilating capacity and increased risk of coronary spasm and myocardial ischemia in older people.
Marijic
J
J
Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA 90095-7115, USA.
Li
Q
Q
Song
M
M
Nishimaru
K
K
Stefani
E
E
Toro
L
L
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D011916:Rats, Inbred F344; D014661:Vasoconstriction / Q000187:drug effects
C494841:KCNMA1 protein, human; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; C064719:iberiotoxin; D002118:Calcium