Decreased expression of voltage- and Ca2+-activated K+ channels in coronary smooth muscle during aging

Aging is the main risk factor for coronary artery disease. One characterist ic of aging coronary arteries is their enhanced contractile responses to en dothelial vasoconstricting factors, which increase the risk of coronary vas ospasm in older people. Because large-conductance voltage and Ca2+-activate d 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 a nd electrophysiological methods, we demonstrate that the number of MaxiK ch annels is dramatically diminished in aged coronary arteries from old F344 r ats. 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 diminish ed by approximate to 50%. Moreover, the age-related decrease in the channel protein expression was also evident in humans, which showed approximate to 80% reduction in 61- to 70-year-old subjects compared with 3- to 18-year-o ld youngsters and approximate to 45% reduction compared with 19- to 56-year -old adults. In agreement with a reduction of MaxiK channel numbers in agin g coronary arteries, old coronary arteries from F344 rats contract less eff ectively (approximate to 70% reduction) than young coronary arteries when e xposed to the MaxiK channel blocker iberiotoxin. The contraction studies in dicate that under physiological conditions, MaxiK channels are tonically ac tive, serving as a hyperpolarizing force that opposes contraction. Thus, re duced 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.