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1 Department of Anaesthesiology, Division of Molecular Medicine
2 Department of Molecular and Medical Pharmacology
3 Department of Physiology
4 Brain Research Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095-1778, USA
Large-conductance, voltage- and Ca2+-activated K+ channels (MaxiK, BK) are key regulators of vascular tone. Vascular MaxiK are formed by the pore-forming 
subunit and the modulatory ß1 subunit, which imprints unique kinetics, Ca2+/voltage sensitivities and pharmacology to the channel. As age progresses, subunit functional expression and protein levels diminish in coronary myocytes. However, whether ageing modifies ß1 subunit expression or the mechanism of subunit reduction is unknown. Thus, we examined functional and pharmacological characteristics of MaxiK, as well as and ß1 transcript levels in coronary myocytes from young and old F344 rats. The mechanism of age-dependent subunit protein reduction involves its transcript downregulation. A corresponding loss of ß1 transcripts was also detected in old myocytes, suggesting a proportional age-dependent decrease of ß1 to subunit protein. Indeed, MaxiK channel properties, defined by coassembly of ß1 and subunits, were equivalent in young versus old, for example in terms of (i) activation kinetics, (ii) sensitivity to Ca2+ levels > 1 µM (iii) dehydrosoyasaponin-I-induced activation, and (iv) iberiotoxin blockade. Consistent with less MaxiK expression/function in older myocytes, the ability of iberiotoxin to contract coronary rings was reduced 
50% with ageing confirming our previous findings. 5-Hydroxytryptamine (5-HT) contractile efficacy was reduced by iberiotoxin pretreatment in young > old coronary arteries (explained by larger iberiotoxin-induced contraction and decreased dynamic range for 5-HT contraction in young versus old) with no apparent differences in nitroglycerine-induced relaxation. We propose that the age-related MaxiK reduction involves a parallel decrease of and ß1 functional expression via a transcript downregulatory mechanism; a major impact on basal and possibly stimulated coronary contraction may contribute to altered coronary flow regulation and coronary morbidity in the elderly.
(Received 24 May 2004;
accepted after revision 16 July 2004;
first published online 22 July 2004)
Corresponding author L. Toro: Division of Molecular Medicine, Department of Anaesthesiology, David Geffen School of Medicine at UCLA, BH-509A CHS, Box 957115, Los Angeles, CA 90095-7115, USA. Email: ltoro{at}ucla.edu
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