Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 305, Issue 12, Pages H1698-H1708Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00377.2013
Keywords
cerebral blood flow; 20-hydroxyeicosatetraenoic acid; autoregulation; canonical transient receptor potential; potassium channels; large-conductance Ca2+-activated K+ channels
Funding
- American Heart Association
- American Federation for Aging Research
- Oklahoma Center for the Advancement of Science and Technology
- Nemzeti Fejlesztesi ugynokseg [SROP-4.2.2.a-11/1/KONV-2012-0024, SROP-4.2.2.a-11/1/KONV-2012-0017, SPOR-4.2.1/b-10/2/KONV-2010-0012]
- Hungarian Scientific Research Fund (OTKA) [K 108444]
- National Center for Complementary and Alternative Medicine [R01-AT006526]
- National Institute on Aging [AG031085, AG038747]
- Ellison Medical Foundation
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Hypertension in the elderly substantially increases the risk of stroke and vascular cognitive impairment in part due to an impaired functional adaptation of aged cerebral arteries to high blood pressure. To elucidate the mechanisms underlying impaired autoregulatory protection in aging, hypertension was induced in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic infusion of angiotensin II and pressure-induced changes in smooth muscle cell (SMC) intracellular Ca2+ concentration ([Ca2+](i)) and myogenic constriction of middle cerebral arteries (MCA) were assessed. In MCAs from young hypertensive mice, pressure-induced increases in vascular SMC [Ca2+](i) and myogenic tone were increased, and these adaptive responses were inhibited by the cytochrome P-450 omega-hydroxylase inhibitor HET0016 and the transient receptor potential (TRP) channel blocker SKF96365. Administration of 20-hydroxyeicosatetraenoic acid (HETE) increased SMC [Ca2+](i) and constricted MCAs, and these responses were inhibited by SKF96365. MCAs from aged hypertensive mice did not show adaptive increases in pressure-induced calcium signal and myogenic tone and responses to HET0016 and SKF96365 were blunted. Inhibition of large-conductance Ca2+-activated K+ (BK) channels by iberiotoxin enhanced SMC [Ca2+](i) and myogenic constriction in MCAs of young normotensive animals, whereas it was without effect in MCAs of young hypertensive mice. Iberiotoxin did not restore myogenic adaptation in MCAs of aged hypertensive mice. Thus functional maladaptation of aged cerebral arteries to hypertension is due to the dysregulation of pressure-induced 20-HETE and TRP channel-mediated SMC calcium signaling, whereas overactivation of BK channels is unlikely to play a role in this phenomenon.
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