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KMID : 0385219970070010082
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Korean Journal of Gerontology
1997 Volume.7 No. 1 p.82 ~ p.93
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Altered Mechanisms of Vascular Smooth Muscle relaxation in Aging
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Yoshiyuki Miyashita
Cheng Linda
Bagrovm Alexei
Sollott Steven-J.
Kinsella James-L.
Lakatta Edward-G.
Froehlich Jeffrey-P.
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Abstract
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Aging of vascular tissue leads to a decline in smooth muscle relaxation mediated by β3-adrenergic agonists. to elucidate the mechanism of vascular smooth muscle relaxation by β3-adrenergic agonists and determine how this system is down-regulated in aging. We used fura 2 and digital ratiometric fluorescence imaging to investigate the changes in Ca2+ ion metabolism and contractility resulting from the application of β3-adrenergic agonists to freshly-prepared arterial smooth muscle cells (SMC) isolated from the tail artery of young (6 month) and old (30 month) Fischer 344XNB rats. Exposure to the α-agonist, phenylephrine (PE), elicitd SMC contraction together with phasic and tonic increases in intracellular Ca2+, [Ca2+]i, reflecting Ca2+ release from the sarcoplasmic reticulum (SR) and Ca2+ influx via sarcolemmal (SL) Ca2+ channels, respectively. Application of the β3-agonist, isoproterenol (ISO), produced a time-dependent decline in SR Ca2+ stores and a reduction in Ca2+ influx, rendering the cell less responsive to the action of α-agonists. These effects of ISO were mediated by stimulation of the Na+/Ca2+ exchange, which transported Ca2+ spontaneously released from the SR (via ryanodine-sensitive channels) to the extracellular compartment. SR Ca2+ stores remained higher in SMC isolated from old (30 mo.) rats compared to young (6 mo.) rats after exposure to ISO (p<0.01; ANOVA), resulting in a larger contractile response to PE. This was associated with reduced stimulation by ISO if the NA+/K+ pump in aortic tissue slices from old rats as determined by 86Rb+ uptake measurements (p<0.025). We conclude that ISO induces smooth muscle relaxation by depletion of SR Ca2+ stores and a reduction in Ca2+ influx by a mechanism that involves activation of the Na+/K+ pump and Na+/Ca2+ exchange. With aging, ISO-mediated stimulation of the Na+/K+ pump is diminished, resulting in higher residual Ca2+ stores in the SR and a larger contractile response to PE. These alterations may have important consequences for blood pressure regulation.
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KEYWORD
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β3-adrenergic agonist, isoproterenol, vascular smooth muscle, aging, relaxation
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