Delayed arteriolar relaxation after prolonged agonist exposure: functional remodeling involving tyrosine phosphorylation
1 Microvascular Biology Group, School of Medical Sciences, RMIT University, Bundoora, Victoria 3083, Australia; and 2 Department of Medical Physiology, College of Medicine, Texas A&M University, College Station, Texas 77843 Submitted 13 November 2002 ; accepted in final form 23 April 2003 Althou...
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Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2003-08, Vol.285 (2), p.H849-H856 |
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Zusammenfassung: | 1 Microvascular Biology Group, School of Medical
Sciences, RMIT University, Bundoora, Victoria 3083, Australia; and
2 Department of Medical Physiology, College of
Medicine, Texas A&M University, College Station, Texas 77843
Submitted 13 November 2002
; accepted in final form 23 April 2003
Although arteriolar contraction is dependent on
Ca 2 + -induced myosin phosphorylation, other mechanisms
including Ca 2 + sensitization and time-dependent
phenomena such as cytoskeletal and cellular reorganization may contribute to
contractile events. We hypothesized that if arteriolar smooth muscle exhibits
time-dependent behavior this may be manifested in differences in relaxation
after short- and long-term exposure to contractile agonists. Studies were
conducted in isolated arterioles pressurized to 70 mmHg. In initial
experiments ( n = 10), rate of relaxation was measured after acute (5
min) or prolonged (4 h) exposure to 5 µM norepinephrine (NE). Prolonged
exposure to NE resulted in significantly ( P < 0.05) increased time
for relaxation in physiological salt solution. Rapid relaxation of vessels
exposed to NE for 4 h was observed after superfusion with 0 mM
Ca 2 + buffer, indicating that the alteration in
relaxation was reversible and Ca 2 + dependent. A
similarly impaired dilation was not observed with 4-h exposure to KCl (75 mM).
To determine mechanisms contributing to the effects of prolonged NE exposure,
studies were performed in the presence of the microtubule depolymerizing agent
demecolcine (10 µM) or a series of tyrosine phosphorylation inhibitors.
Although demecolcine caused significant vasoconstriction ( P <
0.05) and potentiated NE vasoconstriction, it did not prevent the effect of
long-term NE exposure on relaxation. Genistein, although having no effect on
acute NE-induced contraction, concentration-dependently inhibited prolonged NE
constriction. Similarly, Src (PP1) and p42/44 MAP kinase (PD-98059) inhibitors
prevented maintenance of long-term NE contraction. The data indicate that
prolonged exposure to NE induces biochemical alterations that impair
relaxation after removal of the agonist. The contractile effects are
Ca 2 + dependent and involve tyrosine phosphorylation but
do not appear to involve the polymerization state of the microtubule
network.
myogenic tone; calcium ion; cytoskeleton
Address for reprint requests and other correspondence: M. A. Hill,
Microvascular Biology Group, School of Medical Science, RMIT Univ., Bundoora,
Victoria 3083, Aust |
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ISSN: | 0363-6135 1522-1539 |
DOI: | 10.1152/ajpheart.00986.2002 |