Key result
Tyrosine kinase inhibitors dilated arterioles but did not block myogenic reactivity, indicating that acute arteriolar myogenic constriction does not require tyrosine phosphorylation.
Tyrosine phosphorylation modulates baseline arteriolar tone but is not required for acute myogenic constriction in rat skeletal muscle arterioles.
Tyrosine kinase inhibition modulates baseline tone without affecting myogenic responses in this model; leaves open alternative pathways and human translation.
The present study investigated the role of protein tyrosine phosphorylation in myogenic responsiveness of rat skeletal muscle arterioles. Arteriolar segments were cannulated and pressurized without intraluminal flow. All vessels studied developed spontaneous tone and demonstrated significant myogenic constriction to step changes in pressure with a resultant increase in myogenic tone over an intraluminal pressure range of 50-150 mmHg. Step increases in intraluminal pressure from 50 to 120 mmHg caused a rapid and sustained elevation in intracellular [Ca(2+)], as measured using fura 2. Vessels with myogenic tone dilated in response to tyrosine kinase inhibitors genistein (10 or 30 microM) and tyrphostin A47 (10 or 30 microM) and constricted to the tyrosine phosphatase inhibitor pervanadate (1 or 10 microM). Despite the dilator effect, myogenic reactivity was not blocked by the inhibitors. Daidzein (10 microM), a compound structurally similar to genistein but without tyrosine kinase-inhibiting activity, did not alter vessel tone or myogenic responses. Preincubation of arterioles with genistein or tyrphostin A47 did not significantly alter baseline arteriolar [Ca(2+)], and neither drug reduced the increase in [Ca(2+)] following an acute increase in intraluminal pressure. Constriction induced by pervanadate (10 microM) was not accompanied by a significant increase in intracellular [Ca(2+)], even though removal of extracellular Ca(2+) reversed the constriction. Examination of smooth muscle tyrosine phosphorylation, using a fluorescent phosphotyrosine antibody and confocal microscopy, showed that increased intraluminal pressure resulted in an increase in anti-phosphotyrosine fluorescence. Because manipulation of tyrosine kinase activity was found to alter vessel diameter, these data support a role for tyrosine phosphorylation in modulation of arteriolar tone. However, the results indicate that acute arteriolar myogenic constriction does not require tyrosine phosphorylation.
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Spurrell et al. (2000) studied Myogenic responsiveness in rat skeletal muscle arterioles. Tyrosine kinase inhibitors (genistein, tyrphostin A47) and tyrosine phosphatase inhibitor (pervanadate) was evaluated on Myogenic responsiveness and intracellular Ca(2+) levels. Tyrosine kinase inhibitors dilated arterioles but did not block myogenic reactivity, indicating that acute arteriolar myogenic constriction does not require tyrosine phosphorylation.
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