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ET(A) receptors are the primary mediators of myofilament calcium sensitization induced by ET-1 in rat pulmonary artery smooth muscle: A tyrosine kinase independent pathway

British Journal of Pharmacology, ISSN: 0007-1188, Vol: 127, Issue: 1, Page: 153-160
1999
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1. We have investigated the possibility that ET-1 can induce an increase in myofilament calcium sensitivity in pulmonary artery smooth muscle. Arterial rings were permeabilized using α-toxin (120 μg ml), in the presence of A23187 (10 μM) to 'knock out' Ca stores, and pre-constricted with pCa 6.8 (buffered with 10 mM EGTA). In the presence of this fixed Ca concentration, 1 μM ET-1 induced a sustained, reversible constriction of 0.15 mN. 2. Pulmonary arterial rings were freeze-clamped at the peak of the induced constriction (time matched). Subsequent densitometric analysis revealed that ET-1 (1 μM) increased the level of phosphorylated myosin light chains by 34% compared to an 11% increase in the presence of pCa 6.8 alone. 3. In contrast to ET-1, the selective ET(B) receptor agonist Sarafotoxin S6C (100 nM) failed to induce a significant constriction. 4. The constriction induced by 1 μM ET-1 was reversibly inhibited when the preparation was preincubated (15 min) with the ET(A) receptor antagonist BQ 123 (100 μM). The constriction measured 0.13 mN in the absence and 0.07 mN in the presence of 100 μM BQ 123. 5. In contrast, the constriction induced by 1 μM ET-1 measured 0.19 mN in the absence and 0.175 mN following a 15 min pre-incubation with the ET(B) antagonist BQ 788 (100 μM). 6. The constriction induced by 1 μM ET-1 measured 0.14 mN in the presence and 0.13 mN following pre-incubation with the tyrosine kinase inhibitor Tyrphostin A23 (100 μM). 7. We conclude that ET-1 induced an increase in myofilament calcium sensitivity in rat pulmonary arteries via the activation of ET(A) receptors and by a mechanism(s) independent of tyrosine kinase.

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