Involvement of protein kinase C, tyrosine kinases, and Rho kinase in Ca super(2+) handling of human small arteries
The mechanisms of Ca super(2+) handling and sensitization were investigated in human small omental arteries exposed to norepinephrine (NE) and to the thromboxane A sub(2) analog U-46619. Contractions elicited by NE and U-46619 were associated with an increase in intracellular Ca super(2+) concentrat...
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Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2000-09, Vol.279 (3), p.H1228-H1238 |
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Sprache: | eng |
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Zusammenfassung: | The mechanisms of Ca super(2+) handling and sensitization were investigated in human small omental arteries exposed to norepinephrine (NE) and to the thromboxane A sub(2) analog U-46619. Contractions elicited by NE and U-46619 were associated with an increase in intracellular Ca super(2+) concentration ([Ca super(2+)] sub(i)), an increase in Ca super(2+)-independent signaling pathways, or an enhancement of the sensitivity of the myofilaments to Ca super(2+). The two latter pathways were abolished by protein kinase C (PKC), tyrosine kinase (TK), and Rho-associated protein kinase (ROK) inhibitors. In Ca super(2+)-free medium, both NE and U-46619 elicited an increase in tension that was greatly reduced by PKC inhibitors and abolished by caffeine or ryanodine. After depletion of Ca super(2+) stores with NE and U-46619 in Ca super(2+)-free medium, addition of CaCl sub(2) in the continuous presence of the agonists produced increases in [Ca super(2+)] sub(i) and contractions that were inhibited by nitrendipine and TK inhibitors but not affected by PKC inhibitors. NE and U-46619 induced tyrosine phosphorylation of a 42- or a 58-kDa protein, respectively. These results indicate that the mechanisms leading to contraction elicited by NE and U-46619 in human small omental arteries are composed of Ca super(2+) release from ryanodine-sensitive stores, Ca super(2+) influx through nitrendipine-sensitive channels, and Ca super(2+) sensitization and/or Ca super(2+)-independent pathways. They also show that the TK pathway is involved in the tonic contraction associated with Ca super(2+) entry, whereas TK, PKC, and ROK mechanisms regulate Ca super(2+)-independent signaling pathways or Ca super(2+) sensitization. |
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ISSN: | 0363-6135 |