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Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
A role of myofilament Ca2+ sensitivity in enhanced vascular reactivity in cardiomyopathic hamsters
1Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Insights
Cardiomyopathic hamster aortas show heightened contractions to vasoconstrictors, suggesting increased calcium sensitivity and protein kinase C involvement in vascular reactivity.
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Animal Models of Disease
Background:
- Cardiomyopathy can affect vascular function.
- Understanding vascular reactivity in disease is crucial for therapeutic development.
Purpose of the Study:
- To investigate contractile responses in aortas of cardiomyopathic hamsters.
- To explore the mechanisms underlying enhanced vascular reactivity.
Main Methods:
- Compared contractile responses to vasoconstrictors (phenylephrine, angiotensin II, high K+) in aortas from cardiomyopathic and control hamsters.
- Assessed the role of endothelium, nitric oxide, and prostanoids.
- Investigated the involvement of protein kinase C (PKC) and calcium (Ca2+) sensitivity.
Main Results:
- Cardiomyopathic aortas showed greater contractions to phenylephrine, angiotensin II, and high K+.
- Endothelial factors (nitric oxide, prostanoids) did not explain the enhanced responses.
- Phorbol-12,13-dibutyrate (PDB) increased contractions and Ca2+ sensitization in cardiomyopathic aortas.
- PKC inhibition revealed its partial involvement in phenylephrine responses.
- Increased Ca2+ sensitivity of contractile proteins was observed in cardiomyopathic mesenteric artery smooth muscle.
Conclusions:
- Enhanced vascular reactivity in cardiomyopathic hamsters is likely due to increased Ca2+ sensitivity of contractile proteins.
- Protein kinase C-mediated Ca2+ sensitization may further contribute to this enhanced response.
Abstract:
We compared the contractile responses to vasoconstrictors in aortas from 20- to 22-week old cardiomyopathic hamsters, BIO 53.58 strain, and age-matched F1b strain controls. Aortas from cardiomyopathic hamsters exhibited greater contractions in response to phenylephrine, angiotensin II, and high K+ than did the controls. Neither endothelium removal nor the presence of indomethacin and N(omega)-nitro-L-arginine (L-NNA) affected the enhanced contractile responses to these vasoconstrictors, indicating no involvement of endogenous prostanoids and nitric oxide from the endothelium. The contractile response to phorbol-12,13-dibutyrate (PDB) was also more markedly increased in cardiomyopathic aortas regardless of whether extracellular Ca2+ was present. The contractile response of cardiomyopathic aorta to phenylephrine was more sensitive to the inhibitory actions of the protein kinase C inhibitors staurosporine and calphostin C than was that of control aorta. These results suggest that activation of protein kinase C is partly involved in the enhanced phenylephrine response of cardiomyopathic aorta. None of nifedipine, ryanodine, and cyclopiazonic acid modified the maximum contractions induced by phenylephrine in either cardiomyopathic aortas or controls. The Ca2+ sensitivity of tension was significantly increased in beta-escin-skinned smooth muscle of mesenteric artery from cardiomyopathic hamsters compared to that of controls. PDB induced Ca2+ sensitization, but significantly only in cardiomyopathic hamsters. We propose that the enhanced vascular reactivity in cardiomyopathic hamsters may primarily result from increased Ca2+ sensitivity of contractile proteins. In addition, protein kinase C-mediated Ca2+ sensitization may further contribute to the enhanced vascular response to agonists.
