Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling.
A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly...
| Autori principali: | , , , , , , , , |
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| Natura: | Journal article |
| Lingua: | English |
| Pubblicazione: |
2003
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| _version_ | 1826291012608196608 |
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| author | Sears, C Bryant, S Ashley, E Lygate, C Rakovic, S Wallis, H Neubauer, S Terrar, D Casadei, B |
| author_facet | Sears, C Bryant, S Ashley, E Lygate, C Rakovic, S Wallis, H Neubauer, S Terrar, D Casadei, B |
| author_sort | Sears, C |
| collection | OXFORD |
| description | A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org. |
| first_indexed | 2024-03-07T02:52:59Z |
| format | Journal article |
| id | oxford-uuid:ae50981e-bd6b-4efc-a96c-5fd53b914bdb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:52:59Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:ae50981e-bd6b-4efc-a96c-5fd53b914bdb2022-03-27T03:41:43ZCardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ae50981e-bd6b-4efc-a96c-5fd53b914bdbEnglishSymplectic Elements at Oxford2003Sears, CBryant, SAshley, ELygate, CRakovic, SWallis, HNeubauer, STerrar, DCasadei, BA neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org. |
| spellingShingle | Sears, C Bryant, S Ashley, E Lygate, C Rakovic, S Wallis, H Neubauer, S Terrar, D Casadei, B Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title | Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title_full | Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title_fullStr | Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title_full_unstemmed | Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title_short | Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. |
| title_sort | cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling |
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