TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway.
[Ca2+]i; *Myocardial Contraction; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism; CaMKII; Cardiac/*metabolism; cardiomyocytes; contractility; Inbred C57BL; Knockout; Mice; Myocytes; TRPA1; TRPA1 Cation Channel/deficiency/*metabolism
RATIONALE: Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored. OBJECTIVE: To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action. METHODS AND RESULTS: Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca(2+) concentration ([Ca(2+)]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate that TRPA1 stimulation with AITC results in a dose-dependent increase in peak [Ca(2+)]i and a concomitant increase in CM fractional shortening. Further analysis revealed a dose-dependent acceleration in time to peak [Ca(2+)]i and velocity of shortening as well as an acceleration in [Ca(2+)]i decay and velocity of relengthening. These effects of TRPA1 stimulation were not observed in CMs pre-treated with the TRPA1 antagonist, HC-030031 (10 micromol/L) nor in CMs obtained from TRPA1(-/-) mice. Moreover, we observed no significant increase in cAMP levels or PKA activity in response to TRPA1 stimulation and the PKA inhibitor peptide (PKI
Andrei Spencer R; Ghosh Monica; Sinharoy Pritam; Dey Souvik; Bratz Ian N; Damron Derek S
Channels (Austin, Tex.)
2017
2017-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1080/19336950.2017.1365206" target="_blank" rel="noreferrer noopener">10.1080/19336950.2017.1365206</a>
Role of angiotensin II in sympathetic nervous system induced left ventricular dysfunction
contractility; Physiology; myocardium; Pharmacology & Pharmacy; nitric-oxide; catecholamines; inhibitors; mechanisms; hearts; rabbits; bradykinin; attenuation; calcium channel opener-blocker; captopril; converting-enzyme inhibitor; myocardial; nifedipine; ramiprilat
Experiments were undertaken to determine whether angiotensin (Ang) II concentration increases during massive sympathetic nervous system (SNS) activation and whether such an increase plays a role in the pathogenesis of SNS-induced left ventricular (LV) dysfunction. We also sought to determine whether excessive Ca2+ uptake through L-type channels due to intense adrenoceptor activation is responsible for the LV dysfunction. AngII concentration was measured in the plasma and myocardium before and after massively activating the SNS with an intracisternal injection of veratrine. In separate experiments, rabbits were given losartan, enalaprilat, enalaprilat plus HOE-140, nifedipine, betaBay K 4866, or saline before massively activating the SNS. LV function was evaluated 2.5 h later. The intense SNS activity caused plasma and myocardial AngII to increase by 400 and 437%, respectively. AngII receptor blockade did not prevent LV dysfunction. In contrast, enalaprilat reduced the degree of dysfunction, but its cardioprotection was abolished by HOE-140. Although nifedipine prevented SNS-induced LV dysfunction, administration of the Ca2+ channel opener, betaBay K 4866, did not increase its severity. Our results indicate that AngII is not involved in the pathogenesis of SNS-induced LV dysfunction and that the cardioprotection provided by angiotensin converting enzyme (ACE) inhibition is due to activation of a bradykinin pathway. Furthermore, the finding that the magnitude of the LV dysfunction was reduced by enalaprilat, and not increased by betaBay K 4866, suggests that intense adrenoceptor activation of L-type Ca2+ channels is not the primary pathogenetic mechanism.
Bosso F J; Jarjoura D G; Pilati C F
Canadian Journal of Physiology and Pharmacology
1999
1999-10
Journal Article or Conference Abstract Publication
n/a