PubMed · 6119826
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A Bundgaard, T Ingemann-Hansen, A Schmidt, J Halkjaer-Kristensen. 1981-10-26. [Exercise-induced asthma].. https://pubmed.ncbi.nlm.nih.gov/6119826/
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1. The effects of ventricular myosin heavy chain (MHC) composition on the kinetics of activation and relaxation were examined in both chemically skinned and intact myocardial preparations from adult rats. Thyroid deficiency was induced to alter ventricular MHC isoform expression from approximately 80% alpha-MHC/20% beta-MHC in euthyroid rats to 100% beta-MHC, without altering the expression of thin-filament-associated regulatory proteins. 2. In single skinned myocytes, increased expression of beta-MHC did not significantly affect either maximal Ca2+-activated tension (P0) or the Ca2+ sensitivity of tension (pCa50). However, unloaded shortening velocity (V0) decreased by 80% due to increased beta-MHC expression. 3. The kinetics of activation and relaxation were examined in skinned multicellular preparations using the caged Ca2+ compound DM-nitrophen and caged Ca2+ chelator diazo-2, respectively. Myocardium expressing 100% beta-MHC exhibited apparent rates of submaximal and maximal tension development (kCa) that were 60% lower than in control myocardium, and a 2-fold increase in the half-time for relaxation from steady-state submaximal force. 4. The time courses of cell shortening and intracellular Ca2+ transients were assessed in living, electrically paced myocytes, both with and without beta-adrenergic stimulation (70 nM isoproterenol (isoprenaline)). Thyroid deficiency had no affect on either the extent of myocyte shortening or the resting or peak fura-2 fluorescence ratios. However, induction of beta-MHC expression by thyroid deficiency was associated with increased half-times for myocyte shortening and relengthening and increased half-time for the decay of the fura-2 fluorescence ratio. Qualitatively similar results were obtained in both the absence and the presence of beta-adrenergic stimulation although the beta-agonist accelerated the kinetics of the twitch and the Ca2+ transient. 5. Collectively, these data provide evidence that increased beta-MHC expression contributes significantly to the observed depression of contractile function in thyroid deficient myocardium by slowing the rates of both force development and force relaxation.
1. Confocal laser scanning microscopy was used to visualize intercellular transmission of Ca2+ waves in intact rat ventricular trabeculae micro-injected with the calcium indicator fluo-3. 2. Ca2+ waves usually failed to be transmitted from cell to cell. At identified individual end-to-end cell contacts, successful transmission interspersed with failure, which sometimes occurred despite an apparent small spritz of Ca2+ between cells. The probability of cell to cell transmission (Ptran) was 0.13. 3. Ca2+ waves arose preferentially near junctions of connected cells, where connexin-43 was found, but randomly in enzymatically disconnected heart cells. 4. beta-Adrenergic stimulation significantly increased Ptran (to 0.22) and heptanol, an uncoupler of gap junction channels, significantly decreased it (to 0.045). 5. In regions of high [Ca2+]i due to damage, wave frequency decreased markedly with each cell-cell junction passed. 6. The Ca2+ permeability of cardiac gap junctions may be regulated, and the low ability of cardiac gap junctions to transmit Ca2+ may help control the spread of Ca2+ from damaged regions.
Beta1- and beta2-adrenoceptors in heart muscle cells mediate the catecholamine-induced increase in the force and frequency of cardiac contraction. Recently, in addition, we demonstrated the functional expression of beta3-adrenoceptors in the human heart. Their stimulation, in marked contrast with that of beta1- and beta2-adrenoceptors, induces a decrease in contractility through presently unknown mechanisms. In the present study, we examined the role of a nitric oxide (NO) synthase pathway in mediating the beta3-adrenoceptor effect on the contractility of human endomyocardial biopsies. The negative inotropic effects of a beta3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of alpha- and beta1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester. The effect of the NOS inhibitors was reversed by an excess of L-arginine, the natural substrate of NOS, but not by D-arginine. Moreover, the effects of the beta3-adrenoceptor agonist on contractility were associated with parallel increases in the production of NO and intracellular cGMP, which were also inhibited by NOS inhibitors. Immunohistochemical staining of human ventricular biopsies showed the expression of the endothelial constitutive (eNOS), but not the inducible (iNOS) isoform of NOS in both ventricular myocytes and endothelial cells. These results demonstrate that beta3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway. Changes in the expression of this pathway may alter the balance between positive and negative inotropic effects of catecholamines on the heart potentially leading to myocardial dysfunction.