Stimulation and Homologous Desensitization of Calcitonin Gene-Related Peptide Receptors in Cultured Beating Rat Heart Cells*

Fisher, Rory A.; Robertson, Susan; Olson, Merle S.

doi:10.1210/endo-123-1-106

Cited by 26 publications

(7 citation statements)

References 27 publications

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“…In recent decades, CGRP has been reported to exert positive effects on the cardiovascular system, increasing the heart rate in neonatal cardiomyocytes, regulating the spontaneous beating of the rat right atrium [20,21,22], enhancing coronary flow in isolated perfused rat hearts [23], and exerting positive inotropic effects in rat ventricular cardiomyocytes [24]. However, cardiac hypertrophy, inflammation, cell death, fibrosis and mortality were all exacerbated in the absence of CGRP in pressure-overloaded hearts [25].…”

Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells

Duan

Han²,

Zhang³

et al. 2015

Cardiology

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Objectives: The aim of this work was to investigate whether calcitonin gene-related peptide (CGRP) plays a protective role in cardiomyocytes against hypoxia-induced inflammation and apoptosis via an NO-mediated pathway. Methods: H9c2 cardiac cells were exposed to hypoxia for 2 h to establish a model of myocardial hypoxic-ischemic injury. The cells were pretreated with either CGRP or nitric oxide synthase (NOS) inhibitor (L-NAME) before being exposed to hypoxia for 30 min. Cell viability was analyzed using a cell counter kit 8 (CCK-8). The levels of IL-6 and TNF-α were determined by the corresponding enzyme-linked immunosorbent assay. The expression levels of several apoptosis proteins (p53, caspase-3, cytochrome C) and NOS were detected by Western blot assays. An NO kit was used to evaluate the production of NO. Results: Pretreatment of H9c2 cardiac cells with CGRP for 30 min prior to exposure to hypoxia markedly improved cell viability (83.57 ± 3.21 vs. 62.83 ± 8.30%, p < 0.001); the same effect was observed following pretreatment with the NOS inhibitor L-NAME (89.34 ± 5.95 vs. 75.01 ± 5.61%, p < 0.01). Pretreatment with CGRP also significantly attenuated the inflammatory responses induced by hypoxia, as evidenced by decreases of the levels of both IL-6 (193.21 ± 13.54 vs. 293.38 ± 56.49%, p < 0.001) and TNF-α (207.71 ± 44.27 vs. 281.46 ± 64.88%, p < 0.001). Additionally, CGRP significantly decreased the hypoxia-induced overexpression of the apoptotic proteins (p53: 0.27 ± 0.10 vs. 0.87 ± 0.30, p < 0.001; caspase-3: 0.65 ± 0.15 vs. 0.98 ± 0.26, p < 0.001; cytochrome C: 1.51 ± 0.39 vs. 2.80 ± 0.69, p < 0.001) and enhanced the expression of both endothelial NOS (eNOS; 0.59 ± 0.24 vs. 0.37 ± 0.14, p < 0.05) and phosphorylated eNOS (0.60 ± 0.13 vs. 0.40 ± 0.07, p < 0.05). Furthermore, the application of both L-NAME and CGRP attenuated the hypoxia-induced expression of inducible NOS (iNOS; p < 0.05) and enhanced a hypoxia-mediated decrease in NO (p < 0.01). Interestingly, the expression levels of cell apoptosis (p < 0.05), iNOS and eNOS (p < 0.05) were decreased with L-NAME and CGRP cotreatment following 2 h of acute hypoxia, but the apoptotic factors (p < 0.05) were increased compared with only CGRP pretreatment. Conclusion: CGRP protects cardiomyocytes from hypoxia-induced inflammation and apoptosis by modulating NO production.

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Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells

Duan

Han²,

Zhang³

et al. 2015

Cardiology

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“…4), both of which increased the intracellular cAMP level (Table 1), indicating that cAMP mediates the secretory response to CGRP and 5-HT in rat tracheal epithelia. It has been shown that CGRP acts on target tissues through activation of the cAMP signal transduction pathway [12,24], and that 5-HT increases Cl -secretion in human jejunal mucosa via the activation of 5-HT 4 receptors [21], whose action is mediated by cAMP.…”

Section: Discussionmentioning

confidence: 99%

Cl - secretion induced by 5-hydroxytryptamine and calcitonin gene-related peptide in rat tracheal epithelia

Jung

Kim

et al. 1997

Pfl�gers Archiv European Journal of Physiology

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The effects of 5-hydroxytryptamine (5-HT) and calcitonin gene-related peptide (CGRP), which are colocalized in nerve terminals in the airway, on Cl- secretion in rat tracheal epithelia were tested. Short-circuit current (Isc) was measured after rat tracheal epithelial monolayers were cultured on porous filters. In rat tracheal monolayers 5-HT and CGRP increased Isc upon addition to the serosal compartment, in a dose-dependent manner with EC50 values at 5 micromol/l and 5 nmol/l, respectively. The responses were dependent on the presence of Cl- in the bathing solution and were inhibited by 100 micromol/l bumetanide. When 5-HT or CGRP was added after the administration of forskolin, the responses were not observed. 5-HT and CGRP increased the intracellular cAMP concentration. Low-Ca2+ buffer (0.1 mmol/l) and pretreatment with BAPTA/AM (10 micromol/l), thapsigargin (1 micromol/l) or indomethacin (10 micromol/l) did not affect the responses to 5-HT and CGRP. The 5-HT-induced response was not inhibited by 5-HT2 and/or 5-HT4 antagonists. These results indicate that in the rat tracheal epithelia 5-HT and CGRP increase Cl- secretion by an increase in intracellular cAMP concentration via direct activation of basolateral receptors, and that the response to 5-HT is not mediated via 5-HT4 receptors.

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“…We have reported that CGRP can result in desensitization in bull-frog heart, although high concentrations (3 x 10' M) are needed . Fisher et al (1988) have also shown that low concentrations of CGRP (10-8 M) can cause desensitization of the CGRP receptor in mammalian heart. However, in guinea-pig myocytes even a very high concentration of CGRP (3 x 10-7 M) produced a maintained increase in ICa.…”

Section: Cgrp-induced Activation Of Ik and The Action Potential Changementioning

confidence: 95%

“…CGRP increased ICa transiently in bull-frog atria but its effect was well maintained in guinea-pig atria. The transient nature of the CGRP effect in bull-frog heart might be due to desensitizatioin of the CGRP receptor (Fisher et al 1988). We have reported that CGRP can result in desensitization in bull-frog heart, although high concentrations (3 x 10' M) are needed .…”

Section: Cgrp-induced Activation Of Ik and The Action Potential Changementioning

confidence: 96%

“…Recently, CGRP has been reported to increase intracellular cyclic AMP in the heart (Fisher, Robertson & Olson, 1988) by activation of membrane adenylate cyclase (Ishikawa, Okamura, Saito & Goto, 1987;Ishikawa et al 1988). An increase in tissue cyclic AMP levels by CGRP has also been reported in other tissues (Kubota, Moseley, Butera, Dusting, MacDonald & Martin, 1985;Barsony & Marx, 1988).…”

Section: Introdltctionmentioning

confidence: 99%

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Electrophysiological effects of calcitonin gene‐related peptide in bull‐frog and guinea‐pig atrial myocytes.

Ono

Giles

1991

The Journal of Physiology

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SUMMARY1. Electrophysiological effects of calcitonin gene-related peptide (CGRP) on action potentials and corresponding transmembrane currents in single myocytes from bull-frog and guinea-pig atria were studied using a whole-cell voltage-clamp method.2. CGRP at relatively low concentrations increased the height of the action potential plateau in a dose-dependent manner in both bull-frog and guinea-pig myocytes. In addition, in bull-frog cells CGRP accelerated the early phase of repolarization, thus shortening the overall duration of the action potential. In contrast, in guinea-pig myocytes CGRP prolonged the action potential duration at all concentrations that were studied.3. Voltage-clamp measurements demonstrated that CGRP increased transmembrane calcium current (ICa) in guinea-pig myocytes without a significant change in its voltage dependence. The ED50 value for this effect on ICa was 1P28 + 0 55 x 10-8 M (n = 4). The time course of the inactivation of ICa was not affected by CGRP.4. CGRP increased the delayed rectifier K+ current (IK) at relatively low concentrations in bull-frog atria, whereas relatively high concentrations were needed to increase 'K in guinea-pig myocytes. This effect was observed even after complete inhibition Of Ica-5. CGRP had no significant effect on the inwardly rectifying background K+ current, IK., even at very high concentrations.6. Comparison of the time course of ICa augmentation in bull-frog and guinea-pig myocytes revealed an important difference in the effect of CGRP in these two types of cells. CGRP at maximal concentrations increased ICa transiently in bull-frog myocytes, whereas this response was sustained in guinea-pig myocytes. Isoprenaline (Iso) induced sustained increase in ICa in both species. When ICa was fully activated by Iso, CGRP at high concentrations strongly inhibited ICa in the bull-frog, whereas it had little effect on Ic. in guinea-pig myocytes.7. Intracellular application of GTPyS (guanosine 5'-O-(3-thiotriphosphate), l0-4 M) greatly potentiated the CGRP effect on ICa; in contrast, GDP/IS (guanosine * To whom all correspondence and reprint requests should be sent. MS 85287 -2

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Stimulation and Homologous Desensitization of Calcitonin Gene-Related Peptide Receptors in Cultured Beating Rat Heart Cells*

Cited by 26 publications

References 27 publications

Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells

Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells

Cl - secretion induced by 5-hydroxytryptamine and calcitonin gene-related peptide in rat tracheal epithelia

Electrophysiological effects of calcitonin gene‐related peptide in bull‐frog and guinea‐pig atrial myocytes.

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