cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors
Background: NO donors exert a positive chronotropic effect by stimulating the pacemaker current If in sino-atrial node cells via a mechanism requiring guanylyl cyclase (GC) and cGMP, and involving mobilization of sarcoplasmic (SR) Ca2+. Cyclic GMP can directly stimulate If but it is ∼10-fold less po...
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| Format: | Journal article |
| Language: | English |
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2000
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| _version_ | 1797094990987395072 |
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| author | Musialek, P Paterson, D Casadei, B |
| author_facet | Musialek, P Paterson, D Casadei, B |
| author_sort | Musialek, P |
| collection | OXFORD |
| description | Background: NO donors exert a positive chronotropic effect by stimulating the pacemaker current If in sino-atrial node cells via a mechanism requiring guanylyl cyclase (GC) and cGMP, and involving mobilization of sarcoplasmic (SR) Ca2+. Cyclic GMP can directly stimulate If but it is ∼10-fold less potent than the 'physiological' If-gating nucleotide, cAMP. In ventricular myocytes, NO can increase cAMP levels through a cGMP-dependent inhibition of PDE3. Aim: To elucidate the role of PDE3, PKA and PKG in mediating the NO-If-dependent increase in HR. Methods and Results: In isolated guinea-pig atria with basal HR (B/L) of 174±3 bpm (n=69), we evaluated the HR response to increasing concentrations (from 0.1 to 100μmol/L) of the NO donors DEA-NO (n=8) or SIN-1 (+SOD 100 U/mL, n=6) or to 10 μmol/L SNP (n=9), (1) alone, and (2) after pretreatment (ca. 40min) with inhibitors of (i) PDE3 (milrinone, trequinsin or Ro-13-6482, n=22) or (ii) PKA (KT5720 or H-89, n=15) or (iii) PKG (KT5823 or Rp-8-pCPT-cGMPs, n=16). Whereas PKG inhibition had no effect on the magnitude of the increase in HR with DEA-NO (see Fig; bars show the peak increase in HR, mean± SEM; =p<0.05 vs. B/L, †=p<0.05 vs. the HR response DEA-NO alone), inhibition of PDE3 or PKA markedly attenuated the HR response to DEA-NO (and, similarly, to SIN-1 or SNP; not shown). Conclusion: cGMP-PDE3-cAMP signalling plays a significant part in eliciting the 'direct' positive chronotropic response to NO donors. Since PKA is known to stimulate SR Ca2+ release by phosphorylating ryanodine receptors, the present findings provide an important link between the activation of GC with NO donors and the NO-dependent mobilization of SR Ca2+ in SA node which we reported previously. (Graph Presented). |
| first_indexed | 2024-03-07T04:21:37Z |
| format | Journal article |
| id | oxford-uuid:cb35e77f-85b3-4f0d-b98d-a94f9c0ee263 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:21:37Z |
| publishDate | 2000 |
| record_format | dspace |
| spelling | oxford-uuid:cb35e77f-85b3-4f0d-b98d-a94f9c0ee2632022-03-27T07:13:12ZcGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:cb35e77f-85b3-4f0d-b98d-a94f9c0ee263EnglishSymplectic Elements at Oxford2000Musialek, PPaterson, DCasadei, BBackground: NO donors exert a positive chronotropic effect by stimulating the pacemaker current If in sino-atrial node cells via a mechanism requiring guanylyl cyclase (GC) and cGMP, and involving mobilization of sarcoplasmic (SR) Ca2+. Cyclic GMP can directly stimulate If but it is ∼10-fold less potent than the 'physiological' If-gating nucleotide, cAMP. In ventricular myocytes, NO can increase cAMP levels through a cGMP-dependent inhibition of PDE3. Aim: To elucidate the role of PDE3, PKA and PKG in mediating the NO-If-dependent increase in HR. Methods and Results: In isolated guinea-pig atria with basal HR (B/L) of 174±3 bpm (n=69), we evaluated the HR response to increasing concentrations (from 0.1 to 100μmol/L) of the NO donors DEA-NO (n=8) or SIN-1 (+SOD 100 U/mL, n=6) or to 10 μmol/L SNP (n=9), (1) alone, and (2) after pretreatment (ca. 40min) with inhibitors of (i) PDE3 (milrinone, trequinsin or Ro-13-6482, n=22) or (ii) PKA (KT5720 or H-89, n=15) or (iii) PKG (KT5823 or Rp-8-pCPT-cGMPs, n=16). Whereas PKG inhibition had no effect on the magnitude of the increase in HR with DEA-NO (see Fig; bars show the peak increase in HR, mean± SEM; =p<0.05 vs. B/L, †=p<0.05 vs. the HR response DEA-NO alone), inhibition of PDE3 or PKA markedly attenuated the HR response to DEA-NO (and, similarly, to SIN-1 or SNP; not shown). Conclusion: cGMP-PDE3-cAMP signalling plays a significant part in eliciting the 'direct' positive chronotropic response to NO donors. Since PKA is known to stimulate SR Ca2+ release by phosphorylating ryanodine receptors, the present findings provide an important link between the activation of GC with NO donors and the NO-dependent mobilization of SR Ca2+ in SA node which we reported previously. (Graph Presented). |
| spellingShingle | Musialek, P Paterson, D Casadei, B cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title | cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title_full | cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title_fullStr | cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title_full_unstemmed | cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title_short | cGMP-inhibited phosphodiesterase of cAMP (PDE3) and protein kinase a (PKA) play an important role in eliciting the positive chronotropic effect of Nitric Oxide (NO) donors |
| title_sort | cgmp inhibited phosphodiesterase of camp pde3 and protein kinase a pka play an important role in eliciting the positive chronotropic effect of nitric oxide no donors |
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