Premium
Potentiation of slow component of delayed rectifier K + currentby cGMP via two distinct mechanisms: inhibition of phosphodiesterase 3 and activation of protein kinase G
Author(s) -
Shimizu Kentaro,
Shintani Yutaka,
Ding WeiGuang,
Matsuura Hiroshi,
Bamba Tadao
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704843
Subject(s) - phosphodiesterase 3 , ibmx , milrinone , phosphodiesterase , protein kinase a , pde10a , intracellular , cyclic guanosine monophosphate , medicine , endocrinology , chemistry , phosphodiesterase inhibitor , second messenger system , atrial natriuretic peptide , guanosine , cgmp dependent protein kinase , kinase , stimulation , biology , biochemistry , forskolin , nitric oxide , enzyme , mitogen activated protein kinase kinase , inotrope
Regulation of the slowly activating component of delayed rectifier K + current ( I Ks ) by intracellular guanosine 3′5′ cyclic monophosphate (cGMP) was investigated in guinea‐pig sino‐atrial (SA) node cells using the whole‐cell patch‐clamp method. When a cell was dialyzed with pipette solution containing 100 μ M cGMP, I Ks started to gradually increase and reached a maximum increase of a factor of 2.37±0.39 ( n =4) about 10–15 min after rupture of patch membrane. Atrial natriuretic peptide (ANP, 100 n M ) also potentiated I Ks , consistent with intracellular cGMP‐induced enhancement of I Ks . Bath application of a selective blocker of the cGMP‐inhibited phosphodiesterase (PDE3) milrinone (100 μ M ) enhanced I Ks by a factor of 1.50±0.09 ( n =4) but failed to further enhance I Ks after a maximum stimulation by intracellular cGMP (100 μ M ), suggesting that blockade of PDE3 activity is involved in the enhancement of I Ks . A potent but nonspecific PDE inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX, 100 μ M ) further increased I Ks stimulated by 100 μ M milrinone, indicating that PDE subtypes other than PDE3 are also involved in the regulation of basal I Ks in guinea‐pig SA node cells. Bath application of 100 μ M 8‐bromoguanosine 3′5′ cyclic monophosphate (8‐Br‐cGMP) increased I Ks by a factor of 1.48±0.11 ( n =5) and this stimulatory effect was totally abolished by cGMP‐dependent protein kinase (PKG) inhibitor KT‐5823 (500 n M ), suggesting that the activation of PKG also mediates cGMP‐induced potentiation of I Ks . These results strongly suggest that intracellular cGMP potentiates I Ks not only by blocking PDE3 but also by activating PKG in guinea‐pig SA node cells.British Journal of Pharmacology (2002) 137 , 127–137. doi: 10.1038/sj.bjp.0704843