Potentiation of slow component of delayed rectifier K+ currentby cGMP via two distinct mechanisms: inhibition of phosphodiesterase 3 and activation of protein kinase G

• Published in: British journal of pharmacology Vol. 137; no. 1; pp. 127 - 137
• Main Authors: Shimizu, Kentaro, Shintani, Yutaka, Ding, Wei‐Guang, Matsuura, Hiroshi, Bamba, Tadao
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2002
• Subjects: 8‐bromo‐cyclic GMP; atrial natriuretic peptide; cGMP; cyclic GMP‐inhibited phosphodiesterase; guinea‐pig; milrinone; protein kinase G; sino‐atrial node cells; Slowly activating component of delayed rectifier K+ current
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704843

Regulation of the slowly activating component of delayed rectifier K+ current (IKs) 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 μM cGMP, IKs 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 nM) also potentiated IKs, consistent with intracellular cGMP‐induced enhancement of IKs. Bath application of a selective blocker of the cGMP‐inhibited phosphodiesterase (PDE3) milrinone (100 μM) enhanced IKs by a factor of 1.50±0.09 (n=4) but failed to further enhance IKs after a maximum stimulation by intracellular cGMP (100 μM), suggesting that blockade of PDE3 activity is involved in the enhancement of IKs. A potent but nonspecific PDE inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX, 100 μM) further increased IKs stimulated by 100 μM milrinone, indicating that PDE subtypes other than PDE3 are also involved in the regulation of basal IKs in guinea‐pig SA node cells. Bath application of 100 μM 8‐bromoguanosine 3′5′ cyclic monophosphate (8‐Br‐cGMP) increased IKs 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 nM), suggesting that the activation of PKG also mediates cGMP‐induced potentiation of IKs. These results strongly suggest that intracellular cGMP potentiates IKs 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