Saegusa Noriko, Sato Toshiaki, Saito Tomoaki, Tamagawa Masaji, Komuro Issei, Nakaya Haruaki
Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Cardiovasc Res. 2005 Jul 1;67(1):60-8. doi: 10.1016/j.cardiores.2005.03.011. Epub 2005 Apr 20.
While atrial natriuretic peptide (ANP) has been shown to be released mainly from cardiac muscle cells in response to atrial distension, the regulatory mechanisms of ANP secretion are still not fully understood. We sought to determine whether the ATP-sensitive K+ (K(ATP)) channel modulates the secretion of ANP, using mice with homozygous knockout of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene.
K(ATP) channel currents were recorded from isolated mouse atrial cells with patch-clamp techniques. Plasma ANP concentrations in anesthetized mice and ANP content and secretion in isolated atrial preparations were determined by radioimmunoassay. Action potentials were recorded from the isolated atria.
Exposure to 2,4-dinitrophenol (100 microM) evoked a glibenclamide-sensitive K(ATP) channel current in atrial cells from wild-type (WT) but not Kir6.2 knockout (Kir6.2 KO) mice. Although there were no significant differences in the basal plasma ANP levels between WT and Kir6.2 KO mice, volume expansion caused a significant elevation of plasma ANP concentration in Kir6.2 KO but not WT mice with accompanying hypotension. When isolated left atria were stretched, ANP secreted into the bath from Kir6.2 KO atria was significantly higher than that from WT atria. Furthermore, stretching the atria from WT but not Kir6.2 KO mice significantly shortened the action potential duration. A hypotonic stretch of the membrane induced the glibenclamide-sensitive K(ATP) channel current in atrial cells from WT but not Kir6.2 KO mice.
Kir6.2 is essential for the function of K(ATP) channel in mouse atrial cells. Given that Kir6.2 KO mice are susceptible to stretch-induced secretion of ANP, our results suggest that K(ATP) channels may act as a negative feedback mechanism for the control of ANP secretion.
虽然已表明心房利钠肽（ANP）主要在心房扩张时从心肌细胞释放，但ANP分泌的调节机制仍未完全阐明。我们试图通过使用Kir6.2（心脏ATP敏感性钾通道（K(ATP)）的一个孔形成亚基）基因纯合敲除的小鼠，来确定ATP敏感性钾通道是否调节ANP的分泌。
采用膜片钳技术记录分离的小鼠心房细胞中的K(ATP)通道电流。通过放射免疫测定法测定麻醉小鼠的血浆ANP浓度以及分离的心房标本中的ANP含量和分泌情况。从分离的心房记录动作电位。
暴露于2,4-二硝基苯酚（100μM）可诱发野生型（WT）小鼠而非Kir6.2基因敲除（Kir6.2 KO）小鼠心房细胞中的格列本脲敏感的K(ATP)通道电流。虽然WT小鼠和Kir6.2 KO小鼠的基础血浆ANP水平无显著差异，但容量扩张导致Kir6.2 KO小鼠而非WT小鼠的血浆ANP浓度显著升高，并伴有低血压。当分离的左心房被拉伸时，从Kir6.2 KO心房分泌到浴液中的ANP明显高于WT心房。此外，拉伸WT小鼠而非Kir6.2 KO小鼠的心房可显著缩短动作电位时程。膜的低渗拉伸可诱发WT小鼠而非Kir6.2 KO小鼠心房细胞中的格列本脲敏感的K(ATP)通道电流。
Kir6.2对小鼠心房细胞中K(ATP)通道的功能至关重要。鉴于Kir6.2 KO小鼠易受拉伸诱导的ANP分泌影响，我们的结果表明K(ATP)通道可能作为控制ANP分泌的负反馈机制。
