Influence of cardiac dysfunction on fast sodium current regulation by Forskolin.
There are several reports of an altered beta-adrenergic pathway in heart failure. Since the fast cardiac sodium current (INa+) is also subject to beta-receptor dependent regulation, we investigated its regulation in a model of cardiac dysfunction. Adenylyl cyclase was stimulated directly with forskolin as one step in the beta-adrenergic pathway. Twelve-week-old Wistar rats were infarcted by ligation of the left anterior descending coronary artery. Eight weeks later, the induced hemodynamic changes were evaluated. The left ventricular end-diastolic pressure (LVEDP) was used as a measure of the hemodynamic effects of the myocardial infarction. With the loose patch clamp technique, INa+ was measured in intact papillary muscles at an external sodium concentration of 150 mmol/L. Potential dependent availability was tested with pulses to 0 mV from various conditioning potentials. In animals with minor infarction (n = 7, LVEDP = 7.7 +/- 0.9 mmHg), forskolin (3 mumol/L) increased the maximal available INa+ to 109% +/- 13% of baseline values. This increase was nearly the same in the group with significant infarctions (n = 7, LVEDP = 15.7 +/- 1.6 mmHg) to 113% +/- 6%. Thus, although we previously observed a reduction of the isoproterenol induced increase of INa+ in rats with significant myocardial infarctions, this increase remains the same when adenylyl cyclase is stimulated directly. This is consistent with a direct beta-receptor down-regulation or desensitization.
Kirstein
M
M
Medizinische Universitätsklinik, Würzburg, Germany.
Katzer
A
A
Hu
K
K
Gaudron
P
P
Ertl
G
G
Langenfeld
H
H
Kochsiek
K
K
D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005576:Colforsin / Q000008:administration & dosage / Q000627:therapeutic use*; D003971:Diastole; D015536:Down-Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels; D005576:Colforsin; D012964:Sodium; D000262:Adenylyl Cyclases; D007545:Isoproterenol