Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin.
Transient and sustained K(+) currents were measured in isolated rat ventricular myocytes obtained from control, steptozotocin-induced (Type 1) diabetic, and hypothyroid rats. Both currents, attenuated by the endocrine abnormalities, were significantly augmented by in vitro incubation (>6 h) with the angiotensin-converting enzyme inhibitor quinapril or the angiotensin II (ANG II) receptor blocker saralasin. Western blots indicated a parallel increase in Kv4.2 and Kv1.2, channel proteins that underlie the transient and (part of the) sustained currents. Under diabetic and hypothyroid conditions, both currents were also augmented by an endothelin receptor blocker (PD142893) or by an endothelin-converting enzyme inhibitor. Kv4.2 density was also enhanced by PD142893. Incubation (>5 h) with the PKC inhibitor bis-indolylmaleimide augmented both currents, whereas the PKC activator dioctanoyl-rac-glycerol (DiC8) prevented the augmentation of currents by quinapril. DiC8 also prevented the augmentation of Kv4.2 density by quinapril. Specific peptides that activate PKC translocation indicated that PKC-epsilon and not PKC-delta is involved in ANG II action on these currents. In control myocytes, quinapril and PD142893 augmented the sustained late current but had no effect on peak current. It is concluded that an autocrine release of angiotensin and endothelin in diabetic and hypothyroid conditions attenuates K(+) currents by suppressing the synthesis of some K(+) channel proteins, with the effects mediated at least partially by PKC-epsilon.
Shimoni
Yakhin
Y
Cardiovascular Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1. shimoni@ucalgary.ca
Liu
Xiu-Fang
XF
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000809:Angiotensins / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004075:Diglycerides / Q000494:pharmacology; D004553:Electric Conductivity; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D006706:Homeostasis; D007037:Hypothyroidism / Q000503:physiopathology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D012504:Saralasin / Q000494:pharmacology; D051672:Shal Potassium Channels; D044005:Tetrahydroisoquinolines; D013965:Thyroidectomy
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D004075:Diglycerides; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C497020:Kcnd2 protein, rat; C497023:Kcnd3 protein, rat; D009842:Oligopeptides; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D044005:Tetrahydroisoquinolines; C044295:1,2-dioctanoylglycerol; C076213:PD 142893; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D012504:Saralasin; D000077583:Quinapril