| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Cardiovascular Diseases, Tokyo Medical and Dental University, Japan.
1. The patch-clamp method was used to study the effects of pinacidil on the adenosine 5'-triphosphate (ATP)-sensitive K+ channel current in guinea-pig ventricular myocytes. 2. In the inside-out configuration of the patch membranes, the channel activity revealed a nearly fully open state in the absence of ATP, whereas application of ATP (0.1-5 mM) markedly suppressed the channel opening. Addition of pinacidil (0.02-1.0 mM) antagonized the inhibitory action of ATP and induced channel opening without marked change in conductance. An increase in ATP concentration depressed the maximal effect of pinacidil. Consequently, the dose-response relationship of ATP inhibition was shifted to the right, but the shift approached a limiting value as pinacidil concentration was increased. The results indicate that the antagonism between pinacidil and ATP is not competitive. 3. The dose-response curve for activation of the channel by pinacidil examined at -50 mV showed a sigmoidal shape but at +50 mV it had a convex shape, revealing asymmetry in the activating effects of pinacidil at these two voltages. 4. In the absence of ATP, pinacidil produced a voltage-dependent block at positive voltages by decreasing the mean open time and increasing the mean closed time, whereas no such effects were observed at negative voltages. The concentration-block relation at a given voltage was fitted to a first-order Hill saturation function. The Kd (dissociation constant) decreased with depolarization from 2.2 mM at +20 mV to 0.15 mM at + 80 mV. 5. The kinetics of block and unblock by pinacidil were shown to be slow, and were expressed by a first-order transition model. The blocking and unblocking rate constants were voltage dependent. 6. The slow block of single-channel current showed an exponential decay in the ensemble current. The time constant of the decay was voltage dependent, reaching a maximal value at around +50 mV. 7. In the absence of ATP, the channel activity gradually decreased and eventually stopped within 12-20 min, a process known as run-down of channel activity. Calcium accelerated this run-down process. Application of pinacidil partially reactivated the channel. Such channel reactivation by pinacidil during the course of run-down depended upon the conditions of the patch and the time course of the run-down. Pretreatment of the channel with ATP markedly strengthened the reactivation effect of pinacidil. 8. These results indicate that there are multiple sites or processes for interaction of pinacidil with the ATP-sensitive K+ channel.
This article has been cited by other articles:
|
|
 |
|
  G. R. Ferrier and S. E. Howlett Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 823 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Hilgemann From a pump to a pore: How palytoxin opens the gates PNAS, January 21, 2003; 100(2): 386 - 388. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Haruna, H. Yoshida, T. Y. Nakamura, L.-H. Xie, H. Otani, T. Ninomiya, M. Takano, W. A. Coetzee, and M. Horie {alpha}1-Adrenoceptor-Mediated Breakdown of Phosphatidylinositol 4,5-Bisphosphate Inhibits Pinacidil-Activated ATP-Sensitive K+ Currents in Rat Ventricular Myocytes Circ. Res., August 9, 2002; 91(3): 232 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dabrowski, F. M. Ashcroft, R. Ashfield, P. Lebrun, B. Pirotte, J. Egebjerg, J. Bondo Hansen, and P. Wahl The Novel Diazoxide Analog 3-Isopropylamino-7-Methoxy-4H-1,2,4-Benzothiadiazine 1,1-Dioxide Is a Selective Kir6.2/SUR1 Channel Opener Diabetes, June 1, 2002; 51(6): 1896 - 1906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Cui, W. Wang, and Z. Fan Cytoplasmic Vestibule of the Weak Inward Rectifier Kir6.2 Potassium Channel J. Biol. Chem., March 15, 2002; 277(12): 10523 - 10530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Gribble, F. Reimann, R. Ashfield, and F. M. Ashcroft Nucleotide Modulation of Pinacidil Stimulation of the Cloned KATP Channel Kir6.2/SUR2A Mol. Pharmacol., June 1, 2000; 57(6): 1256 - 1261. [Abstract] [Full Text]
|
|
|
|
|
|
L.-H. Xie, M. Horie, and M. Takano Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism PNAS, December 21, 1999; 96(26): 15292 - 15297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Chutkow, J. C. Makielski, D. J. Nelson, C. F. Burant, and Z. Fan Alternative Splicing of sur2 Exon 17 Regulates Nucleotide Sensitivity of the ATP-sensitive Potassium Channel J. Biol. Chem., May 7, 1999; 274(19): 13656 - 13665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hiraoka and T. Furukawa Functional Modulation of Cardiac ATP-Sensitive K+ Channels Physiology, June 1, 1998; 13(3): 131 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Shinbo, K. Ono, and T. Iijima Activation of Cardiac ATP-Sensitive K+ Channels by KRN4884, a Novel K+ Channel Opener J. Pharmacol. Exp. Ther., November 1, 1997; 283(2): 770 - 777. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. S. Lawton, G. C. Harrington, C. T. Allen, P.-W. Hsia, and R. J. Damiano Jr Myocardial Protection With Pinacidil Cardioplegia in the Blood-Perfused Heart Ann. Thorac. Surg., June 1, 1996; 61(6): 1680 - 1688. [Abstract] [Full Text]
|
|
|
|
|
|
N. Inagaki, Y. Tsuura, N. Namba, K. Masuda, T. Gonoi, M. Horie, Y. Seino, M. Mizuta, and S. Seino Cloning and Functional Characterization of a Novel ATP-sensitive Potassium Channel Ubiquitously Expressed in Rat Tissues, including Pancreatic Islets, Pituitary, Skeletal Muscle, and Heart J. Biol. Chem., March 17, 1995; 270(11): 5691 - 5694. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
