Inhibition of inositol(1,4,5)Trisphosphate generation by endothelin-1 during postischemic reperfusion: A novel antiarrhythmic mechanism.
BACKGROUND
Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-1 causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P3) and arrhythmias. The present study investigates the effect of endothelin-1 on these responses.


RESULTS
Ins 1,4,5P3 generation was quantified by use of [3H] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [3H]Ins 1,4,5P3 from 2828+/-265 to 5033+/-650 cpm/g tissue in the presence of thrombin 2.5 IU/mL and to 4561+/-286 cpm/g tissue in response to release of norepinephrine (n=4, P<0.01) in both cases. Reperfusion in the presence of endothelin-1 alone caused no change in Ins 1,4,5P3 (2762+/-240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P3 responses to 2313+/-197 and 1764+/-168 cpm/g tissue, respectively (n=4, P<0.01 in both cases). Similar inhibitory interactions between endothelin-1 10 nmol/L and thrombin 2.5 IU/mL were observed under normoxic conditions in nonperfused ventricle, eliminating the possibility that excessive vasoconstriction was responsible. In parallel studies, endothelin-1 suppressed the development of reperfusion arrhythmias initiated by either thrombin (ventricular fibrillation, 75% to 39%, n=16 to 18) or norepinephrine (83% to 8%, n=12 to 22) (P<0.01 in both cases).


CONCLUSIONS
Inhibition of Ins 1,4,5P3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.
Woodcock
E A
EA
Cellular Biochemistry Laboratory, Baker Medical Research Institute, Melbourne, Victoria, Australia.liz.woodcock@baker.edu.au
Reyes
N
N
Jacobsen
A N
AN
Du
X J
XJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D006490:Hemostatics / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology