Role of endothelin-A receptors in ischemic contracture and reperfusion injury.

Circulating endothelin (ET)-1 is elevated in ischemia/reperfusion and may exert proischemic effects. The aim of the present study was to characterize the effects of ET-1 in rat isolated hearts using subtype-selective ET receptor antagonists, agents modulating the cytosolic Ca2+ concentration, or the activity of cGMP-dependent protein kinase.
Rat hearts perfused at constant pressure were made ischemic by reducing flow to 0.2 mL x min(-1) x g(-1), followed by reperfusion at normal pressure (each phase, 25 minutes). Drugs were infused during the ischemic phase only. Parameters monitored were extent and time-to-onset of contracture in ischemia, left ventricular developed pressure (LVDevP), coronary flow (CF), and diastolic relaxation during reperfusion. The ET(A) receptor-selective antagonist PD 155080 (50 nmol/L) reduced peak ischemic contracture (-49%) and delayed its time to onset (+56%) and improved recovery of reperfusion LVDevP (+12%), CF (+16%), and diastolic relaxation (+50%). Infusion of an ET(A)/ET(B)-nonselective antagonist, PD 142893 (200 nmol/L), had similar effects on all parameters, whereas infusion of BQ-788 (20 nmol/L), an ET(B) receptor-selective antagonist, was without effect. Exogenous ET-1 (100 pmol/L) hastened contracture and increased its extent (+23%) and reduced recovery of both LVDevP (-31%) and CF (-18%), effects that were counteracted by HOE 642 (10 micromol/L), a Na+/H+ exchange inhibitor, but not by nicardipine (30 micromol/L), a Ca2+ entry blocker; activation of cGMP-dependent protein kinase by the cell-permeable cGMP analog Sp-8-p-chlorophenylthioguanosine-3',5'-cyclic monophosphorothioate (10 micromol/L) improved function without preventing the effects of ET-1.
The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET(A) receptors via a mechanism likely involving activation of Na+/H- exchange in this model.
AuthorsF Brunner, L H Opie
JournalCirculation (Circulation) Vol. 97 Issue 4 Pg. 391-8 (Feb 3 1998) ISSN: 0009-7322 [Print] UNITED STATES
PMID9468213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Endothelin-1
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • Cyclic GMP-Dependent Protein Kinases
  • Animals
  • Coronary Vessels (physiopathology)
  • Cyclic GMP-Dependent Protein Kinases (physiology)
  • Endothelin-1 (metabolism, pharmacology)
  • Female
  • Heart (physiopathology)
  • Heart Rate (physiology)
  • Intracellular Membranes (metabolism)
  • Male
  • Myocardial Contraction (drug effects, physiology)
  • Myocardial Ischemia (physiopathology)
  • Myocardial Reperfusion Injury (physiopathology)
  • Myocardium (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A
  • Receptors, Endothelin (physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: