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Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts.
Eur J Pharmacol. 1999 Sep 03; 380(1):13-21.EJ

Abstract

Two angiotensin AT1 receptor antagonists with different receptor binding characteristics, candesartan (insurmountable antagonism) and losartan (surmountable antagonism), were compared as regards their effects on angiotensin II-induced vasoconstriction and on myocardial ischemia/reperfusion injury. In isolated rat hearts perfused under constant flow, it was found that at equipotent concentrations candesartan (10 nM) and losartan (3 microM) almost completely inhibited the angiotensin II-induced increase in coronary perfusion pressure. However, if a washout period was introduced before the angiotensin II challenge, the effect of losartan quickly vanished, while that of candesartan remained. In hearts subjected to 25 min of global ischemia and 45 min of reperfusion, pre-treatment with candesartan (10 nM) or losartan (3 microM) immediately prior to ischemia improved the recovery of left ventricular developed pressure as compared to the effect of vehicle (69 +/- 3.2 and 64 +/- 2.3 vs. 44 +/- 6.2%, respectively; mean +/- S.E.M, P < 0.05). When ischemia was initiated following 30 min of washout after drug administration, the recovery of left ventricular developed pressure was higher in the candesartan group (73 +/- 3.2%, P < 0.05), but not in the losartan group (63 +/- 2.8%), than in the vehicle group (58 +/- 4.8%). The cumulative creatine kinase release during the first 30 min of reperfusion in the washout experiments was lower in the candesartan group (28.5 +/- 2.30 U, P < 0.05), but not in the losartan (40.8 +/- 6.73 U) group, than in the vehicle group (48.1 +/- 4.35 U). No significant difference between groups in left ventricular end-diastolic pressure and coronary perfusion pressure was found. The present results demonstrate that angiotensin AT1 receptor antagonists at equipotent concentrations could differ in their cardioprotective effects in hearts subjected to ischemia/reperfusion. It is suggested that the insurmountable AT1 receptor characteristics of candesartan could provide more persistent cardioprotection than the surmountable receptor characteristics of losartan.

Authors+Show Affiliations

Pharmacology CV, Astra Hässle, Mölndal, Sweden.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

10513555

Citation

Wang, Q D., and P O. Sjöquist. "Effects of the Insurmountable Angiotensin AT1 Receptor Antagonist Candesartan and the Surmountable Antagonist Losartan On Ischemia/reperfusion Injury in Rat Hearts." European Journal of Pharmacology, vol. 380, no. 1, 1999, pp. 13-21.
Wang QD, Sjöquist PO. Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts. Eur J Pharmacol. 1999;380(1):13-21.
Wang, Q. D., & Sjöquist, P. O. (1999). Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts. European Journal of Pharmacology, 380(1), 13-21.
Wang QD, Sjöquist PO. Effects of the Insurmountable Angiotensin AT1 Receptor Antagonist Candesartan and the Surmountable Antagonist Losartan On Ischemia/reperfusion Injury in Rat Hearts. Eur J Pharmacol. 1999 Sep 3;380(1):13-21. PubMed PMID: 10513555.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts. AU - Wang,Q D, AU - Sjöquist,P O, PY - 1999/10/8/pubmed PY - 1999/10/8/medline PY - 1999/10/8/entrez SP - 13 EP - 21 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 380 IS - 1 N2 - Two angiotensin AT1 receptor antagonists with different receptor binding characteristics, candesartan (insurmountable antagonism) and losartan (surmountable antagonism), were compared as regards their effects on angiotensin II-induced vasoconstriction and on myocardial ischemia/reperfusion injury. In isolated rat hearts perfused under constant flow, it was found that at equipotent concentrations candesartan (10 nM) and losartan (3 microM) almost completely inhibited the angiotensin II-induced increase in coronary perfusion pressure. However, if a washout period was introduced before the angiotensin II challenge, the effect of losartan quickly vanished, while that of candesartan remained. In hearts subjected to 25 min of global ischemia and 45 min of reperfusion, pre-treatment with candesartan (10 nM) or losartan (3 microM) immediately prior to ischemia improved the recovery of left ventricular developed pressure as compared to the effect of vehicle (69 +/- 3.2 and 64 +/- 2.3 vs. 44 +/- 6.2%, respectively; mean +/- S.E.M, P < 0.05). When ischemia was initiated following 30 min of washout after drug administration, the recovery of left ventricular developed pressure was higher in the candesartan group (73 +/- 3.2%, P < 0.05), but not in the losartan group (63 +/- 2.8%), than in the vehicle group (58 +/- 4.8%). The cumulative creatine kinase release during the first 30 min of reperfusion in the washout experiments was lower in the candesartan group (28.5 +/- 2.30 U, P < 0.05), but not in the losartan (40.8 +/- 6.73 U) group, than in the vehicle group (48.1 +/- 4.35 U). No significant difference between groups in left ventricular end-diastolic pressure and coronary perfusion pressure was found. The present results demonstrate that angiotensin AT1 receptor antagonists at equipotent concentrations could differ in their cardioprotective effects in hearts subjected to ischemia/reperfusion. It is suggested that the insurmountable AT1 receptor characteristics of candesartan could provide more persistent cardioprotection than the surmountable receptor characteristics of losartan. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/10513555/Effects_of_the_insurmountable_angiotensin_AT1_receptor_antagonist_candesartan_and_the_surmountable_antagonist_losartan_on_ischemia/reperfusion_injury_in_rat_hearts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(99)00499-9 DB - PRIME DP - Unbound Medicine ER -