Role of Bradykinin in Protection of Ischemic Preconditioning in Rabbit Hearts

Abstract

Bradykinin receptor activation has been proposed to be involved in ischemic preconditioning. In the present study, we further investigated the role of this agent in preconditioning in both isolated and in situ rabbit hearts. All hearts were subjected to 30 minutes of regional ischemia followed by reperfusion for 2 hours (in vitro hearts) and 3 hours (in situ hearts). Infarct size was measured by tetrazolium staining and expressed as a percentage of the size of the risk zone. Preconditioning in situ hearts with 5 minutes of ischemia and 10 minutes of reperfusion significantly reduced infarct size to 10.2 +/- 2.2% of the risk region (P < .0005 versus control infarct size of 36.7 +/- 2.6%). Pretreatment with HOE 140 (26 micrograms/kg), a bradykinin B2 receptor blocker, did not alter infarct size in nonpreconditioned hearts (40.6 +/- 5.3% infarction) but abolished protection from ischemic preconditioning (34.1 +/- 1.6% infarction). However, when HOE 140 was administered during the initial reflow period following 5 minutes of ischemia, protection was no longer abolished (15.6 +/- 3.9% infarction versus 13.3 +/- 3.8% without HOE 140, P = NS). Bradykinin infusion in isolated hearts mimicked preconditioning, and protection was not affected by pretreatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester or the prostaglandin synthesis inhibitor indomethacin but could be completely abolished by the protein kinase C (PKC) inhibitors polymyxin B and staurosporine as well as by HOE 140. HOE 140 could not block the protection of ischemic preconditioning in isolated hearts. That failure was apparently due to the absence of blood-borne kininogens rather than autonomic nerves. When the preconditioning stimulus in the in situ model was amplified with four cycles of 5-minute ischemia/10-minute reperfusion, HOE 140 pretreatment could no longer block protection (infarct size was 10.7 +/- 3.5% versus 6.4 +/- 2.0% without HOE 140, P = NS). We propose that bradykinin receptors protect by coupling to PKC as do adenosine receptors, and blockade of either receptor will diminish the total stimulus of PKC below threshold and prevent protection. A more intense preconditioning ischemic stimulus can overcome bradykinin receptor blockade, however, by simply enhancing the amount of adenosine and possibly other agonists released.

Sulprostone‐induced reduction of myocardial infarct size in the rabbit by activation of ATP‐sensitive potassium channels

“…Thus it is possible that pretreatment with sulprostone only leads to a degree of PKC activation which is below the threshold for a long-lasting opening of KATP channels. This hypothesis is supported by the finding that a specific degree of PKC activation ('Threshold Hypothesis') is required to initiate cardioprotection (Goto et al, 1995).…”

Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF‐α

“…Knowledge of the underlying principles might help to design pharmacological interventions, keeping tissues at risk in a 'permanent state of preconditioning' (21). Accordingly, numerous studies have been performed to elucidate the mechanisms behind preconditioning, but the results have suggested nearly as many different mediators, including adenosine (5), acetylcholine (22), catecholamines (4), angiotensin II (23), bradykinin (24), nitric oxide (25), and reactive oxygen species (8). To make things even more complicated, the cellular targets of preconditioning seem to be heterogeneous.…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…These important findings demonstrated that IPC was a receptor-mediated phenomenon and suggested that the infarctlimiting effects of IPC could be mimicked by a pharmacological agent [22]. Other GPCR ligands have been implicated as triggers of IPC such as bradykinin [23,24], opioids [25], acetylcholine [26], catecholamines [27], angiotensin II [28], and endothelin-1 [29]. The IPC triggers are highly redundant with multiple cycles of IPC able to overcome the effect of antagonism at a single receptor [24].…”

“…Other GPCR ligands have been implicated as triggers of IPC such as bradykinin [23,24], opioids [25], acetylcholine [26], catecholamines [27], angiotensin II [28], and endothelin-1 [29]. The IPC triggers are highly redundant with multiple cycles of IPC able to overcome the effect of antagonism at a single receptor [24]. The simultaneous activation of these GPCRs during the IPC stimulus suggested that the cardioprotective signal probably converges on a single downstream mediator, protein kinase C (PKC), which mediates the memory effect of IPC.…”