Effects of spontaneous or induced brain ischemia on vessel reactivity: The role of inducible nitric oxide synthase
Introduction
Ischemic preconditioning of the heart is a powerful mode of myocardial protection which results in improved contractile function, increased coronary flow, and reduced infarct size when performed immediately (classic) or 24–72 hours (delayed) before sustained ischemia. The preconditioning process involves trigger substance(s), signal transduction pathways, and probably synthesis of organ effector(s) of protection. Nitric oxide (NO) has been suggested as a trigger and a mediator of the preconditioning response [1]. Delayed preconditioning of the heart may be mediated by inducible nitric oxide synthase (iNOS), as preconditioning is inhibited by iNOS blockers such as aminoguanidine and S-methylisothiourea [2]. In addition, it was recently shown that mice with targeted disruption of the iNOS gene could not be preconditioned [3]. Pharmacological preconditioning by lipopolysaccharide or monophosphoryl lipid A not only protects the heart against ischemic injury [5], [6], but also results in systemic vasodilatory effects [4], [5], [6]. The beneficial effects of these agents appear to be mediated by iNOS, as the effects are abolished by pharmacological or genetical iNOS inhibition [5], [7], [8], [9].
During the last few years remote preconditioning, which can be both classic and delayed, has been discovered. Thus, short episodes of ischemia and reperfusion of the limb [10], colon [11], and kidney [12] protects not only the organ itself, but also the heart. The mechanisms of remote preconditioning are not clarified. We have demonstrated that spontaneous ischemic events in hearts or brains of mice with severe atherosclerosis protects their isolated hearts against induced ischemia 24–36 hours later [13]. Preconditioning of other organs to evoke myocardial protection indicates that a general as well as an organ specific protection is induced. The possible involvement of NO and iNOS as mediators of remote protection indicates that preconditioning may affect vascular function; however, to the author’s knowledge there are no publications on this.
The aim of the present study was therefore to investigate if delayed, remote preconditioning induced by brain ischemia influences vessel reactivity in vitro, and whether iNOS is involved as a mediator of this effect.
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Animals
The study was performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US NIH, and was approved by the Ethics Committee for Animal Research at the Karolinska Institute. Apolipoprotein E and low density lipoprotein receptor double knockout mice (ApoE/LDLr KO) of either sex on C57BL6 background were purchased from Bomholtgård (Bomholt, Denmark), and fed an atherogenic diet containing 21% fat and 0.15% cholesterol (R683, AnalyCen, Lidköping, Sweden) for
Response to ACh and PGF2α in mice with induced brain ischemia
ACh evoked a concentration-dependent relaxation of aortic rings from both C57BL6 and iNOS KO mice. In C57BL6 mice, the relaxations induced by ACh were enhanced in mice with induced brain ischemia. The highest concentration of ACh (10 μmol/L) relaxed the vessels by 79 ± 4% in mice without brain ischemia, and by 92 ± 3% in mice with induced brain ischemia (Fig. 1A, p < 0.05). The enhanced response to ACh was abolished by pre-incubation with aminoguanidine (Fig. 1B). In iNOS KO mice, the response
Discussion
In the present study in vitro reactivity of thoracic aortic rings from animals with spontaneous or induced brain ischemia was investigated. These animals had a preconditioning-like protection of heart function and infarct size when their hearts were Langendorff-perfused and subjected to global ischemia and reperfusion [13]. The present study investigated whether this was associated with changes of vessel reactivity and expression of iNOS/eNOS protein. The main findings were that induced brain
Acknowledgements
The work has been supported by grants from the Swedish Medical Research Council (10857 and 12665), the Swedish Heart–Lung Foundation, Jeanssonska Stiftelserna, Fredrik and Ingrid Thuring Foundation, King Gustav V:s and Queen Victorias Foundation, and the Karolinska Institute. Shinichi Tokuno was supported by a grant from the Japanese Self Defense Force.
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Present address: Section of Military and Emergency Medicine, Medical Service School of Japanese Ground Self Defence Force, Tokyo, Japan.