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Phosphorylated heat shock protein 27 is involved in enhanced heart tolerance to ischemia in short-term type 1 diabetic rats

To examine the tolerance of type 1 diabetic hearts to ischemia and reperfusion injury. Myocardial contents of 27-kDa and 70-kDa heat shock proteins (hsp) as well as phosphorylated hsp27 were also determined.Hearts from hyperglycemic rats 3 weeks after streptozocin injection and age-matched normal rats were subjected to ischemia and reperfusion in vitro. Cardiac function and electrocardiogram were recorded throughout experiments. Myocardial heat shock proteins were detected with Western blot.Despite depressed systolic function at the baseline, diabetic hearts exhibited considerable enhancement in post-ischemic heart function, manifested by an increase in the maximal rate of left ventricular pressure rise and fall (post-ischemic dp/dtmax and dp/dtmin were 560+/-117 and -313+/-68 mmHg/s in control, n=7, 1249+/-57 and -1204+/-36 mmHg/s in diabetes, n=10, P0.01). Reperfusion ventricular fibrillation in the diabetic group were attenuated compared with controls (1.5+/-0.3 vs 7.2+/-2.1 min in control, P0.01). The increased heart resistance to ischemia in diabetes was associated with hyperglycemia and accompanied by enhanced expression of myocardial phosphorylated hsp27 with normal aortic vessel relaxation. Cardioprotection was abrogated by metabolic correction with insulin and accompanied by phospho-hsp27 reduction.Heart resistance to ischemia is increased in type 1 diabetes, and hyperglycemia may present a mild yet stressful stimulus leading to upregulation of endogenous stress protein, which may play a potential role in cardioprotection and compensate for detrimental effects of hyperglycemia in diabetes.

To examine the effects of urotensin II, a recently discovered endogenous peptide, on coronary flow (CF), cardiac function, and endothelial nitric oxide synthase (eNOS) expression in isolated rat hearts.Heart was isolated and perfused retrogradely via the aorta in Langendorff mode. Rat urotensin II was administered in the perfusion solution. The eNOS content in myocardium was determined by Western blot.Rat urotensin II had no effect on the heart rate, left ventricular systolic pressure, left ventricular end-diastolic pressure, or +/-dp/dt(max). While rat urotensin II dose-dependently increased CF. CF was increased by 11.43 %, 6.67 %, 6.62 %, 6.56 %, 6.36 %, and 5.86 % respectively in a time-dependent manner at 5, 10, 15, 20, 25, and 30 min after injection of rat urotensin II 6.66 x 10(-2) microg. The maximal effect on CF was found at 5 min following urotensin II administration. N(G)-nitro-L-arginine methyl ester (L-NAME) did not prevent the increased CF in response to urotensin II. Rat urotensin II dose-dependently increased the cardiac eNOS protein expression and this effect was not inhibited by L-NAME.Rat urotensin II did not alter cardiac function but increased CF and the amount of myocardial eNOS protein in the isolated rat heart. The increased CF was independent of the involvement of eNOS.

The present study was designed to test a hypothesis that nonfatal ventricular arrhythmia such as ventricular premature beats (VPB) is a contributing factor in the elevation of blood pressure variability (BPV).Blood pressure (BP) and electrocardiogram were continuously recorded. The relation between VPB and BPV was observed under conscious state in chronic myocardial infarction (MI) rats one month after ligation of the left coronary artery, and further verified under anesthetized state in rat model of ventricular arrhythmia produced by acute intravenous infusion of aconitine.MI rats exhibited a big difference in the count and pattern of VPB, and were divided into no VPB, occasional VPB, and frequent VPB groups. Among the three groups, there were no differences in BP, heart period (HP), and MI size. However, BPV was markedly higher in frequent not occasional VPB rats, and HP variability (HPV) was larger in both frequent and occasional VPB rats, when compared with no VPB rats. In the whole population of MI rats, BPV was positively correlated with VPB and HPV, not with BP, HP and MI size. Infusion of aconitine had no effect on BP, HP, BPV, and HPV during the period without VPB. Frequent VPB after several minutes of aconitine infusion induced significant increase in BPV and HPV with no change in BP and HP. BPV was also positively correlated with VPB and HPV, not with BP and HP. Hemodynamics in aconitine-evoked ventricular tachycardia was characterized as lower BP, higher BPV, and higher HPV.High BPV can be caused by frequent not occasional VPB in rats.

To determine the effects of hypertonic solution on myocardial ischemia and reperfusion injury in normal and stroke-prone hypertensive rat hearts in vitro.Hearts were perfused in an isolated-perfused Langendorff apparatus and perfused with normal or hypertonic solution (360 mOsm/L, by addition of NaCl to the normal perfusate of 300 mOsm/L) before subjected to 30 min ischemia followed by 40 min isotonic reperfusion. Heart function, myocardial creatine kinase leakage, norepinephrine release, and ventricular calcium content were determined.Normal rat hearts with hypertonic perfusion showed higher recovery rate of spontaneous beating than control hearts after ischemia. Hypertensive rat hearts perfused with hypertonic solution also had better recovery in diastolic function and less creatine kinase leakage than hypertensive controls. Concomitantly, myocardial release of norepinephrine was also reduced from hypertensive hearts perfused with hypertonic solution. There was no significant difference in myocardial calcium content between normal and hypertonic perfused hypertensive hearts.Hypertonic perfusion may precondition the hearts and protect them from ischemia and reperfusion injury in both normal and hypertensive rats. The modulation of hypertonic perfusion on myocardial norepinephrine release and its role in cardioprotection needs further investigation.

Angiotensin II and AT1 receptor are the major effector components of renin-angiotensin system (RAS), and also the main growth-stimulating factors in cardiovascular system. The present study was to observe these two factors in the hypertrophied ventricles and aortas of sinoaortic-denervated rats.Rats were examined at 2, 10, and 16 weeks after sinoaortic denervation (SAD). The hypertrophy was evaluated by the ratio of organ weight to body weight. Angiotensin II concentration and AT1 receptor mRNA expression were measured by radioimmunoassay and RT-PCR respectively, using a positive control of candesartan treatment.Aortic hypertrophy existed in 2-, 10-, and 16-week SAD rats, left ventricular hypertrophy in 10- and 16-week SAD rats, and right ventricular hypertrophy in 16-week SAD rats. In all three kinds of examined SAD rats, plasma angiotensin II levels remained unchanged, indicating circulating RAS is at normal level in the chronic phase of SAD. However, cardiovascular tissue RAS was activated, as evidenced by increase of aortic angiotensin II concentrations at 10 and 16 weeks after SAD, and up-regulation of aortic and left ventricular AT1 receptor mRNA expressions at 16 weeks after SAD.The activated tissue RAS is secondary to the hypertrophy, and probably involved in the maintenance of cardiovascular hypertrophy following SAD.

To investigate the role of non N-methyl-D-aspartate acid (non-NMDA) receptors within the caudal ventrolateral medulla (CVLM) in mediating the baroreflex.In urethane-anesthetized, paralyzed, and artificially ventilated rats, the effects of 6-cyano-7-nitroquinoxaline-2,3-dinoe (CNQX, a selective non-NMDA receptors antagonist) locally injected into the CVLM on the depressor responses evoked by aortic nerve stimulation and the barosensitivity of the rostral ventrolateral medulla (RVLM) barosensitive neurons were observed.Bilateral microinjection of CNQX (200 pmol in 100 nL for each side) into the CVLM significantly (P0.01) increased the blood pressure (BP) and heart rate, and markedly (P0.01) attenuated the depressor response to the aortic nerve stimulation. CNQX (200 pmol in 100 nL) unilaterally injected into the CVLM significantly (P0.01) increased the firing rate of the ipsilateral RVLM barosensitive neurons and reduced the inhibitory responses of neurons evoked by stimulation of aortic nerve and elevation of BP, and partially inhibited the neuronal cardiac cycle-related rhythm.The CVLM played an important role in maintaining the tonic excitatory cardiovascular activities and transmitting the baroreceptor information via activation of non-NMDA receptors.

To observe the effects of endothelin receptor subtype A (ETA) and B (ETB) antagonists on acute ischemic arrhythmia in isolated rat heart, and to determine whether endogenous endothelin (ET) was implicated in the pathophysiological process of arrhythmia induced by acute myocardial ischemia.Fifty-three SD male rats were randomized into 8 groups. Heart was isolated and perfused in Langendorff mode and acute ischemia model was established by ligation of the left anterior descending (LAD) coronary artery. The effects of ETA receptor antagonist PD156707 and ETB receptor antagonist IRL1038 on arrhythmia, heart function, the myocardial activity of superoxide dismutase (SOD), and the content of melondialdehyde (MDA) during the acute 60-min ischemic phase were analyzed.Pretreatment with PD156707 (20-500 nmol/L) dose-dependently improved the ischemic isolated heart function, enhanced SOD activity and decreased MDA content in the ischemic myocardium, and suppressed the acute ischemic arrhythmia. Conversely pretreatment with IRL1038 did not change the heart function, SOD activity, MDA content, and the acute ischemic arrhythmia significantly as compared with the occlusion control.ETA receptor antagonist effectively improved heart function, enhanced anti-oxidative function of the myocardium and reduced arrhythmia during the acute ischemic phase in isolated rat hearts, while ETB receptor antagonist did not exert protective effects, suggesting that endogenous ET-1, acting through ETA receptor, may be one of the factors implicated in arrhythmia and impairment to heart function during the acute ischemic phase.