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Background: Stroke is the second most common cause of death and a major cause of disability worldwide. Risperidone is an atypical antipsychotic drug that may increase the risk of stroke. The present work examined whether risperidone enhances the vulnerability to stroke in hypertensive rats and the potential mechanisms underlying such action. Methods: Experiment 1: Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHR-SPs) were treated with risperidone (0.8 and 2.4 mg/kg/d) or vehicle for 30 consecutive days. Tissue damage in response to middle cerebral artery occlusion (MCAO) was measured microscopically. The activity of superoxide dismutase, glutathione peroxidase, the levels of malondialdehyde were also determined. Experiment 2: Survival data were recorded in SHR-SPs that received daily risperidone perpetually. Experiment 3: Effect of risperidone on interleukin-6 and tumor necrosis factor-α was examined in quiescent or LPS-activated cortical microglias from WKY rats. Experiment 4: Potential damage of risperidone exposure to neurons was examined in primary neuronal culture obtained from WKY rats, SHRs, and SHR-SPs. Results: Risperidone increased infarct areas upon MCAO in SHR-SPs and SHRs, but not in WKY rats. Survival time in SHR-SPs was shortened by risperidone. Apoptosis was augmented by risperidone through enhanced Bax. Risperidone also increased endothelial injury. Conclusions: Risperidone enhances the vulnerability to stroke in hypertensive rats through increasing neuronal apoptosis and endothelial injury. © 2012 Blackwell Publishing Ltd.

Aims Angiogenesis is critical for re-establishing blood supply to ischaemic myocardium after myocardial infarction (MI). Human studies have associated arterial baroreflex (ABR) deficiency with higher rate of sudden death after MI. The present work was designed to examine whether ABR deficiency affects angiogenesis in MI rats. Methods and results Baroreflex sensitivity (BRS) was determined in conscious rats at 1 month after occlusion of the left anterior descending coronary artery. The survival time was significantly shorter in Sprague-Dawley rats with BRS

AIM This study was designed to investigate the effects of telmisartan and amlodipine on reduction of blood pressure (BP), myocardial hypertrophy, and renal injury in hypertensive rats. METHOD In acute experiments, the BP was measured in conscious freely moving rats. Spontaneously hypertensive rats were treated with intragastric administration of amlodipine (1, 2, 4 mg/kg), telmisartan (4, 8, 12, 16, 20 mg/kg), and their different combinations (4 + 4, 2 + 4, 4 + 8, 4 + 12, 1 + 4, 2 + 8, 4 + 16, 2 + 12, 1 + 8, 2 + 16, 2 + 20, 1 + 12, 1 + 16, 1 + 20 mg/kg). The probability sum test (q test) was used to evaluate the synergistic action on BP reduction. In two-kidney, one-clip rats, the effects of amlodipine (1 mg/kg), telmisartan (6 mg/kg) and their combination on BP reduction were observed. In the chronic study, spontaneously hypertensive rats were treated with amlodipine (1 mg/kg), telmisartan (6 mg/kg), and their combination for 4 months. Histopathologic examinations were performed after the determination of BP and BP variability. RESULTS There is a synergistic interaction between amlodipine and telmisartan on BP reduction. The optimal dose ratio was found at 1:6. The synergistic effect of this dose ratio (1:6) was also seen in two-kidney, one-clip rats. Long-term treatment with this combination results in a beneficial effect on the reduction of BP and BP variability. The end-organ damage, including myocardial hypertrophy, glomerular atrophy, and fibrosis, was significantly attenuated by this combination. CONCLUSION The optimal dose ratio of amlodipine and telmisartan on BP was 1:6. This combination is beneficial for the BP and BP variability reduction and end-organ damage prevention.

Background Endothelium‐derived acetylcholine ( eAC h) plays an important role in the regulation of vascular actions in response to hypoxia, whereas arterial baroreflex (ABR) dysfunction impairs the eAC h system. We investigated the effects of ABR dysfunction on ischemia‐induced angiogenesis in animal models of hindlimb ischemia with a special focus on eAC h/nicotinic ACh receptor ( nAChR ) signaling activation. Methods and Results Male Sprague‐Dawley rats were randomly assigned to 1 of 3 groups that received (1) sham operation (control group), (2) sinoaortic denervation (SAD)‐induced ABR dysfunction (SAD group), or (3) SAD rats on diet with an acetylcholinesterase inhibitor pyridostigmine (30 mg/kg per day, SAD+Pyr group). After 4 weeks of the SAD intervention, unilateral limb ischemia was surgically induced in all animals. At postoperative day 14, SAD rats exhibited impaired angiogenic action (skin temperature and capillary density) and decreased angiogenic factor expressions (vascular endothelial growth factor [VEGF] and hypoxic inducible factor [HIF]‐1α) in ischemic muscles. These changes were restored by acetylcholinesterase inhibition. Rats with ABR dysfunction had lower eAC h levels than did control rats, and this effect was recovered in SAD+Pyr rats. In α7‐ nAChR knockout mice, pyridostigmine improved ischemia‐induced angiogenic responses and increased the levels of VEGF and HIF‐1α. Moreover, nicotinic receptor blocker inhibited VEGF expression and VEGF receptor 2 phosphorylation (p‐VEGFR2) induced by ACh analog. Conclusions Thus, ABR dysfunction appears to impair ischemia‐induced angiogenesis through the reduction of eAC h/α7‐ nAChR ‐dependent and ‐independent HIF‐1α/VEGF‐VEGFR2 signaling activation.

Ghrelin, an endogenous ligand for the GH secretagogue receptor, has been shown to decrease arterial pressure. Obestatin, a sibling of ghrelin derived from preproghrelin, opposes several physiological actions of ghrelin. The aim of this study was to determine the effects of bolus intravenous injection of obestatin on blood pressure in spontaneously hypertensive rats. Three different dosages of obestatin (10, 50, and 100 microg/kg) and one dosage of ghrelin (10 microg/kg) were applied. The mean arterial pressure and heart period were continuously recorded for 30 min after injection of drugs. Baroreflex sensitivity was also investigated. In this study, we first demonstrated that intravenous injection of obestatin showed no significant effects on mean blood pressure (10 microg/kg: 113.8+/-2.0 mmHg vs. 114.4+/-1.6 mmHg; 50 microg/kg: 110+/-2.4 mmHg vs. 109+/-3.2 mmHg; 100 microg/kg: 115.9+/-1.5 mmHg vs. 115.8+/-2.4 mmHg; all P0.05), heart period (10 microg/kg: 184.7+/-3.9 ms vs. 185.5+/-4.1ms; 50 microg/kg: 185.9+/-4.1 ms vs. 193.4+/-4.5 ms; 100 microg/kg: 137.7+/-4.5 ms vs. 143.9+/-5.6 ms; all P0.05), or baroreflex sensitivity (10 microg/kg: 0.414+/-0.03 ms/mmHg vs. 0.442+/-0.02 ms/mmHg; 50 microg/kg: 0.453+/-0.04 ms/mmHg vs. 0.439+/-0.01 ms/mmHg; 100 microg/kg: 0.398+/-0.02 ms/mmHg vs. 0.401+/-0.01 ms/mmHg; all P0.05), however, intravenous injection of ghrelin could decrease mean arterial pressure (115.9+/-1.5 mmHg vs. 108.6+/-3.6 mmHg, P0.01) and increase heart period (132.4+/-2.8 ms vs. 152.6+/-7.4 ms, P0.05), but did not change baroreflex sensitivity (0.36+/-0.009 ms/mmHg, P0.05) in spontaneously hypertensive rats.

Since humanin, a 24-amino acid polypeptide, was first found in the surviving neurons of human patients with Alzheimer disease in 2001, it was reported that humanin protected neurons from beta-amyloid-induced apoptosis by binding to specific receptor and triggering a Jak/STAT prosurvival pathway [1]. As we know, apoptosis and Jak/STAT prosurvival pathway were also mechanisms involved in cell responses induced by anoxia, ischemia, and so on [2]. But the effects of humanin on neurons induced by anoxia or ischemia remain unknown. In particular, anoxia responses of cells occurred through a number of mechanisms including electrophysiological mechanism. Voltage-dependent potassium ion currents, such as transient outward potassium current (Ito) and delayed rectifier potassium current (IK), are known to initiate apoptosis in Alzheimer disease [3]. So, based on the hypothesis that humanin could protect neuronal cells from anoxia impairment as well as from beta-amyloid impairment, the effect of humanin (Sigma, St. Louis, MO, USA) 2 mmol/L on activity and on potassium currents of hippocampal neurons in presence of dithionite (Sigma) was investigated. The neuronal viability and potassium currents in neurons being cultured for 12 days were determined by MTT method and patch clamp technique, after dissociated from hippocampus of neonatal Wistar rats as reported [4]. Voltage-dependent potassium ion currents, both IK and Ito (shown in Figure 1A–C), were recorded using a patch clamp amplifier (EPC-10, HEKA, Pfalz, Lambrecht, Germany) and Pulse 8.5 software (HEKA) by whole-cell manner. Tetrodotoxin 1 lmol/L was employed to abolish sodium ion current of neurons. Cultures treated by external solution containing dithionite 2 mmol/L for 5 min by a continuous perfusion pump were referred to as anoxia, as dithionite deprived oxygen out of the neurons [5]. Compared with that of controls, the viability of neurons treated by dithionite 2 mmol/L for 6 h decreased to 63 10% (n = 10) significantly (P < 0.05),but not the neurons treated by mixture of humanin and dithionite 2 mmol/L for 6 h. Meanwhile, neuronal viability was not decreased significantly by anoxia, even if anoxia could change potassium current properties. Anoxia significantly decreased Ito amplitudes (P < 0.05), but had no significant effect on IK amplitude. IK amplitudes of neurons were significantly decreased (P < 0.05) by humanin or by mixture of humanin and anoxia. Pretreatment with humanin for 5 min, anoxia did not decrease Ito amplitudes significantly any more. While humanin and dithionite were washed out, IK and Ito amplitudes recovered partly within several minutes. The effect of humanin on Ito amplitudes was not found in the present experiment (shown in Figure 1D,E). Steady-state activation of IK and Ito was fitted by Boltzmann function as follows: G/Gmax = [1 + exp(V V1/2)/k] , in which Gmax is the maximal membrane conductance, V1/2 is the potential at which the conductance is half steady activation, and k is a factor describing the slope of the activation curves. As shown in Table 1, after anoxia, V1/2 of IK and Ito was altered significantly (P < 0.05) toward depolarization. On the contrary, humanin shifted V1/2 of IK significantly toward repolarization (P < 0.05), but not altered V1/2 of Ito. Meanwhile, mixture of humanin and anoxia had no effect on V1/2 of IK or Ito, and neither humanin nor anoxia altered k slope as well.

Background Ketanserin, a 5-hydroxytryptamine receptor antagonist, is clinically used as an antihypertensive agent and could enhance baroreflex function. The present work tested the hypothesis that restoration of baroreflex function is an effective treatment for lipopolysaccharide (LPS)-induced shock. Methods Kunming mice were injected with LPS (30 mg/kg; intraperitoneal) to induce endotoxic shock. Ketanserin (0.3, 1, 3, or 10 mg/kg; intraperitoneal) was administered immediately after LPS injection. Survival time was monitored, and serum cytokines were analyzed after the onset of LPS. Effects of ketanserin were also examined in IL-10-deficient mice and mice with sinoaortic denervation. Finally, effects of ketanserin on blood pressure, heart rate, and baroreflex sensitivity were examined in Wistar-Kyoto (WKY) rats with endotoxic shock. Results Ketanserin significantly increased survival time and decreased serum levels of tumor necrosis factor α and interleukin (IL) 1β in mice with endotoxic shock. At a dose of 10 mg/kg, ketanserin also significantly increased serum IL-10 concentration. The antishock effect of ketanserin was also apparent in IL-10-knockout mice. In mice with sinoaortic denervation, however, ketanserin had little antishock effects. In WKY rats, ketanserin significantly prevented the baroreflex impairment induced by LPS and prolonged the survival time. Conclusions Ketanserin could ameliorate endotoxic shock by restoring baroreflex function.

Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation–induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR −/− mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.

To reinvestigate the characteristics of reserpine-induced gastric mucosal lesions (GMLs). The GML-inducing effect of reserpine and the time-course of recovery from reserpine-induced GMLs were examined in Sprague-Dawley (SD) rats. The GML-inducing and blood pressure-decreasing effects of Compound Hypotensive Tablets (CHTs) were investigated in spontaneously hypertensive rats (SHRs). Intracerebroventricular (icv) injection and vagotomy were performed to verify the central vagal mechanism in reserpine-induced GMLs. Single intraperitoneal (ip) injections of reserpine (0.25, 0.5, 1, 2, 4, and 6 mg/kg) dose-dependently induced GMLs in SD rats. Both single and repeated (2 weeks) oral administrations of reserpine led to slight GMLs at doses of 24 mg/kg and 10 mg/kg, respectively. Blood pressure was significantly decreased in SHRs after 2 months of CHT administration (0.01 and 0.03 mg/kg; doses were expressed as the amount of reserpine in the CHT). CHT doses of 0.3 mg/kg induced GMLs, but 0.1 mg/kg did not. Examining the time course of recovery from GMLs, severe GMLs occurred 18 h after ip reserpine (4 mg/kg), obviously lessened at 1 week and healed spontaneously at 3 weeks. Intracerebroventricular injections of reserpine caused GMLs at much lower doses (0.08 and 0.4 mg/kg), and reserpine-induced GMLs were greatly inhibited by vagotomy, suggesting the involvement of a central vagal mechanism. Reserpine-induced GMLs were dose-dependent, and the lesions healed spontaneously within 3 weeks. Long-term treatment with CHT at doses adequate to decrease blood pressure will not induce GMLs. A central vagal mechanism was involved in reserpine-induced GMLs.