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Although numerous studies have confirmed the beneficial effects of pharmacological therapy for arterial stiffness and endothelial dysfunction, which are predictors/therapeutic targets for cardiovascular diseases, only a few overall quantitative evaluations of MRAs (mineralocorticoid receptor antagonists) exist. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) for randomized trials evaluating MRA effects on arterial stiffness measured by pulse wave velocity (PWV) or augmentation index and endothelial function measured by flow-mediated dilation. Data from the included trials were pooled by using random-effects meta-analysis of the weighted mean difference (MD) between the comparator groups. The primary outcome was the MD of PWV. In 11 trials including 515 patients, the MRA treatment reduced the PWV when compared with control (MD, −0.75 m/s [95% CI, −1.12 to −0.39], P P =0.705 for heterogeneity). The effects of MRA on PWV were independent of blood pressure reduction related to the treatment according to meta-regression analysis. The MRA treatment reduced the augmentation index compared with control in 5 trials including 283 patients (MD, −6.74% [95% CI, −10.26 to −3.21], P =0.0002) and increased the flow-mediated dilation in 11 trials including 570 patients (MD, 1.18% [95% CI, 0.14 to 2.23], P =0.03). In conclusion, the current meta-analysis demonstrates the beneficial effects of MRA on PWV, augmentation index, and flow-mediated dilation.

Objective: Aminopeptidase A (APA) have important role in conversion of Ang II to Ang III. Intravenous APA administration lowers blood pressure in hypertensive rats. In contrast, APA inhibition in the brain lowers blood pressure in hypertensive rats. Therefore APA might have different role on cardiovascular regulation. However, a role of APA and Ang III on cardiovascular regulation especially in the brain has not been fully understood. Our purpose of present study was to investigate a role of APA and Ang III in the brain on cardiovascular regulation in conscious state. Method: 12-13 weeks old Wistar Kyoto rat (WKY) and 12-16 weeks old spontaneously hypertensive rat (SHR) were used. i) APA distribution in the brain was evaluated by immunohistochemistry. Protein expression of APA was evaluated by Western blotting. Enzymatic activity of APA was evaluated using L-glutamic acid γ-(4-nitroanilide) as a substrate. ii) WKY received icv administration of Ang II 25ng/2μL and Ang III 25ng/2μL. We recorded change in mean arterial pressure (MAP) in conscious and unrestraied state and measured induced drinking time. iii) SHR received icv administeration of recombinant APA 400ng/4μL. We recorded change in MAP in conscious and unrestraied state and measured induced drinking time. Result: i) APA was diffusely immunostained in the cells of brain stem including cardiovascular regulatory area such as rostral ventrolateral medulla. Protein expression and APA activity in the brain were similar between WKY (n=3) and SHR (n=3).ii) Icv administration of Ang II increased MAP by 33.8±3.8 mmHg and induced drinking behavior for 405±90 seconds (n=4). Icv administration of Ang III also increased MAP by 24.7±2.4 mmHg and induced drinking behavior for 258±62 seconds (n=3). These vasopressor activity and induced drinking behavior was completely blocked by pretretment of angiotensin receptor type 1 blocker.iii) Icv administration of APA increased MAP by 10.0±1.7 mmHg (n=3). Conclusion: These results suggested that Ang III in the brain increase blood pressure by Angiotensin type 1 receptor dependent mechanism and APA in the brain may involved in blood pressure regulation as a vasopressor enzyme.

Objectives: Bone marrow-derived cells (BMCs) include mesenchymal stem cells (MSC) play critical role in repairing damaged tissue and anti-inflammation. We reported that intracerebroventricular (icv) administration of autologous BMCs attenuate slow pressor Ang II initiated hypertension via attenuating Ang II mediated sympathetic activation in rats. However, mechanisms of this observation have not been elucidated. We hypothesized that BMCs in the brain would attenuate inflammation and modulate overactive renin angiotensin system (RAS) in the brain of Ang II initiated hypertensive rats. Therefore we examined characteristics of BMCs prepared with identical cultural condition to previous experiment and examined expression of inflammation related cytokines and RAS component in the brain of Ang II initiated hypertensive rats. Methods: Aspirated bone marrow cells underwent red blood cell lysis protocol were seeded in an individual dish in Dulbecco Modified Eagle Media with 10% fetal bovine serum. Floating cells were removed and plastic adherent cells were allowed to glow for 3 weeks at passage 3. The number of BMCs proliferated more than 10 6 were used for immunocytochemical, flowcytometric, BrdU uptake, and Western blot analysis. TGF-beta, IL-10 and AT1 receptor protein expression were examined in brains of Ang II initiated hypertensive rats. Results: Cultured BMCs expressed CD29, a marker of mesenchymal stem cell. Flowcytometric analysis revealed that 38% of BMCs were CD29+ CD34-. Endothelial cell (EC) proliferation assay exhibited 52% higher BrdU uptake with conditioned media from BMCs than the media from ECs. Expression of angiotensin converting enzyme (ACE) was 87% lower in BMCs than in ECs, whereas ACE2 expression was 142% higher in BMCs. Furthermore, Ang II infusion significantly increased expression of TGF-beta and AT1 receptor in the brain by 146% and 135% respectively and icv administration of BMCs attenuated the increases of both expressions (39%, 59% respectively). Ang II infusion with or without BMCs icv did not affect to IL-10 expression in the brain. Conclusion: BMCs in the brain may have protective role against Ang II induced sympathetic activation via attenuation of brain inflammation and increase in AT1 receptors.

Objectives: Administration of deoxycorticosterone acetate (DOCA) in combination with salt loading and surgical removal of one kidney induces hypertension. Central mechanism is involved in this hypertension. Bone marrow-derived cells (BMCs) include mesenchymal stem cells play critical role in repairing damaged tissue and anti-inflammation. We hypothesized that increase in number of BMCs in the brain would attenuate the DOCA-salt hypertension. Methods: Sprague-Dawley rats underwent unilateral nephrectomy were divided into following 4 groups: rats received sham treatment with intracerebroventricular (icv) administration of medium (S/M group, n=5); rats received sham treatment with icv administration of BMCs (S/B group, n=5); rats received DOCA-salt treatment with icv administration of medium (D/M group, n=4); rats received DOCA-salt treatment with icv administration of BMCs (D/B group, n=7). Three weeks following the initiation of DOCA-salt treatment, rats had surgery to implant arterial and venous catheters. Resting mean arterial pressure (MAP) of rats was recorded in conscious unrestrained state and resting sympathetic tone was evaluated with a peak depressor response produced by hexamethonium (C6) injection. Results: Resting MAPs of S/M, S/B, D/M and D/B group were 116±4, 120±5, 194±4, 172±9 mmHg, respectively. DOCA-salt treatment significantly increased MAP in both D/M and D/B group. D/B group tended to have lower MAP than D/M group, however, post hoc analysis did not reach significant. The peak depressor responses to C6 injection in S/M, S/B, D/M and D/B group were 41±2, 46±5, 97±10, 69±5 mmHg, respectively. DOCA-salt treatment significantly increased the peak depressor response to C6 and icv administration of BMCs attenuated the increase in peak depressor response. Conclusion: BMCs in the brain may have protective role against sympathetic hyperactivity caused by DOCA-salt treatment.

Background: Vascular remodeling and inflammation contribute to the pathogenesis and/or development of pulmonary hypertension. Bone marrow-derived cells (BMCs) include mesenchymal stem cells and progenitor cells play critical role in tissue repair as well as anti-inflammatory effects. Aim of this study was to investigate the effect of intratracheal delivered BMCs on monocrotaline (MCT)-induced muscuralization and inflammation in rat lung. METHODS: BMCs were isolated and cultured for 3 weeks. Seven days following MCT (60 mg/kg) treatment, DiI labeled autologous BMCs were intratracheally delivered to male Sprague-Dawley rats. Twenty-eight days following the MCT treatment, rats had hemodynamic studies. Hearts and lungs were removed to evaluate right ventricular (RV) hypertrophy and lung pathologies. Results: MCT treated rats had increased RV systolic pressure (RVSP), RV weight as well as wall thickness of small pulmonary arteries and alveolar septum thickness than those of placebo-treated control rats (all p values Conclusion: Intratracheal delivery of autologous BMCs prevented MCT-induced pulmonary hypertension by attenuation of vascular muscularization and inflammation in rat lung.

Objectives: Subcutaneous infusion of non-pressor doses of angiotensin II (Ang II) gradually produces hypertension in part via central mechanism. Bone marrow-derived cells (BMC) have an ability to secrete paracrine factors leading to improvements in tissue injury. We hypothesized that implantation of autologous BMCs in the brain would attenuate Ang II initiated neurogenic hypertension via secreted paracrine factors. METHODS: Sprague-Dawley rats were divided into following 4 groups: rats received vehicle infusion with intracerebroventricular (icv) administration of medium (V/M group, n=5); rats received vehicle infusion with icv administration of DiI labeled BMCs (V/B group, n=3); rats received Ang II infusion (150 ng/kg/min) with icv administration of medium (A/M group, n=4); rats received Ang II infusion with icv administration of BMCs (A/B group, n=5). Three weeks following initiation of the infusion, rats had surgery to implant arterial and venous catheters. Resting mean arterial pressure (MAP) of rats was recorded in conscious unrestrained state and resting sympathetic tone was evaluated with a peak depressor response produced by hexamethonium (C6) injection. Results: Systolic blood pressure (SBP) measured by tailcuff method was similar among the groups, only A/M group had a trend to increase in SBP. Resting MAPs of V/M, V/B, A/M and A/B group were 125±2, 116±2, 174±7, 134±8 mmHg, respectively. Ang II infusion significantly increased MAP in A/M group, however in A/B group, icv administration of BMCs attenuated the Ang II mediated increase in MAP. Heart rate was similar among the groups. The peak depressor responses to C6 injection in V/M, V/B, A/M and A/B group were 38±3, 46±6, 77±5, 48±1 mmHg, respectively. Ang II infusion significantly increased the peak depressor response to C6 and icv administration of BMCs attenuated the increase in peak depressor response. DiI positive cells were distributed to the choroid plexus, surface of ventricle, and subventricular zone but not to the subfornical organ. Conclusion: Icv administration of autologous BMCs attenuate slow pressor Ang II initiated hypertension via attenuating the Ang II mediated sympathetic activation in rats. Paracrine factors secreted from the BMCs may be involved in this process.