Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Ischaemic-Reperfused Hearts in Adult Rats with Established Chronic Kidney Disease

BACKGROUND AND OBJECTIVES: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are adult multipotent non-haematopoietic stem cells that have regeneration potential. The current study aimed to detect the ability of BM-MSCs to improve kidney and cardiac functions in adult rats with established chronic kidney disease. METHODS: Rats were divided into sham-operated control, untreated sub totally nephrectomised and treated sub totally nephrectomised groups. Body weight, kidney and cardiac tissue weights, plasma creatinine and urea levels and arterial blood pressure were measured. ECG was recorded, and an in vitro isolated heart study was performed. Results: Stem cell treatment decreased the elevated plasma creatinine and urea levels and decreased systolic, diastolic and mean arterial blood pressure values. These changes were accompanied by a decrease in glomerular hypertrophy with apparent normal renal parenchyma. Additionally, BM-MSCs shortened Q-To and Q-Tc intervals, all time to peak tension values, the half relaxation value at 30 min of reperfusion and the contraction time at 15 and 30 min of reperfusion. Moreover, stem cell treatment significantly increased the heart rate, QRS voltage, the peak tension at the 15- and 30-min reperfusion time points and the peak tension per left ventricle at the 30-min reperfusion time point compared to the pre-ischaemia baseline. BM-MSCs resolve inter muscular oedema and lead to the re-appearance of normal cardiomyocytes. This improvement occurs with the observations of BM-MSCs in renal and heart tissues. CONCLUSIONS: BM-MSCs can attenuate chronic kidney disease progression and the associated cardiac electrophysiological and inotropic dysfunction.

Effects of garlic on myocardial dysfunction and plasma levels of nitric oxide, C-reactive protein and leptin hormone in diabetic rats

It is now accepted that allocin, the main biologically active compound in garlic, exhibits antioxidant activity. As well, garlic has been well known for its protective effects against cardiovascular disease. Diabetes mellitus is reported to be accompanied by severe oxidative stress. Since heart disease is the leading cause of death in diabetes, this study was carried out to determine the effect of garlic supplementation on cardiac performance as well as. on the cardiac responses to Badrenergic stimulation and on plasma levels of nitric oxide [NO], C-reactive protein [CRP] and leptin hormone in streptozotocin [STZ] diabetic rats. The study was carried out on 58 adult male albino rats, allocated into 4 groups: Group 1 included non-diabetic control rats [n = 12] that received a single i.p. injection of citrate buffer, in a volume equal to that used as solvent for STZ used to induce diabetes in the test groups. Group 2 included nondiabetic garlic-treated rats [n = 14], which were injected i.p. with garlic in a dose of 200 mg/kg/day, 6 days/week, for 1 month. Group 3 included diabetic rats [n = 15], diabetes being induced by a single i.p. injection of STZ in a dose of 40 mg/kg. Group 4 included diabetic garlic-treated rats [n = 17], that received a single dose of STZ as in group: and then treated with garlic in a dose of 200 mg/kg/day, given i.p., 6 days/week for 1 month. On the day of sacrifice, blood samples were taken from the aorta for estimation of plasma glucose, nitrate, CRP and leptin levels. Thereafter, the hearts were excised and subjected to in vitro cardiac studies to demonstrate the response of isolated hearts to isoproterenol [ISU] infusion. Hearts isolated from diabetic rats showed impairment of both intrinsic chronotropic and inotropic functions as shown by the diminished spontaneous beating rate [BR], peak developed tension [PT] and myocardial flow rate [MFR] together with prolonged time to peak tension [TPT]. Their response to the different doses of ISU stimulation was also diminished. Further, diabetes was found to be associated with increased plasma glucose, nitrate and CRP, with non significant change in plasma leptin level. Garlic administration to diabetic rats enhanced chronotropy, evidenced by increased BR, as well as inotropy as shown by the shortening of TPT. Garlic also caused significant reduction in blood glucose levels indicating its hypoglycemic effect, together with reduction of the elevated nitrate and CRP levels, yet no effect on leptin was detected. It can be concluded from the present study that diabetes caused impairment of cardiac functions, both basal and in response to ISU infusion. Moreover, the inflammatory effect of diabetes was manifested by the increase in CRP, whereas the high level of NO could be attributed to the oxidative stress induced iNOS activation. Garlic supplementation antagonized the diabetic adverse effects on cardiac functions through its cardioprotective, hypoglycemic, anti-inflammatory and antioxidant effects

Hematological and cardiac effects of excess zinc in rats

In this work administration of zinc sulphate at a dose of 20 mg/kg/day. 6 days/week for 4 successive weeks, resulted in significant decrease in RBCs count, hemoglobin content, hematocrit value and mean corpuscular hemoglobin concentration in zinc treated group compared to control group. Biochemical studies showed significant decrease in plasma triglyceride, and malondialdehyde levels in zinc treated group compared to control group. However, non significant difference was found between the two groups as regards plasma zinc level. ECG study demonstrated significant increase in heart rate [HR] in zinc treated group compared to control group. This was accompanied by shortening of QRS and prolongation in Q-Tc durations in zinc treated group compared to control group. In vitro study of isolated hearts perfused in a Langendorff preparation, significant increase in basal HR was shown in zinc treated group compared to control group. The maximal HR upon isoproterenol infusion [ISU], when expressed as percentage ratio from baseline values, showed significant decrease in zinc treated group compared to control group. As regards baseline peak tension [PT] and peak tension/left ventricular weight [PT/LV,], significant increase was found in zinc treated group compared to control group. Also, the PT maximal response upon ISU infusion, either absolute or upon correction of left ventricular weight, showed significant increase in zinc treated group. Significant shortening in baseline time to peak tension [TPT] and half relaxation time [l/2RT,] were noticed in zinc treated group compared to control group. However, basal myocardial flow rate [MFR] as well as MFR/L V showed non significant difference between the 2 studied groups. Post ischemic reperfusion responses showed non significant difference as regards HR between the 2 studied groups. The recovery of PT and PT/LV were significantly higher at 20, 25, and 30 minutes of reperfusion in zinc treated group compared to control group. As regard TPT reperfusion values, significant prolongation at 10 minute was noticed in zinc treated group compared to control group. However 1/2RT, MFR and MFR/LV reperfusion values, non significant differences were recorded between the two studied groups. From this study, it can be concluded that zinc administration at a dose of 20 mg/kg/day for 4 successive weeks, has a protective effect against the risk of atherosclerosis and oxidative stress in vivo. Also, zinc treatment maintained or even enhanced the intrinsic cardiac functions, both chronotropic and inotropic, and their responses to B-adrenergic stimulation. In addition, zinc proved to be a beneficial cardioprotective agent as it attenuated the detrimental effects of post-ischemia reperfusion on the myocardial contractility

Effect of vitamin E supplementation on cardiovascular function and structure in subtotal nephrectomized rats and on the progression of renal failure

Cardiovascular disease is the most common cause of premature death in patients with end stage renal disease, possibly due to a specific [uremic cardiomyopathy]. Furthermore, uremia is a state of increased oxidative stress. Thus, this study was designed to determine whether alpha-tocopherol [a known anti-oxidant] can interfere with the development of abnormal cardiovascullar function and structure in subtotal nephrectomized [STNx] rats, and whether it can modulate progression of renal failure after its supplementation to STNx rats. Thirty two male albino rats were subjected to partial renal ablation [subtotal nephrectomy; STNx], or to sham operation [n = 11]. STNx rats were either left untreated [n = 11], or received the antioxidant alpha-tocopherol at a dose of 200 mg/Kg body weight/day, orally [n = 10]. This study was terminated after 12 weeks from the renal ablation, blood pressure was measured, blood samples were collected for estimation of hemoglobin level, plasma malondialdehyde, creatinine and blood urea nitrogen levels. Then, followed by ischemia reperfusion of isolated hearts, the weights of whole heart and left ventricle were estimated. The hearts, kidneys, and aortae were subjected to histopathological examinations. Results of the present study showed significant elevation in blood pressure in untreated STNx group compared to treated STNx group, and to sham-operated group [149 +/- 7.6 versus 106 +/- 4.3 and 111 +/- 6.2 mmHg, respectively]. In vitro study of isolated hearts perfused in a Langendorff preparation showed a significant reduction in baseline peak tensions [PT] in untreated and treated STNx group compared to sham-operated group [9.5 +/- 0.9] and 10.4 +/- 1.2 versus 15.2 +/- 1.6 g. respectively]. Also, a significant prolongation of baseline time to peak tensions [TPT] in untreated and treated STNx group were, shown compared to sham-operated group [82 +/- 7.4 and 72 +/- 6.1 versus 40 +/- 3.0 msec, respectively]. In addition, untreated STNx group showed significant decrease in baseline myocardial flow rate in comparison to sham-operated group. After ischemia and reperfusion, heart rate [HR] recovery at 30 minute of reperfusion in untreated STNx group was worse than that in sham-operated group. As well peak developed tension, time to peak tension and myocardial flow rate recoveries at 30 minute of reperfusion in untreated STNx group were worse compared to sham operated group, and to treated STNx group. Biochemical studies confirmed that there were significant elevation in plasma malondialdehyde, creatinine and blood urea nitrogen levels in untreated STNx group compared to treated STNx group [5.5 +/- 0.38 versus 3.5 +/- 0.29 umol/L], [1.6 +/- 0.1 versus 0.7 +/- 0.05 mg/dl], [49.2 +/- 3.0 versus 26.3 +/- 1.7 mg/dl, respectively]. In addition, untreated STNx group showed significant reduction in hemoglobin level compared to treated STNx group and to sham-operated group [8.3 +/- 0.5 versus 10.4 +/- 0.8 and 11.9 +/- 0.3 g%, respectively]. Histopathological examinations showed glomerulosclerosis and thick basement membrane in remnant kidney models in untreated STNx group, also thick aortic intima with left ventricular hypertrophy were also observed in untreated STNx rats, events inhibited by vitamin E administration to STNx rats

Estrogen replacement therapy in OVX-STNx rats and its nephroprotective role against progression of renal failure

Inspite of estrogen replacement therapy being extensively used in clinical and experimental studies without renal impairment, there are no long-term studies concerning estrogen replacement in chronic renal failure. This study was performed to explore whether estrogen has a nephroprotective role against progression of renal failure. This study was carried out on 41 adult female albino rats, that were allocated into 3 groups; Group 1 [n = 10] sham-operated rats, that received the solvent [sesame oil] and used as control group, Group II [n = 17], ovariectomized-subtotal nephrectomized rats [OVX-STNx] without treatment, that received the solvent, group III [n = 14], OVX-STNx rats treated with estrogen, subcutaneous [s.c.] at a dose of 30 micro g/kg/day for 10 weeks, started on the second day after ovariectomy. Mean Blood pressure was measured on the day of sacrifice. Blood urea nitrogen [BUN], serum creatinine, malondialdehyde [MDA] and platelet aggregation were estimated. Kidneys were excised and examined histologically. The results of the present study showed that untreated OVX-STNx rats showed significant elevation in mean blood pressure compared to treated OVX-STNx rats [129 +/- 2.2 versus 97 +/- 3.2 mmHg]. The untreated OVX-STNx rats showed significant elevation in BUN and serum creatinine levels compared to sham-operated rats [85.9 +/- 4.0 versus 19.4 +/- 1.6 mg/dl; and 2.6 +/- 0.13 versus 0.16 +/- 0.02 mg/dl, respectively], while, the treated OVX-STNx group showed significant reduction in BUN and serum creatinine levels, compared to untreated OVX-STNx group [24.8 +/- 1.6 versus 85.9 +/- 4.0 mg/dl; and 0.38 +/- 0.04 versus 2.6 +/- 0.13 mg/dl, respectively]. In addition, serum MDA level was elevated in untreated OVX-STNx group compared to sham-operated and to treated group [6.6 +/- 0.4 versus 3.6 +/- 0.3 and 4.8 +/- 0.3 /micro mol/L, respectively]. Also, ADP-stimulated platelet aggregation showed significant reduction in untreated OVX-STNx group in comparison to sham-operated and to treated group [46.8% +/- 2.6 versus 76.5% +/- 1.8 and 65.1% +/- 3.6 respectively]. Histological examination of the remnant kidney models in untreated OVX-STNx group showed a picture of focal glomerulosclerosis, this finding was minimally seen in treated OVX-STNx group

Differential effects of vitamin E supplementation on cardiovascular risk factors and on cardiac vulnerability to ischemia and reperfusion in rats

The present study was performed to examine the effects of vitamin E on hemodynamics, electrocardiogram [ECG] pattern, plasma levels of lipid profile, enzymes reflecting myocardial cell integrity creatine kinase [CK] and lactate dehydrogenase [LDH] and rate of lipid peroxidation as well as on myocardial performance after ischemia-reperfusion injury in isolated rat hearts. Vitamin E-treated rats were injected with vitamin E in a dose of 4 mg/100g body weight [b.w.] daily, for 6 consecutive days. Control rats were treated with vitamin E-solvent, daily, for the same duration. Then, rats were sacrificed, and the isolated heart were subjected to 30 min. ischemia followed by 30 min period of reperfusion. The present study demonstrated that administration of vitamin E in normal rats did not produce any appreciable hemodynamic effects as regards heart rate [HR], mean arterial pressure [MAP,], and pressure rate product[PRP]. The ECG pattern showed no arrhythmias or ischemic changes compared to control group. Concerning changes in plasma lipid profile, vitamin E-treated rats showed significant reduction in both total cholesterol [TC], and low density lipoprotein-cholesterol [LDL-C] Moreover, high density lipoprotein-cholesterol / total cholesterol [HDL-C/TC] was significantly elevated, in contrast to a non significant decrease in both low density lipoprotein-cholesterol/ total cholesterol [LDL-C /TC] and LDL-C /HDL-C ratios, when compared with controls. Myocardial cellular integrity, estimated by the plasma level of CK and LDH, was preserved by the administration of vitamin E, revealed evidently by the significant decrease in CK and LDH release in plasma of rats treated with vitamin E as compared to control rats. Moreover, the plasma level of malondialdehyde, as an index for the degree of lipid peroxidation, was significantly reduced. The preischemic, baseline activity of the isolated hearts obtained from rats treated with vitamin E, revealed non significant changes in myocardial inotropy except for prolongation of half relaxation time. Also there was a significant reduction in both heart rate and LDH release in the coronary effluent, while there was a non significant change in tile coronary flow rate. The results of the isolated hearts subjected to reperfusion following 30 minutes ischemic period, showed that vitamin E decreased the detrimental effect of reperfusion on the inotropic activity observed in the control group, evident by superior recovery of postischemic reperfusion myocardial functions. Manifested by elevated peak developed tension, and tension generation per unit time, concomitant with shortening of time to peak tension, and half relaxation time, along the reperfusion period. In addition, the percentage recovery of the heart rate was better during the whole reperfusion period but the difference was statistically significant only at 15-minute of reperfusion, and as well myocardial flow rate percentage .showed significant superior recovery in vitamin E-treated rat hearts. Moreover, there was a significant reduction in both CK and LDH release in the coronary effluent of vitamin E treated rat hearts, compared to control hearts. It could be concluded that vitamin E administration has a favorable potential against the risk of atherosclerosis and lipid peroxidation and as well it may attenuate the detrimental effects of postischemic reperfusion on the myocardial contractility