Makoto Nagasaka

Renal protective effects of chronic exercise and antihypertensive therapy in hypertensive rats with chronic renal failure

Objectives Patients with chronic renal failure are restricted to mild physical activity and tend to a lack of exercise. However, there have been few reports regarding the influence of chronic exercise on the progression of renal disease. Similarly, there are few animal models concerned with the effect of exercise training on improving renal function. Therefore, we assessed the renal effects of moderate chronic treadmill exercise in a remnant kidney model of spontaneously hypertensive rats (SHR) with chronic renal failure. We also assessed the effects of exercise and antihypertensive therapy on renal function. Design and methods Eight-week-old SHR were subjected to 5/6 nephrectomy by removal of the left kidney and excision of two-thirds of the right kidney. The rats were divided into four groups: (i) no exercise (Non-EX); (ii) moderate exercise with treadmill running (20 m/min, 0 grade incline for 60 min) (EX); (iii) EX with an angiotensin converting enzyme (ACE) inhibitor, enalapril (2 mg/kg per day, i.p.); and (iv) EX with an angiotensin receptor antagonist, losartan (5 mg/kg per day, i.p.), for 4 weeks. Results Chronic EX significantly attenuated the increase in proteinuria (P < 0.01) and significantly protected against increases in the index of glomerular sclerosis (IGS). Both enalapril and losartan with EX significantly decreased blood pressure (P < 0.001), and further decreased the IGS. In the stepwise multiple regression analysis, only antihypertensive drug remained in the model as a significant predictor of IGS (P < 0.0001). In contrast, exercise, antihypertensive drug and mean systolic blood pressure (weeks 1–4) remained in the model as a significant predictors of mean proteinuria (weeks 1–4) (all P < 0.0001). Conclusions These results suggest that exercise does not worsen renal function and has renal-protective effects in this model of rats. Moreover, the antihypertensive therapy has additional renal-protective effects in this model of rats.

Effect of low-voltage electrical stimulation on angiogenic growth factors in ischaemic rat skeletal muscle.

1 Low‐voltage electrical stimulation (LVES) in skeletal muscle at a level far below the threshold of muscle contraction has been reported to promote local angiogenesis. However, the mechanism underlying the promotion of local angiogenesis by LVES has not been fully elucidated. In the present study, we evaluated whether angiogenic factors, such as vascular endotherial growth factor (VEGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF), as well as other disadvantageous factors, such as inflammation (interleukin (IL)‐6) and hypoxia (hypoxia‐inducible factor (HIF)‐1α), contribute to the local angiogenesis produced by LVES. 2 We completely excised bilateral femoral arteries of male Sprague‐Dawley rats. After the operation, electrodes were implanted onto the centre of the fascia of the bilateral tibialis anterior (TA) muscles, tunnelled subcutaneously and exteriorized at the level of the scapulae. The right TA muscles of rats were stimulated continuously at a stimulus frequency of 50 Hz, with a 0.1 V stimulus strength and no interval, for 5 days. The left TA muscles served as controls. 3 We found that both VEGF and HGF protein were significantly increased by LVES in stimulated muscles compared with control. The VEGF level of the LVES group was 89.10 ± 17.19 ng/g, whereas that of the control group was 65.07 ± 12.88 ng/g, as determined by ELISA (P < 0.05). The HGF level of the LVES and control groups was 8.52 ± 1.96 and 5.80 ± 2.14 ng/g, respectively (P < 0.05). In contrast, there was no difference in FGF, IL‐6 and HIF‐1α between the LVES and control groups. 4 These results suggest that LVES in a hindlimb ischaemia model of rats increases not only VEGF, but also HGF, production, which may be the main mechanism responsible for the angiogenesis produced by LVES.

Electrical Stimulation of Skeletal Muscles

The aim of this study was to investigate whether electrical stimulation of skeletal muscles could represent a rehabilitation alternative for patients with chronic heart failure (CHF). Thirty patients with CHF and NYHA class II-III were randomly assigned to a rehabilitation program using either electrical stimulation of skeletal muscles or bicycle training. Patients in the first group (n = 15) had 8 weeks of home-based low-frequency electrical stimulation (LFES) applied simultaneously to the quadriceps and calf muscles of both legs (1 h/day for 7 days/week); patients in the second group (n = 15) underwent 8 weeks of 40 minute aerobic exercise (3 times a week). After the 8-week period significant increases in several functional parameters were observed in both groups: maximal VO2 uptake (LFES group: from 17.5 +/- 4.4 mL/kg/min to 18.3 +/- 4.2 mL/kg/min, P < 0.05; bicycle group: from 18.1 +/- 3.9 mL/kg/min to 19.3 +/- 4.1 mL/kg/min, P < 0.01), maximal workload (LFES group: from 84.3 +/- 15.2 W to 95.9 +/- 9.8 W, P < 0.05; bicycle group: from 91.2 +/- 13.4 W to 112.9 +/- 10.8 W, P < 0.01), distance walked in 6 minutes (LFES group: from 398 +/- 105 m to 435 +/- 112 m, P < 0.05; bicycle group: from 425 +/- 118 m to 483 +/- 120 m, P < 0.03), and exercise duration (LFES group: from 488 +/- 45 seconds to 568 +/- 120 seconds, P < 0.05; bicycle group: from 510 +/- 90 seconds to 611 +/- 112 seconds, P < 0.03). These results demonstrate that an improvement of exercise capacities can be achieved either by classical exercise training or by home-based electrical stimulation. LFES should be considered as a valuable alternative to classical exercise training in patients with CHF.

Effects of exercise and β-blocker on blood pressure and baroreflexes in spontaneously hypertensive rats

Abstract Background Exercise training or β-blocker decreases high blood pressure (BP) and improves abnormal baroreflex function associated with hypertension. This study was undertaken to examine whether the effects of exercise training are additive to β-blocker in spontaneously hypertensive rats (SHR). Methods At 5 weeks of age, SHR were allocated to four groups: sedentary control, exercise training, treatment with moderate dose of bisoprolol, and their combination. Systolic BP was monitored by the tail-cuff method under restrained conditions. Sigmoidal mean arterial pressure (MAP)–heart rate (HR) reflex curves were obtained in rats at 17 weeks of age under quiet conditions before and after atenolol to ensure sympathetic blockade and to determine the vagal component of gain. After studying baroreflex function, intrinsic HR was obtained by additional administration of atropine. Results Before atenolol, both exercise training alone and bisoprolol alone lowered resting MAP and HR, and decreased upper plateau (maximal tachycardia) and lower plateau (maximal bradycardia), resulting in decreased sympathetic component of HR range (upper plateau − intrinsic HR) and increased vagal component of HR range (intrinsic HR − lower plateau). After atenolol, both exercise training alone and bisoprolol alone increased the gain of vagal component. Exercise training had no additive effect on any parameters to bisoprolol except for systolic BP and HR measured by the tail-cuff method. Conclusions Exercise training and bisoprolol have similar effects concerning resting hemodynamics and baroreflex function in SHR. Although additive effects of exercise training to bisoprolol are not evident under quiet, nonstressful conditions, some additive effects may be obtained under stress such as restrain.

Effects of angiotensin-converting enzyme inhibitor and exercise training on exercise capacity and skeletal muscle.

Objective Physical fitness is closely related with cardiovascular health. We examined the effects of angiotensin-converting enzyme inhibitor, exercise training and their combination on exercise capacity as well as skeletal muscle fiber type and capillarity in spontaneously hypertensive rats (SHR). Methods Seven-week-old male SHR were allocated to four groups: sedentary control (C), treatment with perindopril (3 mg/kg per day) (Per), exercise training on a treadmill (EX), and their combination (Per + EX). Following 8-week interventions, rats were submitted to a stepwise exercise test on a treadmill. After experiments, fiber type and capillarity in soleus muscle were examined. Results Exercise capacity significantly increased in Per compared with in C. Combination of exercise training and perindopril further increased exercise capacity compared with perindopril alone, whereas there was no significant difference in exercise capacity between EX and Per + EX. Capillary density increased similarly in Per and EX compared with in C. Combination of exercise training and perindopril further increased capillary density compared with exercise training alone. The percentage of type I fiber increased only in Per + EX. Conclusions We found that in growing SHR, chronic treatment with perindopril enhances untrained exercise capacity, while it does not affect acquired exercise capacity as a result of exercise training. We also found that perindopril promotes adaptive changes of skeletal muscle in response to exercise such as increases in capillary density and percentage of type I fiber.

Effects of Estradiol, Angiotensin-Converting Enzyme Inhibitor and Exercise Training on Exercise Capacity and Skeletal Muscle in Old Female Rats

Physical fitness is closely related to cardiovascular health. We examined the effects of estradiol, angiotensin-converting enzyme inhibitor, exercise training, and their combination on exercise capacity as well as skeletal muscle fiber type and capillarity in old female rats. Twelve-month-old female Wistar-Kyoto rats were allocated to six groups: control (C), treatment with 17 beta-estradiol (0.025 mg/kg/dose, i.p. twice a week) (Est), perindopril (2 mg/kg/day) (Per), exercise training on a treadmill (15 m/min, 10 grade incline, 60 min/day, 5 days/week) (Exe), and combinations of a drug and exercise training (Exe+Est and Exe+Per). Following 6-month interventions, the rats were submitted to a stepwise exercise test on a treadmill. Moreover, fiber type and capillarity in both the soleus and gastrocnemius muscles were examined. Exercise capacity, capillary density, and the percentage of type I fiber significantly increased in Exe, Exe+Est, and Exe+Per compared to C. There were no significant differences in exercise capacity, capillary density, and percentage of type I fiber among C, Est, and Per. The combination of exercise training and perindopril further increased capillary density in both the soleus and gastrocnemius muscles, and the percentage of type I fiber in the gastrocnemius muscle compared to exercise training alone. We found that in old female rats, chronic treatment with estradiol or perindopril affected neither untrained exercise capacity nor exercise capacity acquired as a result of exercise training. However, we found that perindopril promotes adaptive changes of skeletal muscle in response to exercise such as increases in capillary density and the percentage of type I fiber.

Effects of antihypertensive drugs and exercise training on insulin sensitivity in spontaneously hypertensive rats.

We examined the effects of antihypertensive drugs, exercise training, and combinations thereof on insulin sensitivity (IS), and the association between this relation and sympathetic activity, muscle fiber composition, and capillary density in spontaneously hypertensive rats (SHR). Six-week-old male SHR were allocated to 7 groups: a control group (C), and groups treated with azelnidipine (Aze) (a calcium channel blocker), olmesartan (Olm) (an angiotensin II type 1 receptor blocker), exercise training (Exe), and combinations of drugs and exercise training (Aze+Exe, Olm+Exe, and Olm+Aze+Exe). At age 18 weeks, IS and sympathetic activity were evaluated by an euglycemic hyperinsulinemic glucose clamp technique and power spectral analysis of systolic blood pressure, respectively. After the experiments, capillary density and muscle fiber composition in soleus muscle were examined. Aze or Exe alone significantly increased IS associated with a significant reduction in sympathetic activity. Olm alone tended to increase IS with little change in sympathetic activity. Aze, Olm, or Exe significantly increased the capillary density and percentage of insulin-sensitive type I fiber. A combination of Aze and Exe or a combination of Olm and Exe tended to increase IS compared with each drug therapy alone. There were significant correlations between IS and sympathetic activity, capillary density, and the percentage of type I fiber in all the rats. We found that Aze improved IS more substantially compared with Olm in SHR. We also found that Aze, Olm, Exe, and combinations thereof improved IS, probably through the modulation of sympathetic activity or capillarity and muscle fiber type in skeletal muscles.

Mechanism behind Augmentation in Baroreflex Sensitivity after Acute Exercise in Spontaneously Hypertensive Rats

A single bout of dynamic exercise increases baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR). We examined whether change in hemodynamics (increases in blood pressure and heart rate) associated with dynamic exercise contribute to the post-exercise modulation of BRS. SHR aged 12 weeks were chronically instrumented with a carotid artery catheter and jugular vein catheter. They were then allocated to three groups submitted to 40 min of 1) running on a treadmill at 12 m/min (Run), 2) concomitant infusion of isoproterenol and a relatively high dose of phenylephrine (Iso+Phe(high)), or 3) concomitant infusion of isoproterenol and a relatively low dose of phenylephrine (Iso+Phe(low)). Arterial pressure and heart rate were continuously recorded throughout the experiments. BRS estimated by heart rate responses to phenylephrine injection and systolic blood pressure–low frequency power amplitude (SBP-LFamp) evaluated by power spectral analysis of SBP, a marker of sympathetic activity, were examined before and after running (Run group), or administration of drugs (Iso+Phe(high) or Iso+Phe(low) groups). BRS increased significantly from 1.4 to 1.9 bpm/mmHg after running, but not after administration of Iso+Phe(high) or Iso+Phe(low). Blood pressure and SBP-LFamp significantly decreased in each of the Run, Iso+Phe(high) and Iso+Phe(low) groups. These results suggest that hemodynamic change alone does not contribute to post-exercise modulation of BRS, while hemodynamic change or sympathetic activation during exercise contributes to post-exercise hypotension associated with a reduction of sympathetic activity.

EFFECT OF HIGH-SALT DIET OR CHRONIC CAPTOPRIL TREATMENT ON EXERCISE CAPACITY IN NORMOTENSIVE RATS

1. We investigated whether chronic suppression of the renin–angiotensin system, which is known to be associated with reductions in microvascular density and vasodilator responsiveness of skeletal muscle, could affect exercise capacity in normotensive rats.

Renal-protective effect of nondepressor dose of cicletanine in diabetic rats with hypertension.

We assessed the renal and cardiac benefits of cicletanine (CIC), a furopyridine derivative drug with diuretic and antihypertensive properties, in diabetic spontaneously hypertensive rats with renal impairment. Uninephrectomized streptozotocin (STZ)-diabetic spontaneously hypertensive Izmo rats (SHRIzm) (10 weeks old) were randomly assigned to receive vehicle or CIC (100 mg/kg/day, orally), and age-matched, uninephrectomized STZ diabetic Wistar-Kyoto Izmo rats (WKYIzm) were assigned to receive vehicle for up to 12 weeks. Blood pressure increased progressively in diabetic SHRIzm but not in diabetic WKYIzm. Urinary albumin excretion increased significantly in both diabetic SHRIzm and diabetic WKYIzm throughout the experiment. The antihypertensive effect of CIC was not significantly observed in diabetic SHRIzm. However, the subdepressor doses of CIC significantly decreased urinary albumin excretion, serum creatinine, and blood urea nitrogen in diabetic SHRIzm. These results were confirmed by morphological analysis of kidneys in each group of rats. The index of focal glomerular sclerosis (FGS) in diabetic SHRIzm was significantly higher than that in diabetic WKYIzm. The CIC treatment significantly and effectively protected against an increase in the index of FGS in diabetic SHRIzm. Moreover, CIC treatment significantly attenuated the increase in the heart weight to body weight ratio in diabetic SHRIzm. Treatment with CIC did not affect urinary and blood glucose concentrations at this dose. These results suggest that CIC has a renal-protective action, which is not related to improvement of diabetes or improvement of high blood pressure in diabetic rats with hypertension. The action might be due to the reduction of intraglomerular capillary pressure or protection of the renal glomerular vascular endothelial cell injury and mesangial cell injury through stimulation of PGI2 generation or elimination of free radicals, although the mechanism remains to be further investigated.