Diabetes-induced stimulation of the renin-angiotensin system in the rat brain cortex

Cerebrovascular disease is a threat to people with diabetes and hypertension. Diabetes can damage the brain by stimulating the renin-angiotensin system (RAS), leading to neurological deficits and brain strokes. Diabetes-induced components of the RAS, including angiotensin-converting enzyme (ACE), angiotensin-II (Ang-II), and angiotensin type 1 receptor (AT1R), have been linked to various neurological disorders in the brain. In this study, we investigated how diabetes and high blood pressure affected the regulation of these major RAS components in the frontal cortex of the rat brain. We dissected, homogenized, and processed the brain cortex tissues of control, streptozotocin-induced diabetic, spontaneously hypertensive (SHR), and streptozotocin-induced SHR rats for biochemical and Western blot analyses. We found that systolic blood pressure was elevated in SHR rats, but there was no significant difference between SHR and diabetic-SHR rats. In contrast to SHR rats, the heartbeat of diabetic SHR rats was low. Western blot analysis showed that the frontal cortexes of the brain expressed angiotensinogen, AT1R, and MAS receptor. There were no significant differences in angiotensinogen levels across the rat groups. However, the AT1R level was increased in diabetic and hypertensive rats compared to controls, whereas the MAS receptor was downregulated (p < 0.05). These findings suggest that RAS overactivation caused by diabetes may have negative consequences for the brain's cortex, leading to neurodegeneration and cognitive impairment.     

Chronic low-sodium diet in rats: responses to severe heat exposure

To determine the effects of sodium (Na+) deficiency on the responses to severe heat stress (35.5 degrees C), immature (mean wt 150.4 g) male rats (n = 21) were fed a low-Na+ diet for 71 days. Rates of weight gain and food consumption were significantly (P less than 0.001) reduced in the low-Na+ group, whereas water consumption was unaffected. Prior to heat exposure circulating Na+ levels were unaffected by dietary Na+ restriction, but both circulating potassium (K+) and hematocrit levels were significantly (P less than 0.001) increased. After 24-h exposure to severe heat stress, circulating Na+ levels did manifest a significant (P less than 0.001) decrement in the low-Na+ group. K+ levels increased significantly (P less than 0.01) in the control group after 6 h of heat exposure but remained depressed in comparison with the low-Na+ group after 48 and 72 h. Although plasma renin activity (PRA) was not increased by chronic consumption of the low-Na+ diet or by severe heat exposure in the control group, severe heat stress in the low-Na+ group did elicit significant (P less than 0.005) increments in PRA after 24 h of exposure. Alternatively, plasma aldosterone levels were significantly (P less than 0.001) elevated by both the low-Na+ diet and heat stress. We concluded from these studies that chronic consumption of the low-Na+ diet had severe effects on hematologic, endocrinological, and thermoregulatory variables as well as thermal sensitivity to prolonged and sedentary exposure to severe heat stress.     

肾脏中肾素-血管紧张素系统的生理和病理生理作用

肾脏中肾素-血管紧张素系统(RAS)在肾脏生理功能的调节中有重要作用.近年来,肾脏RAS的新成分及新作用机制不断被发现.转基因动物研究使肾脏血管紧张素Ⅱ(AngⅡ)在血压及水钠平衡调节中的作用进一步阐明;AngⅡ的非血流动力学作用已经确立;血管紧张素转换酶2(ACE2)及Ang 1～7对肾功能的调节作用也已得到认可.肾素/前肾素特异性受体、ACE的信号转导功能,以及AT1受体的转激活功能等,已成为肾脏生理科学研究的热点.这些研究对于人们认识肾脏局部RAS功能,探讨延缓慢性肾脏病的进展的治疗策略具有重要意义.     

Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet

Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat. ET and its receptors are present in sensory nerves. Therefore, we examined whether ET receptor blockade altered the responsiveness of the renal sensory nerves. In anesthetized rats fed high-sodium diet, renal pelvic administration of the ETBR antagonist BQ-788 reduced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mmHg from 26+/-3 to 9+/-3% and the PGE2-mediated renal pelvic release of substance P from 9+/-1 to 3+/-1 pg/min. Conversely, in rats fed low-sodium diet, renal pelvic administration of the ETAR antagonist BQ-123 enhanced the ARNA response to increased renal pelvic pressure from 9+/-2 to 23+/-6% and the PGE2-mediated renal pelvic release of substance P from 0+/-0 to 6+/-1 pg/min. Adding the ETAR antagonist to ETBR-blocked renal pelvises restored the responsiveness of renal sensory nerves in rats fed a high-sodium diet. Adding the ETBR antagonist to ETAR-blocked pelvises suppressed the responsiveness of the renal sensory nerves in rats fed a low-sodium diet. In conclusion, activation of ETBR and ETAR contributes to the enhanced and suppressed responsiveness of renal sensory nerves in conditions of high- and low-sodium dietary intake, respectively. Impaired renorenal reflexes may contribute to the salt-sensitive hypertension in the ETBR-deficient rat.     

Analysis of the renin-angiotensin system during fasting in adult male rabbits.

Caloric deprivation for 3 days in adult male rabbits induced significant increases in daily urinary Na+ excretion, urinary volume and fluid intake as previously reported. These changes were accompanied by: (a) a significant reduction in plasma renin concentration; (b) an unchanged plasma renin activity; (c) a marked increase in the plasma angiotensinogen concentration; (d) a significant reduction in plasma angiotensin I; and (e) a significant increase in plasma angiotensin II. In a separate group of adult male rabbits, 3 days of caloric deprivation significantly increased the amount of converting enzyme in pulmonary parenchymal tissue. These findings correlate with the previously reported enhancement of mineralocortical hormone secretion and limiting effect of the latter on the natriuresis of caloric withdrawal. Since the increased mineralocortical hormone secretion does not prevent the natriuresis, the possibility that these striking changes in the components of the renin-angiotensin system during caloric deprivation may exert intrarenal effects is discussed.     

Cardiovascular effects of static carotid baroreceptor stimulation during water immersion in humans

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (-22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 +/- 1 mmHg, P < 0.05) and less during WI + NS (4 +/- 1 mmHg) and NS (3 +/- 1 mmHg). The decrease in heart rate (HR) by 13 +/- 1 beats/min (P < 0.05) and the increase in arterial pulse pressure (PP) by 17 +/- 4 mmHg (P < 0.05) during supine was more pronounced (P < 0.05) than during WI + NS (10 +/- 2 beats/min and 7 +/- 2 mmHg, respectively) and WI (8 +/- 2 beats/min and 6 +/- 1 mmHg, respectively, P < 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephrine, in addition, decreased during WI + NS (P < 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change.     

Role of the renin-angiotensin system during alterations of sodium intake in conscious mice

The present studies were performed to quantify circulating components of the renin-angiotensin-aldosterone axis and to determine the functional importance of this system during alterations in sodium intake in conscious mice. Increasing sodium intake from approximately 200 to 1,000 microeq/day significantly decreased plasma renin concentration from 472 +/- 96 to 304 +/- 83 ng ANG I. ml(-1). h(-1) (n = 5) but did not alter plasma renin activity from the low-sodium level of 7.7 +/- 1.1 ng ANG I. ml(-1). h(-1). Despite the elevated plasma renin concentration, plasma ANG II in mice on low-sodium level averaged 14 +/- 3 pg/ml and was significantly suppressed to 6 +/- 1 pg/ml by high-sodium intake (n = 7). Consistent with the modulation of ANG II, plasma aldosterone significantly decreased from 41 +/- 8 to 8 +/- 3 ng/dl when sodium intake was elevated (n = 6). In a final set of experiments, the continuous infusion of ANG II (20 ng. kg(-1). min(-1)) led to a mild salt-sensitive increase in mean arterial pressure from 108 +/- 2 to 131 +/- 2 mmHg as sodium intake was varied from low to high (n = 7). In vehicle-infused mice, mean arterial pressure was unaltered from 109 +/- 2 mmHg when sodium intake was increased (n = 6). These studies indicate that the physiological suppression of circulating ANG II may be required to maintain a constancy of arterial pressure during alterations in sodium intake in normal mice.     

Venous responses during exercise in rainbow trout, Oncorhynchus mykiss: alpha-adrenergic control and the antihypotensive function of the renin-angiotensin system

The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of venous function during exercise in rainbow trout. It is also the first study to suggest that the RAS may be an important modulator of venous pressure and capacitance in fish.     

Changes in late components of somatosensory evoked potentials in humans during repetitive stimulation

Human evoked potentials to somatosensory stimuli of non-painful and painful intensity recorded from the vertex have been studied. The indices of variability of N150 and P250 components registered in the same subject as well as indices of interrelationship between spontaneous changes of these components decreased when stimulus intensity increased. A supposition is advanced that the role of general source responsible for generations N150 and P250 components diminished when stimulus intensity increased, accordingly participation of autonomic sources became more prominent.     

Cerebrovascular and corticomotor function during progressive passive hyperthermia in humans

The present study examined the integrative effects of passive heating on cerebral perfusion and alterations in central motor drive. Eight participants underwent passive hyperthermia [0.5°C increments in core temperature (Tc) from normothermia (37 ± 0.3°C) to their limit of thermal tolerance (T-LIM; 39.0 ± 0.4°C)]. Blood flow velocity in the middle cerebral artery (CBFv) and respiratory responses were measured continuously. Arterial blood gases and blood pressure were obtained intermittently. At baseline and each Tc level, supramaximal femoral nerve stimulation and transcranial magnetic stimulation (TMS) were performed to assess neuromuscular and cortical function, respectively. At T-LIM, measures were (in a randomized order) also made during a period of breathing 5% CO(2) gas to restore eucapnia (+5% CO(2)). Mean heating time was 179 ± 51 min, with each 0.5°C increment in Tc taking 40 ± 10 min. CBFv was reduced by ～20% below baseline from +0.5°C until T-LIM. Maximal voluntary contraction (MVC) of the knee extensors was decreased at T-LIM (-9 ± 10%; P < 0.05), and cortical voluntary activation (VA), assessed by TMS, was decreased at +1.5°C and T-LIM by 11 ± 8 and 22 ± 23%, respectively (P < 0.05). Corticospinal excitability (measured as the EMG response produced by TMS) was unaltered. Reductions in cortical VA were related to changes in ventilation (Ve; R(2) = 0.76; P < 0.05) and partial pressure of end-tidal CO(2) (Pet(CO(2)); R(2) = 0.63; P < 0.05) and to changes in CBFv (R(2) = 0.61; P = 0.067). Interestingly, although CBFv was not fully restored, MVC and cortical VA were restored towards baseline values during inhalation of 5% CO(2). These results indicate that descending voluntary drive becomes progressively impaired as Tc is increased, presumably due, in part, to reductions in CBFv and to hyperthermia-induced hyperventilation and subsequent hypocapnia.