Dose-different effects of orexin-A on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats

Previous studies have demonstrated that central injection of orexin-A affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in both anesthetized and unanesthetized rats. In the present study, we examined, using urethane-anesthetized rats, the dose-dependent effects of intravenous (iv) or intralateral cerebral ventricular (LCV) injection of various doses of orexin-A on RSNA and BP. We found that injection of a low dose of orexin-A (10 ng iv or 0.01 ng LCV) suppressed RSNA and BP significantly. Conversely, a high dose (1000 ng iv or 10 ng LCV) of orexin-A elevated both RSNA and BP significantly. Pretreatment with either iv or LCV injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of orexin-A on both RSNA and BP. Both iv and LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of orexin-A on RSNA and BP. Furthermore, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of both low and high doses of orexin-A on RSNA and BP. These findings suggest that orexin-A affects RSNA and BP in a dose-dependent manner and that the SCN and histaminergic nerve may be involved in the dose-different effects of orexin-A in rats.     

Influence of pontine A5 region on renal sympathetic nerve activity in conscious rabbits

The effects of inhibiting the neural activity in the pontine A5 region on renal sympathetic responses to baroreflex and/or chemoreflex activation were examined in conscious rabbits. Eight rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the A5 area and an electrode for measuring renal sympathetic nerve activity (RSNA). Baroreflex curves were obtained under conditions of normoxia and hypoxia (10% O(2) + 3% CO(2)) after injections into the A5 region of the GABA receptor agonist muscimol or vehicle solution. Under normoxia, injections of muscimol did not affect resting RSNA or blood pressure but increased the range of the RSNA baroreflex by 24 and 33% at doses of 175 or 875 pmol, respectively, without affecting the reflex gain. Hypoxia alone increased resting RSNA by 63%, as well as the range and gain of the RSNA baroreflex by 53 and 89%, respectively, without affecting blood pressure. However, under hypoxia, muscimol increased resting RSNA by 37 and 47% but decreased the gain of the RSNA baroreflex by 19 and 34% at doses of 175 or 875 pmol, respectively, without affecting the reflex range. The effects of muscimol on RSNA were mediated via changes in the amplitude of the sympathetic bursts, whereas burst frequency remained unaffected. These data suggest that the A5 region has a little tonic influence on RSNA in conscious rabbits but serves to limit the renal sympathetic responses to baroreceptor unloading or chemoreceptor stimulation. The different changes in the baroreflex range and gain evoked by muscimol under normoxia and hypoxia indicate that the A5 modulatory action may depend on the activity of the afferent inputs to this region.     

Effects of central injection of L-carnosine on sympathetic nerve activity innervating brown adipose tissue and body temperature in rats

In the present study, using urethane-anesthetized rats, we examined the effects of intralateral cerebral ventricular (LCV) injection of various doses of L-carnosine on neural activity innervating brown adipose tissue (BAT-SNA) and body temperature (BT). We found that injection of a low dose of L-carnosine (0.01 microg) suppressed BAT-SNA significantly. Conversely, a high dose (100 microg) of L-carnosine significantly elevated BAT-SNA. In the light period (14:00), brown adipose tissue temperature (BAT-T) and BT were suppressed after low and elevated after high dose injection of L-carnosine whereas in the dark period (2:00), these parameters remained unchanged with L-carnosine treatment. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of low and high doses of L-carnosine on BAT-SNA, BAT-T and BT. Furthermore, high dose treatment with L-carnosine altered c-Fos induction in the SCN and the PVN. These results suggest that l-carnosine affects BAT-SNA, BAT-T and BT in a dose-dependent manner in the rat, and that the SCN may be involved in these effects.     

Effect of blockade of endogenous angiotensin II on baroreflex function in conscious diabetic rats

Little is known about baroreflex control of renal nerve sympathetic activity (RSNA) or the effect of angiotensin II (ANG II) on the baroreflex in diabetes. We examined baroreflex control of RSNA and heart rate (HR) in conscious, chronically instrumented rats 2 wk after citrate vehicle (normal) or 55 mg/kg iv streptozotocin (diabetic) before and after losartan (5 mg/kg iv) or enalapril (2.5 mg/kg iv). Resting HR and RSNA were lower in diabetic versus normal rats. The range of baroreflex control of HR and the gain of baroreflex-mediated bradycardia were impaired in diabetic rats. Maximum gain was unchanged. The baroreflex control of RSNA was reset to lower pressures in the diabetic rats but remained otherwise unchanged. Losartan decreased mean arterial pressure (MAP) and increased HR and RSNA in both groups but had no influence on the baroreflex. Enalapril decreased MAP only in normal rats, yet the increase in HR and RSNA was similar in both groups. Thus in diabetic rats enalapril produced a pressure-independent increase in HR and RSNA. Enalapril exerted no effect on the baroreflex control of HR or RSNA in either group. These data indicate that in conscious rats resting RSNA is lower but baroreflex control of RSNA is preserved after 2 wk of diabetes. At this time, the baroreflex control of HR is already impaired and blockade of endogenous ANG II does not improve this dysfunction.     

颈动脉内注入腺苷对呼吸,血压和肾交感神经活动的影响

在33只麻醉家兔,观察了颈动脉内注入腺苷所诱发的平均动脉压、心率,呼吸和肾交感神经活动的变化。结果如下:(1)颈动脉内注入腺苷后,平均动脉压呈剂量依赖性下降;呼吸加快,深度变化不明显,剪断窦神经后注入腺苷,仍引起平均动脉压下降,而呼吸变化消失。(2)隔离的颈动脉窦灌流液内加入腺苷后,平均动脉压下降,心率减慢;颈动脉体(CB)失活后反应消失。(3)将腺苷灌注到颈动脉窦区后,平均动脉压下降,肾交感神经传出放电活动增加,CB 失活或剪断窦神经后,反应消失。由此提示:腺苷可作为兴奋 CB 的一种物质,引起平均动脉压降低,心率减慢,呼吸加强和肾交感神经放电活动增加。     

最后区微量注射辣椒素对大鼠血压、心率和肾交感神经放电的影响

在36只麻醉Sprague-Dawley大鼠, 观察了最后区内微量注射辣椒素(10 μmol/L, 50 nl)对平均动脉压(MAP)、心率(HR)和肾交感神经放电(RSNA)的影响.实验结果如下:(1)最后区内注射辣椒素可引起 MAP、HR 和RSNA明显增加, 分别由12.34±0.53 kPa、 328.52±7.54 bpm 和100±0% 增至15.17±0.25 kPa (P<0.001)、 354.81±8.54 bpm (P<0.001) 和156.95±7.57% (P<0.001);(2) 静脉注射辣椒素受体阻断剂钌红(100 mmol/L, 0.2 ml) 后, 辣椒素的上述效应可被明显抑制;(3) 预先应用NMDA 受体阻断剂MK-801 (500 μg/kg, 0.2 ml, iv)也明显抑制辣椒素的兴奋效应.以上结果提示, 最后区微量注射辣椒素对血压、心率和肾交感神经放电有兴奋作用, 而此作用由辣椒素受体介导并有谷氨酸参与.     

Effects of disinhibition of neurons in the dorsomedial hypothalamus on central respiratory drive

Neurons within the dorsomedial hypothalamus (DMH) play a critical role in subserving the cardiovascular and neuroendocrine response to psychological stress. An increase in respiratory activity is also a characteristic feature of the physiological response to psychological stress, but there have been few studies of the role of DMH neurons in regulating respiratory activity. In this study we determined the effects of activation of DMH neurons on respiratory activity (assessed by measuring phrenic nerve activity, PNA) and the relationship between evoked changes in respiratory activity and changes in sympathetic vasomotor activity in spontaneously breathing urethane-anesthetized rats. Microinjections of bicuculline (4-40 pmol in 20 nl) into the DMH evoked dose-dependent increases in PNA burst frequency and amplitude. These were accompanied by dose-dependent decreases in mean tracheal CO(2) levels, indicative of hyperventilation. In control experiments, microinjections of bicuculline into sites adjacent to the DMH evoked much smaller or no changes in PNA. In experiments where renal sympathetic nerve activity (RSNA) was also measured, cycle-triggered averaging revealed that RSNA under resting conditions was partly correlated with the PNA, but in response to DMH disinhibition there was no consistent change in the amplitude of the respiratory-related variations in RSNA. The results indicate that DMH neurons can exert a powerful stimulatory effect on respiratory activity, causing hyperventilation. This is not associated with an increase in the degree of coupling between PNA and RSNA, indicating that the DMH-evoked increase in RSNA is not a consequence of increased central respiratory drive.     

最后区注射腺苷对大鼠血压、心率和肾交感神经放电的影响

在 5 3只麻醉Sprague Dawley大鼠观察了最后区内微量注射腺苷 (1ng/ 6 0nl)对平均动脉压 (MAP)、心率(HR)和肾交感神经放电 (RSNA)的影响。实验结果如下 :(1)最后区内微量注射Ado后 ,MAP、HR和RSNA分别由13 76± 0 46kPa、35 6 2 8± 4 2 5bpm和 10 0± 0 %下降至 11 2 3± 0 49kPa (P <0 0 0 1)、336 91± 5 2 3bpm (P <0 0 1)和70 95± 5 19% (P <0 0 0 1) ;(2 )静脉注射非选择性腺苷受体拮抗剂 8 苯茶碱 (8 phenyltheophylline,15 0 μg/kg ,0 2ml)和选择性腺苷A1受体拮抗剂 (8 cyclopentyl 1,3 dipropylxanthine,5 0 0 μg /kg ,0 2ml)后 ,腺苷的上述抑制效应可被完全阻断 ;(3)静脉注射ATP敏感性钾通道阻断剂格列苯脲 (5mg/kg ,0 2ml)后 ,腺苷的上述效应也被消除。以上结果提示 ,最后区微量注射腺苷对血压、心率和肾交感神经放电有抑制作用 ,此作用与A1受体介导的ATP敏感性钾通道开放有关。     

Forebrain renin-angiotensin system has a tonic excitatory influence on renal sympathetic nerve activity

All elements of the renin-angiotensin system (RAS) are present in the forebrain, particularly in circumventricular organs surrounding the third cerebral ventricle. We tested the hypothesis that forebrain angiotensin-converting enzyme (ACE) has a tonic excitatory influence on sympathetic drive. Neurally intact and sinoaortic-denervated pentobarbital-anesthetized rats were treated with forebrain-directed intracarotid artery (ICA) versus intravenous injections of angiotensin I (ANG I) and of the ACE inhibitor captopril. In intact rats, ICA ANG I elicited a rise in arterial pressure and a concomitant reduction in renal sympathetic nerve activity (RSNA; ICA captopril elicited the opposite responses). In barodenervated rats, ICA ANG I increased and ICA captopril decreased arterial pressure and RSNA in parallel; intravenous ANG I had no effect on RSNA. The findings suggest that the intrinsic forebrain RAS has a tonic excitatory influence on sympathetic drive that is overshadowed in normal rats by baroreflex mechanisms, but may assume a more prominent role in pathophysiological states (e.g., heart failure) in which baroreflex mechanisms are impaired and RAS activity is augmented.     

最后区注射腺苷对大鼠血压,心率和肾交感神经放电影响

The effects of microinjection of adenosine (Ado) into area postrema (AP) on mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were examined in 53 anesthetized Sprague Dawley rats. The results obtained are as follows. (1) Following microinjection of Ado (1 ng/60 nl) into AP, MAP, HR and RSNA were decreased from 13.76+/-0.46 kPa, 356.28+/-4.25 bpm and 100+/-0% to 11.23+/-0.49 kPa (P<0.001), 336.91+/-5.23 bpm (P<0.01) and 70.95+/-5.19% (P<0.001), respectively; (2) 8-phenyltheophylline (150 microgram/kg, 0.2 ml,iv), a nonselective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine (500 microgram/kg, 0.2 ml, iv), a selective A(1) adenosine receptor antagonist, blocked the inhibitory effect of Ado completely; and (3) glibenclamide (5 mg/kg, 0.2 ml, iv), a blocker of ATP-sensitive potassium channel, also abolished the effect of Ado. The above results indicate that microinjection of Ado into AP induces inhibitory effects on MAP, HR and RSNA, which may be related to activation of ATP-sensitive potassium channels mediated by A(1) receptors.     

Central and peripheral administration of amylin induces energy expenditure in anesthetized rats

Amylin is a peptide hormone that is co-released with insulin from pancreatic β-cells following a meal. Intracerebroventricular (icv) administration of amylin (1–100 pmol), or an amylin agonist, salmon calcitonin, elicited dose-dependent thermogenic, tachycardic, and hyperthermic responses in urethane-anesthetized rats. Intravenous (iv) administration of higher doses of amylin (100 pmol–20 nmol) also induced similar responses, although the amplitudes of these responses were significantly smaller than those elicited by icv administration, suggesting the primary action of amylin to be in the brain. However, the iv administration of amylin induced the responses slightly faster than the icv injection, the former responses occurring <4 min and the latter, at 8–10 min, after the administration. The iv but not the icv injection of amylin increased the respiratory exchange ratio transiently (<20 min), though the thermogenic response lasted for a longer period after both injections, indicating a shift from mixed fuel to predominantly carbohydrate utilization in the initial phase of thermogenesis induced by the iv injection of amylin. The differences in substrate utilization and latency of the responses suggest that the actions of amylin include partly different targets when administered centrally and peripherally. Moreover, pretreatment with a β-adrenergic blocker, propranolol (5 mg kg⁻¹, iv), blocked all responses elicited by either icv or iv administration of amylin, whereas ablation of the area postrema in the hindbrain did not influence the effects of icv-administered amylin. These results suggest the involvement of amylin in postprandial energy expenditure, mediated by peripheral β-adrenoceptors.     

Dose-dependent effects of L-carnosine on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats

The physiological function of L-carnosine (beta-alanyl-L-histidine) synthesized in mammalian muscles has been unclear. Previously, we observed that intravenous (i.v.) injection of L-carnosine suppressed renal sympathetic nerve activity (RSNA) in urethane-anesthetized rats, and L-carnosine administered via the diet inhibited the elevation of blood pressure (BP) in deoxycorticosterone acetate salt hypertensive rats. To identify the mechanism, we examined effects of i.v. or intralateral cerebral ventricular (l.c.v.) injection of various doses of L-carnosine on RSNA and BP in urethane-anesthetized rats. Lower doses (1 microg i.v.; 0.01 microg l.c.v.) of L-carnosine significantly suppressed RSNA and BP, whereas higher doses (100 microg i.v.; 10 microg l.c.v.) elevated RSNA and BP. Furthermore, we examined effects of antagonists of histaminergic (H1 and H3) receptors on L-carnosine-induced effects. When peripherally and centrally given, thioperamide, an H3 receptor antagonist, blocked RSNA and BP decreases induced by the lower doses of peripheral L-carnosine, whereas diphenhydramine, an H1 receptor antagonist, inhibited increases induced by the higher doses of peripheral L-carnosine. Moreover, bilateral lesions of the hypothalamic suprachiasmatic nucleus eliminated both effects on RSNA and BP induced by the lower (1 microg) and higher (100 microg) doses of peripheral L-carnosine. These findings suggest that low-dose L-carnosine suppresses and high-dose L-carnosine stimulates RSNA and BP, that the suprachiasmatic nucleus and histaminergic nerve are involved in the activities, and that L-carnosine acts in the brain and possibly other organs.     

Effect of peripheral administration of leptin on the renal sympathetic nerve activity in high-fat diet-related hypertensive rats

A previous study of ours demonstrated that a high-fat diet (FAT) causes body fat accumulation, as well as elevation of plasma leptin level, renal sympathetic nerve activity (RSNA), and blood pressure (BP). In the study reported here, we analyzed the role of leptin in these elevations of the RSNA and BP due to FAT feeding by assessing sympathetic and cardiovascular responses to intravenous (IV) administration of leptin in rats fed either a FAT or a high-carbohydrate diet (CHO). The results showed that baseline body fat, plasma leptin level, RSNA and BP were significantly higher in the FAT group than in the CHO group, and that IV administration of leptin elevated RSNA and plasma leptin levels but lowered BP in the CHO group. However, these effects of leptin were eliminated in the FAT group. These findings suggest that FAT-fed rats which expose basal elevation of plasma leptin levels, RSNA and BP might be hyposensitive to endogenous leptin. Therefore, leptin resistance appeared obviously in FAT-induced hypertension might indicate that leptin is implicated in generating the elevation of RSNA and BP induced by long-term FAT feeding.     

Stimulation of NTS A1 adenosine receptors differentially resets baroreflex control of regional sympathetic outputs

Previously we showed that pressor and differential regional sympathoexcitatory responses (adrenal > renal >/= lumbar) evoked by stimulation of A(1) adenosine receptors located in the nucleus of the solitary tract (NTS) were attenuated/abolished by baroreceptor denervation or blockade of glutamatergic transmission in the NTS, suggesting A(1) receptor-elicited inhibition of glutamatergic transmission in baroreflex pathways. Therefore we tested the hypothesis that stimulation of NTS A(1) adenosine receptors differentially inhibits/resets baroreflex responses of preganglionic adrenal (pre-ASNA), renal (RSNA), and lumbar (LSNA) sympathetic nerve activity. In urethane-chloralose-anesthetized male Sprague-Dawley rats (n = 65) we compared baroreflex-response curves (iv nitroprusside and phenylephrine) evoked before and after bilateral microinjections into the NTS of A(1) adenosine receptor agonist (N(6)-cyclopentyladenosine, CPA; 0.033-330 pmol/50 nl). CPA evoked typical dose-dependent pressor and differential sympathoexcitatory responses and similarly shifted baroreflex curves for pre-ASNA, RSNA, and LSNA toward higher mean arterial pressure (MAP) in a dose-dependent manner; the maximal shifts were 52.6 +/- 2.8, 48.0 +/- 3.6, and 56.8 +/- 6.7 mmHg for pre-ASNA, RSNA, and LSNA, respectively. These shifts were not a result of simple baroreceptor resetting because they were two to three times greater than respective increases in baseline MAP evoked by CPA. Baroreflex curves for pre-ASNA were additionally shifted upward: the maximal increases of upper and lower plateaus were 41.8 +/- 16.4% and 45.3 +/- 8.7%, respectively. Maximal gain (%/mmHg) measured before vs. after CPA increased for pre-ASNA (3.0 +/- 0.6 vs. 4.9 +/- 1.3), decreased for RSNA (4.1 +/- 0.6 vs. 2.3 +/- 0.3), and remained unaltered for LSNA (2.1 +/- 0.2 vs. 2.0 +/- 0.1). Vehicle control did not alter the baroreflex curves. We conclude that the activation of NTS A(1) adenosine receptors differentially inhibits/resets baroreflex control of regional sympathetic outputs.     

Roles of adrenomedullin 2 in regulating the cardiovascular and sympathetic nervous systems in conscious rats

Recently, a new member of the calcitonin gene-related peptide (CGRP) family, adrenomedullin 2 (AM2) or intermedin (IMD), was identified. AM2/IMD has been shown to have a vasodilator effect in mice and rats and an effect on urine formation in rats. In the present study, we investigated the effects of intravenously infused rat AM2 (rAM2) on blood pressure (BP), heart rate (HR), renal sympathetic nerve activity (RSNA), and renal blood flow (RBF) in conscious unrestrained rats relative to the effects of rat adrenomedullin (rAM) and proadrenomedullin NH2-terminal 20 peptide (rPAMP). Intravenous infusion of rAM2 (5 nmol/kg) significantly decreased BP and increased HR, RSNA, and RBF. These hypotensive and sympathoexcitatory effects diminished after 20 min, and HR returned to control levels 30 min after cessation of the infusion. In contrast, a significant increase in RBF was still evident 60 min after cessation of the peptide infusion. The duration of BP, HR, and RSNA responses was longer with rAM (5 nmol/kg) than with rAM2 infusion, whereas the increases in RBF induced by rAM2 and rAM were similar in their amplitude and duration. Infusion of rPAMP (200 nmol/kg) increased HR and RSNA but had no effect on RBF. Baroreceptor denervation suppressed, but did not diminish, the increases in HR and RSNA to rAM2. These findings indicate that the physiological roles of rAM2 and rAM are similar and that rAM2 also has a long-lasting vasodilator action on the renal vascular bed.     

Differential role of the paraventricular nucleus of the hypothalamus in modulating the sympathoexcitatory component of peripheral and central chemoreflexes

In the present study we investigated the involvement of the hypothalamic paraventricular nucleus (PVN) in the modulation of sympathoexcitatory reflex activated by peripheral and central chemoreceptors. We measured mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) before and after blocking neurotransmission within the PVN by bilateral microinjection of 2% lidocaine (100 nl) during specific stimulation of peripheral chemoreceptors by potassium cyanide (KCN, 75 microg/kg iv, bolus dose) or stimulation of central chemoreceptors with hypercapnia (10% CO(2)). Typically stimulation of peripheral chemoreceptors evoked a reflex response characterized by an increase in MAP, RSNA, and PNA and a decrease in HR. Bilateral microinjection of 2% lidocaine into the PVN had no effect on basal sympathetic and cardiorespiratory variables; however, the RSNA and PNA responses evoked by peripheral chemoreceptor stimulation were attenuated (P < 0.05). Bilateral microinjection of bicuculline (50 pmol/50 nl, n = 5) into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation (P < 0.05). Conversely, the GABA agonist muscimol (0.2 nmol/50 nl, n = 5) injected into the PVN attenuated these reflex responses (P < 0.05). Blocking neurotransmission within the PVN had no effect on the hypercapnia-induced central chemoreflex responses in carotid body denervated animals. These results suggest a selective role of the PVN in processing the sympathoexcitatory and ventilatory component of the peripheral, but not central, chemoreflex.     

Aldosterone-induced brain MAPK signaling and sympathetic excitation are angiotensin II type-1 receptor dependent

Angiotensin II (ANG II)-induced mitogen-activated protein kinase (MAPK) signaling upregulates angiotensin II type-1 receptors (AT(1)R) in hypothalamic paraventricular nucleus (PVN) and contributes to AT(1)R-mediated sympathetic excitation in heart failure. Aldosterone has similar effects to increase AT(1)R expression in the PVN and sympathetic drive. The present study was undertaken to determine whether aldosterone also activates the sympathetic nervous system via MAPK signaling and, if so, whether its effect is independent of ANG II and AT(1)R. In anesthetized rats, a 4-h intravenous infusion of aldosterone induced increases (P < 0.05) in phosphorylated (p-) p44/42 MAPK in PVN, PVN neuronal excitation, renal sympathetic nerve activity (RSNA), mean blood pressure (MBP), and heart rate (HR). Intracerebroventricular or bilateral PVN microinjection of the p44/42 MAPK inhibitor PD-98059 reduced the aldosterone-induced RSNA, HR, and MBP responses. Intracerebroventricular pretreatment (5 days earlier) with pooled small interfering RNAs targeting p44/42 MAPK reduced total and p-p44/42 MAPK, aldosterone-induced c-Fos expression in the PVN, and the aldosterone-induced increases in RSNA, HR, and MBP. Intracerebroventricular infusion of either the mineralocorticoid receptor antagonist RU-28318 or the AT(1)R antagonist losartan blocked aldosterone-induced phosphorylation of p44/42 MAPK and prevented the increases in RSNA, HR, and MBP. These data suggest that aldosterone-induced sympathetic excitation depends upon that AT(1)R-induced MAPK signaling in the brain. The short time course of this interaction suggests a nongenomic mechanism, perhaps via an aldosterone-induced transactivation of the AT(1)R as described in peripheral tissues.     

Glucocorticoid modulation of cardiovascular and autonomic function in preterm lambs: role of ANG II

The mechanisms by which antenatal glucocorticoids facilitate postnatal circulatory function in preterm infants are uncertain but may be related to augmented angiotensinergic functions. To test the hypothesis that the effects of glucocorticoids on postnatal cardiovascular and sympathetic activity are mediated via the renin-angiotensin system, we studied the effects of AT(1) receptor blockade on postnatal changes in heart rate (HR), mean arterial blood pressure (MABP), renal sympathetic nerve activity (RSNA), and baroreflex control of HR in prematurely delivered lambs. After maternal administration of betamethasone (12 mg im 48 and 24 h before delivery), chronically instrumented preterm lambs (118- to 123-day gestation, term 145 days) were studied before and after delivery by cesarean section; fetuses received either the AT(1) receptor antagonist losartan (10 mg iv, n = 6) or saline (n = 6) 1 h before delivery. A third group of animals (n = 6) received losartan without prior exposure to betamethasone. Compared with fetal values, betamethasone-treated animals demonstrated significant increases (P < 0.05) in MABP (47 +/- 2 to 58 +/- 2 mmHg) and RSNA (181 +/- 80% of fetal value) 1 h after delivery. Betamethasone + losartan-treated lambs also displayed increases in MABP (48 +/- 1 to 55 +/- 3 mmHg) and RSNA (198 +/- 96% of fetal value) 60 min after birth, similar to betamethasone alone lambs. Losartan alone treated animals had no postnatal increase in either MABP or RSNA, responses similar to those seen in nontreated sheep delivered at the same gestational age. The sensitivity of baroreflex-mediated changes in HR in response to increases in MABP was less in both groups of betamethasone-treated animals; no effect was seen with losartan. These results suggest the postnatal increases in MABP and RSNA seen with antenatal glucocorticoid treatment are not mediated by stimulation of peripherally accessible AT(1) receptors. We speculate that augmented cardiovascular function in glucocorticoid-treated premature lambs is dependent, in part, on a generalized sympathoexcitatory response and that this effect of glucocorticoids is mediated by central mechanisms.     

alpha(2)-Adrenergic receptors in NTS facilitate baroreflex function in adult spontaneously hypertensive rats

We examined the effect of alpha(2)-adrenoreceptor blockade in the nucleus of the solitary tract (NTS) on baroreflex responses elicited by electrical stimulation of the left aortic depressor nerve (ADN) in urethane-anesthetized spontaneously hypertensive rats (SHR, n = 11) and normotensive Wistar-Kyoto rats (WKY, n = 11). ADN stimulation produced a frequency-dependent decrease in mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and heart rate (HR). In SHR, unilateral microinjection of idazoxan into the NTS markedly reduced baroreflex control of MAP, RSNA, and HR and had a disproportionately greater influence on baroreflex control of MAP than of RSNA. In WKY, idazoxan microinjections did not significantly alter baroreflex function relative to control vehicle injections. These results suggest that baroreflex regulation of arterial pressure in SHR is highly dependent on NTS adrenergic mechanisms. The reflex regulation of sympathetic outflow to the kidney is less influenced by the altered alpha(2)-adrenoreceptor mechanisms in SHR.     

Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells

It is well established that obesity is a risk factor for breast cancer and that blood levels of adiponectin, a hormone mainly secreted by white adipocytes, are inversely correlated with the body fat mass. As adiponectin elicits anti-proliferative effects in some cell types, we tested the hypothesis that adiponectin could influence human breast cancer MCF-7 cell growth. Here we show that MCF-7 cells express adiponectin receptors and respond to human recombinant adiponectin by reducing their growth, AMPkinase activation, and p42/p44 MAPkinase inactivation. Further, we demonstrate that the anti-proliferative effect of adiponectin involves activation of cell apoptosis and inhibition of cell cycle. These findings suggest that adiponectin could act in vivo as a paracrine/endocrine growth inhibitor towards mammary epithelial cells. Moreover, adipose adiponectin production being strongly reduced in obesity, this study may help to explain why obesity is a risk factor of developing breast cancers.