Exercise pressor reflex in humans with end-stage renal disease

Previous work has suggested that end-stage renal disease (ESRD) patients may have an exaggerated sympathetic nervous system (SNS) response during exercise. We hypothesized that ESRD patients have an exaggerated blood pressure (BP) response during moderate static handgrip exercise (SHG 30%) and that the exaggerated BP response is mediated by SNS overactivation, characterized by augmented mechanoreceptor activation and blunted metaboreceptor control, as has been described in other chronic diseases. We measured hemodynamics and muscle sympathetic nerve activity (MSNA) in 13 ESRD and 16 controls during: 1) passive hand movement (PHM; mechanoreceptor isolation); 2) low-level rhythmic handgrip exercise (RHG 20%; central command and mechanoreceptor activation); 3) SHG 30%, followed by posthandgrip circulatory arrest (PHGCA; metaboreceptor activation); and 4) cold pressor test (CPT; nonexercise stimulus). ESRD patients had exaggerated increases in systolic BP during SHG 30%; however, the absolute and relative increase in MSNA was not augmented, excluding SNS overactivation as the cause of the exaggerated BP response. Increase in MSNA was not exaggerated during RHG 20% and PHM, demonstrating that mechanoreceptor activation is not heightened in ESRD. During PHGCA, MSNA remained elevated in controls but decreased rapidly to baseline levels in ESRD, indicative of markedly blunted metaboreceptor control of MSNA. MSNA response to CPT was virtually identical in ESRD and controls, excluding a generalized sympathetic hyporeactivity in ESRD. In conclusion, ESRD patients have an exaggerated increase in SBP during SHG 30% that is not mediated by overactivation of the SNS directed to muscle. SBP responses were also exaggerated during mechanoreceptor activation and metaboreceptor activation, but without concomitant augmentation in MSNA responses. Metaboreceptor control of MSNA was blunted in ESRD, but the overall ability to mount a SNS response was not impaired. Other mechanisms besides SNS overactivation, such as impaired vasodilatation, should be explored to explain the exaggerated exercise pressor reflex in ESRD.     

Gender-specific genetic determinants of blood pressure and organ weight: pharmacogenetic approach

A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F(2) intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases.     

Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity

Recent studies have implicated reactive oxygen species (ROS) in the pathogenesis of hypertension and activation of the sympathetic nervous system (SNS). Because nitric oxide (NO) exerts a tonic inhibition of central SNS activity, increased production of ROS could enhance inactivation of NO and result in activation of the SNS. To test the hypothesis that ROS may modulate SNS activity, we infused Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), a superoxide dismutase mimetic, or vehicle either intravenously (250 microg x kg(-1) x min(-1)) or in the lateral ventricle (50 microg x kg body wt(-1) x min(-1)), and we determined the effects on blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamus (PH) measured by the microdialysis technique, renal sympathetic nerve activity (RSNA) measured by direct microneurography, the abundance of neuronal NO synthase (nNOS)-mRNA in the PH, paraventricular nuclei (PVN), and locus coeruleus (LC) measured by RT-PCR, and the secretion of nitrate/nitrite (NO(x)) in the dialysate collected from the PH of Sprague-Dawley rats. Tempol reduced BP whether infused intravenously or intracerebroventricularly. Tempol reduced NE secretion from the PH and RSNA when infused intracerebroventricularly but raised NE secretion from the PH and RSNA when infused intravenously. The effects of intravenous Tempol on SNS activity were blunted or abolished by sinoaortic denervation. Tempol increased the abundance of nNOS in the PH, PVN, and LC when infused intracerebroventricularly, but it decreased the abundance of nNOS when infused intravenously. When given intracerebroventricularly, Tempol also reduced the concentration of NO(x) in the dialysate collected from the PH. Pretreatment with N(omega)-nitro-l-arginine methyl ester did not abolish the effects of intracerebral Tempol on BP, heart rate, NE secretion from the PH, and RSNA suggesting that the effects of Tempol on SNS activity may be in part dependent and in part independent of NO. In all, these studies support the notion that ROS may raise BP via activation of the SNS. This activation may be mediated in part by downregulation of nNOS and NO production, in part by mechanisms independent of NO. The discrepancy in results between intracerebroventricular and intravenous infusion of Tempol can be best explained by direct inhibitory actions on SNS activity when given intracerebral. By contrast, Tempol may exert direct vasodilation of the peripheral circulation and reflex activation of the SNS when given intravenously.     

Reduced sympathetic nervous system activity in rats with ventromedial hypothalamic lesions

To determine if alterations in sympathetic nervous system (SNS) activity occur in rats with ventromedial hypothalamic (VMH) lesions, norepinephrine (NE) turnover rates were examined in various tissues of lesioned and control, weanling rats. VMH-lesioned rats fed a high-carbohydrate diet ad libitum for 4 weeks following surgery were not hyperphagic, but they gained 50% more body energy than control rats. VMH lesions extended the half-life of ³H-NE in interscapular brown adipose tissue (BAT) by 42%, in abdominal white adipose tissue (WAT) by 201%, in heart by 61% and in pancreas by 85%, and reduced total NE turnover (ng/organ/hr) in BAT (38%), WAT (57%), heart (30%) and pancreas (53%). Reduced SNS activity in BAT is consistent with the decreased energy expenditure (heat production) and increased energy efficiency observed in VMH-lesioned rats. In WAT, decreased SNS activity coupled with hyperinsulinemia would facilitate energy storage as fat by reducing lipid mobilization. In the pancreas, reduced SNS activity would contribute to hyperinsulinemia. These results support the hypothesis that VMH lesions decrease SNS activity in several organs. This change in autonomic tone is very likely a major factor in the development of obesity in VMH-lesioned animals.     

The participation of brain NO synthase in blood pressure control of adult spontaneously hypertensive rats

Increased blood pressure (BP) in genetic hypertension is usually caused by high activity of sympathetic nervous system (SNS) which is enhanced by central angiotensin II but lowered by central nitric oxide (NO). We have therefore evaluated NO synthase (NOS) activity as well as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) protein expression in brainstem and midbrain of adult spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. We also studied possible participation of brain NO in antihypertensive effects of chronic captopril treatment of adult SHR. NOS activity was increased in midbrain of SHR compared to Wistar-Kyoto (WKY) rats. This could be ascribed to enhanced iNOS expression, whereas nNOS expression was unchanged and eNOS expression was reduced in this brain region. In contrast, no significant changes of NOS activity were found in brainstem of SHR in which nNOS and iNOS expression was unchanged, but eNOS expression was increased. Chronic captopril administration lowered BP of adult SHR mainly by attenuation of sympathetic tone, whereas the reduction of angiotensin II-dependent vasoconstriction and the decrease of residual BP (amelioration of structural remodeling of resistance vessels) were less important. This treatment did not affect significantly either NOS activity or expression of any NOS isoform in the two brain regions. Our data do not support the hypothesis that altered brain NO formation contributes to sympathetic hyperactivity and high BP of adult SHR with established hypertension.     

Sodium-induced rise in blood pressure is suppressed by androgen receptor blockade

Our objective was to test the hypothesis that 1) a high Na (HNa, 3%) diet would increase blood pressure (BP) in male Wistar-Kyoto (WKY) and spontaneously hypertensive Y chromosome (SHR/y) rat strains in a territorial colony; 2) sympathetic nervous system (SNS) blockade using clonidine would lower BP on a HNa diet; and 3) prepubertal androgen receptor blockade with flutamide would lower BP on a HNa diet. A 2 x 4 factorial design used rat strains (WKY, SHR/y) and treatment [0.3% normal Na (NNa), 3% HNa, HNa/clonidine, and HNa/flutamide]. BP increased in both strains on the HNa diet (P < 0.0001). There was no significant decrease in BP in either strain with clonidine treatment. Androgen receptor blockade with flutamide significantly decreased BP in both strains (P < 0.0001) and normalized BP in the SHR/y colony. Neither heart rate nor activity could explain these BP differences. In conclusion, a Na sensitivity was observed in both strains, which was reduced to normotensive values by androgen blockade but not by SNS blockade.     

Effects of CH-19 Sweet, a non-pungent cultivar of red pepper, on sympathetic nervous activity, body temperature, heart rate, and blood pressure in humans

We investigated the changes in autonomic nervous activity, body temperature, blood pressure (BP), and heart rate (HR) after intake of the non-pungent pepper CH-19 Sweet and of hot red pepper in humans to elucidate the mechanisms of diet-induced thermogenesis (DIT) due to CH-19 Sweet. We found that CH-19 Sweet activates the sympathetic nervous system (SNS) and enhances thermogenesis as effectively as hot red pepper, ant that the heat loss effect due to CH-19 Sweet is weaker than that due to hot red pepper. Furthermore, we found that intake of CH-19 Sweet does not affect systolic BP or HR, while hot red pepper transiently elevates them. These results indicate that DIT due to CH-19 Sweet can be induced via the activation of SNS as well as hot red pepper, but that the changes in BP, HR, and heat loss effect are different between these peppers.     

Neuroprotective action of FK-506 (tacrolimus) after seizures induced with pilocarpine: quantitative and topographic elemental analysis of brain tissue

In the present work, X-ray fluorescence microscopy with a synchrotron source for the exciting radiation was applied for topographic and quantitative elemental analysis of rat brain tissue in pilocarpine-induced epilepsy and neuroprotection with FK-506. The mass per unit area of the elements P, S, Cl, K, Ca, Fe, Cu, Zn, Se, Br, and Rb was determined in four fields of the hippocampal formation (sectors 1 and 3 of Ammon’s horn–CA1, CA3; dentate gyrus; hilus of dentate gyrus) and the parietal cortex. The results obtained for epileptic rats treated with FK-506 (SNF) were compared with data obtained previously for epileptic rats (SNS) and a control group. Many statistically significant differences in elemental composition were observed between the SNF and SNS groups. Higher mass per unit area of P was noticed in CA1 and CA3 regions of the hippocampus of SNF rats in comparison with SNS rats. A similar relation was observed for K in all five brain areas analyzed. Also, Fe in CA3 and dentate gyrus, Cu in the parietal cortex, and Zn in CA3 and in the cortex were present at a higher level in the SNF group in comparison with the SNS group. The findings obtained in the present study suggest that the neuroprotective action of FK-506 in epileptic rat brain may involve not only the inhibition of calcineurin but also blockade of the K⁺ channels.     

Dietary salt restriction in hyperthyroid rats. Differential influence on left and right ventricular mass

This study assessed the impact of salt restriction on cardiac morphology and biochemistry and its effects on hemodynamic and renal variables in experimental hyperthyroidism. Four groups of male Wistar rats were used: control, hyperthyroid, and the same groups under low salt intake. Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 4 weeks. Morphologic, metabolic, plasma, cardiac, and renal variables were also measured. Low salt intake decreased BP in T₄-treated rats but not in controls. Low salt intake reduced relative left ventricular mass but increased absolute right ventricular weight and right ventricular weight/BW ratio in both control and hyperthyroid groups. Low salt intake increased Na⁺/H⁺ exchanger-1 (NHE-1) protein abundance in both ventricles in normal rats but not in hyperthyroid rats, independently of its effect on ventricular mass. Mammalian target of rapamycin (mTOR) protein abundance was not related to left or right ventricular mass in hyperthyroid or controls rats under normal or low salt conditions. Proteinuria was increased in hyperthyroid rats and attenuated by low salt intake. In this study, low salt intake produced an increase in right ventricular mass in normal and hyperthyroid rats. Changes in the left or right ventricular mass of control and hyperthyroid rats under low salt intake were not explained by the NHE-1 or mTOR protein abundance values observed. In hyperthyroid rats, low salt intake also slightly reduced BP and decreased HR, proteinuria, and water and sodium balances.     

Sensory or sympathetic white adipose tissue denervation differentially affects depot growth and cellularity

Functional and histological evidence for the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) exists for several species; however, its sensory innervation has only been shown in laboratory rats, and its function is unclear. We tested the effects of sensory and SNS innervation of Siberian hamster epididymal and inguinal WAT (EWAT and IWAT) by assessing calcitonin gene-related peptide (CGRP)- and tyrosine hydroxylase-immunoreactivity (ir), respectively. Next, we tested the role of the sensory innervation of WAT on growth and cellularity because WAT surgical denervation increases pad mass via selective increases in fat cell number, an effect ascribed to SNS denervation but that could be due to the accompanying surgical disruption of WAT sensory innervation. Sensory denervation was accomplished via multiple local microinjections of capsaicin into WAT, and its effects were compared with those of surgical denervation. Surgically denervated IWAT and EWAT showed significantly decreased tyrosine hydroxylase-ir and CGRP-ir, whereas capsaicin-treated WAT had only significantly decreased CGRP-ir. Surgically denervated pad masses were significantly increased; this was accompanied by increased total fat cell number in IWAT, with no change in fat cell size. EWAT only showed a significant increase in the number of small- to medium-sized adipocytes (75-125 mum diameter). By contrast, sensory-denervated pad masses were unchanged, but IWAT showed significantly increased average fat cell size. Collectively, these data provide immunohistochemical evidence for sensory and SNS innervation of WAT in Siberian hamsters and differential control of WAT cellularity by these innervations, as well as the ability of locally applied capsaicin to selectively reduce WAT sensory innervation.     

Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin

Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 microg leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 microg leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots.     

Interleukin-1beta and neurogenic control of blood pressure in normal rats and rats with chronic renal failure

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO(2)/NO(3) production. Because interleukin (IL)-1beta may activate nitric oxide in the brain, we have tested the hypothesis that IL-1beta may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1beta in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1beta-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1beta mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1beta modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.     

Lack of increase in concentrations of cerebrospinal fluid sodium in rats with various stages of DOCA-salt hypertension

Experiments were conducted in conscious rats to determine whether DOCA-salt treatment could cause an elevation of sodium concentration of cerebrospinal fluid (CSF), which may be responsible for the enhanced activity of sympathetic nervous system (SNS) and increased secretion of vasopressin (AVP). Systolic blood pressure (SBP) and mean arterial pressure (MAP) were gradually but consistently increased by DOCA-salt treatment. Serum Na concentration was similarly increased with time by DOCA-salt, and significantly higher than control in the 4th treatment week. In contrast, DOCA-salt did not alter the CSF Na levels at any time during treatment. A relationship between SBP and CSF Na was never evident at any stage of the DOCA-salt hypertension. The decrease in MAP following administration of the vasopressin V1-receptor antagonist, d(CH2)5Tyr(Me)AVP (30 micrograms/kg), or hexamethonium (30 mg/kg) was enhanced in the DOCA-treated rats, as compared to findings in the controls. These hypotensive effects were gradually, but progressively enhanced with the development of hypertension by DOCA-salt treatment. We tentatively conclude that mechanisms accounting for the enhanced activity of SNS and AVP in DOCA-salt hypertensive rats are independent of an increased Na concentration in the CSF.     

Effect of acute adrenalectomy on sympathetic responses to peripheral lipopolysaccharide or central PGE(2)

The impact of plasma corticosterone levels on the sympathetic nervous system (SNS) response to intravenous lipopolysaccharide (LPS) or intracerebroventricular injections of PG was studied in anesthetized (urethan-chloralose) male Sprague-Dawley rats. For this, electrophysiological recordings of splenic and renal nerves were completed in control or adrenalectomized (ADX) rats. LPS (10 microgram iv) similarly increased splenic and renal nerve activity in control rats with a shorter onset latency for the splenic nerve. Acute ADX enhanced the response of both nerves to LPS (P < 0.005) and reduced the onset latency of the renal nerve (P < 0.05). PGE(2) (2 microgram icv) rapidly increased the activity of both nerves but preferentially (magnitude and onset latency) stimulated the renal nerve (P < 0.05). The magnitude of the splenic nerve response to PGE(2) was unaffected by ADX. Unexpectedly, PGE(2) was less effective at stimulating renal nerve activity in ADX animals relative to intact controls (P < 0.05). Pretreatment of ADX rats with a CRF antagonist ([D-Phe(12), Nle(21,38), Calpha-MeLeu(37)]CRF-(12-41)) reversed this effect such that the renal nerve responded to central PGE(2) to a greater extent than the splenic nerve (P < 0.05), as was the case in non-ADX rats. These data indicate that enhanced sensitivity of central sympathetic pathways does not account for the enhanced SNS responses to LPS in ADX rats. Also, a CRF-related process appears to diminish renal sympathetic outflow in ADX rats.     

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

Increased dietary sodium enhances both excitatory and inhibitory blood pressure responses to stimulation of the central sympathetic nervous system (SNS) centers. In addition, long-term (hours to days) administration of ANG II increases blood pressure by activation of the SNS. These studies investigated the effects of increased dietary sodium on SNS control of blood pressure during 0- to 24-h infusion of ANG II in conscious, male rats consuming either tap water or isotonic saline (Iso) for 2 to 3 wk. The SNS component (evaluated by ganglionic blockade with trimetaphan) of both control blood pressure and the pressor response to intravenous ANG II was reduced in Iso animals. Furthermore, although the pressor response to intravenous ANG II infusion was similar between groups, the baroreflex-induced bradycardia during the initial 6 h of ANG II infusion was significantly greater, whereas the tachycardia accompanying longer infusion periods was significantly attenuated in Iso animals. These data suggest that in normal rats increased dietary sodium enhances sympathoinhibitory responses during intravenous ANG II.     

Central infusion of leptin improves insulin resistance and suppresses β-cell function,but not β-cell mass,primarily through the sympathetic nervous system in a type 2 diabetic rat model

AimsWe investigated whether hypothalamic leptin alters β-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states.Main methodsThe 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300 ng/kg bw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3 h as a short-term study. After finishing the infusion study, ICV leptin (3 μg/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4 weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed.Key findingsAcute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic β-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual β-cell size and concomitantly increased β-cell apoptosis in Sham rats.SignificanceLeptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic β-cell mass.     

The Effects of Angiotensin II and Angiotensin-(1–7) in the Rostral Ventrolateral Medulla of Rats on Stress-Induced Hypertension

We have shown that angiotensin II (Ang II) and angiotensin-(1–7) [Ang-(1–7)] increased arterial blood pressure (BP) via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM) in normotensive rats (control). In the present study, we tested the hypothesis that Ang II and Ang-(1–7) in the RVLM are differentially activated in stress-induced hypertension (SIH) by comparing the effects of microinjection of Ang II, Ang-(1–7), and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate) and less inhibitory (taurine and γ-aminobutyric acid) amino acid release in SIH than in control animals. Losartan, a selective AT₁ receptor (AT₁R) antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT₂ receptor (AT₂R) antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1–7) and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT₁R, ACE protein expression (western blot) and ACE mRNA (real-time PCR) were significantly higher, whereas AT₂R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT₁R, not Ang-(1–7), system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release.     

Resetting baroreceptors to a lower arterial pressure level by enalapril avoids baroreflex mediated activation of sympathetic nervous system by nifedipine.

Baroreceptor-unloading-mediated activation of sympathetic nervous system (SNS) by antihypertensive agents, such as dihydropyridine calcium channel blockers (CCB), has been considered to compromise the beneficial effects of the therapy and lead to unsatisfying clinical outcome. The present study was aimed at finding a novel way of using CCB without activating SNS. In anaesthetized Wistar rats, baroreceptor-unloading-mediated reflex activation of SNS, as indicated by tachycardia and increase of plasma catecholamines, was observed after mean arterial pressure (MAP) was decreased by 15 mmHg during 4-h administration of nifedipine, a CCB. However an angiotensin-converting enzyme inhibitor (ACEI), enalapril did not cause tachycardia or increase plasma catecholamine levels when it decreased MAP by 15 mmHg. After 100 min (supposedly baroreceptor resetting or adaptation to hypotension had occurred), enalapril infusion was gradually replaced by nifedipine infusion in 40 min. Nifedipine was infused for another 100 min, which kept the lowered MAP unchanged and did not activate SNS. In anaesthetized spontaneously hypertensive rats (SHR), baroreceptor-mediated reflex activation of SNS was observed after MAP was decreased by 25 mmHg during 4-h nifedipine administration. However enalapril did not cause tachycardia or increase plasma catecholamine levels when it decreased MAP by 25 mmHg. After 100 min, enalapril infusion was gradually replaced by nifedipine infusion in 40 min. Nifedipine was then infused for another 100 min, which kept the lowered MAP unchanged and did not activate SNS. The present study indicated that reflex activation of SNS caused by antihypertensive effect of CCB could be avoided if, prior to CCB administration, baroreceptors have been reset to a lower MAP by a drug that does not activate baroreceptor reflex.     

Stressful animal housing conditions and their potential effect on sympathetic neurotransmission in mice

Although the sympathetic nervous system (SNS) plays a major role in mediating the peripheral stress response, due consideration is not usually given to the effects of prolonged stress on the SNS. The present study examined changes in neurotransmission in the SNS after exposure of mice (BALB/c) to stressful housing conditions. Focal extracellular recording of excitatory junction currents (EJCs) was used as a relative measure of neurotransmitter release from different regions of large surface areas of the mouse vas deferens. Mice were either group housed (control), isolation housed (social deprivation), group housed in a room containing rats (rat odor stress), or isolation housed in a room containing rats (concurrent stress). Social deprivation and concurrent stressors induced an increase of 30 and 335% in EJC amplitude, respectively. The success rate of recording EJCs from sets of varicosities in the concurrent stressor group was greater compared with all other groups. The present study has shown that some common animal housing conditions act as stressors and induce significant changes in sympathetic neurotransmission.     

Regulation of hepatic expression of IGF I and fetal IGF binding protein mRNA in streptozotocin-diabetic rats

Hepatic mRNA levels of insulin-like growth factor I (IGF I) and of the fetal, nonglycosylated 32 kDa IGF-binding protein (BP) were analysed in diabetic, diabetic insulin- and IGF I-treated rats as well as in age-matched, healthy control animals. IGF ImRNA levels are reduced in diabetic rats and increased by insulin treatment. In contrast, the infusion of IGF I does not significantly upregulate IGF I mRNA levels. Fetal IGF BP mRNA expression is very low in healthy control animals, but high levels are found in diabetic rats. Insulin therapy lowers fetal IGF BP mRNA levels, whereas IGF I has no effect. We propose that insulin is a major regulator of the 32 kDa IGF BP levels in adult rats.