Blunted nitric oxide-mediated inhibition of renal nerve discharge within PVN of rats with heart failure

We have demonstrated a decreased neuronal nitric oxide (NO) synthase (nNOS) message in the hypothalamus of rats with heart failure (HF). Subsequently, we have demonstrated that NADPH diaphorase (a commonly used marker for nNOS activity) positive neurons are decreased in paraventricular nucleus (PVN) of rats with coronary artery ligation model of HF. The goal of the present study was to examine the influence of endogenous NO within the PVN on renal sympathetic nerve discharge (RSND) during HF. In alpha-chloralose- and urethane-anesthetized rats, an inhibitor of NO synthase, N(G)-monomethyl-L-arginine (L-NMMA) microinjected into the PVN (50, 100, and 200 pmol in 50-200 nl) produced a dose-dependent increase in RSND, blood pressure, and heart rate in control and HF rats. These responses were attenuated in rats with HF compared with control rats. On the other hand, the NO agonist, sodium nitroprusside, microinjected in PVN produced a dose-dependent decrease in RSND and blood pressure in control and HF rats. These responses were less in rats with HF compared with control rats. These data suggest that the endogenous NO-mediated effect within the PVN of HF rats is less potent in suppressing RSND compared with control rats. These data support the conclusion that the NO system within the PVN involved in controlling autonomic outflow is altered during HF and may contribute to the elevated levels of renal sympathoexcitation commonly observed in HF.     

Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide

The paraventricular nucleus (PVN) of the hypothalamus is known to be an important site of integration in the central nervous system for sympathetic outflow. ANG II and nitric oxide (NO) play an important role in regulation of sympathetic nerve activity. The purpose of the present study was to examine how the interaction between NO and ANG II within the PVN affects sympathetic outflow in rats. Renal sympathetic nerve discharge (RSND), arterial blood pressure (AP), and heart rate (HR) were measured in response to administration of ANG II and N(G)-monomethyl-l-arginine (L-NMMA) into the PVN. Microinjection of ANG II (0.05, 0.5, and 1.0 nmol) into the PVN increased RSND, AP, and HR in a dose-dependent manner, resulting in increases of 53 +/- 9%, 19 +/- 3 mmHg, and 32 +/- 12 beats/min from baseline, respectively, at the highest dose. These responses were significantly enhanced by prior microinjection of L-NMMA and were blocked by losartan, an ANG II type 1 receptor antagonist. Similarly, administration of antisense to neuronal NO synthase within the PVN also potentiated the ANG II responses. Conversely, overexpression of neuronal NOS within the PVN with adenoviral gene transfer significantly attenuated ANG II responses. Push-pull administration of ANG II (1 nmol) into the PVN induced an increase in NO release. Our data indicate that ANG II type 1 receptors within the PVN mediate an excitatory effect on RSND, AP, and HR. NO in the PVN, which can be induced by ANG II stimulation, in turn inhibits the ANG II-mediated increase in sympathetic nerve activity. This negative-feedback mechanism within the PVN may play an important role in maintaining the overall balance and tone of sympathetic outflow.     

兔室旁核对血量扩张引起促纳排泄与利尿的作用

在室旁核 (PVN)假损毁兔与PVN损毁兔血量扩张 (VE)引起尿流量增加 ,峰值分别为 0 5 9± 0 0 9与0 3 1± 0 0 3ml/min (P <0 0 1) ,排钠量增加峰值分别为 66 76± 6 74与 3 6 0 5± 3 4 4μmol/min (P <0 0 1) ,而在PVN假损毁兔与PVN完好兔对VE的反应无显著差别 (P >0 0 5 ) ,表明PVN损伤可明显减弱VE引起的促钠排泄与利尿效应。颈迷走神经切断并不能改变PVN损伤的上述作用。双侧肾神经切断兔损毁PVN对VE引起促钠排泄效应无显著影响 ,但显著减弱其利尿效应 (P <0 0 2 )。PVN损毁对VE时肾小球滤过率 (GFR)与肾血浆流量 (RPF)无显著影响。结果表明PVN参与VE通过迷走传入神经引起促钠排泄与利尿反应的调节 ,而肾交感传出神经参与其中促钠排泄的作用     

Changes in renal hemodynamics and excretory function induced by a reduction of ANG II effects during renal development

The aim was to evaluate whether blockade of ANG II effects during renal development modifies the renal response to an increment of plasma amino acid concentration. It was also examined in anesthetized rats whether the reduction of the renal ability to eliminate an acute volume expansion (VE), elicited by blockade of ANG II during renal development, is sex and/or age dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT(1)-receptor antagonist (ARA) during postnatal nephrogenesis. Amino acid infusion induced increments (P < 0.05) of glomerular filtration rate (31 +/- 6%) and renal plasma flow (26 +/- 5%) in male but not in female vehicle-treated rats. Natriuretic and diuretic responses to amino acid infusion were similar in male and female vehicle-treated rats. These renal hemodynamics and excretory responses to amino acid infusion were abolished in ARA-treated rats. Renal responses to VE were evaluated at 3-4 and 9-10 mo of age in vehicle and ARA-treated rats. VE-induced natriuresis and diuresis were reduced by more than 38% (P < 0.05) in 3- to 4-mo-old male and female ARA-treated rats. An age-dependent reduction (P < 0.05) in the renal ability to eliminate VE was found in male but not in female rats treated with ARA. Our results demonstrate that the renal effects induced by an increment in amino acids are abolished when ANG II effects have been reduced during nephrogenesis. In addition, this reduction of ANG II effects elicits an impairment of the renal ability to eliminate an acute VE in males and females, which is aggravated by age only in male rats.     

Reduced endogenous GABA-mediated inhibition in the PVN on renal nerve discharge in rats with heart failure

One characteristic of heart failure (HF) is increased sympathetic activation. The paraventricular nucleus (PVN) of the hypothalamus (involved in control of sympathetic outflow) has been shown to have increased neuronal activation during HF. This study examined the influence of endogenous GABA input (inhibitory in nature) into the PVN on renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR) in rats with HF induced by coronary artery ligation. In alpha-chloralose- and urethane-anesthetized rats, microinjection of bicuculline (a GABA antagonist) into the PVN produced a dose-dependent increase in RSND, BP, and HR in both sham-operated control and HF rats. Bicuculline attenuated the increase in RSND and BP in HF rats compared with control rats. Alternatively, microinjection of the GABA agonist muscimol produced a dose-dependent decrease in RSND, BP, and HR in both control and HF rats. Muscimol was also less effective in decreasing RSND, BP, and HR in HF rats than in control rats. These results suggest that endogenous GABA-mediated input into the PVN of rats with HF is less effective in suppressing RSND and BP compared with control rats. This is partly due to the post-release actions of GABA, possibly caused by altered function of post-synaptic GABA receptors in the PVN of rats with HF. Reduced GABA-mediated inhibition in the PVN may contribute to increased sympathetic outflow, which is commonly observed during HF.     

Chronic angiotensin II infusion attenuates the renal sympathoinhibitory response to acute volume expansion

In this study the hypothesis was tested that chronic infusion of ANG II attenuates acute volume expansion (VE)-induced inhibition of renal sympathetic nerve activity (SNA). Rats received intravenous infusion of either vehicle or ANG II (12 ng. kg(-1). min(-1)) for 7 days. ANG II-infused animals displayed an increased contribution of SNA to the maintenance of mean arterial pressure (MAP) as indicated by ganglionic blockade, which produced a significantly (P < 0.01) greater decrease in MAP (75 +/- 3 mmHg) than was observed in vehicle-infused (47 +/- 8 mmHg) controls. Rats were then anesthetized, and changes in MAP, mean right atrial pressure (MRAP), heart rate (HR), and renal SNA were recorded in response to right atrial infusion of isotonic saline (20% estimated blood volume in 5 min). Baseline MAP, HR, and hematocrit were not different between groups. Likewise, MAP was unchanged by acute VE in vehicle-infused animals, whereas VE induced a significant bradycardia (P < 0.05) and increase in MRAP (P < 0.05). MAP, MRAP, and HR responses to VE were not statistically different between animals infused with vehicle vs. ANG II. In contrast, VE significantly (P < 0.001) reduced renal SNA by 33.5 +/- 8% in vehicle-infused animals but was without effect on renal SNA in those infused chronically with ANG II. Acutely administered losartan (3 mg/kg iv) restored VE-induced inhibition of renal SNA (P < 0.001) in rats chronically infused with ANG II. In contrast, this treatment had no effect in the vehicle-infused group. Therefore, it appears that chronic infusion of ANG II can attenuate VE-induced renal sympathoinhibition through a mechanism requiring AT(1) receptor activation. The attenuated sympathoinhibitory response to VE in ANG II-infused animals remained after arterial barodenervation and systemic vasopressin V(1) receptor antagonism and appeared to depend on ANG II being chronically increased because ANG II given acutely had no effect on VE-induced renal sympathoinhibition.     

Vascular and renal effects of dopamine during extracellular volume expansion: Role of nitric oxide pathway

OBJECTIVE: The aim of the study was to determine the possible role of NO-system activation in vascular and renal effects of the dopaminergic system and the probable interaction between both systems during acute volume expansion in rats. DESIGN AND METHODS: Expanded (10% bw) and non-expanded anaesthetized male Wistar rats were treated with haloperidol, a DA receptor antagonist (3 mg/kg bw, ip). Mean arterial pressure, diuresis, natriuresis, renal plasma flow, glomerular filtration rate, nitrites and nitrates excretion (NOx) were determined. NADPH diaphorase activity was measured using a histochemistry technique in kidney, aorta and renal arteries. NOS activity in kidney and aorta from expanded and non-expanded animals was determined with L-[U14C]-arginine substrate, in basal conditions and after DA (1 microM) administration. RESULTS: The hypotensive effect of L-arg and hypertension induced by L-NAME were not modified by haloperidol. This blocker reverted the increase in diuresis, natriuresis and RPF induced by L-arg in both groups. Dopaminergic blockade induced a decrease in NOx excretion and in NADPH-diaphorase activity in glomeruli, proximal tubule and medullar collecting duct and in endothelium and vascular smooth muscle of renal arteries. DA induced an increase in NOS activity in renal medulla and cortex in both groups, but no changes in the aorta were observed. CONCLUSIONS: Our results suggest that renal DA would be associated with the renal response induced by NO during extracellular volume expansion. NO-system activation would be one of the mechanisms involved in renal DA activity during saline load, but NO appears not to be involved in DA vascular effects.     

Anatomical distribution and function of dopamine receptors in the kidney.

Dopamine receptors of DA-1 and DA-2 subtypes are localized in various regions within the kidney including the renal vasculature (DA-1) as well as sympathetic nerve terminals innervating the renal blood vessels (DA-2). More recent studies using receptor-ligand binding and receptor autoradiography have shown that DA-1 receptors are localized at both the luminal and basolateral membranes at the level of the proximal tubules. Activation of these DA-1 receptors by dopamine and by selective DA-1 receptor agonists results in natriuresis and diuresis. The cellular signaling mechanisms responsible for this response appear to be DA-1 receptor-induced activation of adenylate cyclase and phospholipase C, which via the generation of various intracellular messenger systems cause inhibition of Na(+)-H+ antiport (luminal) and Na+, K(+)-ATPase (basolateral), respectively. Both of these events consequently inhibit sodium reabsorption leading to natriuresis and diuresis. It is also known that dopamine can be synthesized within proximal tubular cells from L-dopa, which is taken up from the tubular lumen, and this locally produced dopamine plays an important role in the regulation of sodium excretion particularly during increases in sodium intake. Furthermore, a defect in the renal dopaminergic mechanism may be one of the pathogenic factors in certain forms of hypertension. Finally, whereas DA-1 receptor agonists are shown to be of therapeutic benefit in the treatment of hypertension, heart failure, and acute renal failure, some selective DA-2 receptor agonists are effective antihypertensive agents.     

Role of plasma renin activity and the renal nerves in the natriuresis of L-NMMA infusion in rats

The objective of this study was to determine the effect of N(G)-monomethyl-L-arginine (L-NMMA) infusion on plasma renin activity (PRA) in the presence or absence of the renal nerves in normotensive Wistar-Kyoto (WKY) rats and Okamoto spontaneously hypertensive rats (SHR). All rats were unilaterally nephrectomized two weeks before the acute experiment. On the day of the experiment, acute renal denervation (Dnx) of the remaining kidney was performed in one group of WKY rats (Dnx-WKY; n= 10) and one group of SHRs (Dnx-SHR: n=7). The renal nerves were left intact in a group of WKY rats (Inn-WKY; n=8) and SHRs (Inn-SHR; n=9). After a control clearance period, L-NMMA was administered i.v. (15 mg/kg bolus followed by 500 microg/kg/min infusion) and another clearance period of 20 min was taken. In all experimental groups L-NMMA infusion resulted in a significant natriuresis. L-NMMA infusion increased fractional excretion of sodium (FE(Na)) to a greater extent in the Inn-SHR than in the Inn-WKY (delta FE(Na) = 5.23+/-0.87% vs delta FE(Na) = 2.87+/-0.73% respectively; P=0.05), PRA did not change in the SHR with the infusion of L-NMMA. However, in the Inn-WKY group, the natriuresis of L-NMMA infusion was associated with a tendency for lower PRA levels as compared to a group of time control Inn-WKY rats. In Dnx-WKY, the natriuresis of L-NMMA infusion (delta FE(Na) = 4.60+/-0.52%) was associated with a significantly lower level of PRA (4.26+/-1.18 ng AI/ml/hr) as compared to a group of time control Dnx-WKY rats (9.83+/-1.32 ng AI/ml/hr; P<0.05). In the Dnx-SHR, the natriuretic response to L-NMMA infusion was significantly attenuated by renal denervation (delta FE(Na) = 2.36+/-0.34%) and PRA was unchanged. In conclusion, the natriuretic effect of systemic inhibition of nitric oxide (NO) synthesis was associated with decreased PRA in the Dnx-WKY suggesting that a potential interaction exists between NO and the renal nerves in the modulation of PRA in the normotensive WKY rat. Whereas, the natriuretic effect of L-NMMA infusion in the SHR in the presence and absence of the renal nerves, were independent of changes in PRA.     

Dopaminergic mediation of the diuretic and natriuretic effects of ANF in the rat

Atrial natriuretic factor (ANF) increases sodium (Na+) and water excretion 8-10 fold on repeated administration to anesthetized rats. SCH-23390 (80 micrograms/kg i.v.) and R-sulpiride (80 micrograms/kg i.v.), selective antagonists of dopamine receptors in the renal vasculature, inhibited diuresis and natriuresis induced by AP III and dopamine. These findings suggest that ANF exerts its effects on renal Na+ and water handling via a dopaminergic mechanism; however, changes in intrarenal hemodynamics secondary to dopamine receptor blockade may attenuate the actions of ANF.     

Adverse effects of tempol on hidrosaline balance in rats with acute sodium overload

We studied the effects of tempol, an oxygen radical scavenger, on hydrosaline balance in rats with acute sodium overload. Male rats with free access to water were injected with isotonic (control group) or hypertonic saline solution (0.80 mol/l NaCl) either alone (Na group) or with tempol (Na-T group). Hydrosaline balance was determined during a 90 min experimental period. Protein expressions of aquaporin 1 (AQP1), aquaporin 2 (AQP2), angiotensin II (Ang II) and endothelial nitric oxide synthase (eNOS) were measured in renal tissue. Water intake, creatinine clearance, diuresis and natriuresis increased in the Na group. Under conditions of sodium overload, tempol increased plasma sodium and protein levels and increased diuresis, natriuresis and sodium excretion. Tempol also decreased water intake without affecting creatinine clearance. AQP1 and eNOS were increased and Ang II decreased in the renal cortex of the Na group, whereas AQP2 was increased in the renal medulla. Nonglycosylated AQP1 and eNOS were increased further in the renal cortex of the Na-T group, whereas AQP2 was decreased in the renal medulla and was localized mainly in the cell membrane. Moreover, p47-phox immunostaining was increased in the hypothalamus of Na group, and this increase was prevented by tempol. Our findings suggest that tempol causes hypernatremia after acute sodium overload by inhibiting the thirst mechanism and facilitating diuresis, despite increasing renal eNOS expression and natriuresis.     

Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6-8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18-20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 +/- 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 +/- 5.4% of baseline, which was significantly attenuated compared with sham rats (P < 0.01). In sham rats, the pressor response was completely abolished by alpha-receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of HR responses. The tachycardia could not be abolished by the beta(1)-blocker metoprolol. However, the muscarinic receptor antagonist atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.     

Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure

Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6-8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25-100 mug/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, N(G)-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.     

Endogenous central kappa-opioid systems augment renal sympathetic nerve activity to maximally retain urinary sodium during hypotonic saline volume expansion

Intracerebroventricular injection of kappa-opioid agonists produces diuresis, antinatriuresis, and a concurrent increase in renal sympathetic nerve activity (RSNA). The present study examined whether endogenous central kappa-opioid systems contribute to the renal excretory responses produced by the stress of an acute hypotonic saline volume expansion (HSVE). Cardiovascular, renal excretory, and RSNA responses were measured during control, acute HSVE (5% body weight, 0.45 M saline over 30 min), and recovery (70 min) in conscious rats pretreated intracerebroventricularly with vehicle or the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). In vehicle-pretreated rats, HSVE produced a marked increase in urine flow rate but only a low-magnitude and delayed natriuresis. RSNA was not significantly suppressed during the HSVE or recovery periods. In nor-BNI-treated rats, HSVE produced a pattern of diuresis similar to that observed in vehicle-treated rats. However, during the HSVE and recovery periods, RSNA was significantly decreased, and urinary sodium excretion increased in nor-BNI-treated animals. In other studies performed in chronic bilateral renal denervated rats, HSVE produced similar diuretic and blunted natriuretic responses in animals pretreated intracerebroventricularly with vehicle or nor-BNI. Thus removal of the renal nerves prevented nor-BNI from enhancing urinary sodium excretion during HSVE. These findings indicate that in conscious rats, endogenous central kappa-opioid systems are activated during hypotonic saline volume expansion to maximize urinary sodium retention by a renal sympathoexcitatory pathway that requires intact renal nerves.     

Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on renal excretion of hydro-saline

Renal effects of Dopamine (DA, subpressor dosage 0.1 microgram X kg -1 X min -1) during hypotonic polyuria in moderate hydro-saline retention are variously modified by either d- or l-Sulpiride isomers. In the presence of d-Sulpiride, DA effects, such as an increase in diuresis, free water clearance (CH20) and kaliuresis are suppressed, while increases of saluresis and natriuresis are significantly blunted. In the presence of l-Sulpiride no changes are observed in both saluresis and natriuresis, while decreases occur in diuresis, CH20 and kaliuresis. The inhibitory DA effects on isosmotic sodium reabsorption as a percentage of sodium filtered load are prevented by either isomer as well. A possible role of ineffective renal vascular DA action can be involved in such defective tubular inhibition. However is also suggested a pharmacological blockade of proximal tubular specific DA receptors.     

Rapid non-genomic effects of aldosterone on the renal vasculature

There is increasing evidence for the importance of rapid non-genomic effects of aldosterone on the human vasculature including renal vessels. Arima and colleagues by examining isolated perfused afferent and efferent arterioles from rabbit kidneys found a vasoconstriction in both. In another study the same group showed that endothelium-derived nitric oxide (NO) modulates the vasoconstrictor response to aldosterone in rabbit preglomerular afferent arterioles. Disrupting the endothelium as well as blockade of endothelial NO synthase (eNOS) augmented aldosterone-induced vasoconstriction in this study. Uhrenholt et al. found no effect of aldosterone alone to afferent arterioles but a suppression of depolarisation-induced vasoconstriction. After the blockade of eNOS the aldosterone effect was completely suppressed. In a clinical study in healthy male volunteers injection of aldosterone had no statistically significant effects. Co-infusion of the eNOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) changed the effect of aldosterone on renal hemodynamics. Aldosterone in co-infusion with L-NMMA decreased renal plasma flow (RPF) much stronger than L-NMMA alone. Infusion of L-NMMA alone increased GFR whereas aldosterone/L-NMMA lowered GFR slightly. Aldosterone co-infused with L-NMMA strongly increased renal vascular resistance (RVR). The increase was on top of the smaller increase that was induced by L-NMMA infusion. These data indicate that aldosterone acts via rapid non-genomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial nitric oxide synthase unmasks these effects. Therefore, rapid non-genomic aldosterone effects increase renal vascular resistance and thereby may mediate arterial hypertension if endothelial dysfunction is present.     

Exercise training improves endogenous nitric oxide mechanisms within the paraventricular nucleus in rats with heart failure

Previously, we have demonstrated that an altered endogenous nitric oxide (NO) mechanism within the paraventricular nucleus (PVN) contributes to increased renal sympathetic nerve activity (RSNA) in heart failure (HF) rats. The goal of this study was to examine the effect of exercise training (ExT) in improving the endogenous NO mechanism within the PVN involved in the regulation of RSNA in rats with HF. ExT significantly restored the decreased number of neuronal NO synthase (nNOS)-positive neurons in the PVN (129 +/- 17 vs. 99 +/- 6). nNOS mRNA expression and protein levels in the PVN were also significantly increased in HF-ExT rats compared with HF-sedentary rats. To examine the functional role of NO within the PVN, an inhibitor of NOS, N(G)-monomethyl-L-arginine, was microinjected into the PVN. Dose-dependent increases in RSNA, arterial blood pressure (BP), and heart rate (HR) were produced in all rats. There was a blunted increase in these parameters in HF rats compared with the sham-operated rats. ExT significantly augmented RSNA responses in rats with HF (33% vs. 20% at the highest dose), thus normalizing the responses. The NO donor sodium nitroprusside, microinjected into the PVN, produced dose-dependent decreases in RSNA, BP, and HR in both sham and HF rats. ExT significantly improved the blunted decrease in RSNA in HF rats (36% vs. 17% at the highest dose). In conclusion, our data indicate that ExT improves the altered NO mechanism within the PVN and restores NO-mediated changes in RSNA in rats with HF.     

Role of paraventricular nucleus in regulation of sympathetic nerve frequency components

Autospectral and coherence analyses were used to determine the role of and interactions between paraventricular nucleus (PVN) nitric oxide, gamma-aminobutyric acid (GABA), and the N-methyl-D-aspartic acid (NMDA)-glutamate receptor in regulation of sympathetic nerve discharge (SND) frequency components in anesthetized rats. Four observations were made. First, PVN microinjection of bicuculline (BIC) (GABA(A) receptor antagonist), but not single PVN injections of NMDA (excitatory amino acid) or N(G)-monomethyl-L-arginine (L-NMMA; a nitric oxide synthase inhibitor), altered SND frequency components. Second, combined PVN microinjections of L-NMMA and NMDA changed the SND bursting pattern; however, the observed pattern change was different from that produced by PVN BIC and not observed after sinoaortic denervation. Third, PVN microinjection of kynurenic acid prevented and reversed BIC-induced changes in the SND bursting pattern. Finally, vascular resistance (renal and splenic) was significantly increased after PVN BIC microinjection despite the lack of change in the level of renal and splenic SND. These data demonstrate that the PVN contains the neural substrate for altering SND frequency components and suggest complex interactions between specific PVN neurotransmitters and between PVN neurotransmitters and the arterial baroreceptor reflex in SND regulation.     

Regulation of arterial pressure: role of pressure natriuresis and diuresis

The importance of the renal pressure natriuresis and diuresis mechanisms in long-term control of body fluid volumes and arterial pressure has been controversial and difficult to quantitate experimentally. Recent studies, however, have demonstrated that in several forms of chronic hypertension caused by aldosterone, angiotensin II (AngII), vasopressin, or norepinephrine and adrenocorticotropin, increased renal arterial pressure is essential for maintaining normal excretion of sodium and water in the face of reduced renal excretory capability. When renal arterial pressure was servo-controlled in these models of hypertension, sodium and water retention continued unabated, causing ascites, pulmonary edema, or even complete circulatory collapse within a few days. Apparently, other mechanisms for volume homeostasis, such as the various natriuretic and diuretic factors that have been postulated, are not sufficiently powerful to maintain fluid balance in the absence of increased renal arterial pressure when renal excretory function is reduced in these forms of hypertension. The intrarenal mechanisms responsible for pressure natriuresis and diuresis are not entirely clear, but they seem to involve small increases in glomerular filtration rate and filtered load as well as reductions in fractional reabsorption in proximal and distal tubules. During chronic disturbances of arterial pressure additional factors, especially changes in AngII and aldosterone formation, act to amplify the effectiveness of the basic renal pressure natriuresis and diuresis mechanisms in regulating arterial pressure and body fluid volumes.     

大鼠脑胆碱能系统对血量扩张引起利尿与尿钠排泄...

The role of brain cholinergic system on diuresis and natriuresis induced by volume expansion was studied in conscious rats. In a series of experiments, the diuretic, natriuretic and kaliuretic responses induced by volume expansion were compared in three groups of conscious rats pretreated respectively with intracerebroventricular (icv) injection of artificial cerebrospinal fluid (ACSF), atropine and hexamethonium. The natriuretic, kaliuretic and diuretic responses induced by volume expansion were much less in the animals with icv injection of atropine than in the control group with injection of ACSF (P less than 0.01). While the group pretreated with icv injection of hexamethonium showed no significant decrease in these responses of volume expansion than that of the control (P greater than 0.05). Volume expansion produced no change in insulin and PAH clearance in both the atropine and the ACSF group. Thus the atropine suppressed diuresis, natriuresis and kaliuresis are independent of changes in GFR and RPF. It is inferred from the results of the present investigation that volume expansion induced diuresis and natriuresis appear to be due to inhibition of water and sodium reabsorption in the renal tubules and regulated by certain brain cholinergic system.