ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure.

Chronic heart failure (CHF) is characterized by sympathoexcitation, and the cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex. Our previous studies have shown that the CSAR was enhanced in CHF. In addition, central angiotensin II (ANG II) is an important modulator of this reflex. This study was performed to determine whether the CSAR evoked by stimulation of cardiac sympathetic afferent nerves (CSAN) in rats with coronary ligation-induced CHF is enhanced by ANG II in the paraventricular nucleus (PVN). Under alpha-chloralose and urethane anesthesia, renal sympathetic nerve activity (RSNA) was recorded. The RSNA responses to electrical stimulation (5, 10, 20, and 30 Hz) of the CSAN were evaluated. Bilateral microinjection of the AT1-receptor antagonist losartan (50 nmol) into the PVN had no significant effects in the sham group, but it abolished the enhanced RSNA response to stimulation in the CHF group. Unilateral microinjection of three doses of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to stimulation. Although ANG II also potentiated the RSNA response to electrical stimulation in sham rats, the RSNA responses to stimulation after ANG II into the PVN in rats with CHF were much greater than in sham rats. The effects of ANG II were prevented by pretreatment with losartan into the PVN in CHF rats. These results suggest that the central gain of the CSAR is enhanced in rats with coronary ligation-induced CHF and that ANG II in the PVN augments the CSAR evoked by CSAN, which is mediated by the central angiotensin AT1 receptors in rats with CHF.     

Microinjection of ANG II into paraventricular nucleus enhances cardiac sympathetic afferent reflex in rats

The aims of present study were to determine whether angiotensin II (ANG II) in the paraventricular nucleus (PVN) is involved in the central integration of the cardiac sympathetic afferent reflex and whether this effect is mediated by the ANG type 1 (AT(1)) receptor. While the animals were under alpha-chloralose and urethane anesthesia, mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded in sinoaortic-denervated and cervical-vagotomized rats. A cannula was inserted into the left PVN for microinjection of ANG II. The cardiac sympathetic afferent reflex was tested by electrical stimulation (5, 10, 20, and 30 Hz in 10 V and 1 ms) of the afferent cardiac sympathetic nerves or epicardial application of bradykinin (BK) (0.04 and 0.4 microg in 2 microl). Microinjection of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to electrical stimulation. The percent change of RSNA response to 20- and 30-Hz stimulation increased significantly at the highest dose of ANG II (3 nmol). The effects of ANG II were prevented by pretreatment with losartan (50 nmol) into the PVN. Microinjection of ANG II (0.3 nmol) into the PVN significantly enhanced the RSNA responses to epicardial application of BK, which was abolished by pretreatment with losartan (50 nmol) into the PVN. These results suggest that exogenous ANG II in the PVN augments the cardiac sympathetic afferent reflex evoked by both electrical stimulation of cardiac sympathetic afferent nerves and epicardial application of BK. These central effects of ANG II are mediated by AT(1) receptors.     

Effects of synthetic ANF (rANF(3-28)) on sympathetic neurotransmission in the isolated perfused rat kidney.

The effects of synthetic atrial natriuretic factor (rANF(3-28)) on sympathetic neurotransmission in the isolated perfused rat kidney was examined. ANF (10(-10)-10(-7) M) had no significant effect on stimulus-induced (1 Hz, 2 min) overflow of endogenous norepinephrine (NE) from the rat kidney. ANF also failed to affect stimulus-induced overflow which was markedly enhanced as a result of prejunctional beta-adrenoceptor activation with isoproterenol (10(-6)M). However, over the same concentration range ANF markedly attenuated the vasoconstrictor response to nerve stimulation. In addition, ANF significantly reduced the renal vasoconstrictor responses to intra-arterial injections of NE and angiotensin II. These results suggest that, while ANF potently inhibits renal sympathetic neurotransmission by inhibition of vascular responsiveness to vasoconstrictor stimuli, ANF does not appear to have a prejunctional effect to alter NE release from renal sympathetic nerves.     

Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure

Chronic angiotensin-converting enzyme (ACE) inhibition has been shown to improve cardiac sympathetic nerve terminal function in heart failure. To determine whether similar effects could be produced by angiotensin II AT(1) receptor blockade, we administered the ACE inhibitor quinapril, angiotensin II AT(1) receptor blocker losartan, or both agents together, to rabbits with pacing-induced heart failure. Chronic rapid pacing produced left ventricular dilation and decline of fractional shortening, increased plasma norepinephrine (NE), and caused reductions of myocardial NE uptake activity, NE histofluorescence profile, and tyrosine hydroxylase immunostained profile. Administration of quinapril or losartan retarded the progression of left ventricular dysfunction and attenuated cardiac sympathetic nerve terminal abnormalities in heart failure. Quinapril and losartan together produced greater effects than either agent alone. The effect of renin-angiotensin system inhibition on improvement of left ventricular function and remodeling, however, was not sustained. Our results suggest that the effects of ACE inhibitors are mediated via the reduction of angiotensin II and that angiotensin II plays a pivotal role in modulating cardiac sympathetic nerve terminal function during development of heart failure. The combined effect of ACE inhibition and angiotensin II AT(1) receptor blockade on cardiac sympathetic nerve terminal dysfunction may contribute to the beneficial effects on cardiac function in heart failure.     

Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.     

Effect of losartan on insulin plasma concentrations and LPL activity in adipose tissue of hypertensive rats.

The aim of this study is to determine the effect of losartan on insulin and angiotensin II (Ang II) concentrations in plasma as well as on lipoprotein lipase activity (LPL) and angiotensin II content in the adipose tissue of hypertensive rats. Fifty male rats were divided in five groups. Group A served as controls. Group B underwent renal artery stenosis. Group C were administered losartan (10 mg/kg/day) per os, while rats in group D were submitted to renal artery stenosis and were treated with losartan as above. Group E was used as sham-operated control. The animals were sacrificed at day 21. Blood samples were collected, and perirenal adipose tissue was isolated. Furthermore, adrenal's were removed and their relative weight (adrenal weight/body weight) was used as an index of sympathetic stimulation. According to our results, renovascular hypertension resulted in lower insulin concentrations and higher Ang II content in plasma. In hypertensive rats, LPL activity was decreased, while the adrenals' relative weight was elevated. On the other hand, losartan administration resulted in normalization of insulin concentrations in plasma and adrenals' relative weight, with consequent up regulation of LPL activity in adipose tissue. In conclusion, renovascular hypertension interferes in lipid metabolism by reducing LPL activity in adipose tissue, while losartan administration reverses this effect by enhancing insulin release and reducing sympathetic nervous system (SNS) stimulation.     

Cardiac sympathetic afferent stimulation impairs baroreflex control of renal sympathetic nerve activity in rats

It is well known that cardiac sympathetic afferent reflexes contribute to increases in sympathetic outflow and that sympathetic activity can antagonize arterial baroreflex function. In this study, we tested the hypothesis that in normal rats, chemical and electrical stimulation of cardiac sympathetic afferents results in a decrease in the arterial baroreflex function by increasing sympathetic nerve activity. Under alpha-chloralose (40 mg/kg) and urethane (800 mg/kg i.p.) anesthesia, renal sympathetic nerve activity, mean arterial pressure, and heart rate were recorded. The arterial baroreceptor reflex was evaluated by infusion of nitroglycerin (25 microg i.v.) and phenylephrine (10 microg i.v.). Left ventricular epicardial application of capsaicin (0.4 microg in 2 microl) blunted arterial baroreflex function by 46% (maximum slope 3.5 +/- 0.3 to 1.9 +/- 0.2%/mmHg, P < 0.01). When the central end of the left cardiac sympathetic nerve was electrically stimulated (7 V, 1 ms, 20 Hz), the sensitivity of the arterial baroreflex was similarly decreased by 42% (maximum slope 3.2 +/- 0.3 to 1.9 +/- 0.4%/mmHg; P < 0.05). Pretreatment with intracerebroventricular injection of losartan (500 nmol in 1 microl of artificial cerebrospinal fluid) completely prevented the impairment of arterial baroreflex function induced by electrical stimulation of the central end of the left cardiac sympathetic nerve (maximum slope 3.6 +/- 0.4 to 3.1 +/- 0.5%/mmHg). These results suggest that the both chemical and electrical stimulation of the cardiac sympathetic afferents reduces arterial baroreflex sensitivity and the impairment of arterial baroreflex function induced by cardiac sympathetic afferent stimulation is mediated by central angiotensin type 1 receptors.     

Chronic losartan treatment decreases angiotensin II-mediated facilitation of noradrenaline release in the caudal artery of spontaneously hypertensive rats

Sympathetic activity is modulated by angiotensin II (AII), both at pre- and postsynaptic level in the rat caudal artery. In the spontaneously hypertensive rat (SHR), this artery receives more dense sympathetic innervation than blood vessels of normotensive strains. This fact seems to be linked to the enhanced pressor responses elicited by noradrenaline in SHR. In this work we describe, in the SHR, the effect of a chronic treatment with the angiotensin II AT1-receptor antagonist, losartan, in modulating noradrenergic mechanisms involved in caudal artery contraction. The effect of losartan is compared to that of captopril, given at doses leading to a similar decrease of both arterial blood pressure and left ventricular hypertrophy. The contractile response of caudal artery rings induced by endogenous noradrenaline released by low frequency transmural nerve stimulation (TNS) has been studied. Under our conditions, TNS (0.5-1 Hz) induced higher contractile responses in SHR treated with losartan than in the control and captopril-treated groups. This difference seems to be due to an increase of the postsynaptic effect of noradrenaline (NA) rather than to an increase of noradrenaline release from sympathetic endings, since i) DE50 value for NA was lower in losartan-treated SHR than in the other groups, and ii) AII induced a dose-dependent increase of TNS-evoked release of radioactivity from caudal artery segments loaded with [3H]-NA, in both control and captopril-treated groups but had no effect in the losartan-treated group. These results show that chronic treatment with losartan, although slightly enhancing the pressor effect of NA at postsynaptic level, fully supresses the facilitatory role of AII on NA release.     

Norepinephrine reuptake, baroreflex dynamics, and arterial pressure variability in rats

This study examined the effect of norepinephrine reuptake blockade with desipramine (DMI) on the spontaneous variability of the simultaneously recorded arterial pressure (AP) and renal sympathetic nerve activity (SNA) in conscious rats. Acute DMI administration (2 mg/kg iv) depressed AP Mayer waves ( approximately 0.4 Hz) and increased low-frequency (<0.2 Hz) components of AP variability. DMI decreased renal SNA variability, especially due to the abolition of oscillations related to Mayer waves. To examine whether DMI-induced changes in AP and renal SNA variabilities could be explained by alterations in the dynamic characteristics of the baroreceptor reflex loop, the frequency responses of mean AP to aortic depressor nerve stimulation were studied in urethan-anesthetized rats. DMI accentuated the low-pass filter properties of the transfer function without significantly altering the fixed time delay. The frequency responses of iliac vascular conductance to stimulation of the lumbar sympathetic chain were studied in an additional group of anesthetized rats. DMI did not markedly alter the low-pass filter properties of the transfer function and slightly increased the fixed time delay. These results suggest that the DMI-induced decrease in the dynamic gain of the baroreceptor reflex is responsible for the decreased spontaneous renal SNA variability and the accompanying increased AP variability. The "slowing down" of baroreflex responses cannot be attributed to an effect of DMI at the vascular neuroeffector junction.     

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.     

Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) A2a receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of beta-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS A1 adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS A1 receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinejctions into the NTS of the selective A1 receptor agonist N6-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after beta-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS A1 receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral beta-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in iliac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS A1 receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS A1 receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and beta-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors.     

Brain angiotensin-converting enzyme activity and autonomic regulation in heart failure

Several recent studies suggest an important role for the brain renin-angiotensin system in the pathogenesis of heart failure. Angiotensin-converting enzyme (ACE) activity and binding of angiotensin type 1 (AT1) receptors, which mediate the central effects of ANG II, are increased in heart failure. The present study examined the relationship between brain ACE activity and the autonomic dysregulation characteristic of rats with congestive heart failure. Rats with heart failure (HF) induced by coronary artery ligation and sham-operated control (SHAM) rats were treated with chronic (28 days) third cerebral ventricle [intracerebroventricular (ICV)] or intraperitoneal (IP) infusion of a low dose of the ACE inhibitor enalaprilat (ENL) or vehicle (VEH). VEH-treated HF rats had increased sodium consumption, reduced urine sodium and urine volume, and increased sympathetic nerve activity with impaired baroreflex regulation. These responses were minimized or prevented by ICV ENL started 24 h after coronary ligation. IP ENL at the low dose used in these studies had no beneficial effects on HF rats. Neither IP nor ICV ENL had any substantial effect on the SHAM rats. The findings confirm a critically important contribution of the brain renin-angiotensin system to the pathophysiology of congestive heart failure.     

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.     

Cardiac sympathetic afferent stimulation augments the arterial chemoreceptor reflex in anesthetized rats.

Chronic heart failure (CHF) is well known to be associated with both an enhanced chemoreceptor reflex and an augmented cardiac "sympathetic afferent reflex" (CSAR). The augmentation of the CSAR may play an important role in the enhanced chemoreceptor reflex in the CHF state because the same central areas are involved in the sympathetic outputs of both reflexes. We determined whether chemical and electrical stimulation of the CSAR augments chemoreceptor reflex function in normal rats. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The chemoreceptor reflex was tested by unilateral intra-carotid artery bolus injection of potassium cyanide (KCN) and nicotine. We found that 1) left ventricular epicardial application of capsaicin increased the pressor responses and the RSNA responses to chemoreflex activation induced by both KCN and nicotine; 2) when the central end of the left cardiac sympathetic nerve was electrically stimulated, both the pressor and the RSNA responses to chemoreflex activation induced by KCN were increased; 3) pretreatment with intracerebroventricular injection of losartan (500 nmol) completely prevented the enhanced chemoreceptor reflex induced by electrical stimulation of the cardiac sympathetic nerve; and 4) bilateral microinjection of losartan (250 pmol) into the nucleus tractus solitarii (NTS) completely abolished the enhanced chemoreceptor reflex by epicardial application of capsaicin. These results suggest that both the chemical and electrical stimulation of the CSAR augments chemoreceptor reflex and that central ANG II, specially located in the NTS, plays a major role in these reflex interactions.     

Sympathetic responses to exercise in myocardial infarction rats: a role of central command

In congestive heart failure (CHF), exaggerated sympathetic activation is observed during exercise, which elicits excess peripheral vasoconstriction. The mechanisms causing this abnormality are not fully understood. Central command is a central neural process that induces parallel activation of motor and cardiovascular systems. This study was undertaken to determine whether central command serves as a mechanism that contributes to the exaggerated sympathetic response to exercise in CHF. In decerebrated rats, renal and lumbar sympathetic nerve responses (RSNA and LSNA, respectively) to 30 s of fictive locomotion were examined. The fictive locomotion was induced by electrical stimulation of the mesencephalic locomotor region (MLR). The study was performed in control animals (fractional shortening > 40%) and animals with myocardial infarctions (MI; fractional shortening < 30%). With low stimulation of the MLR (current intensity = 20 microA), the sympathetic responses were not significantly different in the control (RSNA: +18 +/- 4%; LSNA: +3 +/- 2%) and MI rats (RSNA: +16 +/- 5%; LSNA: +8 +/- 3%). With intense stimulation of the MLR (50 microA), the responses were significantly greater in MI rats (RSNA: +127 +/- 15%; LSNA: +57 +/- 10%) than in the control rats (RSNA: +62 +/- 5%; LSNA: +21 +/- 6%). In this study, the data demonstrate that RSNA and LSNA responses to intense stimulation of the MLR are exaggerated in MI rats. We suggest that intense activation of central command may play a role in evoking exaggerated sympathetic activation and inducing excessive peripheral vasoconstriction during exercise in CHF.     

Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: role of superoxide anion

Studies have shown that the superoxide mechanism is involved in angiotensin II (ANG II) signaling in the central nervous system. We hypothesized that ANG II activates sympathetic outflow by stimulation of superoxide anion in the paraventricular nucleus (PVN) of streptozotocin (STZ)-induced diabetic rats. In α-chloralose- and urethane-anesthetized rats, microinjection of ANG II into the PVN (50, 100, and 200 pmol) produced dose-dependent increases in renal sympathetic nerve activity (RSNA), arterial pressure (AP), and heart rate (HR) in control and STZ-induced diabetic rats. There was a potentiation of the increase in RSNA (35.0 ± 5.0 vs. 23.0 ± 4.3%, P < 0.05), AP, and HR due to ANG II type I (AT(1)) receptor activation in diabetic rats compared with control rats. Blocking endogenous AT(1) receptors within the PVN with AT(1) receptor antagonist losartan produced significantly greater decreases in RSNA, AP, and HR in diabetic rats compared with control rats. Concomitantly, there were significant increases in mRNA and protein expression of AT(1) receptor with increased superoxide levels and expression of NAD(P)H oxidase subunits p22(phox), p47(phox), and p67(phox) in the PVN of rats with diabetes. Pretreatment with losartan (10 mg·kg(-1)·day(-1) in drinking water for 3 wk) significantly reduced protein expression of NAD(P)H oxidase subunits (p22(phox) and p47(phox)) in the PVN of diabetic rats. Pretreatment with adenoviral vector-mediated overexpression of human cytoplasmic superoxide dismutase (AdCuZnSOD) within the PVN attenuated the increased central responses to ANG II in diabetes (RSNA: 20.4 ± 0.7 vs. 27.7 ± 2.1%, n = 6, P < 0.05). These data support the concept that superoxide anion contributes to an enhanced ANG II-mediated signaling in the PVN involved with the exaggerated sympathoexcitation in diabetes.     

Inhibition of vasoconstrictor responses by 6-keto-PGE1 in the feline mesenteric vascular bed

The effects of 6-keto-PGE₁ on vascular resistance and vascular responses to sympathetic nerve stimulation and vasoconstrictor hormones were investigated in the feline mesenteric vascular bed. Infusions of 6-keto-PGE₁ into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin II. The effects of 6-keto-PGE₁ and PGE₁ on vascular resistance and vasoconstrictor responses were quite similar and both substances inhibited responses to nerve stimulation and pressor hormones in a reversible manner. Responses to nerve stimulation, norepinephrine and angiotensin II were inhibited to a similar extent during infusion of 6-keto-PGE₁ and PGE₁. Results of these studies suggest that 6-keto-PGE₁, a newly identified prostaglandin metabolite, and PGE₁ possess the ability to inhibit the vasconstrictor effects of sympathetic nerve stimulation and pressor hormones by a nonspecific action on vascular smooth muscle in the feline small intestine.     

Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin

Increasing renal pelvic pressure results in PGE(2)-mediated release of substance P. Substance P increases afferent renal nerve activity (ARNA), which leads to a reflex increase in urinary sodium excretion (U(Na)V). Endogenous ANG II modulates the responsiveness of renal mechanosensory nerves. The ARNA and U(Na)V responses are suppressed by low- and enhanced by high-sodium diet. We examined whether the ARNA responses are altered in rats with congestive heart failure (CHF), a condition characterized by increased ANG II and sodium retention. The ARNA responses to increasing renal pelvic pressure 相似文献   

Dynamic relationship between sympathetic nerve activity and renal blood flow: a frequency domain approach

Blood pressure displays an oscillation at 0.1 Hz in humans that is well established to be due to oscillations in sympathetic nerve activity (SNA). However, the mechanisms that control the strength or frequency of this oscillation are poorly understood. The aim of the present study was to define the dynamic relationship between SNA and the vasculature. The sympathetic nerves to the kidney were electrically stimulated in six pentobarbital-sodium anesthetized rabbits, and the renal blood flow response was recorded. A pseudo-random binary sequence (PRBS) was applied to the renal nerves, which contains equal spectral power at frequencies in the range of interest (<1 Hz). Transfer function analysis revealed a complex system composed of low-pass filter characteristics but also with regions of constant gain. A model was developed that accounted for this relationship composed of a 2 zero/4 pole transfer function. Although the position of the poles and zeros varied among animals, the model structure was consistent. We also found the time delay between the stimulus and the RBF responses to be consistent among animals (mean 672 +/- 22 ms). We propose that the identification of the precise relationship between SNA and renal blood flow (RBF) is a fundamental and necessary step toward understanding the interaction between SNA and other physiological mediators of RBF.     

AT1 receptors in the nucleus tractus solitarii mediate the interaction between the baroreflex and the cardiac sympathetic afferent reflex in anesthetized rats

The cardiac "sympathetic afferent" reflex (CSAR) has been reported to increase sympathetic outflow and depress baroreflex function via a central angiotensin II (ANG II) mechanism. In the present study, we examined the role of ANG II type 1 (AT(1)) receptors in the nucleus tractus solitarii (NTS) in mediating the interaction between the CSAR and the baroreflex in anesthetized rats. We examined the effects of bilateral microinjection of AT(1) receptor antagonist losartan (100 pmol) into the NTS on baroreflex control of renal sympathetic nerve activity (RSNA) before and after CSAR activation by epicardial application of capsaicin (0.4 microg). Using single-unit extracellular recording, we further examined the effects of CSAR activation on the barosensitivity of barosensitive NTS neurons and the effects of intravenous losartan (2 mg/kg) on CSAR-induced changes in activity of NTS barosensitive neurons. Bilateral NTS microinjection of losartan significantly attenuated the increases in arterial pressure, heart rate, and RSNA evoked by capsaicin but also markedly (P < 0.01) reversed the CSAR-induced blunted baroreflex control of RSNA (Gain(max) from 1.65 +/- 0.10 to 2.22 +/- 0.11%/mmHg). In 17 of 24 (70.8%) NTS barosensitive neurons, CSAR activation significantly (P < 0.01) inhibited the baseline neuronal activity and attenuated the neuronal barosensitivity. In 11 NTS barosensitive neurons, intravenous losartan effectively (P < 0.01) normalized the decreased neuronal barosensitivity induced by CSAR activation. In conclusion, blockade of NTS AT(1) receptors improved the blunted baroreflex during CSAR activation, suggesting that the NTS plays an important role in processing the interaction between the baroreflex and the CSAR via an AT(1) receptor-dependent mechanism.