Functional properties of Pfr(Tic)amide and BIBP3226 at human neuropeptide FF2 receptors

The functional characteristics of two putative neuropeptide FF (NPFF) antagonists, BIBP3226 and PFR(Tic)amide, on the human neuropeptide FF receptor subtype 2 (hNPFF2) were investigated. Surprisingly, PFR(Tic)amide was shown to exhibit agonist properties in the [³⁵S]guanosine-5′-O-(3-thio)triphosphate ([³⁵S]GTPγS) binding assay. The efficacy of PFR(Tic)amide was significantly greater than that of (1DMe)Y8Fa, a stable analog of NPFF, and PFR(Tic)amide can therefore be classified as a ‘super-agonist’. BIBP3226 did act as a reversible competitive antagonist on the hNPFF2 receptor. However, high concentrations of BIBP3226 also non-specifically increased [³⁵S]GTPγS binding. The usefulness of BIBP3226 as an antagonist tool on the NPFF receptor is thus limited.     

Modulation of naloxone-precipitated morphine withdrawal syndromes in rats by neuropeptide FF analogs

Neuropeptide FF (NPFF) has been reported to be an endogenous anti-opioid peptide that has significant effects on morphine tolerance and dependence. In the present study, we examined the chronic effects of NPFF and its synthetic analogs: the putative agonist, PFRFamide, and the putative antagonists, dansyl-PQRamide and PFR(Tic)amide on naloxone-precipitated morphine withdrawal syndromes in rats. After a 5-day co-administration with morphine [5 mg/kg, intraperitoneally (i.p.), twice per day (b.i.d.)] and the tested peptide [intracerebroventricularly (i.c.v.) or i.p., b.i.d.], naloxone (4 mg/kg, i.p.) was given systemically to evaluate the severity of the morphine withdrawal syndromes. Our results revealed that NPFF significantly potentiated the overall morphine withdrawal syndromes and, on the contrary, dansyl-PQRamide attenuated these syndromes. These results clearly indicate that modulation of the NPFF system in the mammalian central nervous system has significant effects on opiate dependence. In addition, morphine withdrawal syndromes could be practically applied as a valid parameter to functionally characterize the putative NPFF agonists and antagonists.     

Rat NPFF(1) receptor-mediated signaling: functional comparison of neuropeptide FF (NPFF), FMRFamide and PFR(Tic)amide

Neuropeptide FF (NPFF) participates in many physiological functions associated with opioids in the mammalian CNS. We established a pheochromocytoma PC-12 cell line clone stably expressing rat NPFF1 receptors. Both NPFF and FMRFamide activated NPFF1 receptors to couple with Gi/o protein and inhibited adenylyl cyclase activity in PC-12/rNPFF1 cells, but there were no effects on MAPKs (ERK1/2 and p38 MAPK) or PI3K/Akt pathway. FMRFamide also inhibited DARPP-32/Thr34 phosphorylation in the presence of forskolin. Similarly, PFR(Tic)amide, a 'super-agonist' of NPFF receptors, inhibited the production of cAMP and slightly decreased DARPP-32/Thr34 phosphorylation in PC-12/rNPFF1 cells. Intracerebroventricular injections of PFR(Tic)amide blocked behavioral sensitization of locomotor activity to amphetamine, and intrathecal injection of PFR(Tic)amide caused a dose-dependent antinociception in vivo in rats. Thus, "over-activation" of NPFF receptors by PFR(Tic)amide induced different bio-effects from those induced by NPFF in vivo.     

In vitro and in vivo studies of dansylated compounds, the putative agonists and antagonists on neuropeptide FF receptors

To further evaluate the importance of C-terminal modification of neuropeptide FF (NPFF), in the present work, four dansylated NPFF analogues, including two putative agonists (dansyl-PQRFamide and dansyl-GSRFamide) and two putative antagonists (dansyl-PQRamide and dansyl-GSRamide), were synthesized and investigated to address their potencies and efficacies in a series of in vitro and in vivo assays. (1) In the isolated mouse colon bioassay, the four dansylated compounds showed agonistic profiles: both dansyl-GSRFamide (1-10 microM) and dansyl-GSRamide (1-10 microM) dose-dependently caused colonic contractions, which were attenuated by pretreatment with BIBP3226; dansyl-PQRFamide and dansyl-PQRamide evoked modest colonic contractions at a high dose of 50 microM. (2) In urethane-anaesthetized rats, both dansyl-PQRFamide (50-300 nmol/kg, i.v.) and dansyl-GSRFamide (15-50 nmol/kg, i.v.) dose-dependently increased the mean arterial pressure and heart rate in a manner similar to NPFF (50-300 nmol/kg, i.v.); on the contrary, the two putative antagonists (100-800 nmol/kg, i.v.) decreased blood pressure in a dose-dependent manner. All the results suggest that dansyl-PQRFamide and dansyl-GSRFamide are NPFF full agonists; in contrast, dansyl-GSRamide and dansyl-PQRamide behave as agonists in vitro and antagonists in vivo on NPFF receptors. The findings reveal that the C-terminal Phe might be a crucial residue to determine the efficacy. In addition, the novel analogue dansyl-GSRFamide may be developed as a highly potent agonist to investigate the NPFF system.     

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.     

The role of central vasopressin receptors in the modulation of autonomic cardiovascular controls: a spectral analysis study

Although it has been suggested that vasopressin (VP) acts within the central nervous system to modulate autonomic cardiovascular controls, the mechanisms involved are not understood. Using nonpeptide, selective V(1a), V(1b), and V(2) antagonists, in conscious rats, we assessed the roles of central VP receptors, under basal conditions, after the central application of exogenous VP, and after immobilization, on cardiovascular short-term variability. Equidistant sampling of blood pressure (BP) and heart rate (HR) at 20 Hz allowed direct spectral analysis in very-low frequency (VLF-BP), low-frequency (LF-BP), and high-frequency (HF-BP) blood pressure domains. The effect of VP antagonists and of exogenous VP on body temperature (T(b)) was also investigated. Under basal conditions, V(1a) antagonist increased HF-BP and T(b), and this was prevented by metamizol. V(1b) antagonist enhanced HF-BP without affecting T(b), and V(2) antagonist increased VLF-BP variability which could be prevented by quinapril. Immobilization increased BP, LF-BP, HF-BP, and HF-HR variability. V(1a) antagonist prevented BP and HR variability changes induced by immobilization and potentiated tachycardia. V(1b) antagonist prevented BP but not HR variability changes, whereas V(2) antagonist had no effect. Exogenous VP increased systolic arterial pressure (SAP) and HF-SAP variability, and this was prevented by V(1a) and V(1b) but not V(2) antagonist pretreatment. Our results suggest that, under basal conditions, VP, by stimulation of V(1a), V(1b), and cognate V(2) receptors, buffers BP variability, mostly due to thermoregulation. Immobilization and exogenous VP, by stimulation of V(1a) or V(1b), but not V(2) receptors, increases BP variability, revealing cardiorespiratory adjustment to stress and respiratory stimulation, respectively.     

Central vasopressin V(1a) and V(1b) receptors modulate the cardiovascular response to air-jet stress in conscious rats.

This study investigates the contribution of central vasopressin receptors in the modulation of systolic arterial pressure (SAP) and heart rate (HR) response to air-jet stress in conscious Wistar rats equipped with a femoral arterial catheter and intracerebroventricular cannula using novel non-peptide and selective vasopressin V(1a) (SR49059) and V(1b) (SSR149415) antagonists. The effects of stress on SAP and HR were evaluated by measuring the maximal response to stress, the latency of the maximal response, the duration of the recovery period, and the increase in the low frequency (LF) short-term variability component. Stress induced a parallel and almost immediate increase in both SAP and HR, followed by enhanced LF SAP variability in the recovery period. Pretreatment of rats with V(1a) antagonist did not affect the maximal increase or the latency of SAP and HR response to acute stress, but shortened the recovery period of SAP and HR and prevented the increase in LF SAP. The V(1b) antagonist reduced the maximal increase in SAP without affecting HR and their latencies, shortened the recovery period of SAP and inhibited the increase in LF SAP variability. These results indicate that both central V(1a) and V(1b) receptors mediate cardiovascular changes induced by air-jet stress in conscious rats.     

Evidence for a role of AT(2) receptors at the CVLM in the cardiovascular changes induced by low-intensity physical activity in renovascular hypertensive rats

In the present study, we evaluated the involvement of the rennin-angiotensin system (RAS) in the control of the blood pressure (BP), baroreceptor-mediated bradycardia and the reactivity of caudal ventrolateral medulla (CVLM) neurons to Ang II and to AT(2) receptor antagonist in sedentary or trained renovascular hypertensive rats. Physical activity did not significantly change the baseline mean arterial pressure (MAP), heart rate (HR) or the sensitivity of the baroreflex bradycardia in normotensive Sham rats. However, in 2K1C hypertensive rats, physical activity induced a significant fall in baseline MAP and HR and produced an improvement of the baroreflex function (bradycardic component). The microinjections of Ang II into the CVLM produced similar decreases in MAP in all groups, Sham and 2K1C, sedentary and trained rats. The hypotensive effect of Ang II at the CVLM was blocked by previous microinjection of the AT(2) receptors antagonist, PD123319, in all groups of rats. Unexpectedly, microinjection of PD123319 at the CVLM produced a depressor effect in 2K1C sedentary that was attenuated in 2K1C trained rats. No significant changes in MAP were observed after PD123319 in Sham rats, sedentary or trained. These data showed that low-intensity physical activity is effective in lowering blood pressure and restoring the sensitivity of the baroreflex bradycardia, however these cardiovascular effects are not accompanied by changes in the responsiveness to Ang II at CVLM in normotensive or hypertensive, 2K1C rats. In addition, the blood pressure changes observed after AT(2) blockade in 2K1C rats suggest that hypertension may trigger an imbalance of AT(1)/AT(2) receptors at the CVLM that may be restored, at least in part, by low-intensity physical activity.     

Inhibition of neuropeptide FF (NPFF)-induced hypothermia and anti-morphine analgesia by RF9, a new selective NPFF receptors antagonist

Neuropeptide FF (NPFF) belongs to a neuropeptide family including two precursors (pro-NPFF_A and pro-NPFF_B) and two receptors (NPFF₁ and NPFF₂). Very recently, the novel compound RF9 was reported as the truly selective antagonist on NPFF receptors. The present study examined the effects of RF9 on the hypothermia and anti-morphine action induced by NPFF in mice. (1) RF9 injected into the third ventricle was devoid of any residual agonist activity, but it completely antagonized the hypothermic effects of NPFF (30 or 45 nmol) after cerebral administration in mice; (2) RF9 did not alter the tail-flick latency and morphine analgesia in nociceptive test, however, co-administration of RF9 prevented the anti-morphine action of intracerebroventricularly applied NPFF (10 nmol, i.c.v.) in the mouse tail-flick assay. Collectively, our data indicate that RF9, behaving as a truly pure NPFF receptors antagonist, prevents NPFF-induced drops of the body temperature and morphine analgesia in mice. In addition, it further confirms that the hypothermia and anti-morphine action of NPFF are mediated directly by NPFF receptors.     

Histamine receptor H1 in the nucleus tractus solitarii regulates arterial pressure and heart rate in rats

Axons of histamine (HA)-containing neurons are known to project from the posterior hypothalamus to many areas of the brain, including the nucleus tractus solitarii (NTS), a central brain structure that plays an important role in regulating arterial pressure. However, the functional significance of NTS HA is still not fully established. In this study, we microinjected HA or 2-pyridylethylamine, a HA-receptor H(1)-specific agonist, into the NTS of urethane-anesthetized Wister rats to identify the potential functions of NTS HA on cardiovascular regulation. When HA or H(1)-receptor-specific agonist was bilaterally microinjected into the NTS, mean arterial pressure (MAP) and heart rate (HR) were significantly increased, whereas pretreatment with the H(1)-receptor-specific antagonist cetirizine into the NTS significantly inhibited the cardiovascular responses. The maximal responses of MAP and HR changes induced by HA or H(1)-receptor-specific agonist were dose dependent. We also confirmed gene expression of HA receptors in the NTS and that the expression level of H(1) mRNA was higher than that of the other subtypes. In addition, we found that H(1) receptors are mainly expressed in neurons of the NTS. These findings suggested that HA within the NTS may play a role in regulating cardiovascular homeostasis via activation of H(1) receptors expressed in the NTS neurons.     

Neuropeptide FF receptors exert contractile activity via inhibition of nitric oxide release in the mouse distal colon

Neuropeptide FF (NPFF) and NPVF, two closely NPFF related peptides, have different affinities for the two NPFF receptors (NPFF1 and NPFF2). To assess the peripheral effects of NPFF receptors in the gastrointestinal tract motility, NPFF and NPVF were tested in the mouse isolated distal colon. Both NPFF (1-15 microM) and NPVF (1-15 microM) dose-dependently caused significant colonic contractions. Pre-treatment with the putative NPFF antagonist, BIBP3226 (30 microM) abolished the contractile responses to the two neuropeptides (3 microM). They had no additional contractile activities in colonic preparations contracted by Nomega-nitro-L-arginine (30 microM). Moreover, the contractions of these two neuropeptides were weakened by L-arginine (2 mM). The responses to NPFF (5 microM) and NPVF (5 microM) were not modified by atropine or naloxone (1 microM). Furthermore, NPFF (1 microM) and NPVF (1 microM) did not influence the contractive responses to acetylcholine (0.1-10 microM), morphine (1 microM) or nociceptin (0.1 microM). These data suggest that NPFF and NPVF cause contractions of the mouse distal colon via their NPFF receptors and this effect is mediated by NO but not by cholinergic pathways, independently from opioid system. In addition, the isolated bioassay may be applied as a simple parameter to characterize the potential NPFF agonists and antagonists.     

Dansyl-PQRamide, a possible neuropeptide FF receptor antagonist, induces conditioned place preference

Neuropeptide FF (NPFF) is an endogenous anti-opioid peptide. NPFF could potentiate the naloxone-precipitated morphine withdrawal syndromes in morphine-dependent rats, indicating the possible involvement of the endogenous NPFF system in opioid analgesia and dependence. The present study was performed to examine the effects of dansyl-PQRamide (dns-PQRa), a putative NPFF antagonist, on conditioned place preference (CPP), in addition, its interaction with the opioid system. Two CPP experiments were conducted. First, rats were treated with dns-PQRa (4-13 mg/kg, i.p.) and paired with the non-preferred compartment while the vehicle was paired with the preferred compartment. Second, similar to experiment 1 except naloxone (1 mg/kg, i.p.) was given 10 min prior to each dns-PQRa administration. The post-drug place preference was examined after 4 alternative pairings. Another group of animals after repetitive dns-PQRa treatments were analyzed for levels of neurotransmitters in discrete brain areas. Dns-PQRa (4-13 mg/kg, i.p.) induced a significant dose-dependent CPP. The dns-PQRa-induced CPP was completely blocked by pretreatment with 1 mg/kg i.p. naloxone, while naloxone alone did not induce any place aversion. The chronic dns-PQRa-treated (13 mg/kg, i.p., b.i.d.) rats caused a significant increase in 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the olfactory tubercle compared to the vehicle-treated controls. There was also an increase in the turnover of serotonin in the olfactory tubercle, nucleus accumbens and medial prefrontal cortex. These results suggest that blockade of the NPFF system produces rewarding, possibly via an inhibition of the anti-opioid action of NPFF. These results also reveal a close relationship between NPFF, drug rewarding and the dopaminergic and serotoninergic neurons in the mesolimbic system.     

Gender dependency of circadian blood pressure and heart rate profiles in spontaneously hypertensive rats: effects of beta-blockers

This study investigated (i) blood pressure (BP), heart rate (HR), and their relation to urinary NOx and eNOS protein expression in male and female spontaneously hypertensive rats (SHR), as well as (ii) gender-dependent cardiovascular effects of nebivolol (NEB) in comparison to metoprolol (MET) in SHR. BP and HR were measured telemetrically after a single intraperitoneal application of NEB or MET at 07.00 and 19.00 h in male rats and at 19.00 h in proestrus female rats. The two β-blockers varied in time of decreasing BP and HR and also in duration. In males, MET decreased BP and HR for few hours exclusively when applied at the onset of the activity phase (i.e., at 19.00 h), while after its application at 07.00 h, BP and HR were unchanged. In females, MET also caused a short-lasting BP and HR reduction, with the effect being more pronounced than in males. In males, NEB at either dosing time decreased HR and BP to a greater extent than did MET. This effect was evident both during the activity and rest periods and persisted for at least five days. In females, NEB provoked a similar, but more pronounced, effect on BP and HR in comparison to males. These findings demonstrate that significant gender-dependent differences in the circadian profile of BP and HR exist. BP and urinary NOx as well as eNOS expression are inversely correlated, and the cardiovascular effects of NEB and MET vary, depending on the time of application as well as gender.     

Gender Dependency of Circadian Blood Pressure and Heart Rate Profiles in Spontaneously Hypertensive Rats: Effects of Beta‐Blockers

This study investigated (i) blood pressure (BP), heart rate (HR), and their relation to urinary NOx and eNOS protein expression in male and female spontaneously hypertensive rats (SHR), as well as (ii) gender‐dependent cardiovascular effects of nebivolol (NEB) in comparison to metoprolol (MET) in SHR. BP and HR were measured telemetrically after a single intraperitoneal application of NEB or MET at 07.00 and 19.00 h in male rats and at 19.00 h in proestrus female rats. The two β‐blockers varied in time of decreasing BP and HR and also in duration. In males, MET decreased BP and HR for few hours exclusively when applied at the onset of the activity phase (i.e., at 19.00 h), while after its application at 07.00 h, BP and HR were unchanged. In females, MET also caused a short‐lasting BP and HR reduction, with the effect being more pronounced than in males. In males, NEB at either dosing time decreased HR and BP to a greater extent than did MET. This effect was evident both during the activity and rest periods and persisted for at least five days. In females, NEB provoked a similar, but more pronounced, effect on BP and HR in comparison to males. These findings demonstrate that significant gender‐dependent differences in the circadian profile of BP and HR exist. BP and urinary NOx as well as eNOS expression are inversely correlated, and the cardiovascular effects of NEB and MET vary, depending on the time of application as well as gender.     

Study of the N-terminal part of peptidic selective NPFF(2) agonists

Neuropeptide FF (NPFF) has been shown to act as an endogenous anti-analgesic peptide. In this paper, several peptide analogs of the selective ligand dNP(NMe)AFLFQPQRF-NH(2) modified in the putative address segment, were designed to be selective NPFF(2) receptor probes, synthesized and assayed. One peptide dA(NMe)AAFLFQPQRF-NH(2) displays a very high affinity for NPFF(2) receptors transfected in CHO cells, and a high selectivity versus NPFF(1) receptors. The exact residues carried in the N-terminal part of the ligands are not decisive to obtain a high affinity only the length of the peptide in itself seems important to create selectivity.     

Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity

This study examined the importance of direct central nervous system (CNS) actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, completely restored to control values plasma glucose levels (384+/-58 to 102+/-28 and 307+/-38 to 65+/-7 mg/dl, respectively), food intake, BP, and HR (304+/-8 to 364+/-7 and 317+/-13 to 423+/-9 bpm, respectively). Combined blockade of alpha1-, beta1-, and beta2-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of beta3-adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral alpha1, beta1, beta2, and beta3-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via alpha1- and beta1/beta2-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.     

Cardiovascular effects of neuropeptide FF antagonists

The neuropeptide FF (NPFF) antagonist desaminotyrosyl-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH2 dose-dependently reversed NPFF-induced elevation of blood pressure in anesthetized rats after intravenous injection without causing a significant change of blood pressure and heart rate by itself. However, another antagonist dansyl-Pro-Gln-Arg-NH2 produced a significant drop of the mean arterial pressure only at a large dose (10 micromol/kg body weight), but reversal of the NPFF-induced hypertension was modest. Consequently and contrary to the conclusions of a previous study, NPFF antagonists cannot be identified simply by measuring the changes in the hemodynamic parameters upon the injection of the compounds alone and without a subsequent NPFF challenge.     

侧脑室注射一叶萩碱的心血管效应及作用机制

在麻醉大鼠侧脑室注射左旋一叶Ｑｉｕ碱（Ｌ－Ｓｅｃ）,记录动脉血压（ＡＰ）、心率（ＨＲ）及肾交感神经放电（ＲＳＮＤ）,观察前脑室周系统ＧＡＢＡ能紧张性活动改变引起的心血管效应。结果如下：（１）Ｌ－Ｓｅｃ可引起ＲＳＮＤ增加、ＡＰ升高和ＨＲ加快,并呈一定剂量－效应关系;但Ｌ－Ｓ盈余 于ｂｉｃｕｃｕｌｌｉｎｅ（Ｂｉｃ）。（２）Ｌ－Ｓｅｃ既能拮抗ｍｕｓｃｉｍｏｌ（Ｍｕｓ）,又能拮抗ｂａｃｌｏｆｅｎ（Ｂａｃ）     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Putative role of the NTS in alterations in neural control of the circulation following exercise training in rats

Exercise training (ExTr) has been associated with alterations in neural control of the circulation, including effects on arterial baroreflex function. The nucleus tractus solitarius (NTS) is the primary termination site of cardiovascular afferents and critical in the regulation of baroreflex-mediated changes in heart rate (HR) and sympathetic nervous system outflow. The purpose of the present study was to determine whether ExTr is associated with alterations in neurotransmitter regulation of neurons involved in control of cardiovascular function at the level of the NTS. We hypothesized that ExTr would increase glutamatergic and reduce GABAergic transmission in the NTS and that, collectively, these changes would result in a greater overall sympathoinhibitory drive from the NTS in ExTr animals. To test these hypotheses, male Sprague-Dawley rats were treadmill trained or maintained under sedentary conditions for 8-10 wk. NTS microinjections were performed in Inactin-anesthetized animals instrumented to record mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Generalized activation of the NTS with unilateral microinjections of glutamate (1-10 mM, 30 nl) produced dose-dependent decreases in MAP, HR, and LSNA that were unaffected by ExTr. Bilateral inhibition of NTS with the GABAA agonist muscimol (1 mM, 90 nl) produced increases in MAP and LSNA that were blunted by ExTr. In contrast, pressor and sympathoexcitatory responses to bilateral microinjections of the ionotropic glutamate receptor antagonist, kynurenate (40 mM, 90 nl), were similar between groups. Bradycardic responses to bilateral microinjections of the GABAA antagonist bicuculline (0.1 mM, 90 nl) were attenuated by ExTr. These data indicate that alterations in neurotransmission at the level of the NTS contribute importantly to regulation of HR and LSNA in ExTr animals. In addition to alterations at NTS, these experiments suggest indirectly that changes in other cardiovascular nuclei contribute to the observed alterations in neural control of the circulation following ExTr.