Physical training and baroreceptor control of sympathetic nerve activity in humans

In nine sedentary subjects (16.5 +/- 0.4 years, mean +/- SEM) we measured blood pressure (Finapres device), heart rate (electrocardiogram), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) at rest and during intravenous infusion of phenylephrine and nitroprusside. These measurements were performed before and after 10 weeks of endurance training (2 h/d, 5 d/wk) that increased maximum oxygen consumption from 34.8 +/- 2.1 to 40.4 +/- 1.8 mL/kg per minute (P < .02). Basal mean blood pressure and muscle sympathetic nerve activity were lower after than before endurance training (86.5 +/- 2.6 versus 97.5 +/- 1.8 mm Hg, P < .05, and 14.0 +/- 1.8 versus 21.2 +/- 2.3 bursts per minute, P < .02), and the changes in these variables were closely related (r = .95, P < .01). Similar mean blood pressure increases induced by phenylephrine caused greater reductions in heart rate and muscle sympathetic nerve activity after than before endurance training (-8.6 +/- 0.8 versus -6.1 +/- 1.1 beats per minute, P = NS, and -78.0 +/- 4.6% versus -53.6 +/- 4.8%, P < .05). Likewise, similar mean blood pressure reductions induced by nitroprusside caused greater increases in heart rate and muscle sympathetic nerve activity after than before endurance training (18.6 +/- 3.0 versus 12.4 +/- 2.4 beats per minute, P < .05, and 128.1 +/- 26% versus 63.2 +/- 11%, P < .02). No alteration in hemodynamics, oxygen consumption, muscle sympathetic nerve activity, and baroreceptor reflex sensitivity occurred in four other age-matched sedentary subjects studied before and after a 10-week observation period without endurance training.(ABSTRACT TRUNCATED AT 250 WORDS)     

The chronotropic reaction and the dynamics of the blood supply to the forearm during modulation of the baroreceptor reflex activity in patients with arterial hypertension

Original method of baroreflex activation and deactivation was described. Bradycardia and vasodilatation of the forearm vessels were observed at baroreflex activation. Tachycardia and forearm blood flow reduction were observed at baroreflex deactivation. The sensitivity of baroreflex heart component vas shown to depend upon the arterial pressure and a baseline cardiac cycle duration in both normo- and hypertensive subjects.     

Baroreflex control of muscle sympathetic nerve activity is attenuated in the elderly

To determine whether the baroreflex control of sympathetic nerve activity is attenuated in the elderly, muscle sympathetic nerve activity (MSNA) from the tibial nerve was monitored using microneurography, and heart rate and blood pressure were recorded during the depressor (phase II) or pressor (phase IV) period to Valsalva's maneuver in 10 younger subjects and 7 aged subjects. The baroreflex slope for heart rate showed attenuation in the aged subjects during the pressor phase but not during the depressor phase, the baroreflex slope for MSNA was also attenuated in the aged subjects during the pressor and tended to be attenuated during the depressor phases. These data suggest impaired baroreflex function for both heart rate and sympathetic nerve activity in the elderly.     

The impact of mean arterial pressure in the middle trimester upon the outcome of pregnancy

Data on the outcome of pregnancy are based upon a prospective study of 14,833 single births to women whose blood pressures during the fifth and sixth months of gestation were recorded. With each 5 mm, Hg rise in the mean arterial pressure (MAP) there is a progressive increase in the perinatal mortality rate. At each MAP level, the stillbirth rates and neonatal mortality rates are higher in blacks than in whites. When middle-trimester MAP is 90 mm. Hg or more, there is a significant increase in (1) the stillbirth rate, (2) the frequency of proteinuria, hypertension, and diagnosed pre-eclampsia in the third trimester, and (3) the frequency of intrauterine fetal growth retardation. We believe that all of these events are due to an impaired uteroplacental circulation, with which elevated blood pressures are associated. Women who have an average MAP of 90 or more during the fifth and sixth months should be considered in a high-risk category.     

Vasovagal syncope and increased baroreceptor activity: evidence for increased sensibility of the baroreflex and its rapid reversal with acute administration of metoprolol

In 17 patients suffering from recurrent episodes of vasovagal syncope as well as in 21 healthy subjects without clinical episodes of presyncope or syncope, we evaluated the reflex decrease in heart rate evoked by the phenilephrine test. In the syncopal patients, the measurements were taken 4-12 hours after the clinical appearance of syncope. We divided the syncopal patients as follows: 9 patients, undergoing pharmacological treatment, and 8 untreated patients (drug free arm). In the pharmacological arm of the study, an alternate, randomized administration of metoprolol (150 mg twice daily for 2 days) and verapamil (80 mg every 6 hours for 2 days) was provided. Therefore, in the pharmacological arm as well as in drug free patients, we tested again the baroreflex sensitivity, by means of iv phenilephrine bolus, 3 and 7 days after the clinical appearance of the syncopal event. The baroreflex sensitivity values were significantly higher in the syncopal group compared to the control group (21 +/- 5 vs 13 +/- 4.5 ms/mm Hg; p < 0.01). Of the two tested drugs, only the metoprolol produced a fast (day 3) decrease in baroreflex sensitivity. On the basis of measurements taken after 7 days, we noted a pattern of widespread reduction in baroreflex sensitivity values, found in both treated and untreated patients. In conclusion, patients with vasovagal syncope exhibited a more pronounced maximal parasympathetic activation compared to the control group. The high baroreflex sensitivity values were soon (day 3) reduced by metoprolol, but not by verapamil therapy; a spontaneous normalization in baroreflex sensitivity values was found 7 days after the clinical episode, regardless of therapy.     

Facilitation of adrenal sympathetic efferent nerve activity induced by mechanical stimulation of teeth in the rat

The effects of afferent signals from the periodontal mechanoreceptors and muscle spindles of jaw-closing muscles on adrenal nerve activity were examined using anesthetized rats. The adrenal nerve activity increased with pressure stimulation of the teeth and by biting a wooden stick. However, after denervation of the periodontal ligament, the facilitation due to the stick-biting was not observed. These results indicate that periodontal afferents facilitate adrenal nerve activity.     

Inhibition of the LH surge in cyclic rats by stress is not mediated by opioids

The effects of intravenous (iv) administration of the opioid antagonists naloxone and naltrexone on the restraint-induced suppression of the pro-estrous LH surge were studied in cyclic female rats. To minimize stress during repeated blood sampling, the rats were provided with a jugular vein cannula. Restraint stress for 6 hrs starting at t = -1 h (the onset of the LH surge being at t = 0 h) caused a suppression of LH levels (including peak height) during the period of the LH surge. Repeated naloxone injections, given 3 h (1 mg), 4 h (0.5 mg) and 5 h (0.5 mg) after the onset of the LH surge, did not affect the restraint-induced inhibition neither did pretreatment with 1 mg naloxone at t = -75 min (i.e. 15 min before application of restraint). Naltrexone (2 mg) administered at t = -15 min induced higher plasma LH levels at t = -6 min. When rats were subsequently subjected to restraint for 5 hrs starting at t = -5 min, the restraint-induced inhibition of surge levels of LH was not affected. The results indicate that withdrawal of opioid activity in cyclic female rats before the presumed onset of the LH surge results in a premature rise of LH levels. This is in accordance with the notion that LH levels prior to the surge are under tonic inhibition of endogenous opioid peptides (EOP). In addition, the data show that opioid receptor antagonism during or before application of restraint does not alter the restraint-induced suppression of the LH surge. It is therefore concluded that EOP do not mediate the inhibitory effect of restraint stress on the LH surge in cyclic rats.     

Nitric oxide-induced blood-brain barrier dysfunction is not mediated by inhibition of mitochondrial respiratory chain activity and/or energy depletion

The six reported cases were separated into 2 groups: 1) the tumors of sporadic type, carcinoids (n = 2) and neuro-endocrine carcinomas (n = 2); 2) the gastrin-promoted tumors (n = 2). The purpose of this retrospective study was to review for each group of tumors, the clinicopathologic characteristics, prognosis factors and optimal management. In the first group, patients with a small and well differentiated tumor revealed by digestive bleeding, were treated by wedge excision and are alive and well 24 and 22 years later; the patients with large, invasive and poorly differentiated tumors were treated by subtotal (n = 1) and total (n = 1) gastrectomy, and died 1 year and 3 years later with metastases. In the second group, one patient with a small asymptomatic carcinoid tumor revealing chronic atrophic gastritis, was treated by endoscopic resection, without recurrence 3 years later; another patient with asymptomatic multifocal carcinoid tumors (about 100) associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1, was treated by total gastrectomy and is alive and well 7 years later. No patient had carcinoid syndrome. Synaptophysin was the most sensitive marker and secretion of serotonine was detected in 2 tumors. Conclusion: Sporadic carcinoids serotonin and neuro-endocrine carcinomas are life-threatening tumors and need aggressive surgical therapy: their prognosis depends on tumors size, histological differentiation and mostly on tumor extension. In contrast, gastrin-promoted carcinoids do not result in disseminated disease and death, and a rather conservative approach seems appropriate.     

Attenuation of postischaemic dysfunction by ischaemic preconditioning is not mediated by adenosine in the isolated rat heart

OBJECTIVE: The aim was to test the hypothesis that adenosine mediates the cardioprotective effects of ischaemic preconditioning in the isolated rat heart. METHODS: Transient exposure of the hearts to adenosine and the A1 selective agonist, PIA, were tested for the ability to mimic the cardioprotective effects of ischaemic preconditioning in hearts that underwent 40 min normothermic ischaemic followed by 30 min reperfusion. Treated hearts were perfused with 10 or 50 microM adenosine or 10(-7) M R-phenylisopropyladenosine (PIA) for 5 min followed by a 5 min washout period. Preconditioned hearts underwent 5 min of ischaemia and 5 min of reflow prior to the 40 min ischaemic period. The ability of the adenosine receptor antagonist, BW A1433U, to inhibit the cardioprotective effects of ischaemic preconditioning was also tested. The effects of these treatments on metabolite levels and postischaemic haemodynamic function were assessed. RESULTS: Adenosine (50 microM), but not PIA, resulted in enhanced accumulation of lactate after 40 min ischaemia: 122(SEM 8) v 96(5) nmol.mg-1 protein in control hearts (p < 0.002). Adenosine and PIA treatments did not significantly affect myocardial acidosis during ischaemia. Postischaemic contractile function (as assessed by percent recovery of the heart rate x developed pressure) was lower in 50 microM, but not 10 microM, adenosine treated hearts [8.8(2.2)] and PIA treated hearts [11.9(2.5)] than in control hearts [20.4(3.6)] (p < 0.01). Ischaemic preconditioning (1) lowered glycogen levels prior to the 40 min ischaemic period [57(6) v 110(18) nmol glucosyl units.mg-1 protein; p < 0.01]; (2) lowered lactate levels at the end of the 40 min ischaemic period [61(4) v 104(5) nmol.mg-1 protein]; (3) preserved myocardial pH during ischaemia [6.69(0.07) v 6.40(0.07); p < 0.01]; and (4) enhanced recovery of postischaemic contractile function [42.3(4.4)% v 19.7(6.0)%; p < 0.02]. BW A1433U did not prevent these effects of ischaemic preconditioning. CONCLUSIONS: The cardioprotective effects of ischaemic preconditioning are not mediated by adenosine released during the preconditioning period in the isolated rat heart. Also, transient treatment of the heart with A1 adenosine receptor agonists can exacerbate postischaemic contractile dysfunction.     

Effects of microinjection of L-NNA and SNP into ventrolateral medulla on blood pressure, heart rate and renal sympathetic nerve activity in rats

The effects of microinjection of a NO synthase inhibitor--N-nitro-L-arginine (L-NNA) and NO donor-sodium nitroprusside (SNP) into ventrolateral medulla on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were examined in anesthetized rats to define the role of L-arginine: NO pathway in the central regulation of BP and to explore the underlying mechanism. The results obtained were as follows: (1) Following microinjection of L-NNA into rostral ventrolateral medulla (RVLM), both of MAP and RSNA were increased. The effects lasted for more than 30 min and could be reversed by prior intravenous injection of L-arginine. (2) In response to microinjection of SNP into RVLM, MAP and RSNA were decreased, while HR showed no significant change. (3) During microinjection of L-NNA into caudal ventrolateral medulla (CVLM), MAP, HR and RSNA were decreased. (4) Upon injection of SNP into CVLM, MAP and RSNA were increased, but HR showed no significant change. The above-mentioned results indicate that the L-arginine: NO pathway may exhibit a modulatory action on the activity of ventrolateral medulla neurons.     

Role of paraventriculo-spinal pathway in the inhibition of renal sympathetic nerve activity induced by blood volume expansion in rabbits

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized in part by the presence of tissue-bound and circulating antibodies (mostly of IgG) to the basement membrane zone (BMZ). We previously reported that IgG subclasses of BP antibodies were IgG1, IgG2 and IgG4, and that only BP IgG1 fixed complements. In this study, we examined whether BP IgG sub-classes bound to the same epitope of BP antigen or a different epitope. In an inhibition immunofluorescence studies, the complement fixing capability of IgG1 was inhibited by the pretreatment with IgG4 and partially inhibited by IgG2. On immunoblot analysis, IgG1 and IgG4 were bound to the same MW of BP antigen. In enzyme-linked immunosorbent assay (ELISA), the binding capability of IgG subclass fractions from patients with BP to synthetic peptide P1-2, exceeding normal IgG subclass fractions was seen in five IgG1, one IgG2 and two IgG4, from eight BP patients. The binding capability of IgG subclass fractions from the patients with BP to P1-1, exceeding the normal IgG fractions was seen in two IgG1, three IgG2 and one IgG4 from ten BP patients. On inhibition ELISA, the binding activity to P1-2 of IgG4 was partially inhibited by the pretreatment of IgG1 and IgG2. These findings suggest that BP IgG1, IgG2 and IgG4 could bind to the same epitope though considerable variation occurred between patients.     

Protein folding activity of Hsp70 is modified differentially by the hsp40 co-chaperones Sis1 and Ydj1

Specification of Hsp70 action in cellular protein metabolism may occur through the formation of specialized Hsp70:Hsp40 pairs. To test this model, we compared the ability of purified Sis1 and Ydj1 to regulate the ATPase and protein-folding activity of Hsp70 Ssa1 and Ssb1/2 proteins. Ydj1 and Sis1 could both functionally interact with Ssa1, but not the Ssb1/2 proteins, to refold luciferase. Interestingly, Ydj1:Ssa1 could promote up to four times more luciferase folding than Sis1:Ssa1. This functional difference was explored and could not be accounted for by differences in the ability of Sis1 and Ydj1 to regulate Ssa1 ATPase activity. Instead, differences in the chaperone function of Ydj1 and Sis1 were observed. Ydj1 was dramatically more effective than Sis1 at suppressing the thermally induced aggregation of luciferase. Paradoxically, Sis1 and Ydj1 could bind similar quantities of chemically denatured luciferase. The polypeptide binding domain of Sis1 was found to lie between residues 171-352 and correspond to its conserved carboxyl terminus. The conserved carboxyl terminus of Ydj1 is also known to participate in the binding of nonnative polypeptides. Thus, Ydj1 appears more efficient at assisting Ssa1 in folding luciferase because its contains a zinc finger-like region that is absent from Sis1. Ydj1 and Sis1 are structurally and functionally distinct Hsp40 proteins that can specify Ssa1 action by generating Hsp70:Hsp40 pairs that exhibit different chaperone activities.     

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

Camptothecin (an inhibitor of topoisomerase I) and etoposide and amsacrine (inhibitors of topoisomerase II) both capable of triggering programmed cell death in Y79 cells, induced a remarkable dose-dependent increase in the level of cyclin E in these cells. Camptothecin was found to be the most effective compound. The effect was not observed when the cells were treated with other inducers of programmed cell death (C2-ceramide, sodium butyrate, interleukin-1beta and tumor necrosis factor), all of which do not damage DNA. The effect, which was completely prevented by inhibitors of macromolecular synthesis, occurred after a lag phase (12 hrs.) and increased concurrently with the rise in programmed cell death (PCD), reaching a maximum after 36 hrs. of incubation, when a large percentage of cells (95%) showed clear PCD signals. We suggest that cyclin E takes part in the final stage of programmed cell death which is induced by topoisomerase inhibitors in Y79 cells.     

TNF-induced enterocyte apoptosis in mice is mediated by the TNF receptor 1 and does not require p53

Injection of recombinant mouse TNF into mice is known to induce a shrinkage of the duodenal villi, which becomes evident 30-90 min later and is associated with a detachment of enterocytes in the lumen. These cells can be collected by lavage and are all apoptotic, i.e. hypodiploid as seen by flow cytometric analysis. Thus the count of detached cells was used as an evaluation of the TNF-induced cell loss and apoptosis in the mucosa. TNF injection induced a cell loss of similar magnitude in wild-type (+/+) or in mice lacking the TNF receptor (TNFR)2 (p75, TNFR2-/-), while mice lacking the TNFR1 (p55, TNFR1-/-) were completely resistant to this effect. TNF increased the expression of p53 tumor suppressor gene in the enterocytes from the crypts but not from the villi, as seen by Western blots and histochemistry. TNF increased the expression of p53 in both TNFR2-/- and TNFR1-/- mice. Furthermore, enterocyte cell loss was not attenuated in p53-/- mice. The results indicate that TNF, acting on its receptor 1, induces an apoptotic detachment of the enterocytes from the tip of the villi (i.e. the old enterocytes), while in the enterocytes from the crypts (the young enterocytes) TNF increases, via either TNFR1 or TNFR2, the expression of p53, without inducing apoptosis.     

The antiproliferative activity of the tetrapeptide Acetyl-N-SerAspLysPro, an inhibitor of haematopoietic stem cell proliferation, is not mediated by a thymosin beta 4-like effect on actin assembly

Acetyl-N-SerAspLysPro (AcSDKP), known as a negative regulator of haematopoiesis, has been principally reported as an inhibitor of haematopoietic pluripotent stem cell proliferation. The tetrapeptide sequence is identical to the N-terminus of thymosin beta 4 (T beta 4), from which it has been suggested that it may be derived. Recently, evidence was shown that T beta 4 plays a role as a negative regulator of actin polymerization leading to the sequestration of its monomeric form. The structural similarity between the N-terminus of T beta 4 and AcSDKP has raised the possibility that AcSDKP may also participate in intracellular events leading to actin sequestration. The effect of T beta 4 on the proliferation of haematopoietic cells was compared to that of AcSDKP. The results revealed that T beta 4, like AcSDKP, exerts an inhibitory effect on the entry of murine primitive bone marrow cells into cell cycle in vitro. Qualitative electrophoretic analysis and quantitative polymerization assays were used to investigate the role of AcSDKP in actin polymerization. AcSDKP does not affect actin assembly at concentrations up to 50 microM, and does not compete with T beta 4 for binding to G-actin. These results suggest that AcSDKP is not involved in cell cycle regulation via an effect on the process of actin polymerization.     

Role of spinal alpha adrenoceptor in the inhibition of renal sympathetic nerve activity and natriuresis induced by blood volume expansion in rabbits

The effect of spinal alpha adrenoceptor blockage on the inhibition of renal sympathetic nerve activity (RSNA) and natriuresis induced by blood volume expansion was investigated in anesthetized and bilateral sinoaortic denervated rabbits. In the groups of rabbits with intrathecal injection of alpha-adrenoceptor blocker phentolamine or artificial cerebrospinal fluid the inhibition of RSNA induced by blood volume expansion were (-25.4 +/- 5.4)% and (-42.5 +/- 5.2)% respectively (P < 0.05). In the groups of rabbits with intrathecal injection of alpha 1 adtenoceptor blocker prazosin or artificial cerebrospinal fluid the inhibition of RSNA induced by blood volume expansion were (-29.3 +/- 6.1)% and (-42.5 +/- 5.2)% respectively (P < 0.05). These results suggested that both spinal alpha and alpha 1 adrenceptor blockage with attenuated the inhibition of RSNA induced by blood volume expansion. The spinal alpha 1 adrenceptor blockage with intrathecal injection of prazosin also attenuated signiticantly the natriuresis and diuresis induced by blood volume expansion (P < 0.05).