B-type natriuretic peptide levels are decreased by reducing dietary salt intake in patients with compensated heart failure with preserved ejection fraction.

BACKGROUND: Dietary salt restriction is believed to be a mainstay in the management of patients with heart failure. However, the effect of salt intake on heart failure has not been well evaluated in outpatient medical practice. AIMS: The aim of the present study was to assess the hypothesis that B-type natriuretic peptide (BNP) level, as an objective marker of heart failure, is associated with salt intake in patients with heart failure. METHODS: One hundred and thirteen consecutive patients with mild compensated heart failure (77 ± 10 years old, 51 female) were included. We estimated dietary salt intake by the concentration of sodium and creatinine in spot urine. We measured BNP at the time of urine sampling and assessed the relationship between the % changes in BNP levels (%ΔBNP) and the changes in the estimated daily salt excretion (ΔNaCl) during the follow-up period. RESULTS: The baseline median BNP level was 150 (interquartile range: 83-263) pg/mL and the estimated daily salt excretion was 162 ± 45 mmol/day. There was a positive correlation between %ΔBNP and ΔNaCl (r = 0.61, P < 0.01). Multiple regression analysis revealed that %ΔBNP was associated with ΔNaCl (P < 0.01), but not with changes in systolic blood pressure and bodyweight. CONCLUSIONS: Changes in BNP levels were associated with changes in the estimated daily salt excretion in outpatients with compensated heart failure. Salt restriction may be beneficial for the management of patients with heart failure.

Effects of short-term fasting on the Akt-mediated pathway involved in protein metabolism in chicken skeletal muscle.

In the present study, we show that short-term (4 h) fasting significantly decreased the levels of protein synthesis-related factors such as the plasma insulin concentration, skeletal muscle pAkt, and pS6 levels in 2-wk-old chickens (P < 0.05). An intravenous injection of insulin significantly elevated the contents of pAkt and p-S6 in the skeletal muscle (P < 0.01). These findings suggest that decreasing the plasma insulin causes the downregulation of the Akt/S6 pathway in chicken skeletal muscle under short-term fasting conditions. However, protein synthesis was not significantly affected by short-term fasting. In addition, no significant change was observed in the levels of proteolysis-related factors such as plasma Nτ-methylhistidine, phosphorylated forkhead box class O, and muscle ring finger-1 during 4-h fasting, indicating that short-term fasting does not induce skeletal muscle proteolysis in chickens. Interestingly, atrogin-1 expression significantly increased after 2-h fasting (P < 0.05), and insulin injection significantly reversed the fasting-induced atrogin-1 expression in chicken skeletal muscle (P < 0.01). Collectively, these findings suggest that short-term fasting downregulates the insulin-stimulated Akt/S6 pathway but does not significantly affect protein synthesis and proteolysis in chicken skeletal muscle, and that atrogin-1 expression is upregulated in a FOXO1-independent manners.

Low-dose prednisolone ameliorates acute renal failure caused by cholesterol crystal embolism.

AIMS: The prognosis of renal cholesterol crystal embolism (CCE) is poor. Although various treatments for CCE have been attempted, there is no optimal therapy. We tested the effect of low-dose prednisolone (PS) on CCE-related acute renal failure (ARF). PATIENTS AND METHODS: 7 patients (mean age 69 years) diagnosed with CCE-related ARF were treated with oral PS at 15-20 mg/day for 2-4 weeks, which was then tapered at 5 mg/day over 2-4 weeks, followed by 5 mg/day maintenance dose. Recurrent ARF during PS tapering was treated with a larger dose of PS. RESULTS: Inciting factors were identified in four patients: coronary angiography (n=3) and cerebral angiography (n=1). On admission, serum creatinine (SCr) was 2.1 +/- 0.3 mg/dl (mean +/- SEM). SCr and eosinophil count before treatment were 4.2 +/- 0.4 mg/dl and 682 +/- 73/microl, respectively. PS therapy improved ARF in all cases at week 2 (SCr 3.8 +/- 0.5 mg/dl) parallel to a decrease in eosinophilia (116 +/- 30/microl), and at week 4 (3.1 +/- 0.4 mg/dl and 134 +/- 20/microl, respectively). At last follow-up, renal function was improved or maintained in 5 patients compared with that at week 4 post-treatment. One patient died of lung cancer. Another required LDL apheresis and hemodialysis but died due to CCE-related multi-organ failure. A third patient had recurrent ARF and was re-treated with a larger dose of PS, which resulted in an immediate decrease in SCr. However, the patient developed acute renal dysfunction due to congestive heart failure, and required hemodialysis. CONCLUSIONS: Low-dose PS improved CCE-related ARF, probably through amelioration of inflammatory reaction surrounding affected renal vessels.

Parathyroid hormone-related protein in tumor tissues obtained from patients with humoral hypercalcemia of malignancy.

We assessed the relationship between the parathyroid hormone-related protein (PTHrP) and the development of humoral hypercalcemia of malignancy (i.e., hypercalcemia due to the production by solid tumors of hypercalcemic factors) by assaying tumor extracts from hypercalcemic and normocalcemic patients with cancer for immunoreactive PTHrP contents. Immunoreactive PTHrP was demonstrated in extracts of 21 of 22 tumor tissues obtained from 22 patients with humoral hypercalcemia of malignancy. Immunoreactive PTHrP was rarely seen in tumor tissue extracts obtained from 34 normocalcemic patients with cancer and two hypercalcemic patients with cancer with severe bone metastases. Gel filtration studies of tumor extracts revealed a molecular-size heterogeneity of immunoreactive PTHrP. These radioimmunoassay data indicate a close relationship between detection of PTHrP in tumor tissues and the development of humoral hypercalcemia of malignancy.

Dystrophin, utrophin and beta-dystroglycan expression in skeletal muscle from patients with Becker muscular dystrophy.

The precise localization and semiquantitative correlation of dystrophin, utrophin and beta-dystroglycan expression on the sarcolemma of skeletal muscle cells obtained from patients with Becker muscular dystrophy (BMD) was studied using three types of double immunofluorescence. Staining intensity was measured using a confocal laser microscope. Each of these proteins was identified at the same locus on the sarcolemma. The staining intensities of dystrophin and utrophin were approximately reciprocal at sarcolemmal sites where dystrophin expression was obviously observed. The staining intensity of beta-dystroglycan was strong in areas where dystrophin staining was also strong and utrophin expression was weak. Quantitative analysis revealed that the staining intensity of beta-dystroglycan minus that of dystrophin approximated the staining intensity of utrophin, indicating that the sum of dystrophin and utrophin expression corresponds to that of beta-dystroglycan. These results suggest that utrophin may compensate for dystrophin deficiency found in BMD by binding to beta-dystroglycan.

Metabotropic glutamate receptors in the ventrolateral medulla of rats.

We investigated the hypothesis that stimulation of metabotropic excitatory amino acid receptors in the ventrolateral medulla evokes cardiovascular responses. Thus, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic excitatory amino acid receptors, was microinjected into the rostral or caudal ventrolateral medulla of halothane-anesthetized Sprague-Dawley rats. Microinjections of (1S,3R)-ACPD (100 pmol-1 nmol) into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure (+20 +/- 4 mm Hg by 100 pmol and +35 +/- 2 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and integrated splanchnic sympathetic nerve activity (+17 +/- 3% and +46 +/- 4%, respectively, p < 0.01), whereas (1S,3+)-ACPD microinjected into the caudal ventrolateral medulla decreased mean arterial pressure (-28 +/- 2 mm Hg by 100 pmol and -48 +/- 6 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and splanchnic sympathetic nerve activity (-24 +/- 4% and -49 +/- 5%, p < 0.01). The blockade of ionotropic excitatory amino acid receptors by the combined injection of 2-amino-7-phosphonoheptanoic acid (200 pmol) and 6,7-dinitroquinoxaline-2,3-dione (200 pmol), which effectively blocked the responses elicited by either N-methyl-D-aspartate (20 pmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol), failed to affect the responses evoked by either (1S,3R)-ACPD (100 pmol) or L-glutamate (2 nmol) microinjected in the rostral and caudal ventrolateral medulla. These results suggest that metabotropic receptors are present and mediate cardiovascular responses evoked by L-glutamate injections into the rostral and caudal ventrolateral medulla.

Role of metabotropic glutamate receptors in ventrolateral medulla of hypertensive rats.

Evidence is accumulating for the role of metabotropic, as well as ionotropic, glutamate receptors in cardiovascular regulation. We sought to determine whether stimulation of metabotropic glutamate receptors in the rostral ventrolateral medulla would evoke enhanced cardiovascular responses in spontaneously hypertensive rats (SHR). Thus, we microinjected (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic glutamate receptors, into the rostral ventrolateral medulla of urethane-anesthetized adult SHR and age-matched Wistar-Kyoto (WKY) rats. Microinjection of (1S,3R)-ACPD (1 nmol/50 nL) produced increases in mean arterial pressure and splanchnic sympathetic nerve activity in SHR (+41 +/- 6 mm Hg and +34 +/- 4%, respectively) that were significantly greater than those observed in WKY rats (+18 +/- 3 mm Hg and +22 +/- 3%, P < .005 and P < .05, respectively). The pressor responses evoked by microinjection of L-glutamate (2 nmol), N-methyl-D-aspartate (20 pmol), or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol) were also significantly (P < .001) augmented in SHR (+55 +/- 3, +61 +/- 7, and +53 +/- 5 mm Hg, respectively, in SHR versus +31 +/- 1, +30 +/- 3, and +28 +/- 2 mm Hg in WKY rats). Results indicate that stimulation of metabotropic, as well as ionotropic, glutamate receptors in the rostral ventrolateral medulla evokes enhanced cardiovascular responses in SHR, which may contribute to hypertension in this model.

Central adrenomedullin augments the baroreceptor reflex in conscious rabbits.

We examined the roles of central adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP), and calcitonin gene-related peptide (CGRP) on the baroreceptor reflex in conscious rabbits. Intracerebroventricular injection of adrenomedullin (0.2 and 1 nmol/80 microL) elicited dose-related increases in arterial pressure and renal sympathetic nerve activity. On the other hand, a subpressor dose of intracerebroventricular infusion of adrenomedullin (1 nmol/300 microL per hour) caused significant increases in baroreflex sensitivities assessed by renal sympathetic nerve activity and heart rate compared with vehicle infusion (Gmax; -14.9+/-1.7 versus -8.0+/-0.7%/mm Hg, P<0.01, and -8.1+/-0.8 versus -5.1+/-0.5 bpm/mm Hg, P<0.01, respectively). Intracerebroventricular infusion of CGRP (1 nmol/300 microL per hour), which is structurally homologous to adrenomedullin, also enhanced the baroreflex controls of renal sympathetic nerve activity and heart rate. However, the intracerebroventricular infusion of PAMP (30 nmol/300 microL per hour) failed to alter the baseline levels of arterial pressure and baroreflex sensitivities. These results suggest that central adrenomedullin and CGRP, but not PAMP, participate in cardiovascular regulation to augment the baroreflex controls of renal sympathetic nerve activity and heart rate in conscious rabbits.

Enhanced depressor response to nitric oxide in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Possible impairment of the L-arginine-nitric oxide (NO) pathway in the rostral ventrolateral medulla of adult spontaneously hypertensive rats (SHR) was investigated by microinjecting N(G)-nitro-L-arginine methyl ester (L-NAME), NOC 18 (an NO donor), or L-arginine. Unilateral injection of L-NAME (10 nmol/50 nL) into the rostral ventrolateral medulla significantly increased mean arterial pressure (MAP) in both SHR and Wistar-Kyoto rats (WKY). The increases in MAP did not differ significantly between the two strains (15+/-3 versus 10+/-2 mm Hg, respectively; n=8). In contrast, microinjection of L-arginine elicited significant (P<.05) dose-dependent decreases in MAP in both strains, and these depressor responses were significantly greater in SHR than in WKY (in 10 nmol of L-arginine: -29+/-2 versus -15+/-2 mm Hg, respectively; n=8, P<.01). Similarly, microinjection of NOC 18 (10 nmol/50 nL) reduced MAP in both strains, and the depressor response was also significantly greater in SHR than in WKY (-38+/-7 versus -22+/-3 mm Hg, respectively; n=8, P<.05). These results suggest that the L-arginine-NO pathway in the rostral ventrolateral medulla is impaired in SHR and that this impairment may contribute to the increase in arterial pressure in this animal model of genetic hypertension.

Antihypertensive treatment and the responsiveness to glutamate in ventrolateral medulla.

We have recently reported that the cardiovascular responses to excitatory amino acids are augmented in the rostral ventrolateral medulla of spontaneously hypertensive rats (SHR). In the present study, we investigated whether the responsiveness to excitatory amino acids would be normalized by antihypertensive treatment. Thus we treated 4-week-old SHR and age-matched Wistar-Kyoto (WKY) rats with either enalapril (25 mg/kg per day in drinking water) or vehicle for 8 weeks. At 12 weeks of age, systolic blood pressure in the untreated SHR (248+/-9 mm Hg) was significantly (P<.01) higher than that in the enalapril-treated SHR (140+/-4 mm Hg), untreated WKY rats (148+/-4 mm Hg), and enalapril-treated WKY rats (117+/-1 mm Hg). The pressor responses to L-glutamate (2 nmol) microinjected into the rostral ventrolateral medulla were similar in enalapril-treated and untreated SHR (40+/-5 and 47+/-3 mm Hg, respectively, NS), and these responses were significantly greater than that seen in the untreated WKY rats (24+/-2 mm Hg, P<.01). On the other hand, the pressor response to either N-methyl-D-aspartate, an ionotropic glutamate receptor agonist, or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a metabotropic glutamate receptor agonist, in the enalapril-treated SHR was slightly but significantly smaller than that in the untreated SHR but was still markedly greater than those in untreated and enalapril-treated WKY rats. These results suggest that the augmented responsiveness to excitatory amino acids in the rostral ventrolateral medulla of SHR may be at least partly genetically determined and cannot be normalized by the treatment with enalapril.

Single L-type calcium channels in smooth muscle cells from resistance arteries of spontaneously hypertensive rats.

The amplitude of the whole-cell L-type Ca2+ channel current recorded from vascular smooth muscle cells is reportedly greater in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). However, no study has examined properties of single Ca2+ channels in arterial cells from these strains. To further test the hypothesis that activation of L-type Ca2+ channels in arterial smooth muscle cells would be enhanced in SHR, we recorded single Ca2+ channel currents in resistance mesenteric artery cells from SHR and WKY (8 to 9 weeks of age) using a cell-attached patch clamp technique. With 50 mmol/L Ba2+ in the recording pipette, the depolarizing pulse from a holding potential of -40 mV evoked the single L-type Ca2+ channel current. Opening of the single channels was more frequent in cells from SHR than from WKY. Single-channel conductance (20 pS) and open time (1 ms at 0 mV) did not differ in the two strains. The results suggest that an increased amplitude of the whole-cell current can be attributed to the enhanced opening of single Ca2+ channels in the arterial smooth muscle cells from SHR compared with WKY.

Central effect of endothelin on neurohormonal responses in conscious rabbits.

It has been shown that endothelin-1 (ET-1) binding sites exist in the central nervous system and that the injection of intracerebroventricular ET-1 induces a pressor response. Therefore, we determined the neurohormonal and cardiovascular responses to intracerebroventricular ET-1 (25 pmol/kg) in conscious rabbits with chronically instrumented electrodes on the renal sympathetic nerve. Intracerebroventricular ET-1 provoked a prompt increase in arterial pressure and in renal sympathetic nerve activity within 5 minutes, and peak values were obtained at 20 and 40 minutes, respectively. Plasma epinephrine and norepinephrine reached peak values at 5-20 minutes. Plasma vasopressin and plasma glucose levels also increased significantly, but plasma osmolality, hematocrit, and serum sodium and potassium concentrations did not show any changes. Arterial blood gas analysis showed respiratory alkalosis. However, pretreatment with intravenous pentolinium (5 mg/kg), a ganglion blocking agent, abolished these neurohormonal and cardiovascular responses. Conversely, the same dose of intravenous ET-1 (25 pmol/kg) as that used in the intracerebroventricular experiment failed to cause any cardiovascular or renal sympathetic nerve responses. These results suggest that intracerebroventricular ET-1 acts in the central nervous system and causes a pressor response mainly through the enhancement of sympathoadrenal outflow.

Differential modulation by mu- and delta-opioids on baroreceptor reflex in conscious rabbits.

We examined the role of central mu- and delta-opioids on both neurohormonal responses and baroreceptor reflex in conscious rabbits. Both intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-selective agonist, and [D-Ala2,D-Leu5]-enkephalin, a delta-selective agonist, caused dose-related increases in arterial pressure and renal sympathetic nerve activity, whereas intravenous injection of the same maximum dose of these peptides as that used in the intracerebroventricular experiment did not cause any cardiovascular and neuronal responses. On the other hand, increases in plasma epinephrine, norepinephrine, and glucose levels induced by intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin were significantly greater than those by [D-Ala2,D-Leu5]-enkephalin. Both enkephalins did not cause any responses in plasma renin activity, plasma vasopressin, and serum sodium and potassium concentrations. The sensitivity of the baroreceptor reflex control of renal sympathetic nerve activity using a logistic model was enhanced by a subpressor dose of intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 pmol/kg) but not by [D-Ala2,D-Leu5]-enkephalin. Conversely, a mu-selective dose of intravenous naloxone (0.1 mg/kg) attenuated baroreceptor reflex sensitivity. Intravenous naloxone methobromide, which has been shown not to cross the blood-brain barrier, did not change baroreceptor reflex sensitivity, suggesting that naloxone acts at the central nervous system. In conclusion, in conscious rabbits, 1) intracerebroventricular mu- and delta-receptor agonists caused pressor responses and 2) mu-opioid agonist altered baroreceptor reflex control of renal sympathetic nerve activity and produced changes in sympathoadrenal responses.

Angiotensin II increases norepinephrine turnover in the anteroventral third ventricle of spontaneously hypertensive rats.

We evaluated the effect of angiotensin II (Ang II) administered by intracerebroventricular injection on norepinephrine turnover in the anteroventral third ventricle in adult spontaneously hypertensive rats (SHR, n = 35) and age-matched Wistar-Kyoto rats (WKY, n = 38). Ang II (100 ng) or saline (vehicle control) was administered into the cerebral ventricle 30 minutes after injection of alpha-methyl-p-tyrosine (250 mg/kg IP). Norepinephrine turnover was assessed by evaluation of the norepinephrine concentration before and 1 hour after such administration. The pressor response to Ang II administration was significantly greater in SHR than in WKY (+43 +/- 3 versus +23 +/- 2 mm Hg, P < .01). Baseline norepinephrine turnover (response to saline) was reduced in the ventral median preoptic nucleus of SHR. Ang II significantly increased norepinephrine turnover in the organum vasculosum lamina terminalis and ventral median preoptic nucleus of SHR (organum vasculosum lamina terminalis: 40 +/- 5% by Ang II versus 18 +/- 6% by saline, P < .05; ventral median preoptic nucleus: 32 +/- 3% by Ang II versus 21 +/- 2% by saline, P < .05) but not of WKY (37 +/- 5% versus 29 +/- 5%, P = NS, and 30 +/- 2% versus 32 +/- 3%, P = NS, respectively). Thus, norepinephrine turnover in the anteroventral third ventricle region induced by intracerebroventricular administration of Ang II was increased in SHR. This effect may contribute to the enhanced pressor response to central Ang II seen in this model.

Pressor response to NaCl solution administered intracerebroventricularly or intracisternally to conscious normotensive and spontaneously hypertensive rats.

We examined the central action of NaCl on blood pressure using intracerebroventricular (i.c.v.) and intracisternal (i.c.) injections of hypertonic NaCl solution in conscious, unrestrained spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The dose-dependent pressor response produced by i.c.v. hypertonic NaCl was greater in SHR than in WKY rats, while the dose-related pressor action produced by i.c. NaCl did not differ between the two strains. The hyperresponsiveness to i.c.v. NaCl in SHR was abolished by pretreatment with an i.c.v. injection of the angiotensin II (ANG II) analogue 1-Sar, 8-IIeu ANG II. Both ANG II and a combination of ANG II and NaCl given by i.c.v. injection had a greater pressor response in SHR than in WKY rats, although both ANG II and phenylephrine given intravenously elevated blood pressure to the same extent in both strains. Furthermore, i.c.v. ANG II both with and without hypertonic NaCl caused dipsogenic behaviour which lasted longer in SHR than in WKY rats. This response to i.c.v. hypertonic NaCl without ANG II was not substantially different between the two strains. Intracisternal hypertonic NaCl did not induce drinking behaviour. These observations suggest that in the SHR, the third ventricle rather than the brain stem is a more sensitive area to NaCl. The brain renin-angiotensin system in the SHR may play an important role in this accelerated pressor response and may be responsible, at least to some extent, for the enhanced reaction to chronic oral salt loading.

Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.

Cerebrospinal fluid sodium and enhanced hypertension in salt-loaded spontaneously hypertensive rats.

OBJECTIVE AND DESIGN: The present study was designed to determine whether increases in sodium concentration in the cerebrospinal fluid (CSF) play a role in the augmented hypertension induced by long-term salt loading in spontaneously hypertensive rats (SHR), and whether the enhanced arginine vasopressin (AVP) activity and/or the sympathetic nervous system contribute to the increased hypertension. METHODS: Measurement of CSF sodium concentration and systolic blood pressure of SHR during salt loading, with or without uninephrectomy, for 7 weeks. Assessment of the hypotensive response to AVP antagonist and hexamethonium, and the plasma levels of AVP and catecholamines. RESULTS: Salt-loading for 7 weeks led to gradual increase in hypertension in SHR. CSF sodium in the SHR was increased by a combination of uninephrectomy and saline-drinking after 7 weeks, but not 3 weeks. The difference in mean arterial pressure (MAP) among the three groups of SHR disappeared after the combined blockade of AVP and sympathetic nervous function. CSF sodium correlated with both resting MAP and the fall in MAP induced by the combined administration of AVP antagonist and hexamethonium. Plasma levels of AVP were significantly elevated in the salt-loaded uninephrectomized SHR. Plasma catecholamines did not change significantly as a result of treatment. CONCLUSIONS: We tentatively conclude that chronic salt loading may lead to an increase in CSF sodium, in association with an enhancement of sympathetic nerve activity and, to some extent, of AVP release. These events may explain the augmented development of hypertension in SHR.

Central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase in rats.

OBJECTIVE: To study the possible central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase. METHODS: We evaluated neurohormonal and renal responses of Wistar rats to chronic oral administration of 20 and 100 mg/kg per day NG-nitro-L-arginine methyl ester (L-NAME). Effects of intracerebroventricular and intravenous injections of NO donors (NOC-18 and FK-409) and an angiotensin II type 1 receptor antagonist CV-11974, and intravenous injection of alpha-adrenergic receptor antagonist phentolamine after chronic treatment with 100 mg/kg per day L-NAME were also studied. RESULTS: The chronic treatment with L-NAME induced a sustained dose-dependent hypertension with a decrease in heart rate. Urinary levels of norepinephrine and epinephrine decreased with no changes in plasma catecholamine levels, renin activity, and vasopressin level. Serum nitrate/nitrite levels in the rats treated with the high dose of L-NAME decreased. The intracerebroventricular and intravenous injections of the NO donors reduced arterial pressure in L-NAME-treated rats to a significantly greater extent than they did that in control rats. The intravenous but not intracerebroventricular injection of CV-11974 produced a sustained decrease in arterial pressure of L-NAME-treated rats. The depressor responses to intravenous injection of phentolamine of L-NAME-treated and control rats were similar. CONCLUSIONS: Results indicate that L-NAME-induced hypertension is associated with a deficiency of nitric oxide, both peripherally and centrally. Circulating angiotensin II could contribute to the maintenance of hypertension via angiotensin II type 1 receptor while the sympathetic nervous system seems to be suppressed.

Magnesium decreases arterial pressure and inhibits cardiovascular responses induced by N-methyl-D-aspartate and metabotropic glutamate receptors stimulation in rostral ventrolateral medulla.

OBJECTIVE: Magnesium sulfate (MgSO4) is widely used for the treatment of eclampsia. However, effects of Mg2+ in central cardiovascular regulation remain unclear. In the present study, the role of Mg2+ on cardiovascular regulation in the rostral ventrolateral medulla (RVLM) of rats was examined. METHODS: Adult male Wistar rats were anesthetized with urethane, and artificially ventilated. The ventral surface of the medulla was exposed, and the RVLM was identified by microinjection (50 nl) of l-glutamate (l-Glu; 2 nmol). Then, MgSO4 (1, 3, 10 nmol, n = 7 for each dose) and magnesium chloride (MgCl2; 10 nmol, n = 7) were microinjected into the RVLM. l-Glu (2 nmol), N-methyl-D-aspartate (NMDA; 20 pmol), alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA; 5 pmol) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, metabotropic glutamate receptor agonist; 1 nmol] were also microinjected with or without pretreatment of MgSO4 (10 nmol; n = 7 for each drug). RESULTS: MgSO4 dose-dependently decreased mean arterial pressure (MAP) and heart rate (HR). The high dose of MgSO4 (10 nmol) significantly decreased MAP and HR (-25 +/- 4 mmHg and -43 +/- 6 bpm). Similarly, MgCl2 decreased MAP and HR (-27 +/- 4 mmHg and -30 +/- 6 bpm). The pressor response evoked by NMDA or (1S,3R)-ACPD was significantly attenuated by the pretreatment with MgSO4. In contrast, pressor response caused by l-Glu or AMPA was not affected by pretreatment with MgSO4. CONCLUSIONS: These results suggest that Mg2+ has an inhibitory role on the RVLM neurons, and inhibits cardiovascular responses induced by NMDA and metabotropic glutamate receptor agonists.

Disparate circadian variations of blood pressure and body temperature in bedridden elderly patients with cerebral atrophy.

Twenty bedridden elderly patients with normal sleep-wake cycles were studied to evaluate the circadian variations of blood pressure, pulse rate, body core temperature, cortisol, and catecholamines with a focus on their relation to cerebral atrophy. Twenty-four-hour blood pressure (BP) and pulse rate monitorings were done with simultaneous measurement of urinary bladder temperature. Urine was also collected every 4 h to measure 17-hydroxycorticosterone and catecholamines. Based on the brain CT, frontal horn index (FHI: maximal distance between bilateral frontal horns/the corresponding width of the skull) was calculated as an index of cerebral atrophy. Analysis by the cosinor method revealed that the significant circadian rhythm with nocturnal decline was observed in only 9 patients (45%) for BP and in 13 patients (65%) for pulse rate. In contrast, 19 of 20 patients (95%) showed significant circadian rhythms of bladder temperature, with the nadirs appearing between 00:06 and 06:54. In the subgroup of mild cerebral atrophy (FHI < 0.30, n = 11), BP and pulse rate fell modestly but significantly during nighttime, whereas they did not fall in the subgroup of moderate to severe cerebral atrophy (FHI > or = 0.30, n = 9). The possibility could not be excluded that the sleep disturbance might result in the relatively high BP during nighttime. Bladder temperature, 17-hydroxycorticosteroids, and catecholamines showed significant nocturnal falls in both groups. In conclusion, nocturnal fall of BP disappeared in the bedridden elderly patients with cerebral atrophy, which cannot be explained by the change in the circadian variation of the sympathetic nervous system, cortisol, or body core temperature.