Takuya Tsuchihashi

Central Ghrelin Modulates Sympathetic Activity in Conscious Rabbits

Abstract—Ghrelin is an orexigenic peptide originally isolated from the stomach. Intravenous administration of ghrelin has been shown to elicit a decrease in arterial pressure without a significant change in heart rate (HR), suggesting that ghrelin may act on the central nervous system to modulate sympathetic activity. The aim of the present study was to determine the central effects of ghrelin on cardiovascular and sympathetic responses in conscious rabbits. Intravenous injection of ghrelin elicited dose-related decreases in arterial pressure and HR, without a significant change in renal sympathetic nerve activity. On the other hand, intracerebroventricular injection of 1 nmol of ghrelin decreased arterial pressure, HR, and renal sympathetic nerve activity. Peak depressor or sympathoinhibitory responses of mean arterial pressure and renal sympathetic nerve activity (−19.0±1.5 mm Hg and −43.3±5.4%) were observed at 50 and 40 minutes, respectively, after intracerebroventricular injection of 1 nmol of ghrelin. Furthermore, a subdepressor dose of intracerebroventricular infusion of ghrelin (0.3 nmol/150 &mgr;L per hour) significantly augmented the baroreflex sensitivities assessed by renal sympathetic nerve activity and HR compared with those of vehicle infusion (Gmax; −17.8±3.1 versus −9.4±1.6%/mm Hg, P <0.05; −12.5±1.8 versus −6.6±1.2 bpm/mm Hg, P <0.05; respectively). These results suggest that intravenous injection of ghrelin acts, at least in part, on the central nervous system to decrease arterial pressure and renal sympathetic nerve activity, and that central ghrelin participates in the regulations of the sympathetic nerve activity to the kidney and the baroreceptor reflex in conscious rabbits.

Central Orexin-A Augments Sympathoadrenal Outflow in Conscious Rabbits

Abstract—We determined the cardiovascular and neurohormonal responses to intracerebroventricular administration of orexin-A in conscious rabbits. Intracerebroventricular injection of orexin-A elicited dose-related increases in mean arterial pressure and renal sympathetic nerve activity. Peak values of mean arterial pressure and renal sympathetic nerve activity induced by intracerebroventricular injection of 100 pmol of orexin-A (14.0±0.7 mm Hg and 55.4±14.9%, respectively) were obtained at 40 and 25 minutes after injection, respectively. Plasma epinephrine and glucose concentrations were significantly increased at 60 and 90 minutes after intracerebroventricular injection of orexin-A (control versus 90 minutes; for epinephrine, 38.0±12.8 versus 167.5±42.5 pg/mL, P <0.01; for glucose, 6.66±0.18 versus 7.75±0.14 mmol/L, P <0.01). Plasma norepinephrine and insulin concentrations increased at 60 and 90 minutes but did not attain significant values. Intracerebroventricular injection of orexin-A also caused significant increases in plasma vasopressin concentrations. However, pretreatment with an intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, abolished these cardiovascular and neurohormonal responses. On the other hand, intravenous injection of the same dose of orexin-A (100 pmol) used in the intracerebroventricular experiment failed to cause any cardiovascular and renal sympathetic nerve responses. These results suggest that intracerebroventricular orexin-A acts in the central nervous system and activates sympathoadrenal outflow, resulting in increases in arterial pressure and plasma glucose levels in conscious rabbits.

Increased renal resistive index in atherosclerosis and diabetic nephropathy assessed by Doppler sonography

Objective The renal resistive index (RI) and pulsatility index (PI), measured using Doppler ultrasonography, reflect intrarenal vascular resistance. We evaluated the relationship between these indices and pulse wave velocity (PWV), a measure of arterial stiffness, which reflects atherosclerosis, and determined whether renal RI and PI differ depending on the underlying renal disease. Methods A total of 245 inpatients with or without renal impairment who underwent ultrasonographic assessment of the renal artery were enrolled in the study. Patients with renal artery stenosis or severe renal failure (serum creatinine ≥ 6 mg/dl) were excluded from the study. Results In univariate analysis, the RI and PI of the main renal arteries and the interlobar arteries were significantly correlated with PWV. Multivariate analyses showed that PWV was independently associated with the RI of the main renal arteries (P < 0.01, R2 = 0.256). Patients with a creatinine level less than 3 mg/dl were divided into a control group without renal diseases and three groups with different underlying renal diseases: diabetic nephropathy, chronic glomerulonephritis, and nephrosclerosis. The RI and PI of the main renal arteries and the interlobar arteries were significantly higher in patients with diabetic nephropathy than in the other three groups, even after adjusting for multiple variables, including creatinine clearance. Conclusion These results suggest that the increased RI of the renal arteries is associated with the severity of systemic atherosclerosis. Furthermore, the intrarenal vascular resistance differs depending on the underlying renal disease, and appears to increase to a greater extent in diabetic nephropathy.

Report of the Working Group for Dietary Salt Reduction of the Japanese Society of Hypertension: (2) Assessment of Salt Intake in the Management of Hypertension

Restriction of dietary salt is widely recommended in the management of hypertension, but assessment of individual salt intake has drawn little attention. The understanding of salt intake is important as a guide for optimizing salt-restriction strategies. However, precise evaluation of salt intake is difficult. More reliable methods are more difficult to perform, whereas easier methods are less reliable. Thus, the method to assess salt intake should be determined as the situation demands. The Working Group for Dietary Salt Reduction of the Japanese Society of Hypertension recommends the assessment of individual salt intake using one of the following methods in the management of hypertension. 1) The measurement of the sodium (Na) excretion from 24-h urine sampling or nutritionists analysis of the dietary contents, which are reliable but difficult to perform, are suitable for facilities specializing in the treatment of hypertension. 2) Estimation of the Na excretion from the Na/creatinine (Cr) ratio in spot urine is less reliable but practical and is suitable for general medical facilities. 3) Estimation using an electronic salt sensor equipped with a calculation formula is also less reliable but is simple enough that patients can use it themselves. The patients are considered to be compliant with the salt-restriction regimen if salt intake measured by whichever method is less than 6 g (100 mmol)/day.

The Japanese Society of Hypertension Guidelines for Self-monitoring of Blood Pressure at Home (Second Edition)

The Japanese Society of Hypertension Guidelines for Self-monitoring of Blood Pressure at Home (Second Edition)

Neural regulation of blood pressure by leptin and the related peptides

Recent biological advances make it possible to discover new peptides associated with obesity. Leptin, neuropeptide Y, corticotrophin-releasing factor (CRF), alpha-melanocyte stimulating hormone (alpha-MSH), and cocaine- and amphetamine-regulated transcript (CART) peptides are known to participate in appetite and feeding behavior. Various lines of evidence suggest that these peptides participate not only in feeding behavior but also in cardiovascular and sympathetic regulations. Both leptin and ghrelin are secreted from the peripheral tissue; then they reach the brain to modulate sympathetic activity. These two peptides seem to play important roles to transmit peripheral metabolic information to the brain, and to convert it to cardiovascular and sympathetic information. Leptin activates neurons containing alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript peptides, resulting in increases in sympathetic activity and blood pressure. Cardiovascular action of alpha-melanocyte stimulating hormone is mediated through melanocortin-4 receptor, and agouti-related protein (AGRP) plays a role as an endogenous melanocortin-4 receptor antagonist. In contrast, ghrelin and neuropeptide Y in the brain suppress sympathetic activity and decrease blood pressure. Depressor and sympathoinhibitory effects of central neuropeptide Y are inhibited by leptin. Furthermore, central ghrelin modulates baroreflex control of renal sympathetic nerve activity and heart rate. Thus, leptin and the related peptides, which participate in appetite and feeding behavior, seem to function together to regulate cardiovascular system and sympathetic nerve activity, and may play a key role in the association between obesity and hypertension.

Cardiovascular effects of nitric oxide in the rostral ventrolateral medulla of rats

To investigate the cardiovascular role of nitric oxide (NO) in the rostral ventrolateral medulla (RVLM), NOC 18, an NO donor, was microinjected into the RVLM of rats. NOC 18 significantly decreased mean arterial pressure (MAP). Pre-treatment with an NO trapper, carboxy-PTIO, abolished the NOC 18-induced decrease in MAP. Microinjection of L-NAME, an NO synthase inhibitor, increased MAP. L-Arginine reduced MAP and inhibited the pressor response induced by L-NAME. Results suggest that NO acts on the RVLM neurons and plays an important role in cardiovascular regulation.

Report of the Working Group for Dietary Salt Reduction of the Japanese Society of Hypertension: (1) Rationale for Salt Restriction and Salt-Restriction Target Level for the Management of Hypertension

Salt excess is well known to be involved in the pathophysiology of hypertension, and thus restriction of salt intake is widely recommended for management of the disease. Excessive salt intake induces blood pressure (BP)−dependent as well as −independent progression of cardiovascular disease. Although the human body is considered to be adapted to very low salt intake (0.5–3 g/day), restriction to such a low level of salt intake is extremely difficult to accomplish in developed countries. Significant BP reduction has been reported in large-scale clinical studies in which salt intake was decreased to less than 6 g/day, and the results of a meta-analysis have shown that systolic BP was reduced about 1 mmHg with every decrease in salt intake of 1 g/day in hypertensive subjects. Current guidelines for the treatment of hypertension, including Japanese guidelines, recommend dietary salt reduction to 6 g/day or less in hypertensive patients. However, it appears to be fairly difficult to attain this target of salt intake, especially in Japan. There is thus a need for feasible and effective measures to attain this salt restriction target.

Central α-melanocyte-stimulating hormone acts at melanocortin-4 receptor to activate sympathetic nervous system in conscious rabbits

Intracerebroventricular injection of alpha-melanocyte-stimulating hormone (alpha-MSH) elicited increases in arterial pressure and renal sympathetic nerve activity in conscious rabbits. Pretreatment with intracerebroventricular injection of agouti-related protein, an endogenous melanocortin-3 and 4 receptor antagonist, prevented cardiovascular and sympathetic responses to alpha-MSH. Pretreatment with intracerebroventricular injection of JKC-363, a synthetic specific melanocortin-4 receptor antagonist, also prevented cardiovascular and sympathetic responses to alpha-MSH. In contrast, intravenous alpha-MSH (1 nmol) failed to cause any cardiovascular responses. These results suggest that intracerebroventricularly administered alpha-MSH acts at the melanocortin-4 receptor in the brain and activates sympathetic outflow, resulting in an increase in arterial pressure.

Central nitric oxide attenuates the baroreceptor reflex in conscious rabbits

We examined the role of central nitric oxide (NO) in the baroreceptor reflex in conscious rabbits. Intracerebroventricular infusion of 20 μmol of N ω-nitro-l-arginine methyl ester (l-NAME) to block central NO resulted in increases in arterial pressure, renal sympathetic nerve activity (RSNA), and plasma catecholamine levels, and the pressor response was suppressed by pretreatment with pentolinium (5 mg/kg iv). On the other hand, a subpressor dose of intracerebroventricular l-NAME (10 μmol/h) caused significant increases in baroreflex sensitivities assessed by RSNA and heart rate compared with vehicle infusion [maximum gain: -18.2 ± 0.9 vs. -9.6 ± 0.9%/mmHg ( P < 0.001) and -14.3 ± 2.3 vs. -5.7 ± 0.4 beats ⋅ min-1 ⋅ mmHg-1( P < 0.05), respectively]. Conversely, an intracerebroventricular infusion of Et2N[N(O)NO]Na, an NO donor (1 μmol/h) significantly attenuated the baroreflex sensitivities. However, intracerebroventricular infusion of N ω-nitro-d-arginine methyl ester (10 μmol/h), an enantiomer ofl-NAME, failed to alter the baroreflex sensitivities. These results suggest that 1) the pressor response induced by inhibition of central NO synthesis is mainly mediated by the enhanced sympathetic outflow and 2) central NO attenuates the baroreflex control of RSNA and heart rate in conscious rabbits.We examined the role of central nitric oxide (NO) in the baroreceptor reflex in conscious rabbits. Intracerebroventricular infusion of 20 mumol of N omega-nitro-L-arginine methyl ester (L-NAME) to block central NO resulted in increases in arterial pressure, renal sympathetic nerve activity (RSNA), and plasma catecholamine levels, and the pressor response was suppressed by pretreatment with pentolinium (5 mg/kg i.v.). On the other hand, a subpressor dose of intracerebroventricular L-NAME (10 mumol/h) caused significant increases in baroreflex sensitivities assessed by RSNA and heart rate compared with vehicle infusion [maximum gain: -18.2 +/- 0.9 vs. -9.6 +/- 0.9%/mmHg (P < 0.001) and -14.3 +/- 2.3 vs. -5.7 +/- 0.4 beats.min-1.mmHg-1 (P < 0.05), respectively]. Conversely, an intracerebroventricular infusion of Et2N[N(O)NO]Na, an NO donor (1 mumol/h) significantly attenuated the baroreflex sensitivities. However, intracerebroventricular infusion of N omega-nitro-D-arginine methyl ester (10 mumol/h), an enantiomer of L-NAME, failed to alter the baroreflex sensitivities. These results suggest that 1) the pressor response induced by inhibition of central NO synthesis is mainly mediated by the enhanced sympathetic outflow and 2) central NO attenuates the baroreflex control of RSNA and heart rate in conscious rabbits.