Shuntaro Kagiyama

Ghrelin Acts at the Nucleus of the Solitary Tract to Decrease Arterial Pressure in Rats

Abstract—Ghrelin is an orexigenic peptide originally isolated from the stomach. Intracerebroventricular administration of ghrelin has been shown to elicit decreases in arterial pressure and renal sympathetic nerve activity in conscious rabbits. The aim of the present study was to determine the role of ghrelin in the brain stem in cardiovascular responses in rats. Unilateral microinjection of ghrelin into the nucleus of the solitary tract significantly decreased the mean arterial pressure and heart rate (−17.3±0.8 mm Hg and −13.6±3.5 bpm by 20 pmol). The microinjection of ghrelin into the nucleus of the solitary tract also suppressed the renal sympathetic nerve activity (−29.5±3.4%; P <0.0001). Pretreatment with intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, eliminated these cardiovascular responses induced by the microinjection of ghrelin (20 pmol) into the nucleus of the solitary tract; however, pretreatment with intravenous injection of atropine sulfate (0.1 mg/kg), an antagonist of muscarinic acetylcholine receptors, failed to prevent them. In contrast, unilateral microinjection of ghrelin into the area postrema, rostral, and caudal ventrolateral medulla caused no significant changes in the mean arterial pressure and heart rate. On the other hand, immunohistochemical study revealed that the receptor for ghrelin, the growth hormone secretagogue receptor, was expressed in the neuronal cells of the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, but not in the cells of the area postrema. These results suggest that ghrelin acts at the nucleus of the solitary tract to suppress sympathetic activity and to decrease arterial pressure in rats.

Central and peripheral cardiovascular actions of apelin in conscious rats

APJ was cloned as an orphan G protein-coupled receptor and shares a close identity with angiotensin II type 1 receptor (AT1R). Apelin is a peptide that has recently been identified as an endogenous ligand of the APJ. Apelin and APJ mRNA are expressed in peripheral tissue and the central nervous system. However, little is known about the effects of apelin in cardiovascular regulation. To examine the central and peripheral role of apelin, we injected the active fragment of apelin [(Pyr1)apelin-13] intracerebroventricularly (ICV, 5 and 20 nmol, n=6) or intravenously (IV, 20 and 50 nmol, n=4 or 5) in conscious rats. ICV injection of (Pyr1)apelin-13 dose-dependently increased mean arterial pressure (MAP) and heart rate (HR) (19+/-3 mm Hg and 162+/-26 bpm at 20 nmol). Pretreatment with ICV injection of the AT1R antagonist (CV-11974, 20 nmol) did not alter the apelin-induced increase in MAP and HR. IV injection of (Pyr1)apelin-13 also dose-dependently increased MAP and HR (13+/-2 mm Hg and 103+/-18 bpm at 50 nmol); however, the peripheral effects of apelin were relatively weak compared to its central effects. Expression of c-fos in the paraventricular nucleus (PVN) of hypothalamus was increased in the rat that received ICV injection of (Pyr1)apelin-13 but not in the rat that received IV injection of (Pyr1)apelin-13. These results suggest that apelin plays a role in both central and peripheral cardiovascular regulation in conscious rats, and that the cardiovascular effects of apelin are not mediated by the AT1R.

Association between body mass index and mortality in an 80-year-old population.

OBJECTIVES: To evaluate the association between body mass index (BMI) and all‐cause mortality and cardiovascular disease (CVD) in an 80‐year‐old population.

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.

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.

Quality of life and physical fitness in an 85-year-old population

Since little is known about the very elderly population aged 80 years and older, we evaluated the association of quality of life (QoL) in an 85-year-old population with physical fitness measurements assessed at age 80 and 85 years. Two hundred seven individuals (90 males, 117 females) aged 85 years underwent the Short Form-36 (SF-36) questionnaires for QoL assessment and physical fitness measurements (handgrip strength, leg-extensor strength, one-leg standing time, stepping rate of legs, walking speed). In 85-year-olds, significant associations were found, by multiple regression analysis or logistic regression analysis, with adjustment for various influencing factors in QoL assessed by SF-36 with physical fitness measurements examined at the age of 85 and 80 years. Physical scales and scores in SF-36, such as physical functioning (PF), limitation in role functioning for physical reasons (role physical; RP), bodily pain (BP), and the physical component score (PCS) tended to be more tightly associated with fitness measurements than mental scales and scores such as limitation in role functioning for emotional reasons (role emotional; RE), and emotional well-being (mental health; MH), and mental component score (MCS). Three scales the general health perceptions (GH), the vitality (VT), and the social functioning (SF) consisting of both physical and mental components were associated with fitness, the extent being intermediate between physical scales and mental scales. Of the several physical fitness measurements, leg-extensor strength and the walking speed of 85-year-olds, and the stepping rate of 80-year-olds were most closely associated with QoL. In a very elderly population of 85- and 80-year-olds, significant associations were found between QoL by SF-36 and physical fitness measurements, suggesting that increases in the levels of physical fitness, even in the very elderly, can contribute to improvements in QoL.

Role of nitric oxide in the nucleus of the solitary tract of rats

We have determined the role of nitric oxide (NO) in the nucleus of the solitary tract (NTS) of normotensive Wistar rats. The unilateral microinjection of Nomega-nitro-l-arginine methyl ester (10 nmol) to block the synthesis of NO into the NTS significantly decreased the arterial pressure, heart rate (HR) and renal sympathetic nerve activity (RSNA) (-19+/-2 mmHg, -23+/-5 beats/min, -30+/-2%, respectively). The microinjection of carboxy-2-phenyl-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide (Carboxy PTIO) (trapper of NO; 0.1 nmol) into the NTS also decreased arterial pressure and RSNA. Conversely, the microinjection of Et2N[N(O)NO]Na (NOC 18) (NO donor; 10 nmol) caused increases in arterial pressure, HR and RSNA (+14+/-2 mmHg, +11+/-2 beats/min, +38+/-7%, respectively), which was inhibited by the pre-microinjection of Carboxy PTIO (0.1 nmol). On the other hand, not only l-arginine (10 nmol) but also d-arginine (10 nmol), which is inactive to produce NO, significantly decreased the arterial pressure and RSNA. These results suggest that (1) NO acts at the NTS to increase the arterial pressure and RSNA, and (2) the microinjection of l-arginine as well as d-arginine led to decreases in arterial pressure and RSNA that were not mediated by the formation of NO in the NTS.

Physical Fitness and Cognitive Function in an 85-Year-Old Community-Dwelling Population

Background: Little is known about the association between physical fitness and cognitive function in very elderly people (over 80 years of age). Objectives: To evaluate that relationship in 85-year-old community-dwelling individuals. Methods: Out of 207 participants (90 males, 117 females) who were 85 years old and community-dwelling, 205 completed the Mini-Mental State Examination (MMSE) for evaluating cognitive function. The numbers of subjects who completed physical fitness measurements such as hand-grip strength, isometric leg extensor strength, one-leg standing time, stepping rate, and walking speed were 198, 159, 169, 168, and 151, respectively. Results: There were significant associations in MMSE with hand-grip strength (right or left hand), isometric leg extensor strength, stepping rate, and walking speed by simple regression analysis. MMSE was still significantly associated with hand-grip strength (β = 0.305, p = 0.005 for right side; β = 0.309, p = 0.004 for left side), stepping rate (β = 0.183, p = 0.046), and walking speed (β = –0.222, p = 0.014) by multiple regression analysis after adjustments for the amount of education, gender, smoking, drinking, complication of stroke, body weight, body height, regular medical care, serum albumin, blood HbA1c, and marital status. By logistic regression analysis, the prevalence of a normal MMSE score (MMSE ≧24) was increased by 9% with each 1-kg increase in hand-grip strength of the left hand (OR 1.087, 95% CI 1.003–1.179, p = 0.042), and was increased by 6% with each step per 10 s in stepping rate (OR 1.060, 95% CI 1.000–1.122, p = 0.048). Conclusion: In a very elderly population of 85-year-olds, cognitive function was associated with some physical fitness measurements, independent of confounding factors.

Chaos and spectral analyses of heart rate variability during head-up tilting in essential hypertension

To investigate nonlinear and linear components of heart rate variability (HRV) in essential hypertension (EHT), we analyzed HRV by chaos and spectral analyses in patients with EHT (n = 18) and normotensives (n = 10) during head-up tilting. We used the correlation dimension (CD) and Lyapunov exponents as the parameters of chaos. The CD, an index of complexity, was lower at rest in EHT group than in normotensives, and did not change in EHT group in response to head-up tilting, but decreased in normotensives. Head-up tilting did not change the Lyapunov exponents, an index of sensitive dependence on initial condition, a hallmark of chaos, in both groups. In the spectral analysis, the normalized high-frequency component (%HF) was decreased in EHT group at rest, and head-up tilting increased the low- to high-frequency ratio (L/H) and reduced the %HF in both groups. The CD and Lyapunov exponents at rest were correlated with the %HF and L/H. These results suggest that chaos analysis can assess the different aspect of HRV from spectral analysis and that nonlinear components of HRV may be associated with hypertension through an impaired dynamic regulation of HRV.

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.