Yoshiaki Yamashita

Ageing suppresses endothelium-dependent relaxation and generates contraction mediated by the muscarinic receptors in vascular smooth muscle of normotensive Wistar-Kyoto and spontaneously hypertensive rats.

We evaluated the effects of ageing and hypertension on endothelium-dependent relaxation and contraction of vascular smooth muscles. Aortic rings with and without endothelium from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), divided into young, adult and old groups, were examined for relaxation in response to acetylcholine, adenosine triphosphate (ATP) and sodium nitroprusside. Relaxation responses to acetylcholine and ATP in SHR were either equal to or greater than those in WKY. Relaxations induced by ATP were not altered by ageing, while the degree of acetylcholine-induced endothelium-dependent relaxations was in an inverse order of age in both SHR and WKY. In old SHR and WKY and adult SHR, lower doses of acetylcholine caused relaxations, but increases in the dose of acetylcholine induced contraction. Acetylcholine-induced contractions were abolished by indomethacin or endothelium rubbing. We conclude that endothelium-dependent relaxations are not diminished by spontaneous hypertension but the relaxations mediated by the muscarinic receptors are reduced with ageing. Further, acetylcholine causes endothelium-dependent contractions by releasing cyclo-oxygenase products, not only in SHR but also in aged normotensive WKY.

Ambulatory Blood Pressure Monitoring in Patients with Essential Hypertension Treated with a New Calcium Antagonist, Cilnidipine

Cilnidipine (FRC-8653), a new dihydropyridine calcium antagonist, was given to 14 hospitalized patients with essential hypertension, and 24-hour ambulatory blood pressure (BP) monitoring was performed. Once-daily administration of cilnidipine (5–20 mg) for 1–3 weeks decreased the 24-hour average BP significantly from 149 ± 4/88 ± 2 mmHg to 141 ± 3/82 ± 2 mmHg without any change in the pulse rate. The decrease in ambulatory BP by cilnidipine was evident during the daytime (156 ± 4/93 ± 2 mmHg to 143 ± 5/84 ± 2 mmHg, p > 0.01 for systolic BP and p > 0.01 for diastolic BP), while it was mild during nighttime (141 ± 4/80 ± 2 mmHg to 133 ± 4/76 ± 3 mmHg, p > 0.05 for systolic and ns for diastolic BP). The decrease in the ambulatory BP over the whole day and during the nighttime was significantly correlated with the basal ambulatory BP levels. When the subjects were divided into the high ambulatory BP (n = 7) and low ambulatory BP (n = 7) groups, the BP reduction by cilnidipine was evident throughout 24 hours in the high ambulatory BP group, while it was mild and significant only during daytime in the low ambulatory BP group. In summary, once-daily cilnidipine exerts a sufficient and prolonged reduction of BP without an increase in the pulse rate in patients with hypertension. The potency of cilnidipine to decrease ambulatory BP may depend on the basal ambulatory BP level. Cilnidipine is thus a useful antihypertensive drug that may not cause an excessive decrease in BP or a reflex tachycardia.

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 a 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.

Brain renin angiotensin system contributes to the salt-induced enhancement of hypertension in SHR.

The study was performed to determine whether the brain renin angiotensin system may contribute to the acceleration in hypertension following long-term salt loading in spontaneously hypertensive rats (SHR). Five weeks old SHR and normotensive Wistar-Kyoto (WKY) were given 1% NaCl solution or plain tap water as drinking for 7 weeks. The salt treatment exaggerated the development of hypertension in SHR, but did not change the blood pressure (BP) in WKY. The hypotensive actions of intracerebroventricular (ICV) captopril was greater in SHR treated with salt than in those without treatment, whereas ICV AII increased BP to a similar degree between salt and control SHR. In WKY, the effects of ICV captopril and AII were not altered by the salt loading. The increases in BP induced by ICV hypertonic saline were not different between the rats with and without saline drinking in either SHR or WKY. The intravenous (IV) hexamethonium led to a greater fall in BP in SHR treated with saline than in those without salt, while it tended to produce a smaller decrease in BP in WKY with salt overload than in those without loading. Both duration and magnitude of the depressor effects of IV captopril were reduced by the chronic saline treatment in SHR. The plasma renin concentration (PRC) in both SHR and WKY was significantly suppressed by the salt load. The present results suggest that long-term salt overload may result in the enhanced activity of brain renin angiotensin system, which could be responsible for the exaggerated development of hypertension in SHR. Our observations also provide further evidence that the central renin angiotensin system is independent of the peripheral system.

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.

Vasopressin and Sympathetic Nervous Functions Both Contribute to Development and Maintenance of Hypertension in Doca-Salt Rats

We evaluated the time course of changes in the relative contribution of arginine-vasopressin (AVP) and sympathetic nervous system (SNS) during the development of DOCA-salt hypertension in rats. Intravenous administrations of an AVP antagonist (d(CH2)5Tyr(Me) AVP; AVPA) and hexamethonium (C6) were given at 3 and 7 days, and 2 and 4 weeks after the initiation of treatment with DOCA-salt to conscious and unrestrained rats. Mean arterial pressure (MAP) was higher and heart rate (HR) tended to be rapid in the rats on DOCA-salt treatment for over 1 week, compared with those of the control groups. The hypotensive effect of AVPA in the DOCA-salt treated rats was gradually enhanced with the development of hypertension and was significantly greater than in the control rats, at all stages of hypertension, including the prehypertensive phase. The depressor response to intravenous C6 following AVPA also resulted in a gradual enhancement, with time, after DOCA treatment. This decrease in MAP was greater at the hypertensive stage than that in the control rats, although the response was not significantly different among three groups on the 3rd treatment day. It was concluded that the pressor systems AVP and SNS may contribute to the initiation and development as well as maintenance of DOCA-salt hypertension in rats.

Lack of increase in concentrations of cerebrospinal fluid sodium in rats with various stages of DOCA-salt hypertension

Experiments were conducted in conscious rats to determine whether DOCA-salt treatment could cause an elevation of sodium concentration of cerebrospinal fluid (CSF), which may be responsible for the enhanced activity of sympathetic nervous system (SNS) and increased secretion of vasopressin (AVP). Systolic blood pressure (SBP) and mean arterial pressure (MAP) were gradually but consistently increased by DOCA-salt treatment. Serum Na concentration was similarly increased with time by DOCA-salt, and significantly higher than control in the 4th treatment week. In contrast, DOCA-salt did not alter the CSF Na levels at any time during treatment. A relationship between SBP and CSF Na was never evident at any stage of the DOCA-salt hypertension. The decrease in MAP following administration of the vasopressin V1-receptor antagonist, d(CH2)5Tyr(Me)AVP (30 micrograms/kg), or hexamethonium (30 mg/kg) was enhanced in the DOCA-treated rats, as compared to findings in the controls. These hypotensive effects were gradually, but progressively enhanced with the development of hypertension by DOCA-salt treatment. We tentatively conclude that mechanisms accounting for the enhanced activity of SNS and AVP in DOCA-salt hypertensive rats are independent of an increased Na concentration in the CSF.

Circadian Variations of Blood Pressure in Patients With Sequelae of Carbon Monoxide Poisoning

It has been shown that carbon monoxide poisoning causes necrosis of the globus pallidum and the cerebral cortex, and a diffuse demyelination of the cerebral subcortical white matter, resulting in the impairment of the higher brain functions manifested as memory disturbances, apraxia, and agnosia. The purpose of the present study was to determine the effects of the lesions in the brain caused by carbon monoxide poisoning on the circadian changes in blood pressure and pulse rate. We measured the ambulatory blood pressure in 15 male patients with the sequelae of acute carbon monoxide poisoning and 16 age- and sex-matched controls. Using either brain computed tomography or brain magnetic resonance imaging, we determined that seven patients had lesions in the globus pallidum bilaterally, four had lesions in the parietotemporooccipital lobe bilaterally, and five had multiple deep white matter lesions. Circadian variations of blood pressure and pulse rate did not show any significant differences in either group. The average 24-h blood pressures were 120.8 +/- 2.2 (systolic)/74.1 +/- 1.5 mm Hg (diastolic) in the patients and 117.4 +/- 2.7/74.5 +/- 2.1 mm Hg in the controls. The daytime (6:00 to 21:00) and nighttime (21:00 to 6:00) blood pressures were 127.3 +/- 2.3/78.0 +/- 1.5 mm Hg and 109.7 +/- 2.4/67.4 +/- 1.7 mm Hg in the patients, and 121.6 +/- 2.9/77.5 +/- 2.2 mm Hg and 110.0 +/- 2.7/69.3 +/- 1.8 mm Hg in the controls, respectively. Furthermore, there were no differences in cardiovascular and plasma catecholamine responses induced by either a head-up tilt or a cold pressor test between the two groups. It is concluded that diffuse or multiple lesions in bilateral cerebral hemispheres caused by carbon monoxide poisoning per se do not affect the circadian changes in blood pressure and pulse rate observed in normotensive subjects.

Mechanisms of Pressor Responses to Intracisternal Administration of Hypertonic NACL in Conscious, Unrestrained Normotensive and Spontaneously Hypertensive Rats

We evaluated the mechanisms of pressor responses to hypertonic NaCl administered intracisternally (IC) to conscious normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Both mean arterial pressure (MAP) and heart rate (HR) increased immediately after IC NaCl (1.5mol/l, 60 microliters/kg), but MAP returned rapidly to the basal level. Pressor and tachycardic actions at the early phase were mostly abolished by either hexamethonium or phentolamine with the blockade of sympathetic nervous system (SNS), and slightly diminished by the V1-vasopressin blocker. In contrast, at the following phase pressor responses were not suppressed by combined or solitary blockade of SNS, vasopressin and angiotensin II (AII). The pressor effects of IC NaCl were slightly greater in SHR than in WKY. It is concluded that the early-phase increases in MAP by hypertonic NaCl administered IC to conscious SHR and WKY may be attributed mainly to the increased activity of SNS and partly to the increased release of AVP, although the late- phase pressor responses may result from some pressor factor(s), unrelated to SNS, AVP and AII.