Appearance of immunoregulatory RT6+ T cells after successful pancreas transplantation in diabetic BB rats.
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ADP Ribose Transferases↗
Biomedical subjects
A Moriguchi
Publications and source records attributed to A Moriguchi.
The effect of central amino acid neurotransmitters on the antihypertensive response to angiotensin blockade in spontaneous hypertension.
OBJECTIVE: To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974. MATERIALS AND METHODS: We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and gamma-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle. RESULTS: In SHR, CV 11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 +/- 83%) and gamma-aminobutyric acid (363 +/- 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35 +/- 4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, -18 +/- 5 mmHg; nitroglycerin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or gamma-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the gamma-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR. CONCLUSION: The present results suggest that the release of the inhibitory amino acids glycine and gamma-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.
Angiotensin Receptor Antagonists↗
Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats.
We determined the levels of angiotensin I (ANG I), angiotensin II (ANG II), and the heptapeptide angiotensin(1-7) [ANG(1-7)] in the blood and brain of female Hannover Sprague-Dawley (SD) and transgenic hypertensive rats [mRen-2]27 by radioimmunoassay and high performance liquid chromatography. Hypertension was accompanied by higher plasma concentrations of ANG II, no statistical changes in ANG(1-7), and no differences in plasma ANG I levels. In the hypothalamus of transgenic rats, concentrations of ANG II and ANG(1-7) averaged 827% and 168% above values in SD rats (p < 0.005) whereas both ANG I and ANG II increased in the medulla oblongata. The data showed that the established phase of hypertension in rats harboring the mouse Ren-2 gene is associated with overexpression of the renin-angiotensin system in brain regions participating in the endocrine regulation of blood pressure.
Angiotensin I↗
Estrogen augments the contribution of nitric oxide to blood pressure regulation in transgenic hypertensive rats expressing the mouse Ren-2 gene.
Transgenic rats carrying the mouse Ren-2 gene (Ren-2d)27 provide a unique model to study the interplay between the renin-angiotensin system and estrogen in the pathogenesis of hypertension. In this study we measured the effects of ovariectomy and estrogen replacement on blood pressure and the contribution of vascular endothelium relaxing factor, nitric oxide, in female transgenic hypertensive rats and normotensive Sprague-Dawley (SD) rats. Both groups of animals were either ovariectomized or sham-operated at 12 weeks of age. Ovariectomized rats were treated with either 17 beta-estradiol (70 micrograms/day) or placebo for 4 weeks, whereas sham-operated rats received placebo alone. Mean arterial blood pressure measured in conscious rats directly by an arterial catheter was significantly higher in ovariectomized rats, compared with ovariectomized rats given estrogen replacement therapy for both transgenic (167 +/- 5 v 154 +/- 4 mm Hg, P < .05) and SD rats (125 +/- 4 v 113 +/- 5 mm Hg, P < .05). The contribution of endothelium-derived nitric oxide to the maintenance of blood pressure was examined by acute systemic injection of NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg). L-NMMA caused a significantly greater increase in blood pressure in sham-operated transgenic as compared to SD rats (34 +/- 3 v 14 +/- 3 mm Hg, P < .05). The response in ovariectomized transgenic rats was markedly reduced (13 +/- 3 mm Hg), reaching levels that were no different from sham-operated SD rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Differential control of vascular tone and heart rate by different amino acid neurotransmitters in the rostral ventrolateral medulla of the rat.
1. To test the hypothesis that a central mechanism may play a role in the minimal reflex tachycardia noted in response to peripheral converting enzyme inhibition, we compared the effects of intravenous (i.v.) ceronapril (CER) with nitroglycerin (NTG) on neurotransmitter release in the rostral ventrolateral medulla (RVLM), using an in vivo microdialysis method in pentobarbital anaesthetized rats. 2. CER (0.1 mg/kg, i.v.) caused a progressive decrease in glutamate (GLU) release (CER 65 +/- 7% vs NTG 83 +/- 3% of each baseline at 140 min, P < 0.05) and attenuated the increase in glycine (GLY) release (CER 100 +/- 8% vs NTG 122 +/- 9%, P < 0.05). 3. Prevention of blood pressure reduction due to i.v. CER by concomitant infusion of a subpressor dose of angiotensin II (AII) attenuated the progressive reduction of GLU release (87 +/- 4%, P < 0.05 compared with NTG group), whereas GLY release was not affected (106 +/- 5%, NS compared with NTG group). 4. Perfusion of GLU into this area at approximately physiological concentrations resulted in a sustained tachycardia with an attenuation of the depressor effect of i.v. CER and perfusion of GLY solely lowered blood pressure. 5. These results demonstrate that i.v. converting enzyme inhibitor reduces the release of GLU in the RVLM, which was specifically caused by reducing circulating AII, without any effect on GLY release, thus resulting in the reduction of blood pressure with minimal effect on the heart rate.
Anesthesia↗
Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene.
Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2d)27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determined the effects of a 13-day therapy with losartan (10 mg/kg) or lisinopril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiotensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawley (SD) rats. The contribution of endothelium-derived nitric oxide (NO) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either NG-monomethyl-L-arginine (L-NMMA) or endothelin-1. Hypertension in TG rats was associated with decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both strains, the chronic fall in BP produced by lisinopril was accompanied by significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produced by either lisinopril or losartan in SD controls. In contrast, administration of L-NMMA to TG rats given the same therapy did not. The transient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and lisinopril in TG rats. These studies indicate that hypertension in female TG rats is mediated by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene.
The transgenic (TG) rat carrying the mouse renin gene (mRen-2d) has provided a unique opportunity to explore central interactions between the brain renin-angiotensin (RAS) and vasopressin (AVP) systems. To evaluate the hypothalamic vasopressin axis in the TG rat, we measured the central nervous system concentrations of AVP and determined the effect of angiotensin II (ANG II) and its NH2-terminal heptapeptide [angiotensin-(1-7)] on blood pressure, heart rate, and AVP release using brain microdialysis. Intracerebroventricular infusion of ANG II or ANG-(1-7) in control rats increased local AVP release from the paraventricular and supraoptic nuclei. The ANG II infusion was associated with a significant increase in blood pressure not observed with ANG-(1-7). In contrast, the angiotensin peptide-induced central AVP responses and the ANG II-induced blood pressure increase were absent in the TG animal. The plasma AVP responses to ANG II and ANG-(1-7) were comparable in the control and TG rats. The TG rats exhibited a 22-fold higher level of AVP in the dorsal lower brain stem but had lower AVP levels in the posterior pituitary and the median eminence compared with control rats. These results suggest that insertion of the mouse renin gene into the rat genome leads to alterations in the AVP axis in terms of AVP peptide content and angiotensin-induced cardiovascular and AVP responses.
Angiotensins↗
Quinolone antimicrobial agents substituted with morpholines at the 7-position. Syntheses and structure-activity relationships.
A series of novel 7-substituted 1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids have been prepared and tested for antibacterial activities and for convulsive activities in combination with nonsteroidal antiinflammatory drug. Structure-activity relationships revealed that 7-(2-(aminomethyl)morpholino) derivative 28 had a better Gram-positive activity than the reference quinolones, such as ciprofloxacin, norfloxacin, and ofloxacin. Its Gram-negative activity was equipotent with those of norfloxacin and ofloxacin but was inferior to that of ciprofloxacin. In mouse systemic infection models, 28 showed an excellent therapeutic efficacy which might result from the potent antibacterial activity and suitable physicochemical properties. Convulsive activities of 7-morpholino derivatives in combination with nonsteroidal antiinflammatory drug fenbufen or its metabolite biphenylacetic acid markedly diminished as compared to those of 7-piperazino derivatives in the electrophysiological, biochemical, and behavioral experiments. These results suggest that 28 (Y-26611) is a novel quinolone with reduced neurotoxic excitatory adverse reaction.
4-Quinolones↗
Eradication of metastatic tumour cells from lymph nodes by local administration of anti-CD3 antibody.
The possibility of in vivo removal of metastatic tumour cells from lymph nodes by local intradermal administration of an anti-CD3 monoclonal antibody (mAb) was examined. Murine tumour cells in the lymph nodes were completely eradicated by intradermal injections of the mAb. This treatment was effective for removal of Lewis lung cancer cells from lymph nodes, but not for removal of subcutaneous tumours of this cell line. This treatment induced in vivo cytotoxicity in the regional lymph nodes against the syngeneic tumour cells. The following in vitro studies suggested that the cytotoxicity was probably mediated mainly by CD4+ T cells, with slight participation of CD8+ T cells. Normal lymph node and spleen cells showed cytotoxicity after in vitro incubation with the mAb for 2 days. Cell sorting with a fluorescein-activated cell sorter showed that CD4+ T cells developed during the incubation to lyse syngeneic tumor cells directly by themselves, macrophages not being involved in this tumour cell lysis. The lytic activity was detected in the cellular fractions, but not in the culture supernatants of these T cells. Furthermore, it was completely blocked by specific antiserum for tumour necrosis factor-alpha (TNF alpha). An immunoprecipitation study revealed that these T cells expressed TNF alpha molecules of 26 kDa, but not of 17 kDa, suggesting that tumour cell lysis was caused by membrane-integrated integrated TNF alpha molecules. These results strongly suggest that local administration of anti-CD3 antibody is a very effective and appropriate procedure for eradication of metastatic tumour cells from regional lymph nodes.
Animals↗
Evaluation of orthostatic hypotension using power spectral analysis.
To evaluate the pathogenesis of orthostatic hypotension, we studied the autonomic regulation system by measuring heart rate variability during 60 degrees passive head-up tilt using power spectral analysis in 21 patients with orthostatic hypotension (mean age 62 +/- 2 years, five with histories of cerebrovascular accidents, five with Parkinsonism, five with diabetes mellitus, three with pheochromocytoma, and three with unknown causes) and 15 normal healthy subjects as a control (mean age 63 +/- 2 years). We also assessed plasma epinephrine and norepinephrine response to tilt. During tilt, control subjects showed an increase in heart rate with no change in blood pressure. Spectral analysis of heart rate variability demonstrated increases in the low frequency band (LFB, mainly sympathetic) and low frequency band/high frequency band ratio (LFB/HFB, sympatho-vagal balance). All patients with orthostatic hypotension showed a significant reduction in blood pressure with an increase in heart rate. In patients with histories of cerebrovascular accidents and with Parkinsonism, LFB and the LFB/HFB ratio did not increase. However, in other patients with orthostatic hypotension, LFB and the LFB/HFB ratio increased during tilt. Norepinephrine increased in control subjects and in patients with diabetes mellitus, pheochromocytoma, and unknown causes. In contrast, patients with histories of cerebrovascular accidents and patients with Parkinsonism showed no increase in norepinephrine. Epinephrine responses paralleled those of norepinephrine, but the changes were not significant. Thus, neurological response to tilt is not uniform in patients with orthostatic hypotension. Patients with histories of cerebrovascular accidents and patients with Parkinsonism may have impaired function of central neural mechanisms controlling blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Pressure↗
Spectral change in heart rate variability in response to mental arithmetic before and after the beta-adrenoceptor blocker, carteolol.
Spectral analysis of heart rate fluctuation was evaluated before and after administration of carteolol, a non-selective beta-adrenoceptor-blocker, to investigate the neural regulatory mechanisms underlying the haemodynamic changes induced by mental stress. Mental stress increased blood pressure and heart rate, with an increased low frequency band, and low frequency/high frequency ratio of the power spectral analysis which are indices of sympathetic activity. Carteolol did not change basal and pre-mental stress measurements of blood pressure, heart rate and spectral density. However, carteolol altered the response to mental stress with a decrease in spectral density of the low frequency band and low frequency/high frequency ratio, and an increase in the high frequency component. These results confirm that mental stress elevates blood pressure by activating the sympathetic nervous system, and suggest that blockade of the beta-adrenoceptor attenuates the pressor response by preventing the autonomic responses to mental stress.
Blood Pressure↗
[An elderly case of hypertension with persistent orthostatic hypotension].
The authors report the successful control of labile hypertension associated with orthostatic hypotension in a 75-year-old male patient, by means of L-DOPS, a synthetic precursor of norepinephrine in combination with antihypertensive drugs. He had been known to be hypertensive for 15 years and developed a persistent floating sensation 2 years age. Despite good control of hypertension after admission, orthostatic hypotension was still observed. Passive tilt produced a blood pressure reduction of 60/20 mmHg. Spectral analysis of heart rate variability showed a disturbance in the activation of the sympathetic nervous system. Treatment with L-DOPS attenuated the blood pressure reduction in response to passive tilt (35/12 mmHg) and improved the sympathetic response. Because of an increase in blood pressure by L-DOPS, addition of either a calcium channel blocker or an angiotensin-converting enzyme inhibitor was necessary. These combinations of treatment successfully controlled blood pressure as well as orthostatic hypotension.
Aged↗
Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats.
To examine the role of the tissue renin-angiotensin system in left ventricular hypertrophy, converting enzyme inhibitors were administered orally to 12-week-old male spontaneously hypertensive rats (SHR) for 4 weeks, and cardiac tissue angiotensin II was measured. Treatment with enalapril (10 mg/kg per day) and trandolapril (1 mg/kg per day) lowered systolic blood pressure, left ventricular weight and left ventricular angiotensin II content. Plasma angiotensin II concentration was increased by the treatment with enalapril whereas trandolapril did not cause any change. There was significantly positive correlation between left ventricular weight and angiotensin II content. Because angiotensin II promotes cell proliferation, these results suggest that cardiac tissue angiotensin II, rather than circulating angiotensin II, may account for the pathophysiology of left ventricular hypertrophy in SHR.
Angiotensin II↗
Importance of the sympathetic nervous system in blood pressure elevation by subpressor intraventricular NaCl and angiotensin II in the rat.
The present study was performed to examine the effect of chemical sympathectomy with guanethidine on the BP change and humoral factors in rats which received continuous and concomitant infusion of i.c.v. hypertonic NaCl with i.v. Ang II, both at subpressor doses for 7 days. Male rats were divided into 3 groups which received the following infusions using an osmotic minipump at a rate of 1 microliter/min: Group 1 (n = 11), 0.15 M NaCl i.c.v. and Ang II (5.4 pmol/kg/min) i.v.; Group 2 (n = 9), 0.8 M NaCl i.c.v. and Ang II i.v.; Group 3 (n = 5), 0.8 M NaCl i.c.v. and Ang II i.v. with daily i.p. injection of guanethidine (40 mg/kg). Significant increase in BP was observed only in Group 2 (from 103 +/- 3 mmHg to 132 +/- 5 mmHg on day 7, p less than 0.001). Addition of i.p. guanethidine to i.c.v. infusion of 0.8 M NaCl and the subpressor dose of Ang II completely prevented increase in the BP, suggesting that the presence of the intact sympathetic nervous system is necessary for the development of BP elevation in response to i.c.v. hypertonic NaCl plus i.v. Ang II. Thus, the sodium status in the central nervous system is important in the regulation of BP and is closely related to the activity of the sympathetic nervous system.
Angiotensin II↗
Disparate cardiovascular responses to passive tilt and mental stress in young and elderly normotensives.
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Adult↗
Haemodynamic effect of endothelin, a novel potent vasoconstrictor in dogs.
1. The effects of endothelin (40 and 400 pmol/kg, intravenous (i.v.), a novel vasoconstrictor, on haemodynamics were evaluated in normal dogs and dogs treated with hexamethonium. 2. The lower dose of endothelin caused no significant changes in mean blood pressure (MBP), heart rate (HR), cardiac output (CO), or total peripheral resistance (TPR) in normal dogs. In dogs treated with hexamethonium MBP decreased transiently associated with decrease in TPR. 3. In both dogs, the higher dose of endothelin caused MBP increase with CO increase in an early phase, and with TPR increase in a later phase. In normal dogs, the CO decreased 60 min after endothelin, but in dogs treated with hexamethonium the decrease in CO was not significant. 4. Electrocardiograms showed ST changes and arrhythmias. 5. Thus, endothelin has dual effects on both the vasculature and the heart, its effect depending on its dose and the time after its administration: initial vasodilation followed by prolonged vasoconstriction, and cardiostimulation followed by cardiosuppression. The cardiosuppression appears to be mediated in part by a neural mechanism.
Animals↗
Increased plasma level of endothelin with vasoconstriction after dextran infusion.
Our previous study demonstrated that volume expansion with dextran produced blood pressure elevation due to vasoconstriction 3 hours after the cessation of infusion. To examine whether endogenous endothelin contributes to this vasoconstriction, we measured plasma level of endothelin before, immediately after, and 3 hours after the administration of dextran. Plasma level of endothelin decreased immediately after the administration (from 1.5 +/- 0.3 pg/ml to 1.1 +/- 0.2 pg/ml, P less than 0.05), and increased 3 hours after the administration (2.1 +/- 0.3 pg/ml, P less than 0.05). However, the changes in the plasma level of endothelin did not significantly correlated with those in blood pressure or total peripheral resistance. Thus, vasoconstriction after dextran infusion was accompanied by an increase in the plasma level of endothelin, but further evaluation is needed for the direct role of this peptide in the vasoconstrictive blood pressure elevation.
Animals↗
Effect of aspirin on the pressor activity of endothelin.
To examine the inhibition of prostaglandins to the pressor activity of endothelin, hemodynamic changes of dogs pretreated with aspirin in response to endothelin were compared with those of control. In control dogs, endothelin rose blood pressure due to vasoconstriction, with a transient vasodilation in some dogs in the initial phase. In dogs treated with aspirin, the initial vasodilation and the subsequent vasoconstriction were also noted, but the zenith of the total peripheral resistance was observed earlier, compared with control dogs. Thus, prostaglandins do not appear to have a role in the initial vasodilatory action of endothelin, but may modify the long lasting vasoconstriction in the late phase.
Animals↗