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Biomedical subjects

H Rakugi

Publications and source records attributed to H Rakugi.

At least 73 records · Page 4Linked to original sources
PubMed1994

Augmentation of angiotensin II release from isolated mesenteric arteries of Wistar-Kyoto and spontaneously hypertensive rats following nephrectomy.

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.

Angiotensin II↗
PubMed1994

Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation.

BACKGROUND: Angiotensin II (Ang II) induces vascular smooth muscle cell migration and growth in vitro and induces DNA synthesis in vascular smooth muscle in vivo. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists inhibit neointimal hyperplasia in many experimental models of restenosis. However, recent clinical trials (MERCATOR and MARCATOR) reported that treatment with low (antihypertensive) doses of an ACE inhibitor (cilazapril) failed to prevent restenosis. Because ACE activity is induced in the neointima after injury, we hypothesize that the inhibition of neointimal development may be dependent on the suppression of tissue ACE activity, which in turn is dependent on the dose of the ACE inhibitor. METHODS AND RESULTS: To test this hypothesis, we treated rats with increasing doses of an ACE inhibitor, quinapril, before injury of the carotid artery. Blood pressure, serum and tissue ACE activity, and neointimal area were measured. The results demonstrated a dose-dependent inhibition by quinapril of serum and tissue ACE activities and neointima formation. However, the IC50s for blood pressure reduction and serum ACE inhibition were significantly lower than that observed for the suppression of neointima formation. The degree of neointimal formation showed a better correlation with residual tissue ACE than with serum ACE or blood pressure. CONCLUSIONS: These results demonstrate a dissociation of the ability of an ACE inhibitor to decrease blood pressure and inhibit circulating ACE activity from its ability to inhibit tissue ACE activity. These results suggest that the need for a higher dose of an ACE inhibitor for the inhibition of neointima formation may be due to the relative difficulty in inhibiting tissue ACE activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Induction of angiotensin converting enzyme in the neointima after vascular injury. Possible role in restenosis.

Angiotensin II (Ang II) promotes growth of vascular smooth muscle cells in vitro. Consistent with this, Ang II enhances neointimal proliferation in vivo after vascular injury, while angiotensin converting enzyme (ACE) inhibitors attenuate this process. Since tissue ACE plays a key role in the control of local Ang II production, we examined whether vascular injury resulted in an increase in vascular ACE expression that may result in increased Ang II production. Abdominal aorta of Sprague-Dawley rats were injured with a 2 French balloon catheter. Morphometrical changes, ACE enzymatic activity, and localization of ACE by immunohistochemistry in injured and uninjured aorta were analyzed. Vascular ACE activity in the injured aorta was significantly higher than in the uninjured aorta, while serum and lung ACE levels were not different between the two groups. The cellular distribution of the ACE protein in the neointima was similar to that of alpha smooth muscle actin but differed from those of endothelial (von Willebrand factor) or monocytes/macrophages (ED-1) markers, demonstrating that ACE was expressed in neointimal smooth muscle cells. These data demonstrate that vascular injury results in the induction of vascular ACE and suggest that the inhibition of vascular ACE may be important in the prevention of restenosis after balloon injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Differential regulation of brain angiotensin II in genetically hypertensive and normotensive rats after nephrectomy.

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.

Angiotensin II↗
PubMed1994

Effects of an angiotensin II receptor antagonist, CV-11974, on angiotensin II-induced increases in cytosolic free calcium concentration, hyperplasia, and hypertrophy of cultured vascular smooth muscle cells.

The effects of CV-11974, a potent nonpeptide antagonist of the angiotensin II (AII) type-1 receptor (AT1), on cytosolic free calcium concentration ([Ca2+]i), hyperplasia, and hypertrophy of cultured vascular smooth muscle cells (VSMC) from rat aorta were studied. [Ca2+]i was measured by fura 2, and hyperplasia and hypertrophy were determined by incorporation of [3H]thymidine and [3H]leucine, respectively. CV-11974 had no effect on [Ca2+]i itself, but suppressed 10(-7) M AII-induced increase in [Ca2+]i dose dependently at concentrations from 10(-10) M and completely at 10(-7) M. CV-11974 suppressed both Ca2+ release from intracellular Ca2+ stores and Ca2+ influx from the extracellular space. However, CV-11974 had no effect on the increases in [Ca2+]i induced by prostaglandin F2 alpha (PGF2 alpha), a potent vasoconstrictor, or ionomycin, a Ca2+ ionophore. These results indicate that the suppressive effects of CV-11974 act on the binding of AII and its specific receptors. AII 10(-7) M increased the synthesis of DNA and protein to 1.5 and 1.7 times the control values, respectively. CV-11974 had no effect on synthesis of DNA or protein, but suppressed the AII-stimulated synthesis of DNA and protein dose dependently at concentrations > or = 10(-8) and 10(-10) M, respectively and completely at 10(-6) M. These results indicate that AII increases [Ca2+]i and synthesis of DNA and protein in VSMC through activation of AT1. CV-11974 showed no partial agonistic effects on AII. Thus, CV-11974 may act not only as an antihypertensive agent, but also as an inhibitor of vascular injury stimulated by AII.

Angiotensin II↗
PubMed1994

Activated angiotensin II generation and regulation in rat mesenteric arteries following nephrectomy.

The objectives of the present study were to test the hypothesis that vascular angiotensin II (AII) generation may be negatively regulated by circulating AII in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and to clarify the role of this vascular AII in the sustained hypertension seen in SHR following nephrectomy. The mesenteric arteries from kidney-intact and nephrectomised WKY and SHR were perfused, and the level of AII released into the perfusate were measured. The effects of CV-11974, a newly developed nonpeptide AII receptor antagonist, on AII release were examined to investigate the existence of a local feedback system in the blood vessels. Nephrectomy augmented vascular AII release both in WKY and SHR despite the reduction in circulating AII. CV-11974 significantly increased AII release from the mesenteric arteries of kidney-intact rats. There were no significant differences in these responses between WKY and SHR. These results suggest that WKY and SHR share a potent pathway for producing vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension seen in SHR after nephrectomy.

Angiotensin II↗
PubMed1994

Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese.

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.

Angiotensinogen↗
PubMed1993

The role of activated vascular angiotensin II generation in vascular hypertrophy in one-kidney, one clip hypertensive rats.

OBJECTIVE: To investigate the role of vascular angiotensin II (Ang II) in the vascular thickening of one-kidney, one clip (1-K, 1C) hypertensive rats, which show normal plasma renin activity. METHODS: The type 1 Ang II receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme (ACE) inhibitor delapril (20 mg/kg per day), hydralazine (20 mg/kg per day) or vehicle were administered to four groups of 1-K, 1C rats aged 6-10 weeks. Vehicle was also given to uninephrectomized rats. RESULTS: The aortae of 1-K, 1C rats contained significantly higher levels of Ang II than those of uninephrectomized rats and showed hypertrophy, but not hyperplasia of their medial smooth muscle cells. Hypertrophy was estimated by immunohistochemical staining of alpha-actin. Hyperplasia was estimated by DNA content and incorporation of 5-bromo-2'-deoxyuridine. The blood pressure of the 1-K, 1C rats was not affected by either TCV-116 or delapril, even at doses sufficient to induce depressor effects in spontaneously hypertensive rats. However, subdepressor doses of TCV-116 and delapril both significantly reduced the alpha-actin-stained area to 78 and 73%, respectively, of that in the 1-K, 1C rats, whereas a depressor dose of hydralazine did not affect the alpha-actin-stained area. The level of Ang II in the aorta, but not in plasma, was suppressed by delapril but not by hydralazine. CONCLUSIONS: These results suggest strongly that vascular Ang II plays a major role in the development of vascular hypertrophy, independently of plasma Ang II, bradykinin and ACE-independent pathways of Ang II generation, and in the regulation of blood pressure in this normoreninaemic hypertensive model.

Actins↗
PubMed1993

Vascular injury induces angiotensinogen gene expression in the media and neointima.

BACKGROUND: Angiotensin II promotes growth of vascular smooth muscle cells in vitro via the autocrine production of growth factors such as platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-beta. Furthermore, experimental studies have demonstrated that angiotensin infusion can enhance smooth muscle proliferation after balloon injury in vivo. Consistent with this, angiotensin converting enzyme inhibitors have been shown to prevent myointimal proliferation. The origin of vascular angiotensin that participate in this process is of interest. We have demonstrated the presence of angiotensinogen messenger RNA (mRNA) in the adventitial and medial layers of the rat aorta and have speculated that local angiotensinogen production may play an important role during myointimal proliferation. To provide further evidence toward this hypothesis, we compared the localization and expression of angiotensinogen mRNA in control and balloon injured vessels using in situ hybridization. METHODS AND RESULTS: Abdominal aorta of Sprague-Dawley rats were studied before or after injury with a balloon catheter. Neointimal hyperplasia developed as documented morphologically by a progressive increase in the ratio of neointimal to medial thickness from 0.17 at 1 week to 1.17 at 6 weeks after injury. Angiotensinogen mRNA was detected clearly in the adventitia and media of control and injured aorta. However, at 1 week after injury, the medial-to-adventitial angiotensinogen mRNA ratio was higher in the injured aorta, suggesting increased gene expression in the media compared with control. Of potential importance, angiotensinogen mRNA was also detected in the neointima of the injured aorta, and this was also highest at 1 week after injury. CONCLUSIONS: These data are consistent with the hypothesis that balloon injury leads to activation of the vascular renin-angiotensin system, which may participate in the myointimal proliferation.

Angiotensinogen↗
PubMed1990

Evidence for endothelin-1 release from resistance vessels of rats in response to hypoxia.

To elucidate further the contribution of endothelin into endothelium-dependent vasoconstriction evoked by hypoxia, we observed endothelin release during hypoxia. Endothelin was detectable in perfusate from mesenteric artery. Immunoreactive endothelin was confirmed as endothelin-1 by a reverse phase-HPLC. Endothelin release increased 4.1 +/- 1.3 to 12.4 +/- 2.0 pg/30 min without changing perfusion pressure. Thirty minutes of hypoxia stimulated endothelin release by 71 +/- 11% (P less than 0.05) and was associated with an elevation of perfusion pressure. These results suggest that endothelin contributes to endothelium-dependent vasoconstriction by hypoxia in mesenteric artery and may play an important role in the local peripheral vascular tone.

Animals↗
PubMed1990

[A case of recessive dystrophic epidermolysis bullosa associated with dwarfism with special reference to pathophysiological role of growth hormone].

Epidermolysis bullosa is a group of disorders whose common primary feature is the formation of blisters following trivial trauma. Recessive dystrophic epidermolysis bullosa (RDEB), a subtype of epidermolysis bullosa, is frequently associated with growth retardation. This growth retardation has been reported to be caused by trophopathy following protein loss through skin lesions. Endocrine disorders as the cause of growth retardation in RDEB have not been clearly described. An 11-year-old female had a typical RDEB with dwarfism. Her height was 125 cm and weight was 21 kg, both of which were 2.5 SD below the average. The skin lesions were generalized and probably caused by undernourishment, infection, and blood loss through the skin. However, her serum albumin was at the lower normal limit, and the rapid turnover proteins were slightly decreased. Endocrinological examinations revealed that all the basal levels of pituitary, thyroid, and adrenal hormones were normal. Results of the exercise test, the insulin tolerance test, and the growth hormone-releasing factor test indicated the presence of hypothalamic disorder in secretion of growth hormone. This is the first report of RDEB in which hypothalamic disorder in growth hormone secretion was investigated. On the other hand, growth hormone is known to be involved in collagen metabolism, and a decrease in collagen fibrils and an increase in collagenase activities are found in the skin of RDEB. This implies that this hypothalamic disorder in growth hormone secretion may be involved in the pathophysiology of both dwarfism and the skin lesions in RDEB.

Child↗
PubMed1990

Effects of chronic converting enzyme inhibition on the vascular renin-angiotensin system.

1. The effects of chronic oral administration of inhibitors of angiotensin converting enzyme (ACE) on the vascular renin-angiotensin system were studied. 2. Male Sprague-Dawley rats were treated orally with five ACE inhibitors, captopril, enalapril, ramipril, cilazapril and CS-622 (10 mg/kg per day), for periods of 1-2 weeks. Their mesenteric arteries were then isolated and perfused in vitro with Krebs'-Ringer solution, and the angiotensin II (AII) released into the perfusate was measured under unstimulated and isoproterenol-stimulated conditions. The vascular renin activity was also determined after treatments with ACE inhibitors. 3. Treatment with captopril for 1 week suppressed the isoproterenol-stimulated increase in AII release, but had little effect on the baseline release. Oral treatment with captopril for 2 weeks or with other ACE inhibitors for 1 week markedly inhibited both the unstimulated and stimulated release of AII from the mesenteric vasculature. 4. Both the vascular renin activity and the plasma renin activity increased on captopril treatment, but their changes with time were different. 5. These results indicate that virtually complete inhibition of the vascular renin-angiotensin system can be achieved after prolonged treatment with ACE inhibitors, and suggest that the chronic antihypertensive action of ACE inhibitors is not solely due to inhibition of the plasma renin-angiotensin system.

Administration, Oral↗
PubMed1990

Effects of endothelin on neuroeffector junction in mesenteric arteries of hypertensive rats.

The effect of endothelin, a novel vasoconstrictor peptide, on the adrenergic neuroeffector junction was investigated in isolated perfused mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The vasoconstrictor responses to periarterial sympathetic nerve stimulation and exogenous norepinephrine were determined. Infusion of endothelin-1 increased the baseline perfusion pressure dose dependently to similar extents in the two strains. A subpressor dose of endothelin-1 (10(-10) M) enhanced the pressor response to norepinephrine; its effect was greater in WKY rats than in SHR. Endothelin-1 (10(-12) to 10(-10) M) attenuated the pressor response to sympathetic nerve stimulation, and the degree of inhibition tended to be less in SHR than in WKY rats. Higher doses (3 x 10(-10) and 10(-9) M) of endothelin-1 enhanced the pressor response to nerve stimulation in both WKY rats and SHR. Endothelin-1 inhibited norepinephrine release from rat mesenteric arteries; the inhibition was significantly less in SHR than in WKY rats. These results suggest that endothelin enhances the responsiveness of alpha-adrenergic receptors to catecholamines, whereas it inhibits presynaptic adrenergic neurotransmission. Thus, endothelin can interact with the neuroeffector junction in addition to having a vasoconstricting effect in peripheral vessels. The difference in the mode of modulation by endothelin at the vascular neuroeffector junction in SHR from that in WKY rats might explain the maintenance of hypertension.

Animals↗
PubMed1990

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↗
PubMed1990

Endothelin activates the vascular renin-angiotensin system in rat mesenteric arteries.

The effects of endothelin on the vascular renin-angiotensin system were examined in isolated perfused rat mesenteric arteries by measuring vascular renin activity and angiotensin II released into the perfusate. Infusion of endothelin (10(-9)M and 10(-11)M) increased the vascular renin activity and angiotensin II release. Pretreatment with nicardipine (10(-6)M), a calcium channel blocker, significantly suppressed these effects of endothelin. These results suggest that endothelin activates the vascular renin-angiotensin system via intracellular calcium metabolism. Vascular angiotensin II produced by endothelin may modulate the local effect of endothelin on the resistance vessels.

Angiotensin II↗
PubMed1989

[Graves' disease with markedly elevated serum immunoglobulin E].

A 37-year-old female with Graves' disease was reported. An abnormally high concentration of serum IgE was observed by radioimmuno-sorbent test before treatment. Laboratory findings showed no evidence of atopic diseases or other known diseases with hyperglobulinemia E. There is no reported case of Graves' disease associated with remarkably elevated plasma IgE level. In the present patient, a further elevation of serum IgE concentration was observed when the dose of methimazole reached about 500 mg in total. Allergic mechanism may be the cause of this phenomenon. Serum IgE level was decreased gradually after replacement of methimazole by propylthiouracil. IgE level was not parallel with thyroid functions, and even when her thyroid function was normalized after subtotal thyroidectomy, IgE concentration was still increased around 900 IU/ml. The mechanism of hyperglobulinemia E in this case was discussed.

Adult↗