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T Inagami

Publications and source records attributed to T Inagami.

At least 55 records · Page 3Linked to original sources
PubMed1991

The antihypertensive mechanism of delapril, a newly developed converting enzyme inhibitor, is related to the suppression of vascular angiotensin II release in the spontaneously hypertensive rat.

Accumulating evidence suggests an important role of vascular renin-angiotensin system (RAS) in the local control of arterial tone. To further gain insight into the significance of vascular RAS in hypertension, we investigated the relationship between the antihypertensive action of delapril, a newly developed converting enzyme inhibitor (CEI), and its effects on vascular angiotensin II (Ang II) release in spontaneously hypertensive rats (SHR). Male SHRs were given delapril or its active metabolite (5-hydroxydelapril diacid; 5-hydroxy-DPD) orally (10 mg/kg/day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was directly determined by extraction with Sep-Pak C18 cartridges connected to the perfusion system. Both delapril and 5-hydroxy-DPD produced a sustained antihypertensive action. The spontaneous release of Ang II from isolated perfused hind legs of control SHRs was about 50 to 110 pg during the first 30 min of perfusion, and it remained stable up to 3 h. Another active metabolite, delapril diacid (DPD), when added to the perfusion medium (10(-9) to 5 x 10(-5) mol/L), suppressed the Ang II release in a dose-dependent manner. The maximal percent inhibition of Ang II released evoked by DPD (5 x 10(-6) mol/L) was approximately 51%. Oral pretreatment of either delapril or 5-hydroxy-DPD for 2 weeks suppressed the Ang II release by 61% and 73% for delapril and 5-hydroxy-DPD, respectively. These results suggest the presence of a functional RAS in vascular tissues, and that delapril exerts its antihypertensive effect through inhibition of vascular Ang II release in SHRs.

Administration, Oral↗
PubMed1991

Direct proof for local generation and release of angiotensin II in peripheral human vascular tissue.

Previously we reported that immunoreactive angiotensin II (Ang II) release from isolated perfused human umbilical veins was inhibited by the angiotensin-converting enzyme inhibitor captopril. To further investigate the mechanism by which Ang II is generated in the blood vessels of humans, we examined the effects of various inhibitors of the renin-angiotensin system (captopril, delapril, N-acetyl-pepstatin, and human renin inhibitor KRI-1314) on Ang II release from perfused human umbilical cord veins in vitro. Isolated human umbilical veins were perfused with Krebs-Ringer solution, and immunoreactive Ang II released into the perfusate was measured directly by using a Sep-Pak C18 cartridge connected to the perfusion system. Both captopril and delapril diacid (10(-9) to 5 x 10(-6) mol/L), an active metabolite of delapril hydrochloride, suppressed the Ang II release in a dose-dependent fashion; the maximal percent suppression of Ang II release evoked by these inhibitors (5 x 10(-6) mol/L) was 56% and 64%, respectively, for captopril and delapril. Both N-acetyl-pepstatin (10(-9) to 10(-5) mol/L) and KRI-1314 (10(-9) to 10(-6) mol/L) suppressed Ang II release in a dose-related manner. At a 10(-6) mol/L concentration, KRI-1314 produced a 74% reduction in the basal rate of Ang II release, and a reduction threefold greater than the maximal reduction in basal Ang II release produced by N-acetyl-pepstatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1991

Atrial natriuretic factor and hypertension. A review and metaanalysis.

Atrial natriuretic factor (ANF) is a recently discovered, volume responsive hormone with multiple potent antihypertensive actions. This article reviews data supporting hypothetical associations between ANF and essential hypertension, examines reports of plasma ANF concentrations in hypertension, discusses the efficacy of ANF and its analogs in the treatment of hypertension, and reviews future issues in ANF research. ANF has been shown to elicit vasodilatation, suppress plasma renin activity, inhibit the synthesis and release of aldosterone, antagonize sympathetically-mediated release of norepinephrine, and promote diuresis and natriuresis. A metaanalysis of plasma ANF concentrations reported in normal and hypertensive subjects reveals a 5 +/- 19 pg/mL (pooled, weighted mean and standard deviation) higher ANF level in age-matched, untreated hypertensives without evidence of end-organ damage. This difference may be inappropriately low given the increase in atrial filling pressures found in hypertension. Low doses of ANF elicit greater reductions in blood pressure in hypertensive subjects than in normals. Recently, inhibitors of the ANF-degrading enzyme, neutral endopeptidase, and of the ANF "clearance" receptor have enhanced the antihypertensive actions of endogenous or exogenously administered ANF. Human studies are currently in progress testing the antihypertensive efficacy of orally administered neutral endopeptidase inhibitors. The discovery of ANF has led to the elucidation of a family of natriuretic peptides from brain, heart, and kidney, and promises to enlarge our understanding of volume regulation in normal and pathophysiological states. The possibility that essential hypertension is associated with inappropriately low plasma ANF levels or altered responsiveness to ANF may offer new insights into the pathogenesis and treatment of hypertension.

Amino Acid Sequence↗
PubMed1991

Atrial natriuretic peptide and brain natriuretic peptide coexist in the secretory granules of human cardiac myocytes.

To elucidate the intracellular localization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in human cardiac myocytes, an immunocytochemical study was carried out by a double immunogold technique using antisera highly specific for ANP and BNP. Surgical and autoptic tissue specimens of human heart were studied. In the atrial myocytes, ANP was localized in almost all of the secretory granules, whereas BNP was colocalized with ANP in some of the granules. Although very few secretory granules were observed in ventricular myocytes, colocalization of ANP and BNP was basically the same as in atrial myocytes. No immunoreactive products were found in the control studies. These results suggest that secretion of BNP is under a regulatory mechanism similar to that of ANP.

Atrial Natriuretic Factor↗
PubMed1991

Differential response of renin secretion to vasoconstrictors in the isolated perfused rat kidney.

1. We have examined whether an increase of renal vascular resistance is generally accompanied by an inhibition of renin secretion. The effects of vasoconstriction produced by angiotensin II (Ang II), arginine-vasopressin (AVP), and potassium (KCl) depolarization on vascular resistance and on renin release from isolated rat kidneys perfused at constant pressure of 100 mmHg were investigated. 2. Histological examination performed on some representative kidneys revealed that the tubular lumina of all segments within the cortex were patent and the brush borders of the proximal tubules were well preserved. The renal vasculature and the juxtaglomerular region appeared to be morphologically intact. By immunocytochemistry, renin-positive cells were found exclusively in the wall of the afferent arterioles. 3. Basal flow rate through isolated kidneys was 14.5 +/- 2.0 ml min-1 (g kidney weight (gkw))-1 (mean +/- S.E.M., n = 10). Under control conditions renin secretory rates were in the range of 30-40 (ng Ang I h-1) min-1 gkw-1. 4. Ang II (100 pM) caused a decrease of renal flow rate to 42 +/- 2% of control which was accompanied by a reduction of renin secretion rates by a factor of 4. 5. AVP (10 pM to 1 nM) reduced renal perfusate flow in a dose-dependent fashion to a minimum of 25 +/- 3% of control. The vasoconstrictor effect of AVP was paralleled by a concentration-dependent increase of renin secretory rates reaching a factor of maximally 5 when AVP was used at a concentration of 1 nM. The stimulatory effect of AVP on renin release could be mimicked by [deamino-Cys1, D-Arg8]-vasopressin (dDAVP), a vasopressin analogue with prevalent V2 receptor agonistic properties. In the presence of dDAVP (100 nM, 1 microM) renal flow rate reversibly increased by 8 and 12% of control values, respectively. 6. Depolarizing concentrations of KCl (30 mM) decreased perfusate flow to 20 +/- 4% of control. The vasoconstrictor effect of KCl was paralleled by an increase of the arterio-venous difference of perfusate renin activity to such an extent that the rate of renin release remained unaltered. 7. Our findings suggest that there exists no general inverse relationship between renal arteriolar resistance and renin secretion. Our study, moreover, does not support a functional role of potential operated calcium channels in the control of renin secretion. Finally, we conclude that V2 receptors are present on juxtaglomerular epithelioid cell membranes and mediate the stimulatory effect of AVP on renin release from isolated rat kidneys.

Angiotensin II↗
PubMed1991

Renal sympathetic nerves modulate glomerular ANP receptors and filtration.

We examined characteristics of atrial natriuretic peptide (ANP) receptors in glomeruli isolated from subacutely (3-5 days) denervated (DNX) and contralateral nondenervated (non-DNX) kidneys of normal rats (NL) and rats subjected to water deprivation for 48 h (WD). Total ANP receptor density in DNX kidneys of WD rats, measured by competitive inhibition binding between 125I-labeled ANP and ANP, was twofold higher than non-DNX kidneys (726 +/- 96 vs. 384 +/- 32 fmol/mg protein, P less than 0.05). Equilibrium association constant (Ka) was not significantly different (2.33 +/- 0.43 vs. 3.34 +/- 0.78 x 10(9) M-1). In NL rats, there was no difference in ANP receptor density between DNX and non-DNX kidneys (244 +/- 20 and 264 +/- 16 fmol/mg protein). Production of guanosine 3',5'-cyclic monophosphate (cGMP), a putative second messenger of ANP, in response to ANP (10(-7) M) in glomeruli isolated from DNX was significantly larger than non-DNX kidneys of WD rats. To determine whether these changes in ANP receptors have functional consequences in vivo, glomerular capillary ultrafiltration coefficient (Kf) was assessed by micropuncture technique in WD Munich-Wistar rats. In DNX kidneys, ANP infusion (4 micrograms.kg-1.h-1) significantly increased whole kidney glomerular filtration rate (GFR) and single-nephron (SN) GFR (0.64 +/- 0.06 to 0.89 +/- 0.17 ml/min and 25 +/- 2 to 33 +/- 2 nl/min, respectively; n = 7) and Kf (1.26 +/- 0.29 to 2.18 +/- 0.41 nl.min-1.mmHg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Role of vascular wall renin: intracellular and extracellular mechanism.

Inhibitors of angiotensin-converting enzyme, renin and angiotensin II receptor lower the blood pressure of spontaneously hypertensive rats (SHRs) used as a model of essential hypertension. Since their plasma renin levels were normal or subnormal, renin in the vascular tissue was considered to play a key role in the maintenance of the hypertension. To clarify the source and localization of vascular renin in SHRs, the effects on blood pressure of antirenin antibodies, the converting enzyme inhibitors delapril and enalapril, and the angiotensin II receptor antagonist DuP 753 were examined in intact and bilaterally nephrectomized SHRs and their normotensive controls. The efficient hypotensive action of the renin antibody indicated that renin of the renal origin is a dominant factor. The gradual but complete disappearance of the antihypertensive action of these inhibitors of the renin-angiotensin system upon bilateral nephrectomy indicated the importance of membrane-associated renin of the renal origin and angiotensin-converting enzyme in the maintenance of the spontaneous hypertension.

Animals↗
PubMed1991

Isolation of preferentially expressed genes in the kidneys of hypertensive rats.

By differential hybridization, three complementary DNAs designated as S3, S2, and SA were isolated, and the corresponding messenger RNAs (mRNAs) were differentially expressed between the kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. S3 is identical to cytochrome P450 IV A2. SA encoded a protein of 546 amino acid residues, and its carboxyl terminal region had a slight homology to luciferase. No homologous sequence has been reported in S2 sequences. S3 mRNA was about four times more abundantly expressed in the kidneys of 28-day-old SHR than in those of age-matched WKY rats, but there was no difference at age 16 weeks. A low NaCl diet positively modulated the expression of the S3 gene. S2 mRNA was almost undetectable in the kidneys of 28-day-old WKY rats but was clearly detected in those of age-matched SHR. The expression level of S2 mRNA in the livers of 16-week-old SHR was about five times higher than that of age-matched WKY rats. The expression of S2 mRNA in the livers was modulated by dietary NaCl and captopril. SA mRNA was more than 10 times more abundantly expressed in the kidneys of SHR than in those of WKY rats from age 4 weeks. With the administration of captopril, the expressions of SA mRNA in the livers of SHR were positively modulated. Because these three genes are not only differentially expressed between SHR and WKY rats but also related to sodium metabolism or blood pressure control, the identification of these genes may provide important probes to examine the mechanisms of hypertension.

Amino Acid Sequence↗
PubMed1991

Significance of vascular renin for local generation of angiotensins.

The effects of specific renin inhibitors, angiotensin converting enzyme inhibitors, indomethacin, and prostaglandin I2 analogue on the release of angiotensins from isolated and Krebs-Ringer-perfused rabbit mesenteric arteries were examined. Three different renin inhibitors suppressed release of angiotensins in dose-dependent manners. At the highest concentration (10(-7) M), the inhibitors EMD 52,620, EMD 54,388, and EMD 52,742 induced 46%, 52%, and 48% decreases, respectively, in the basal rate of immunoreactive angiotensin II release. These results provide clear evidence that released angiotensins are produced by the specific action of vascular renin and that the renin inhibitors suppress the vascular renin-angiotensin system as well as the circulating renin-angiotensin system and appear to provide a useful mode for the treatment of hypertension. Nonsulfhydryl angiotensin converting enzyme inhibitors cilazapril and delapril were more effective than captopril, and ramipril was equipotent to captopril, suggesting that the effectiveness of angiotensin converting enzyme inhibitors on the vascular renin-angiotensin system cannot be explained only by its inhibitory effect on angiotensin converting enzyme. Indomethacin, which was reported to suppress angiotensin II release from rat hind limbs, elicited a dose-dependent increase of angiotensin release from rabbit mesenteric arteries. These results suggest that a difference exists in the regulatory mechanisms in the release of angiotensins from diverse vascular beds.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Distinct localization of renin and angiotensins in separate subcellular fractions of the rat adrenal cortex.

The subcellular localization of renin and immunoreactive angiotensins I and II was studied in rat adrenal cortical tissues. The identity of the immunoreactive angiotensins was confirmed as angiotensin I and angiotensin II by radioimmunoassay and high-performance liquid chromatography, respectively, with reference to standard compounds. By differential centrifugation of tissue homogenate in 0.25 M sucrose/30 mM Tris-HCl/l mM EDTA, pH 7.4, specific immunoreactive renin was found to be localized principally (60%) in the mitochondrial fraction (P2), whereas about 40% of both angiotensins I and II was contained in the soluble fraction; only 18-20% of both peptides was contained in the P2 fraction. On Percoll density gradient centrifugation of P2, renin was fractionated mostly in a denser band whereas angiotensins I and II were contained in a lighter density area closely corresponding to mitochondrial and lysosomal marker enzymes. These results suggest that renin and angiotensins in the cells of the rat adrenal gland reside in different subcellular compartments and argue against intracellular formation of angiotensins by renin in renin granules.

Adrenal Cortex↗
PubMed1991

Cyclosporine promotes glomerular endothelin binding in vivo.

It has previously been shown that administration of cyclosporine causes a prompt (within 15 min after infusion) increase in circulating level of endothelin 1 and a pattern of glomerular hypoperfusion and hypofiltration which can be ameliorated with antiendothelin antibody. We now show that 60 min after cyclosporine, serum endothelin 1 level falls to less than 2.55 +/- 0.31 pg/mL (N = 6), a value comparable to that found in normal animals (less than 2 pg/mL). The study presented here also examines whether sustained cyclosporine-induced glomerular dysfunction is associated with altered endothelin receptor characteristics. Saturation and competitive inhibition binding studies in isolated glomerular membranes showed two binding sites. Of these, the density of the low-affinity site was affected by cyclosporine treatment (851 +/- 117 versus 425 +/- 61 fmol/mg of protein; P less than 0.05; N = 6) without a change in equilibrium dissociation constant, KD. The high-affinity site was not affected. The receptor characteristics of another vasoconstrictor, angiotensin II, were not affected by cyclosporine. In addition, there was no difference in endothelin binding sites in hepatic tissue between cyclosporine and control rats. These results raise the intriguing possibility that cyclosporine-induced glomerular dysfunction involves upregulation of endothelin binding sites and that altered endothelin receptors appear specific to the kidney.

Animals↗
PubMed1991

A role for atrial natriuretic peptide in endothelin-induced natriuresis.

Systemic administration of low-dose endothelin increases urinary sodium excretion rate despite mild to moderate reductions in renal plasma flow and glomerular filtration rates. The role of atrial natriuretic peptide in endothelin-induced natriuresis was investigated. Administration of 2.50 pmol/min of endothelin to euvolemic rats resulted in increases in plasma atrial natriuretic peptide levels from 127 +/- 18 to 169 +/- 23 pg/mL. However, a lower dose of endothelin (0.63 pmol/min) or saline did not increase plasma levels of atrial natriuretic peptide. Mean arterial pressure was unchanged at the lower dose of endothelin and increased only slightly in rats receiving 2.5 pmol/min. To assess functional significance, renal responses to endothelin (2.5 pmol/min) in the absence and presence of a specific anti-rat atrial natriuretic peptide antibody were compared. Equivalent reductions in renal blood flow were observed. Urinary sodium excretion rates increased significantly in non-ANP-antibody-treated rats by 33 +/- 7 and 82 +/- 20% at 10 and 30 min, respectively. Atrial natriuretic peptide antibody blunted markedly endothelin-induced natriuresis: urinary sodium excretion rates changed insignificantly by 18 +/- 10 and 30 +/- 14%, respectively. Thus, endothelin infusion results in increases in plasma atrial natriuretic peptide levels, which may contribute to endothelin-induced natriuresis, providing evidence for potentially significant interactions between these peptide hormones in the regulation of sodium balance and renal vascular tone.

Animals↗
PubMed1991

Exaggerated response to electrical nerve stimulation of angiotensin II release in isolated perfused hind legs of spontaneously hypertensive rats.

Previously we reported that a large amount of immunoreactive angiotensin II (Ang II) was released from isolated perfused rat hind legs at steady rates for several hours. In view of a recent intriguing hypothesis that the vascular renin-angiotensin system plays an important role in the maintenance of high blood pressure in certain forms of experimental hypertensive models, the release of immunoreactive Ang II from isolated hind legs of spontaneously hypertensive rats (SHR) was examined in comparison with normotensive rats of Wistar-Kyoto strain (WKY) by using a Sep-Pak C18 cartridge directly connected to the perfusion system. We also examined effect of electrically-induced nerve stimulation on the release of immunoreactive Ang II in the two strains. High performance liquid chromatography demonstrated the presence of Ang II in the perfusate. The spontaneous release of immunoreactive Ang II was as high as about 300 to 500 pg/30 min, tended to be higher in SHR rats (435.0 +/- 68.2 pg/30 min) than in WKY rats (342.1 +/- 65.1 pg/30 min), and stable up to 3 hours of perfusion for both strains. Periarterial nerve stimulation elicited a significant increment in the release of immunoreactive Ang II in either SHR (p less than 0.02) or WKY rats (p less than 0.05); however, the amount of released immunoreactive Ang II evoked by nerve stimulation was significantly greater in SHR than in WKY rats (781.3 +/- 89.6 vs 498.8 +/- 54.6 pg/30 min, p less than 0.05). These results further provide evidence for local generation and release of Ang II in peripheral vascular tissues, and are consistent with the hypothesis that the vascular renin-angiotensin system is one of important factors responsible for the maintenance of blood pressure.

Angiotensin II↗
PubMed1991

Juxtaglomerular cells as a source of intrarenal angiotensin II production.

While the contribution of angiotensin (Ang) II to the regulation of various renal functions is recognized, evidence exists that the kidney also is a major site for the production of Ang II. Since circulating renin in plasma accounts for only a small portion of intrarenally produced Ang II, we investigated juxtaglomerular (JG) cells as a source of Ang I and II. Light and electronmicroscopic immunohistochemical methods revealed highly concentrated Ang I and II in JG cells. This finding was supported by the demonstration of colocalization of renin, Ang I, and Ang II in cultured JG cells and in dense granular fractions of rat kidney separated by gradient centrifugation of rat kidney homogenate. Perfusion of rat kidney with Krebs-Ringer buffer containing bovine serum albumin showed that Ang I and Ang II are released in the perfusate in quantities which may account for a greater part of the intrarenal generation of Ang II observed in vivo. These results support the hypothesis that Ang II is intrarenally synthesized inside the JG cells, thereby contributing to the regulation of certain renal functions.

Angiotensin I↗
PubMed1990

ANP-like immunoreactivity in neuronal perikarya and processes associated with vessels of the pia and cerebral parenchyma in dog.

The existence of neocortical neurons displaying processes which penetrate the glia limitans (GL) and closely approach pial as well as intracerebral microvessels was determined in the dog from immunohistochemical localization of atrial natriuretic peptide (ANP). Scattered ANP-positive pyramidal somata located in cortical layers II and III displayed spinous dendritic arbors and delicate, beaded axon collaterals. Dendritic branches, as well as axon collaterals, traversed the GL near blood vessels entering the parenchyma, or encircled microvessels deep to the GL. These findings suggest that single ANP-like immunoreactive cortical neurons may monitor and control local cerebrovascular flow or permeability of the blood-brain barrier.

Animals↗
PubMed1990

Effect of delapril hydrochloride on angiotensin II release from isolated rat hind legs.

The effect of the newly developed angiotensin-converting enzyme (ACE) inhibitor, delapril hydrochrolide (CV-3317), on the release of immunoreactive angiotensin II (irAng II) from isolated rat hind legs was compared with that of captopril. Both ACE inhibitors, added to the perfusion medium (2 X 10(-9) - 10(-6) M), suppressed irAng II release in a dose-dependent manner, but the inhibition was greater with delapril than with captopril. The results provide further support for the concept that vascular tissues produce Ang II and release it in a regulated fashion. The results also suggest a possible link between the antihypertensive mechanism of ACE inhibitors, including delapril, and the suppression of vascular Ang II release.

Angiotensin II↗
PubMed1990

Native form of endothelin receptor in human placental membranes.

Little is known about the native form of endothelin receptor. To clarify its functional and structural properties, we solubilized the receptor from human placenta in an active form using mild detergents CHAPS and digitonin and showed that it is able to bind 125I-endothelin-1 in a specific manner, with a pH optimum between 6 and 8 in contrast to a reported pH optimum of 4. The molecular weight of the receptor was estimated as 340,000 by gel filtration of the solubilized membrane in the presence of 0.2% (w/v) digitonin. When the solubilized membranes were labeled with 125I-endothelin-1 prior to gel filtration, the radioactive ligand also migrated in the position corresponding to a 340 kDa protein. These results indicated that the native form of endothelin receptor in human placenta is a 340 kDa protein.

Chromatography, Gel↗