Porphyrin metabolism abnormalities and its treatment in a uremic patient with porphyria cutanea tarda.
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Adult↗
Biomedical subjects
G Yasuda
Publications and source records attributed to G Yasuda.
Cushing's disease: evaluation of mineralocorticoid-induced hypertension.
A patient (32-year-old female) with Cushing's syndrome due to pituitary adenoma and hypertension with hypokalemia is reviewed. Endocrinological studies demonstrated low plasma renin activity, low plasma aldosterone concentration and high plasma deoxycorticosterone concentration. Blood pressure response to exogenous angiotensin II was enhanced. After the withdrawal of cortisol replacement following surgery, her abnormal endocrinological findings, hypertension and serum potassium level returned to normal and her blood pressure response to exogenous angiotensin II was reduced. These results suggest that in this case deoxycorticosterone might have contributed to the development and maintenance of her hypertension accompanied with hypokalemia.
Adenoma↗
[Molecular biology of alpha-adrenergic receptor and essential hypertension].
The primary physiological agents for adrenergic receptors are only two, epinephrine and norepinephrine, which have been used to differentiate alpha- and beta-adrenoceptors. The pharmacological properties can distinguish subtype alpha 1-, alpha 2-, beta 1- and beta 2-receptors. Recently additional subtypes have been characterized by radioligand binding techniques and molecular biological techniques. Molecular mechanisms of regulation as well as regulatory site of gene expression of alpha-adrenergic receptors has been extensively studied. In addition, the association analysis of alpha 2-adrenergic receptor gene RFLP in essential hypertension has been performed. Eventhough we could not find any association of an alpha 2 C10-Bsu36I RFLP with essential hypertension in Japan, the finding showed significant ethnic RFLP difference at the gene locus for alpha 2 C10. The association of alpha 2 adrenergic receptor RFLP with blood pressure has been also studied using F2 generations of SHR and WKY and Dahl salt sensitive rats and resistant rats. Further studies are now in progress to clarify the role of these alpha-adrenergic receptors in cardiovascular diseases.
Amino Acid Sequence↗
[Angiotensin converting enzyme: its molecular function, new ACE inhibitors and future prospect].
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Amino Acid Sequence↗
Identification of an alpha 2-adrenoceptor in human coronary arteries by radioligand binding assay.
A single high affinity binding site for an alpha 2-adrenoceptor in human coronary arteries was identified by radioligand binding assay. Human coronary arteries were obtained at autopsy within 6 hours of death. A crude membrane solution was incubated with (3H)-rauwolscine at 25 degrees C for 30 min. The binding of (3H)-rauwolscine was rapidly saturable and reversible. Kd was 1.2 +/- 0.2 (SE) nM and Bmax 22 +/- 3 fmol/mg protein. This is the first study which has shown the presence of an alpha 2-adrenoceptor in human coronary arteries using a radioligand binding assay method.
Arteries↗
Characterization of prazosin-sensitive alpha 2 B-adrenoceptors expressed by cultured rat IMCD cells.
alpha 2-Adrenoceptor subtype expression was investigated in cultured rat inner medullary collecting duct (IMCD) cells using radioligand binding studies, Northern blot analysis, and adenosine 3',5'-cyclic monophosphate (cAMP) assays. [3H]rauwolscine bound to a single class of alpha 2-adrenoceptors with high affinity [Kd = 1.7 +/- 0.3 nM, maximum binding (Bmax) = 45.2 +/- 10.8 fmol/mg protein]. alpha 2-Adrenoceptor ligands inhibited [3H]rauwolscine binding with a rank order of potency characteristic of interaction with the alpha 2B-adrenoceptor [inhibitory constant (Ki) values (in nM) rauwolscine (1.95) greater than ARC-239 (8.52) greater than prazosin (237) greater than oxymetazoline (30,000)]. Northern blot analysis was performed using poly(A)+ RNA isolated from 90% confluent rat IMCD cells and probes derived from alpha 2-adrenoceptor DNA sequences from the rat nonglycosylated alpha 2B-adrenoceptor and the human alpha 2A-adrenoceptor. The alpha 2B probe hybridized to a 4.2-kb band under high stringency conditions, but the alpha 2A-adrenoceptor probe did not hybridize to this band. In functional studies, the full alpha 2-adrenoceptor agonists epinephrine and UK-14,304 potently inhibited vasopressin-stimulated cAMP accumulation by 50 to 70% [half-maximal response (EC50) (in nM) epinephrine = 11.2, UK-14,304 = 6.4]. Guanabenz and clonidine were partial agonists, inhibiting cAMP accumulation by 30 to 40% and were less potent than the full agonists [EC50 (in nM) 56.0 guanabenz and 94.5 clonidine]. Epinephrine-induced inhibition of cAMP accumulation was blocked by rauwolscine, prazosin, and ARC-239 but not by the alpha 1-adrenoceptor antagonist corynanthine. We conclude that rat IMCD cells in primary culture express functional alpha 2-adrenoceptors of the alpha 2B-subtype.
Adrenergic alpha-Agonists↗
A comparative study of ribosomal and DNA binding protein II from two thermophilic bacteria, Bacillus caldolyticus strain EP 00275 and Bacillus stearothermophilus.
Ribosomal and DNA binding proteins (DNA bp II) from an extreme thermophilic bacterium, B. caldolyticus strain EP 00275, were investigated for stability and crystallization and compared to the homologous proteins from B. stearothermophilus. Two-dimensional gel electrophoresis of both types of proteins, the amino acid composition and the sequences of some of the peptides of DNA bp II revealed a close relationship between each other. The physico-chemical characteristics of DNA bp II were similar but different from homologous proteins from T. thermophilus and C. pasteurineum. From our results we conclude: B. stearothermophilus and B. caldolyticus strain EP 00275 are similar organisms with regard to their ribosomal and DNA binding proteins.
Bacillus↗
Alpha 2-adrenoceptor stimulation inhibits cellular cyclic AMP production in microdissected human glomeruli.
The physiological role of numerically predominant alpha 2-adrenoceptor in the kidney is still unknown. This study examined the effect of alpha 2-adrenoceptor stimulation on the production of cAMP from isolated human glomeruli. Unaffected portions of human kidneys which had been removed because of renal cell carcinoma were used for the study. Glomeruli were dissected manually under a stereo microscope. In these glomeruli, alpha 2-adrenoceptor stimulation with epinephrine in the presence of propranolol inhibited significantly parathyroid hormone-dependent increases in cAMP production. This inhibitory effect of epinephrine was removed by adding a specific alpha 2-adrenoceptor antagonist, yohimbine, indicating that the inhibitory effect of epinephrine on cAMP formation was due to alpha 2-adrenoceptor stimulation. Thus, alpha 2-adrenoceptors are involved in the inhibition of cAMP production in human glomeruli.
Cyclic AMP↗
Inhibitory effect of human atrial natriuretic peptide on cyclic AMP levels in microdissected human glomeruli.
We studied whether alpha-human atrial natriuretic peptide (alpha-hANP) had the capacity to regulate cyclic AMP (cAMP) levels in human glomeruli, since decreased cAMP in the glomerulus may increase the glomerular filtration rate (GFR) through increasing kf (glomerular capillary ultrafiltration coefficient). Human kidneys were obtained at surgery for carcinoma. Normal cortical tissues from these kidneys were used for the study. After incubating the renal cortical slices with 0.1% collagenase, glomeruli were dissected manually under the stereomicroscope. Two glomeruli were incubated (37 degrees C, 2 min) with parathyroid hormone (PTH) and/or alpha-hANP. cAMP was determined by radioimmunoassay. alpha-hANP at a concentration of 5 x 10(-6) M had no effect on glomerular cAMP accumulation in the basal condition. PTH stimulated cAMP formation in a dose-dependent manner. alpha-hANP inhibited significantly the increase in cAMP formation induced by PTH (p less than 0.01). This action of alpha-hANP was dose-dependent, with a maximum of 50% inhibition. PTH is one of the endogenous substances that are known to increase cAMP formation and decrease kf. Thus, it seems likely that alpha-hANP increased GFR through modulating the production of cAMP in human kidney.
Atrial Natriuretic Factor↗
[Kidney tubular transport disorders. Bartter's syndrome].
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Bartter Syndrome↗
Long-term captopril therapy with no effect on glucose metabolism in patients with essential hypertension.
The long-term antihypertensive response to captopril (25-50 mg/day) and 75g oral glucose tolerance (75g oGTT) following a 6-10 month period of captopril administration was evaluated in 20 patients with essential hypertension without persistent proteinuria. Eleven of these 20 patients exhibited impaired glucose tolerance (IGT), while the remaining nine patients had normal glucose tolerance (NGT). All patients tolerated long-term captopril therapy with no untoward effects. Six months' administration of captopril significantly decreased blood pressure in patients with NGT from 171 +/- 12/105 +/- 5 mm Hg (mean +/- SE) to 146 +/- 7/88 +/- 4 mm Hg. Also in patients with IGT, long-term captopril therapy decreased blood pressure from 165 +/- 3/97 +/- 2 to 143 +/- 5/86 +/- 2 mm Hg. No patient with NGT developed diabetes mellitus. Neither fasting nor post-glucose-load venous blood glucose deteriorated in any of the patients during the therapy. There were no significant changes in the insulinogenic index (delta IRI/delta BG at 30 minutes after glucose load) in both the patients with NGT and IGT. In patients with IGT, the concentration of glycosylated hemoglobin (Hb A1 and Hb A1c slightly but significantly decreased from 8.1 +/- 0.3 to 7.7 +/- 0.4% (P less than 0.05) and from 5.9 +/- 0.3 to 5.5 +/- 0.3% (P less than 0.01) after 6.2 +/- 1.4 months' captopril therapy. These results suggest that in addition to its antihypertensive effects, long-term captopril therapy does not compromise glucose metabolism in hypertensive patients.
Blood Pressure↗
Altered platelet alpha 2-adrenoceptors and adrenaline response in adolescents with borderline hypertension who have a family history of essential hypertension.
We studied the relationship between a family history of essential hypertension and the characteristics of platelet alpha 2-adrenoceptors in male university students. Platelet membranes were prepared by the method of U'Prichard. Tritium-rauwolscine was used for the alpha 2-adrenoceptor binding assay. The maximum number of binding sites (Bmax) of platelet alpha 2-adrenoceptors was higher in borderline hypertensives with a family history of hypertension than in normotensives without it. However, no significant difference in the Bmax was found between the normotensives without and those with a family history. Dissociation constants (Kd) were not significantly different among the three groups. The plasma concentration of adrenaline after 30 min of standing was higher in the borderline hypertensives with a family history than in the normotensives, either with or without a family history. These results suggest that alterations in the alpha 2-adrenoceptor density or affinity for antagonists of platelets may not be linked to a positive family history of essential hypertension. However, an increased alpha 2-adrenoceptor density in platelets and an enhanced adrenaline response may be involved in blood pressure elevation in borderline hypertensives with a family history of hypertension.
Adult↗
Effects of prostaglandins E1, E2, F2 alpha and I2 on adrenergic transmission in guinea pig pulmonary arteries.
Effects of some prostaglandins (PGs) on adrenergic transmission were studied in guinea pig pulmonary arteries preloaded with 3H-norepinephrine. PGE1 and PGE2 at 0.1 to 100 nM concentration-dependently inhibited 3H-release and contraction evoked at 5 Hz. This inhibition was antagonized by diphloretin phosphate. PGF2 alpha at 1 to 100 nM had no effect on evoked 3H-release and contraction. PGI2 at 1 to 100 nM also failed to modify evoked 3H-release, but markedly and concentration-dependently decreased evoked contraction. There exist presynaptic inhibitory PGE1 and PGE2 receptive sites on adrenergic neurons innervating guinea pig pulmonary arteries, whereas PGF2 alpha and PGI2 produced no effect on the adrenergic neurons.
Adrenergic Fibers↗
Identification of an atrial natriuretic peptide specific receptor in human kidney.
A specific receptor for human atrial natriuretic peptide (h-ANP) was identified in the human kidney using the radioligand binding assay. Samples were prepared from non-malignant renal tissues obtained at nephrectomy of patients with renal carcinoma. Binding studies using [125I]hANP were performed at 0 degree C for 20 minutes and terminated by a rapid filtration technique. Scatchard plot analysis revealed [125I]hANP bound to a single class of binding site (Kd = 0.4 +/- 0.2 nM) with a density of 16 +/- 4 fmol/mg protein in the renal cortex (n = 7). The binding was rapid and maximal binding was obtained within 20 minutes after the start of incubation. Radioligand displacement was observed in a dose dependent fashion when cold hANP was entered into the reaction mixture. However, unrelated agents, such as angiotensin II or 1-epinephrine, did not affect the binding. This is the first time characterization of the hANP receptor in the human kidney has been conducted using a Scatchard plot analysis.
Atrial Natriuretic Factor↗
Pharmacokinetics and depressor effect of delapril in patients with essential hypertension.
The pharmacokinetics and depressor effect of a nonsulfhydryl angiotensin-converting enzyme inhibitor, delapril, was assessed by administering a single dose of 30 mg to nine patients with mild to moderate essential hypertension. Orally administered delapril is a prodrug and must be deesterified to its active metabolites, delapril diacid and 5-hydroxy delapril diacid. The pharmacokinetic parameters for delapril, delapril diacid, and 5-hydroxy delapril diacid were, respectively: t 1/2 0.30, 1.21, and 1.40 hours; Cmax 489, 635, and 229 ng/ml; AUC 572, 1859, and 948 ng X hr/ml. Delapril produced significant decreases in systolic blood pressure and angiotensin-converting enzyme activity 24 hours after dosing. There were no significant changes in the endogeneous creatinine clearance after the drug. Thus delapril may represent a useful antihypertensive agent for control of blood pressure in patients with essential hypertension.
Adult↗
Presynaptic angiotensin II receptors and captopril-induced adrenergic transmission failure probably not via converting enzyme inhibition in guinea-pig pulmonary arteries.
This study aimed to clarify whether or not captopril modifies the activity of an intrinsic, presynaptic, angiotensin II receptor system within the vasculature in superfused spiral preparations of guinea-pig pulmonary arteries preloaded with 3H-norepinephrine. Angiotensins I and II dose-dependently facilitated 3H efflux and contraction evoked by transmural field stimulation at 5 Hz. A conversion rate of angiotensin I to angiotensin II calculated from the dose-response curves was 26.7 +/- 2.6%. 1Sar-8Ile-angiotensin II alone did not decrease the evoked 3H efflux and contraction, but antagonized the facilitation induced by angiotensins I and II. Captopril (1 and 10 mumol) inhibited the facilitation by angiotensin I but produced no effect on that by angiotensin II. Captopril alone at 1 mumol attenuated the evoked 3H efflux and contraction without decreasing contractile responses to exogenously applied norepinephrine, but the higher concentrations produced no further dose-dependent attenuation. Indomethacin alone produced no increases in the evoked 3H efflux. Captopril at 1 mumol still attenuated the evoked 3H efflux in the presence of indomethacin. On the other hand, enalaprilat alone (0.1-100 mumol) produced no effect on the evoked 3H efflux and contraction. Thus, in guinea-pig pulmonary arteries, angiotensin I is intramurally converted to angiotensin II, and there are presynaptic angiotensin II receptors to facilitate norepinephrine release. However, captopril-induced presynaptic adrenergic transmission failure appears to be dependent neither on an intrinsic angiotensin system nor on a prostaglandin-related mechanism.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacokinetics of a single dose of ramipril in patients with renal dysfunction: comparison with essential hypertension.
The acute effects and pharmacokinetic properties of an angiotensin converting enzyme (ACE) inhibitor, ramipril, and its potent active diacid metabolite, ramiprilate, were investigated. Hypertensive patients with impaired renal function (IRF; n = 6) and with normal renal function (NRF; n = 5) were studied. The terminal half-life of ramiprilate in IRF was longer than that in NRF. The peak plasma concentrations of ramipril and ramiprilate in IRF were higher than those in NRF. The area under the plasma level-time curves of ramipril and ramiprilate in IRF were greater than those in NRF. A significant inverse correlation was found between creatinine clearance and area under the plasma level-time curve.
Angiotensin-Converting Enzyme Inhibitors↗
Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension.
A single dose of doxazosin, a long-acting postsynaptic alpha 1-adrenoceptor antagonist, was administered to seven patients with essential hypertension. Following administration of a single dose, all the patients except one who was forced to be discharged from the hospital for work, continuously received doxazosin once daily (o.d.) for evaluation of its consecutive dosing effect. The antihypertensive effect, pharmacokinetics, and effects on the plasma renin activity (PRA) of doxazosin were investigated. Following a 2-mg single dose of doxazosin, the systolic blood pressure (SBP) decreased significantly up to 12 h, whereas consecutive dosing produced a significant decrease in the SBP up to 24 h and a significant decrease in the mean blood pressure up to 24 h as compared with placebo. The pharmacokinetic parameters of doxazosin in both single- and consecutive-dose study were 18.9 and 25.8 ng/ml in Cmax, 11.1 and 12.9 h in half life (t1/2), and 182.0 and 273.0 ng h/ml in area under the curve (AUC)24(0), respectively. No significant changes were observed in PRA and plasma concentration of catecholamines. Neither were there any observable changes in endogenous creatinine clearance and in the urinary excretion rates of Na, K, and Cl. Doxazosin was well tolerated by all patients, and no untoward effects were observed. Doxazosin effectively reduces blood pressure and, because of its long t1/2 and minimal effects on PRA catecholamines, and electrolytes, seems to be a useful antihypertensive agent in patients with essential hypertension.
Adult↗