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M Endoh

Publications and source records attributed to M Endoh.

At least 37 records · Page 2Linked to original sources
PubMed1997

Pharmacological differentiation of synergistic contribution of L-type Ca2+ channels and Na+/H+ exchange to the positive inotropic effect of phenylephrine, endothelin-3 and angiotensin II in rabbit ventricular myocardium.

The present study was designed to delineate pharmacologically the role of sarcolemmal L-type Ca2+ channels and Na+/H+ exchange in the positive inotropic effect (PIE) of phenylephrine mediated by alpha-1 adrenoceptors, endothelin (ET) and angiotensin II (Ang II) that stimulate phosphoinositide (PI) hydrolysis in the rabbit ventricular muscle. The PIE of these receptor agonists was compared with the PIE of isoprenaline that accumulates cyclic AMP. For this purpose, we investigated the influence of a Ca2+ antagonist, verapamil, and of an inhibitor of Na+/H+ exchange, 5-(N-ethyl-N-isopropyl) amiloride (EIPA), alone or in combination, on the cumulative concentration-response curve (CRC) for phenylephrine (with 0.3 microM bupranolol). ET-3 and Ang II in isolated right ventricular papillary muscles of the rabbit, which were electrically stimulated at 1 Hz in Krebs-Henseleit solution at 37 degrees C. Verapamil at 0.3 and 1 microM decreased the basal force of contraction to 37.0 +/- 4.0% and 13.2 +/- 1.1% of the control, respectively, while EIPA event at 10 microM affected the basal force to much less extent and decreased it to 87.0 +/- 1.4%. Verapamil (0.3 and 1 microM) and EIPA (1 and 10 microM), when used alone, each significantly attenuated but did not abolish the PIEs induced by phenylephrine, ET-3 and Ang II, while the simultaneous administration of verapamil (1 microM) and EIPA (10 microM) consistently and almost completely inhibited the PIE induced by these receptor agonists. By contrast, the PIE of isoprenaline was retained even in the presence of verapamil and EIPA. These results indicate that both the influx of Ca2+ ions through L-type Ca2+ channels and activation of Na+/ H+ exchange contribute synergistically to the PIE that is mediated by alpha-1 adrenergic, ET and Ang II receptor agonists, while these mechanisms are not essential for the beta-adrenoceptor-mediated PIE.

Amiloride↗
PubMed1997

Late development of bile duct cancer after sphincteroplasty: a ten- to twenty-two-year follow-up study.

BACKGROUND: Transduodenal sphincteroplasty is designed to destroy the sphincteric muscle fibers, producing a terminal choledochoduodenostomy. In the absence of Oddi's sphincter, intestinal contents with both activated pancreatic juice and bacterial flora are refluxed into the bile duct and remain there for a prolonged time. The long-term effect of producing the reflux has not been evaluated to date. METHODS: One hundred nineteen consecutive patients undergoing transduodenal sphincteroplasty between February 1973 and July 1984 were included in this study. Postoperative clinical courses of 108 patients could be evaluated by means of a retrospective review of the hospital records. Median follow-up was 18 years. RESULTS: Eight cases (7.4%) of primary bile duct cancer were found among the 108 cases at intervals of 1 to 20 years after sphincteroplasty. Two patients had concurrent hepatolithiasis. The patency of sphincteroplasty was confirmed in all cases, and the bile was infected in seven cases. Pathologic specimens obtained demonstrated cholangiocarcinomas and various degrees of atypical hyperplastic lesions under the background of chronic cholangitis. CONCLUSIONS: Chronic cholangitis can be an important causative factor in late development of bile duct cancer after sphincteroplasty. Any patients treated with choledochoduodenostomy should be closely monitored for late cholangiocarcinoma.

Adult↗
PubMed1997

Glomerular Fc alphaR expression and disease activity in IgA nephropathy.

In this study, we examined the receptors for the Fc portion of immunoglobulin A (IgA) (Fc alphaR) in the glomeruli as well as circulating polymorphonuclear leukocytes and monocytes at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) assay and at the protein level by an immunohistochemistry/flow cytometry technique using a specific anti-Fc alphaR monoclonal antibody (My 43). Glomeruli were isolated from biopsy specimens of renal tissues from IgA nephropathy (IgAN; 20 cases) and non-IgA mesangial proliferative glomerulonephritis (PGN; 13 cases) patients, and from normal renal tissue specimens obtained from kidneys removed because of malignancies (five cases) applying the microdissection method. There was a relative increase in Fc alphaR in the circulating phagocytes from IgAN patients compared with those from PGN and healthy controls. Fc alphaR expression was present in approximately 40% of glomeruli samples from IgAN patients at the message levels. Fc alphaR-positive specimens were also strongly positive for expression of tumor necrosis factor-alpha, interleukin-1, and interleukin-6 mRNA. Specimens from PGN patients and healthy controls did not show any detectable Fc alphaR message. Serum IgA levels and severity of hematuria were significantly higher in patients with positive Fc alphaR expression. A message for Fc alphaR was detected in the tissues that were more damaged histologically. Our data suggest that there is some in vivo induction of glomerular Fc alphaR expression, possibly mediated by a synergistic stimulus from IgA and inflammatory cytokines, and the expressed receptor is likely to be involved in the disease process of IgAN.

Antigens, CD↗
PubMed1997

Phenotypic characterization of cytokine expression in patients with IgA nephropathy.

To identify the cytokines that play a relevant role in the pathogenesis of IgA nephropathy, we analyzed and compared the gene expression of proinflammatory cytokines, immuno-regulatory cytokines, and growth factors in peripheral blood mononuclear cells (PBMC). Expression of IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-gamma, TGF-beta, TNF-alpha, and PDGF was examined in 28 patients with IgA nephropathy (IgAN), 20 patients with non-IgA mesangial proliferative glomerulonephritis (mesPGN), and 19 healthy controls. Compared with healthy controls, a significant number of IgAN and mesPGN patients showed increased expression of IL-1 beta, IL-4, IL-10, IL-12, and IFN-gamma. The cytokine profile of renal tissue of 10 IgAN and 5 mesPGN biopsies was simultaneously analyzed and compared with that of PBMC. The proinflammatory IL-1 alpha and growth factor PDGF-B were expressed more in renal tissues than in PBMC. Furthermore, the renal profile of IL-alpha, IFN-gamma, and TNF-alpha expression was associated with the expression of IFN-gamma in PBMC. The serum level of IFN-gamma of IgAN correlated significantly (P = 0.0003) with that of IL-12, suggesting a potential role for cross-stimulation. More importantly, expression of IFN-gamma in PBMC and the elevated serum level correlated with the decline in glomerular filtration rate (P = 0.0012) and severity of renal histopathologic grade. To elucidate the role of leukocytes in renal cytokine expression, surface markers of T cells (CD3), monocytes (CD14), natural killer cells (CD16), and B cells (CD19) were also examined in renal tissues. The prominent renal expression of CD3, CD14, and CD16 implicates the leukocytes as the major source of proinflammatory cytokines in IgAN. Collectively, these findings indicate that IFN-gamma plays a prominent role in an interactive network of cytokines that contribute to the pathogenesis and progression of IgA nephropathy.

Adult↗
PubMed1997

In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy.

Progressive expansion of the mesangial matrix is one of the most characteristic histological features of diabetic nephropathy (DN). To determine the balance between the turnover and degradation of extracellular matrix (ECM) in renal tissue of patients with DN, we examined the expression of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type IV collagen (IV-C) mRNAs using a high-resolution in situ hybridization. Patients were divided into three grades: mild (grade I), moderate (grade II) and severe (grade III) mesangial expansion and tubulointerstitial injury. The relationship between the expression of these mRNAs and degree of glomerular mesangial expansion and interstitial injury was also examined. Cells positive for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. A number of tubular epithelial cells and some infiltrating cells in the interstitium also expressed these mRNAs. The expression of MMP-3 mRNA and TIMP-1 mRNA was strongest in glomeruli of grade I and inversely correlated with mesangial expansion. In contrast, the expression of all three types of mRNA was correlated with the degree of interstitial injury. Our results indicate that IV-C, MMP-3 and TIMP-1 mRNAs are expressed in glomerular resident cells, tubular epithelial cells and infiltrating cells in renal tissue of DN, and suggest that their expression changes with the degree of mesangial expansion and interstitial injury. Altered expression of MMP-3 and TIMP-1 may be associated with the progression of DN.

Adult↗
PubMed1997

Effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels in rats.

1. The effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels were investigated in Sprague-Dawley rats. 2. Oral administration of KRN4884 (3 mg kg-1) for 10 days caused a significant reduction in serum triglyceride levels, which was comparable to that of clofibrate (160 mg kg-1). Reduction in serum triglyceride levels by KRN4884 and clofibrate were accompanied by a reduction in triglyceride levels both in chylomicron and in very low density lipoprotein. KRN4884 treatment did not affect serum concentrations of total cholesterol and phospholipid, but did increase free fatty acid levels. Clofibrate reduced total cholesterol, phospholipid and free fatty acid levels. 3. Administration of clofibrate significantly decreased triglyceride secretion rate as measured by the Triton WR-1339 injection procedure, while KRN4884 did not. 4. Rats receiving KRN4884 exhibited an increase in lipoprotein lipase (LPL) activity both in adipose tissue and in skeletal muscle. There was an inverse correlation between serum triglyceride levels and tissue LPL activities. KRN4884 did not change hepatic triglyceride lipase (HTGL) activity. Clofibrate affected neither LPL nor HTGL activities. 5. It is concluded that administration of KRN4884 results in reduced serum triglyceride levels which may be due to the enhancement of LPL activity in peripheral tissues.

ATP-Binding Cassette Transporters↗
PubMed1997

Species-dependent differences in inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium.

1. Species-dependent variations in the positive inotropic effect (PIE) of endothelin-3 (ET-3), and the relationships between the PIE and specific binding sites for [125I]-ET-3 and the PIE and the acceleration of phosphoinositide hydrolysis by ET-3, were studied in ventricular muscles from the rat, guinea-pig, rabbit, ferret and dog. 2. ET-3 in the presence of (+/-)-bupranolol (0.3 microM) and prazosin (0.3 microM) elicited a concentration-dependent PIE in the ventricular muscle from the rat, guinea-pig, rabbit and ferret. The potency of ET-3 and its efficacy in inducing a PIE were highest in the rabbit, intermediate in the rat and guinea-pig and lowest in the ferret. ET-3 did not have any inotropic effect on ventricular muscle from the dog. 3. Specific high-affinity binding of [125I]-ET-3 was observed with membrane fractions derived from the ventricular muscle of the five species. The maximal specific binding (Bmax) of ET-3 was highest in the rat and guinea-pig, intermediate in the rabbit and ferret and lowest in the dog. The values of KD in the rabbit and dog (33 and 52 pM) were lower than those in the rat, guinea-pig and ferret (141-221 pM). 4. In slices of ventricular muscle from all five species, ET-3 increased the accumulation of [3H]-inositol monophosphate (IP1) in a concentration-dependent manner. The extent of accumulation of IP1 was highest in the rat, intermediate in the guinea-pig and rabbit and lowest in the ferret and dog. 5. The results demonstrate the wide range of variations in the PIE of ET-3 on mammalian ventricular muscles. The variations in the coupling processes subsequent to the acceleration of the hydrolysis of PI, triggered by the binding of ET-3 to its receptor, might be important in these species-dependent differences in the PIE of ET-3.

Animals↗
PubMed1997

Pharmacological evidence for alpha(1D)-adrenoceptors in the rabbit ventricular myocardium: analysis with BMY 7378.

1. It was examined by means of BMY 7378, a selective antagonist of alpha 1D-adrenoceptors, whether alpha 1D-adrenoceptors contribute to the regulation of myocardial contractility and hydrolysis of phosphoinositide (PI) in rabbit ventricular muscle. 2. BMY 7378 had a biphasic antagonistic action on the positive inotropic effect (PIE) of phenylephrine depending on the concentration. BMY 7378 at 1-10 nM shifted the concentration-response curve (CRC) for the PIE of phenylephrine to the right and downward and at 100 nM to 1 microM it antagonized the PIE in a competitive manner, the slope of Schild plot being 0.93 and the pA2 being 7.17 +/- 0.09. 3. The inhibitory action of BMY 7378 at 1-10 nM is ascribed to the selective action on alpha 1-adrenoceptors because the PIE of neither isoprenaline nor endothelin-3 and angiotensin II was affected by this compound over this concentration range. 4. In the presence of 100 nM WB 4101, the antagonistic action of BMY 7378 at 1-10 nM remained unchanged but the antagonistic action of BMY 7378 at 100-300 nM disappeared. The antagonistic action of BMY 7378 at 1 nM was unaffected by 100 nM (+)-niguldipine. 5. Following pretreatment with chloroethyldonidine, BMY 7378 at 1 nM inhibited the maximal response to phenylephrine but the pD2 value for phenylephrine was increased in the presence of BMY 7378. The CRC for phenylephrine was shifted to the left in the presence of 10-100 nM BMY 7378 but it was shifted to the right by BMY 7378 at 300 nM. 6. Stimulation of PI hydrolysis induced by phenylephrine was not affected by BMY 7378 up to 10 nM but it was reduced significantly by BMY 7378 at higher concentrations (100 nM to 1 microM). 7. BMY 7378 inhibited the [3H]prazosin specific binding to the rabbit ventricular membrane fraction in a monophasic manner with a pKi value of 7.53 +/- 0.09. 8 The results indicate that in rabbit ventricular muscle, BMY 7378 at 1-10 nM suppressed the maximal response to phenylephrine (probably mediated by alpha 1D-adrenoceptors) and at 10-100 nM it inhibited the negative inotropic effect of phenylephrine, the mechanisms of which remain to be characterized. At higher concentrations (100 nM to 1 microM) BMY 7378 antagonized the functional and biochemical response via a presumed interaction mainly with the alpha 1D-adrenoceptor and partially with the alpha 1A-adrenoceptor.

Adrenergic alpha-Antagonists↗
PubMed1997

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle.

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

Animals↗
PubMed1997

Comparison of characterization among Bordetella calmodulin-like protein, bovine brain calmodulin and Escherichia coli acyl-carrier protein.

We previously reported that Bordetella calmodulin-like protein (CLP), like bovine brain calmodulin (CaM), enhances adenylate cyclase and phosphodiesterase activities. In this communication, antigenic and biochemical characters were compared between CLP and CaM. It was found that anti-CLP and anti-CaM sera obtained reacted with CaM and CLP, respectively. The amino acid composition of CLP was similar to CaM. The similarity was also found in an Escherichia coli acyl-carrier protein (ACP), a Ca(2+)-binding protein. Though the amino acid sequence of N-terminus region of CLP has no significant homology with CaM, ACP has highly homology in its N-terminus similar to CaM. These results suggest that CLP might act as a Ca(2+)-binding protein, and/or an ACP during the activation of adenylate cyclase and phosphodiesterase.

Acyl Carrier Protein↗
PubMed1997

Inhibitory effect of acyl-CoA and acyl-carnitine compounds on the ischemia-inducing activity of Bordetella heat-labile toxin in guinea pig skin.

The ability of Bordetella heat-labile toxin (HLT) to induce ischemic lesions after intracutaneous injection to guinea pig skin was lost following incubation at 37 degrees C with long-chain saturated acyl-CoA and acyl-carnitine compounds. Short-chain unsaturated acyl-CoA compounds, however, were less potent in inhibiting the induction of HLT activity. Long-chain saturated acyl-CoA and acyl-carnitine compounds, potently inhibited the induction of this activity. On incubation with HLT at 0 degrees C, a long-chain saturated acyl-CoA compound, palmitoyl-CoA, did not inhibit HLT activity. When first mixed with bovine serum albumin or dimethyl-beta-cyclodextrin, palmitoyl-CoA lost the ability to inhibit HLT activity. Binding of 14C-palmitoyl-CoA to HLT was measured by Scatchard analysis. The Bmax values of HLT (2.75 mol/mol of protein) were higher than that of acyl-CoA-binding protein from bovine liver (0.95 mol/mol of protein). Neither acyl-CoA hydrolase nor acyl-CoA ligase was detected in the HLT preparation. These results suggest that the acyl-CoA and acyl-carnitine compounds bind directly to HLT and produce a critical change in conformation required for HLT activity.

Acyl Coenzyme A↗
PubMed1997

Two-D distance distribution analysis: an application to HBcAg-positive hepatocytes and its relation to septum formation in cirrhosis.

The morphogenesis of cirrhotic septa in chronic hepatitis B was studied assuming that they arise at the sites of hepatocellular necrosis invoked by host immune reaction against HBcAg-expressing hepatocytes. Sections from three livers with chronic hepatitis B, all in cirrhotic stage, were immunostained with HBcAg and subjected to morphometry to analyze the distribution of HBcAg(+) hepatocytes and its relation with septa. HBcAg(+) cells were not distributed randomly over the nodules but forming focal areas. The septum formation along these foci was shown by 2-D distance distribution analysis, a technique we devised. Upon a sheet of color microphotograph of immunostained section, hundreds of test points each 400 microns apart were arranged by overlaying a tessellated grid. From each of the points hitting the nodules, the distance to the nearest nodulo-septal border D(min) was measured. Measurement was performed on a total of 2,585 test points. It was shown that the mean D(min) in the HBcAg(+) areas was significantly smaller than in HBcAg(-) areas. Thus, the cirrhotic septa are considered to arise at the places of HBcAg(+) foci, connecting them by postnecrotic collapsing.

Chronic Disease↗
PubMed1997

Visual evoked potential guidance for posteroventral pallidotomy in Parkinson's disease.

Visual evoked potentials (VEPs) to photic stimulation of the eyes were used to identify the optic tract and thus determine the location of the globus pallidus internus (GPi) in eight patients with Parkinson's disease who then underwent posteroventral pallidotomy. Distinct waves appeared at 1 or 2 mm below the target (4 to 5 mm below the intercommissural line) and the amplitude significantly increased at 5 or 6 mm below, strongly suggesting that the electrode was in contact with the optic tract. In the medio-lateral direction, potentials were successively recorded in an area of 4 to 8 mm length, indicating the width of the optic tract. The trajectory at the mid point showed the most significant potentials which suggested the center of the optic tract. The site of the first lesion was placed 0 to 2 mm lateral to this trajectory and 5 mm above the point at which the amplitudes of responses increased. The actual lesion site significantly differed from the tentative target in a medio-lateral direction by 1 to 5 mm (mean 3.0 +/- 1.5 mm, n = 6). The Unified Parkinson's Disease Rating Scale score significantly improved and magnetic resonance imaging taken 2 or 3 weeks after the operation showed a lesion within the GPi in each patient. Recording of VEPs greatly facilitates accurate determination of the GPi.

Aged↗
PubMed1997

Expression of thromboxane synthase in kidney tissues from patients with IgA nephropathy.

Thromboxane A2 (TXA2) is a potent vasoconstrictor which is known to be involved in the pathogenesis of experimental glomerulonephritis, although its exact pathogenic significance is not clear in human glomerulonephritis. We have investigated the expression of thromboxane synthase (TXS) in kidney tissues from patients with IgA nephropathy (IgAN), using RT-PCR and immunohistochemical methods. Biopsied renal tissues from thirty-four patients with IgAN (24 whole tissues and 10 isolated glomeruli) and normal renal tissues from 11 nephrectomized kidneys (control, eight whole tissues and three isolated glomeruli) were included in this study. TXS mRNA expression was observed in 10 out of 24 (42%) whole tissue specimens from IgAN, but no such message was disclosed in the control tissue. There was no detectable TXS mRNA expression in the isolated glomeruli either from IgAN patients or controls, although constant mRNA expressions for GAPDH and VPF/VEGF were observed. IgAN patients with positive TXS mRNA had significantly reduced GFR with elevated serum creatinine and serum beta 2-microglobulin levels. Immunostaining, using a monoclonal anti-TXS antibody, identified the localization of the TXS protein in the interstitial areas where monocyte/macrophage infiltration was abundant, as well as in the arterioles of the kidney tissues with advanced tissue damage. It was concluded that TXA2 produced by the interstitial infiltrating cells during the inflammatory process might be involved in the progression of IgA nephropathy.

Creatinine↗
PubMed1997

[A case of unresectable pancreatic cancer successfully treated with continuous venous daily infusion of 5-FU and low-dose CDDP].

This case was a 61-year-old male diagnosed with pancreatic cancer who had a celiotomy. The tumor invasion involved the pancreas body and head. Ultrasonograph examination revealed that all the celiac artery, supramesenteric artery, and portal vein were occluded in the tumor. Because of the unresectability of the tumor, a palliative operation was carried out, and during the following 9 months he was given UFT 300 mg daily. Because abdominal ascites accompanied the tumor growth, the patient underwent combination chemotherapy of cisplatin 5 mg/day x 5/week and continuous infusion of 5-fluorouracil 250 mg/day for 4 weeks. Remarkable reduction of the abdominal ascites and decline of the tumor markers (CEA, CA19-9) was observed in the course of the chemotherapy. Bone marrow function was suppressed by the agents, but granulocyte colony stimulating factor (G-CSF) was very effective for recovery from the damage. Two months after discharge, abdominal ascites recurred. The patient received the same serial chemotherapy for 6 weeks, and now is followed as an outpatient.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

(+/-)-tamsulosin, an alpha 1A-adrenoceptor antagonist, inhibits the positive inotropic effect but not the accumulation of inositol phosphates in rabbit heart.

The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine. (+/-)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by alpha 1-adrenoceptors, did not affect the accumulation of [3H]inositol phosphates that was induced by 10 microM phenylephrine. Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine. These results indicate that the positive inotropic effect, mediated via (+/-)-tamsulosin- and oxymetazoline-sensitive subtype of alpha 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.

Adrenergic alpha-1 Receptor Antagonists↗