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  • 1
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The effects of the ETA receptor antagonist BQ123 and dihydropyridine calcium antagonists on the vasoconstrictor effect of endothlin-1 (ET-1) were studied in human isolated internal mammary artery (IMA). The effect of the calcium antagonist, nisoldipine, on ET-1 levels has also been examined in cultured IMA endothelial cells (IMAEC).2. The results showed that BQ123 and the calcium antagonists nisoldipine, isradipine, nitrendipine and nifedipine fully relaxed IMA precontracted with 3 nmol/L ET-1 with the EC50 values of 7.18 ± 0.09 (-log mol/L) for BQ123, and 7.68 ± 0.07, 7.02 ± 0.12, 6.96 ± 0.08 and 6.89 ± 0.09 for the calcium antagonists, respectively.3. Pretreatment of IMA with 10, 30, 100 and 300 nmol/L nisoldipine significantly depressed the maximal response (Max; 88.3 ± 5.1, 75.2 ± 4.9, 59.3 ± 5.6 and 56.2 ± 4.8% of maximal noradrenaline response versus 99.1 ± 13.2% in control, P〈0.01) of IMA to ET-1 without a significant change in the EC50 values.4. Pretreatment of IMA with 300 nmol/L BQ123 significantly increased both the EC50 (7.97 ± 0.09 vs 8.36 ± 0.08 in the control, P〈0.05) and the Max (138.1 ± 10.2%vs the control, P〈 0.01) of IMA to ET-1.5. Incubation of IMAEC with nisoldipine for 7h resulted in a dose-dependent (10−8–10−5 mol/L) reduction up to 93.1% in ET levels in the conditioned media.6. ET levels in the cell lysates were not detectable either in the absence or in the presence of nisoldipine, suggesting the reduction of ET levels in the media could be due to inhibition of ET synthesis.7. In conclusion, these studies demonstrate that: (i) both BQ123 and the calcium antagonists are potent relaxant agents of human IMA precontracted with ET-1; (ii) BQ123 also increases the Max of IMA to ET-1 and the mechanism is unknown; (iii) the calcium antagonist nisoldipine reduces ET levels in the cultured human IMAEC.
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 18 (1991), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Atrial natriuretic peptide (ANP) is degraded by neutral metalloendopeptidase (NEP) (EC 3.4.24.11) and the kidney is a major site of ANP clearance.2. The regional distribution of NEP in the rat kidney was investigated.3. The activity of NEP, measured with an enzymatic fluorimetric method employing N-dansyl-D-alanyl-glycyl-L-4-nitrophenylalanyl-glycine as a synthetic substrate, was 18 times and eight times higher in the outer stripe of the medulla and inner cortex than in the outer cortex (OC).4. Low concentrations of NEP were found in the OC, inner stripe and inner medulla.5. NEP activity in the rat kidney was inhibited by the specific NEP inhibitors (SCH39370, phosphoramidon and thiorphan) at micromolar concentrations.6. The present result suggests that degradation of ANP by NEP occurs mainly in the proximal tubules of the juxtamedullary nephrons, rather than cortical nephrons, and that the convoluted tubule in the OC is not a major site of location of NEP.7. The relationship between NEP activities in the kidney in vitro and plasma clearance of ANP in vivo remains to be clarified.
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 19 (1992), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. ACE from rat lung and testis was characterized by radioligand binding studies using [125I]-Ro 31-8472, the radioiodinated hydroxy derivative of the potent ACE inhibitor cilazaprilat.2. Analysis of the displacement of [125I]-Ro 31-8472 from ACE by ACE inhibitors of different structure by the ligand program was best fitted by a two binding site model for lung ACE and a one binding site model for testis ACE.3. There was marked variation in ACE inhibitor binding affinity at the two binding sites of lung ACE across the panel of ACE inhibitors studied (equilibrium dissociation constant; Kd; pmol/ L) for site one vs site two: cilazaprilat 40 ± 3 vs 430 ± 92*; lisinopril 25±1 vs 848 ± 107**; and quinaprilat 4 ± 1 vs 1869 ± 720; **P 〈 0.05; **P 〈 0.005, t-test, n= 3). Reduction in binding affinity at site two of lung ACE was related to an increase in ACE inhibitor side chain length or complexity of carboxyl terminal moiety. ACE inhibitor binding affinity at the testis ACE binding site resembled site one of lung ACE.4. Inhibition of bradykinin hydrolysis by lung ACE in the presence of increasing concentrations of cilazaprilat or quinaprilat was similar (F= 0.64; P〉0.05), suggesting that bradykinin cleavage predominates at ACE active site one.5. The differences in ACE inhibitor affinity at the two ACE active sites has implications in physiological substrate selectivity, and may influence the pharmacodynamic effects of different ACE inhibitors.
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 19 (1992), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The acute hormonal, renal and haemodynamic effects of SCH 39370, a new neutral endopeptidase (NEP) inhibitor, were evaluated in rats with congestive heart failure (CHF) produced by coronary ligation.2. Left ventricular systolic pressure and left ventricular end diastolic pressure were significantly decreased by SCH 39370 treatment.3. SCH 39370 improved cardiac function by increasing cardiac index and decreasing total peripheral resistance.4. SCH 39370 induced a transient but significant diuresis and natriuresis.5. These effects were associated with significant increases in urinary atrial natriuretic peptide (ANP) and cyclic GMP excretion, but not with an increase in plasma ANP levels.6. The results suggest that NEP inhibition may be a new therapeutic method for treating CHF possibly by potentiating the biological activities of endogenous ANP.
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  • 5
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. To elucidate the central effect of lisinopril, a new angiotensin converting enzyme (ACE) inhibitor, ACE localization and levels were followed in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug.2. Following acute lisinopril (10 mg/kg p.o.) treatment, serum ACE activity was acutely reduced, but returned to normal by 24 h.3. Levels of ACE in most parts of the brain, including the basal ganglia and choroid plexus of all ventricles were not affected by lisinopril. Lisinopril inhibited brain ACE in the subfornical organ and organum vasculosum of the lamina terminalis, circumventricular organs, where the blood brain barrier is deficient. These regions are rich in ACE and angiotensin II receptors, and are known targets for angiotensin II-induced effects on fluid, electrolyte and blood pressure homeostasis.4. These observations indicate that quantitative in vitro autoradiography is a powerful method to study the access of drugs to the central nervous system.5. This study shows that blood brain barrier plays an important role in limiting the penetration of lisinopril into the central nervous system. The circumventricular organs may be important targets for ACE inhibitors.
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 12 (1985), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The coronary vasodilatory effect of stable adenosine analogues is mediated by adenosine A2 receptors.2. These coronary receptors differ from A2 receptors found in other tissues.
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 7 (1980), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The acute effects of captopril on blood pressure, renin, angiotensin, bra-dykinin and catecholamines were examined in patients with essential (n= 10, Group 1), accelerated (n=6, Group 2) and renal hypertension (n= 14, Group 3).2. Blood pressure showed little change in Group 1, fell significantly in Group 2, with a marked fall in Group 3. Heart rate did not change.3. The fall in blood pressure was positively correlated with pretreatment renin and angiotensin II.4. Angiotensin II fell, with reciprocal increases in renin and angiotensin I. No changes occurred in bradykinin or catecholamines.5. The rise in renin after captopril was greatest in renovascular hypertension which may prove useful as a screening test for such patients.
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 20 (1993), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. A vasopressin binding protein purified from rat liver membranes was used to immunize Balb/c mice and, subsequently, for the screening of hybrids raised in two different cell fusions.2. Three hybrids were obtained which secreted monoclonal antibodies (MoAb) that bound to the purified solubilized receptor as detected by an enzyme-linked immunosorbent assay technique. All three MoAb immunoprecipitated the purified receptor.3. In addition, the MoAb bound in a concentration-dependent manner to crude liver, kidney and anterior pituitary membranes, tissues known to contain arginine vasopressin (AVP) receptors but not to cardiac ventricle membranes which lack AVP receptors.4. However, the binding of [125I]-[d(CH2)5, Sar7]AVP (a specific radiolabelled V1 antagonist) to the membrane-bound receptor was not inhibited by these antibodies.5. These results suggest that MoAb recognize epitopes which are common to rat liver, kidney and anterior pituitary membranes but are not at the ligand binding site.
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 17 (1990), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. To dissociate the effects on the development of diabetic renal injury of angiotensin converting enzyme (ACE) inhibition per se, and a reduction in systemic blood pressure, we have studied the effects of chronic ramapril treatment in streptozotocin diabetic spontaneously hypertensive rats, with modulation of the hypotensive effect by a high salt diet.2. Three weeks following uninephrectomy and induction of diabetes with streptozotocin, spontaneously hypertensive rats were allocated to three treatment groups. Groups 1 and 2 received 1% sodium chloride and Group 3 water as drinking solution. Groups 2 and 3 received 0.4 mg/kg per day ramapril in drinking solution over the subsequent 2 month study period.3. Sodium chloride drinking solution (1%) completely prevented any hypotensive effect of ramapril. Blood pressure was reduced in Group 3 rats over the entire period of study, when compared with Group 2 rats (P〈0.001).4. Urinary protein excretion progressively increased in Group 1 and 2 rats, and was significantly reduced (P〈0.001) in Group 3. After 2 months treatment, urinary protein (expressed as mean and s.e.m.) was 160±30 mg/day in Group 1, 240±50 mg/day in Group 2, and 60±11 mg/day in Group 3.5. Angiotensin converting enzyme inhibition per se was not associated with a reduced protein excretion in diabetic nephropathy, requiring concomitant control of systemic blood pressure to become renoprotective.
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 15 (1988), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. A two-site monoclonal immunoradiometric assay (IRMA) for total renin protein was established to cover the range 0.3–300 μiu. The limit of sensitivity was 2 μiu/ml plasma.2. IRMA after acid activation of plasma prorenin gave the highest and most consistent values for total plasma renin (TPRC = 197 μiu/ml, s.e.m. = 22, in 17 normal adults). In untreated plasma, TPRC measured by IRMA was lower than expected, but in amniotic fluid expected values were obtained.3. Human angiotensinogen at normal concentrations did not interfere with binding of renin to the first antibody, but ovine angiotensinogen displaced the standard curve significantly.4. TPRC measured by IRMA is convenient and highly sensitive, but either the state of activation of the enzyme or another effect of acidification of plasma influences the estimated value.5. Active renal renin may not be the appropriate reference standard for this IRMA unless plasma renin is previously activated.
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