摘要:

SUMMARY1. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+(20 mmol/ L), and full concentration—relaxation curves constructed to cromakalim (0,01–30 μmol/L) in the absence and presence of increasing concentrations of glibenclamide, glipizide, tolbutamide (the sulphonylureas), alinidine (an imidazolidine), phentolamine (an imidazoline), and chlorpromazine (the phenothiazine derivative). Whereas the active sulphonylureas, glibenclamide and glipizide, displayed classical competitive antagonism, the remaining compounds (alinidine, phentolamine and chlorpromazine) caused shifts in the cromakalim concentration—effect curves associated with a reduction in the slope and maximum response.2. A single concentration of each antagonist was selected and the shift in the concentration—effect curve determined. The possibility that sulphonylurea and imidazol(id)ine antagonists act at different sites was tested using the concentration‐ratio method for combined antagonists described by Paton and Rang (1965). The combination of alinidine and phentolamine (collectively called imidazol(id)ines) at a number of different concentrations (10–30 μmol/L) resulted in a concentration‐ratio to cromakalim which was additive, suggesting a common site of action. Similar results were obtained when examining the interaction between two sulphonylurea compounds (glibenclamide and glipizide). However, the interaction between sulphonylurea (glibenclamide) and imidazol(id)ine (alinidine) produced concentration‐ratios which were multiplicative, suggesting a different or additional site of action for compounds from these two groups. Results indicated that chlorpromazine was able to block cromakalim via an action at the same site where alinidine and phentolamine act.3. The results from this study indicate that sulphonylurea—and imidazol(id)ine‐based K+channel antagonists interact at different sites to produce their observed antagonism of the vasorelaxation induced by cromakalim. These results indicate the possibility of multiple sites of action underlying the effects of compounds which antagonize the actions of K+

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01727.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. Calcitonin gene‐related peptide (CGRP) is a potent vaso‐active 37 amino acid peptide, typically elevated in plasma from patients with medullary thyroid cancer (MTC), but undetectable in the plasma of normal subjects.2. The kidney is a major site for the clearance of exogenously infused CGRP but the intrarenal site of this clearance is unknown. Extra‐organ clearance is also significant for CGRP, and whereas the site and mechanism of this degradation remain uncertain, the vasculature has been postulated as the most likely site.3. The isolated perfused rat kidney (IPRK) was studied to (i) localize the intrarenal site of CGRP clearance and (ii) determine the contribution of the renal vasculature to the clearance of CGRP. The half‐life of CGRP in the filtering IPRK was 63.9 ± 4.5 min, whereas blocking of filtration by elevation of the perfusate osmolarity abolished the degradation. This suggests that (i) renal CGRP degradation occurs after glomerular filtration with intratubular metabolism and (ii) that there is no active CGRP degradation in the (glomerular) capillary endothelium.4. These results do not support the theory that renal vascular endothelium plays a major active role in CGRP deg

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01728.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. The relationship between physical fitness (maximal oxygen uptakeVo2max) and incidence of hypertension was investigated through a prospective study for a total of 16525 human‐years of observation.2. This study involved 3305 Japanese males whose blood pressure (BP) was normal when they received their first physical examination before the age of 50. They were monitored from 1983 to 1988. The BP of 425 subjects was diagnosed as hypertension in the fifth year.3. Fitness levels were divided into quintiles according toVo2maxlevels, and were compared with the changes of BP and relative risk of hypertension after adjustment for age, initial percentage of body fat (PFAT), initial BP, alcohol consumption, cigarette smoking status and familial history of hypertension. The increase in BP of subjects in the least fit group was higher than in any other group. Relative risk was calculated using a multiple logistic regression and was 1.9 × higher in the least fit group compared with the fittest group.4. The subjects were classified into three groups: the improvedVo2maxgroup, the deterioratedVo2maxgroup and the unchangedVo2maxgroup. The increase in BP of the improvedVo2maxgroup was significantly lower than the other two groups after adjustment for changes in PFAT, age, initial PFAT, initial BP, fitness level, alcohol consumption, cigarette smoking status and familial history of hypertension.5. It is concluded that lowVo2maxlevel is related to higher incidence of hypertension. An improvedVo2maxwould therefore be able to prevent hypertensi

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01729.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. To determine the long‐term haemodynamic and humoral effects of arginine vasopressin (AVP), a chronic intravenous infusion of AVP was performed in conscious Wistar normotensive rats.2. AVP (1, 10, 50 or 100 ng/h) or saline as a vehicle control was infused continuously into the right jugular vein at a rate of 1 μL/h using an osmotic minipump for 7 days.3. As a result, significant elevations of systolic blood pressure were observed in association with increases in plasma AVP concentration. Significant decreases in heart rate were observed during infusion of 100 ng/h of AVP. Mean arterial pressures measured directly on the sixth day of infusion were significantly higher in the rats given 50 ng/h (125 ± 3 mmHg) or 100 ng/h (125 ± 2 mmHg) compared with control rats (117 ± 2 mmHg). Intravenous injection of the V1antagonist, d(CH2)5Tyr(Me)AVP, significantly reduced the elevated mean arterial pressure induced by 50 or 100 ng/h of AVP (—7 ± 4 and—11 ± 2 mmHg, respectively). Plasma renin and norepinephrine concentrations were not affected by AVP infusion, while plasma epinephrine concentration was lower in the rats given 100 ng/h of AVP. Intravenous infusion of AVP did not alter bodyweight, serum electrolytes or osmolality.4. These results suggest that AVP has a long‐term pressor effect which is attributable to its vasoconstrictor action in c

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01730.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. To characterize the anti‐arrhythmic properties of a new calcium antagonist, monotepil, AJ‐2615, the preventive effects of AJ‐2615 were compared with those of the existing calcium antagonists, diltiazem and verapamil, in experimental models of arrhythmia.2. AJ‐2615 (0.1–3.0 mg/kg, i.v.) suppressed ventricular arrhythmias induced by adrenaline (10 μg/kg, i.v.) in rats. AJ‐2615 (0.1 mg/kg per min for 2 min, i.v.) also suppressed atrial tachycardia induced by aconitine (0.01% aconitine solution) in rats.3. In these activities, AJ‐2615 was comparable to or more potent than diltiazem and verapamil which are widely used for the treatment of arrhythmia.4. In pro‐arrhythmic activity, AJ‐2615 was less potent than diltiazem and verapamil.5. These results suggest that AJ‐2615 would be a safer anti‐arrhythmic agent, with less proarrhythmic liability than d

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01731.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. The effects of peptide histidine isoleucine (PHI) on pancreatic exocrine secretion were investigated in preparations of the isolated and blood‐perfused dog pancreas as compared with those of vasoactive intestinal peptide (VIP), secretin and glucagon.2. Each peptide tested was injected intra‐arterially (i.a.) as a single bolus. Graded doses of PHI (3–300 nmol/kg), VIP (1–100 nmol/kg) and secretin (0.01–0.3 nmol/kg) caused dose‐dependent increases in the secretion of pancreatic juice and bicarbonate outputs, but had little effect on the protein outputs. Glucagon (0.1–10 μmol/kg) produced a bell‐shaped dose—response curve for the secretory rate, bicarbonate and protein outputs.3. The secretory activity of 30 nmol/ kg of PHI corresponded roughly to that of 80 pmol/ kg of secretin, 9 nmol/kg of VIP and 0.6 μmol/kg of glucagon, respectively. Thus, based on administered dose, PHI was about 375 × less potent than secretin, 3 × less potent than VIP and 20 × more potent than glucagon.4. The PHI‐ and VIP‐stimulated secretions were inhibited by a VIP antagonist, but not by a glucagon antagonist, SCH23390 (a dopamine D‐1 antagonist), L‐364718 (a cholecystokinin antagonist) or atropine.5. Each peptide increased cyclic AMP concentration, but not cyclic GMP concentration, concomitant with the increase in pancreatic secretion.6. From these results, it is concluded that PHI produces an increase in pancreatic secretion by acting on VIP‐preferring receptors on the exocrine pancreatic gland of the dogs. This may be mediated at least in part through the increase of intrace

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01732.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. Recent investigations revealed that isoprenoid compounds serve as key substances for cellular proliferation through post‐translational modification. Previously we reported that tissues of spontaneously hypertensive rats (SHR) had a lower activity of isoprenoid biosynthesis when compared with the normotensive control rat (WKY). However, cultured vascular smooth muscle cells (VSMC) of SHR showed an enhanced growth rate. These findings led us to investigate further the effect of isoprenoid compounds on VSMC proliferation.2. When the cells of WKY were stimulated with 5% fetal calf serum (FCS) in the presence of lovastatin, [3H]‐thymidine incorporation decreased in a dose‐dependent manner and was completely inhibited at 30 μmol/L. Exogenously added mevalonate showed a protective effect against lovastatin (81% protection at 0.1 μmol/L).3. Fluoromevalonate (Fmev), an inhibitor of mevalonate‐PP decarboxylase which converts mevalonate‐PP into isoprenoids, showed a dual inhibitory effect. DNA synthesis was partially inhibited at 0.01–1 μmol/L, however at 10 μmol/L there was no detectable inhibition. The inhibitory effect was again observed at concentrations over 10 μmol/L.4. In the presence of lovastatin and Fmev to block both HMG CoA reductase and mevalonate‐PP decarboxylase, exogenous mevalonate dose dependently stimulated [3H]‐thymidine incorporation induced by FCS.5. These data suggest the positive effect of the initial mevalonate derivatives other than isoprenoid compounds on the p

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01733.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. We characterized the endothelial cell‐derived growth factors of SHRSP and Wistar Kyoto rats (WKY), respectively and found that platelet‐derived growth factor (PDGF)‐B chain related growth factor constituted a major portion of the mitogenic activity of the conditioned media of endothelial cells from both animals. There were no remarkable qualitative differences between the endothelial cell‐derived growth factors of SHRSP and WKY.2. Northern analysis revealed that the expression of PDGF‐B chain was 2–4‐fold enhanced in cultured aortic endothelial cells of SHRSP. This enhanced expression of PDGF‐B chain, which may be induced under chronic hypertensive conditions, is suggested to contribute to the increase in endothelial cell‐derived growth factors report

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01734.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. The localization of α‐adrenoceptors in the plasma membranes of human kidney were investigated by radioligand binding, using an α1‐antagonist, [3H]‐bunazosin, and an α2‐antagonist, [3H]‐rauwolscine.2. Both the maximum binding (Bmax) and dissociation constant (Kd) of [3H]‐bunazosin were greater in the cortex than in the medulla. TheBmaxof [3H]‐rauwolscine in the medulla was greater than in the cortex.3. Thus, α1‐adrenoceptors appeared to be localized predominantly in the cortex, while the α2‐adrenoceptors were mainly present in the medul

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01735.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

SUMMARY1. The effects of adenosine receptor agonists and antagonists on human sperm motility have been studied. Specific binding sites for adenosine and its analogues on human sperm were also investigated.2. Agonists stimulated human sperm motility in a dose‐dependent manner with a potency order of 5'‐N‐ethylcarboxamidoadenosine (NECA, EC50= 0.3 μmol/L)>2‐[p‐(carboxyethyl)phenylethylamino]‐5'‐N‐ethylcarboxamidoadenosine(CGS‐21680, EC50= 10 μmol/L)>adenosine (EC50= 100 μmol/L).3. NECA‐stimulated motility was competitively inhibited by various adenosine receptor antagonists. The potency order was 3,7‐dimethy‐l‐propargylxanthine>8‐(p‐sulfophenyl) theophylline>xanthine amino congener.4. The radioligand [3H]‐NECA bound to sperm membrane in a saturable manner with aBmaxof 21.3 pmol/mg protein and equilibriumKdof 4 μmol/L. Adenosine agonists and antagonists competed for [3H]‐NECA binding with the same rank order of potency as for the stimulation of human sperm motility.5. GTPγsinhibited 63% of specific [3H]‐NECA binding with IC50value of 11 nmol/L. This suggests that the [3H]‐NECA binding sites may be coupled to one or more G proteins.6. These results indicate the presence of adenosine A2receptors on human sperm which are responsible for adenos

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1993.tb01736.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY