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At least 667 records · Page 37Linked to original sources
PubMed1994

Alpha 1A-adrenoceptor subtype mediates contraction of the rat urethra.

1. The alpha 1-adrenoceptor-mediated responses of the rat urethra to phenylephrine have been examined in vitro. Phenylephrine caused concentration-dependent contractions of the isolated urethra which were antagonized by WB4101 (3-30 nM) and prazosin (10-100 nM) but not idazoxan (1.5 microM). Schild plot analysis of the antagonism by prazosin and WB4101 yielded straight lines with slopes not significantly different from unity. The pA2 value of 9.0 for WB4101 was significantly greater than the value previously obtained at the alpha 1B-adrenoceptor of the rat spleen. 2. 5-Methylurapidil (30 nM) and abanoquil (1 nM) caused dextral shifts of concentration-response curves yielding pKB values of 8.3 and 9.4 respectively. Maximal responses to phenylephrine were also reduced by this concentration of abanoquil. 3. Preincubation with chloroethylclonidine (25 microM for 40 min) failed to alter responses, but removing extracellular calcium or the presence of nifedipine (1 microM) almost abolished contractions to phenylephrine. 4. These results indicate that the responses of the rat urethra to phenylephrine are mediated via the alpha 1A-adrenoceptor subtype and are dependent on the influx of extracellular calcium.

Aminoquinolines↗
PubMed1995

Influence of adrenoceptor stimulation on aggregation of platelets from diabetic and control rats.

1. Studies of cardiac and vascular responses have previously demonstrated that diabetes influences the sensitivity of these tissues to adrenoceptor stimulation. Adrenoceptors are also present on platelets where they modulate aggregatory responses. The present study investigates the influence of diabetes on these platelet adrenoceptor-mediated responses. 2. Rats were made diabetic with streptozotocin and platelet aggregatory responses to ADP were examined 2 or 12 weeks later. Aggregation to ADP of platelets from 2-week-diabetic rats was similar to that of platelets from age-matched controls, but platelets from 12-week-diabetic animals exhibited an enhanced aggregation to ADP. 3. In all groups studied, beta-adrenoceptor stimulation with isoprenaline caused a concentration-dependent inhibition of aggregation to ADP, whilst alpha-adrenoceptor stimulation with adrenaline was found to potentiate aggregation to ADP. The degree of inhibition or potentiation was found to remain unchanged by diabetes of either 2 or 12 weeks duration. 4. Previously reported increases in cardiac beta-adrenoceptor sensitivity and aortic alpha-adrenoceptor sensitivity were confirmed 2-week-diabetic animals, but these sensitivity changes were not observed in 12-week-diabetic rats. 5. The results indicate that, unlike the heart and vasculature, the influences of adrenoceptor stimulation on platelet aggregation are not altered by diabetes, even when aggregation to ADP is enhanced.

Adenosine Diphosphate↗
PubMed2006

Muscarinic receptor function, density and G-protein coupling in the overactive diabetic rat bladder.

1 Bladder smooth muscle sensitivity to muscarinic agonists is increased in the overactive bladder. Treatment of rats with streptozotocin induces a diabetic state in which the bladder muscle is overactive and also supersensitive to muscarinic agonists. This study has examined bladder contraction, muscarinic receptor density and receptor/G-protein coupling in the streptozotocin-induced overactive bladder of the rat. 2 Diabetes was induced by a single intraperitoneal dose of streptozotocin. Seven days later contraction of isolated detrusor muscle strips was assessed in tissue bath experiments, while receptor density was assayed in saturation experiments with [3H]-QNB (quinuclidinyl benzilate, L-[benzilic-4,4'-3H]) and receptor/G-protein coupling was determined in agonist displacement experiments with this radioligand. 3 Isolated detrusor strips from diabetic animals displayed an enhanced degree of spontaneous activity (0.060 +/- 0.016 g mg(-1), compared with 0.015 +/- 0.004 g mg(-1), P < 0.05). Carbachol produced contractile responses in tissues from both control and diabetic rats, but the diabetic tissues were more sensitive to this agonist, the pEC50 being 6.52 +/- 0.17 compared with 5.93 +/- 0.06 in controls (P < 0.001). Maximum responses to carbachol were similar in both groups of animals. The increase in carbachol potency was accompanied by a 40% increase in receptor density from 158 +/- 5 to 221 +/- 22 fmol mg(-1) protein (P < 0.05), but this was not enough to fully account for the change in tissue sensitivity. 4 In the absence of GTP-gamma-S, carbachol displaced [3H]-QNB from two binding sites, the high-affinity site (pKi = 7.06 +/- 0.26) which represents the receptors coupled to G-proteins made up 43.1 +/- 5.9% of the total binding sites in control tissues and this value was similar (41.0 +/- 4.0%) in the diabetic tissues (pKi = 6.64 +/- 0.31). In the presence of GTP-gamma-S, carbachol displaced [3H]-QNB from a single binding site which had a low-affinity, similar to the low-affinity site observed in the absence of GTP-gamma-S. 5 These data demonstrate that detrusor supersensitivity is observed after only 1 week of untreated diabetes in the rat. The overactivity is associated with an enhanced sensitivity to carbachol, which is partly explained by an increase in receptor density, but there appears to be no change in receptor/G-protein coupling.

Animals↗
PubMed2006

Alpha(1A/L)-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra.

Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional alpha(1)-adrenoceptors. This study characterizes the alpha(1)-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 microm) and corticosterone (10 microm) to inhibit amine uptake and propranolol (1 microm) to antagonize beta-adrenoceptors. The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC(50) values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The alpha(1D)-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The alpha(1A)-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamide (RS17053), which discriminates between responses mediated via alpha(1A) (high affinity) and alpha(1L)-adrenoceptors (low affinity) at concentrations up to 3 microm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the alpha(1A/L)-adrenoceptor, most probably the alpha(1L)-adrenoceptor.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1989

Ventricular fibrillation is reduced in hypothyroid rats with enhanced myocardial alpha-adrenoceptor responsiveness.

1. The severity of ventricular arrhythmias induced by coronary artery occlusion and reperfusion has been examined in control rats and animals made hypothyroid by pretreatment with 6-propylthiouracil (PTU). The maximal driving frequency and sensitivity of isolated left atria and papillary muscles to isoprenaline and to phenylephrine in the presence of propranolol, were also examined in tissues from control and hypothyroid animals. 2. Pretreatment with PTU resulted in a potentiation of responses to the alpha-adrenoceptor agonist phenylephrine in both left atria and papillary muscles, while responses to isoprenaline were depressed in left atria but unaltered in papillary muscles from hypothyroid animals. 3. In rats subject to coronary artery occlusion, PTU pretreatment reduced the incidence of ventricular fibrillation during acute myocardial ischaemia and abolished reperfusion-induced ventricular fibrillation. Mortality during myocardial ischaemia and reperfusion was also abolished. Diastolic blood pressure was similar in hypothyroid and control animals, but there was a small reduction in systolic blood pressure and a marked decrease in heart rate in PTU pretreated animals. 4. These results demonstrate that PTU-induced hypothyroidism represents a condition where cardiac alpha-adrenoceptor-mediated responses are enhanced but the severity of ischaemia- and reperfusion-induced arrhythmias is reduced.

Anesthesia↗
PubMed1990

Enhanced alpha-adrenoceptor responsiveness and receptor number during global ischaemia in the Langendorff perfused rat heart.

1. Idioventricular rate responses and adrenoceptor number have been examined in normal Langendorff hearts perfused at 70 cmH2O and in 'ischaemic' hearts perfused at 10 cmH2O. 2. In hearts perfused at normal pressure, ventricular rate responses to phenylephrine in the presence of propranolol were biphasic with low concentrations of phenylephrine reducing, and high concentrations increasing, ventricular rate. Both responses were abolished in the presence of prazosin (100 nM). In hearts perfused at low pressure, the negative chronotropic responses to phenylephrine were no longer present and positive chronotropic responses were enhanced compared with those of control tissues. The number of ventricular [3H]-prazosin binding sites was also significantly increased during ischaemia. 3. Idioventricular rate responses to isoprenaline were depressed in ischaemic tissues compared with controls, but [3H]-dihydroalprenolol binding was not altered in these hearts. 4. The incidence and duration of arrhythmias which occurred during 30 min of global ischaemia and reperfusion were not significantly altered in the presence of 100 nM prazosin. 5. These results demonstrate that reducing the perfusion pressure of rat isolated hearts enhances alpha-adrenoceptor-mediated responses and increases alpha-adrenoceptor density. Whether the increase in alpha-adrenoceptor responsiveness during ischaemia is involved in arrhythmogenesis requires further investigation.

Animals↗
PubMed1991

Diabetes-induced changes in cardiac beta-adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat.

1. The responses of isolated left atria and papillary muscles to isoprenaline, forskolin and calcium have been examined in 3 week streptozotocin-diabetic rats and the effects of oral ponalrestat administration (25 mg kg-1 daily) on diabetes-induced changes in cardiac responsiveness investigated. 2. Three weeks after animals were made diabetic, cardiac responses to isoprenaline were enhanced and this was accompanied by an increase in the density of ventricular [3H]dihydroalprenolol binding sites. Treatment of animals with ponalrestat prevented the increase in cardiac beta-adrenoceptor responsiveness and receptor number. 3. Diabetes also enhanced the sensitivity of cardiac tissues to forskolin, an effect that was not prevented by the treatment of animals with ponalrestat. 4. Ponalrestat treatment increased the resting and maximum tensions developed by cardiac tissues from diabetic animals and increased the maximum tensions developed by tissues from control animals. Diabetes alone had no effect on resting or maximum developed tensions. 5. Ponalrestat therefore prevents the changes in beta-adrenoceptor density and responsiveness induced by short-term diabetes in the rat and also increases the tension developed by cardiac muscle, an effect observed in diabetic and normal animals.

Aldehyde Reductase↗
PubMed1993

Potentiation of alpha-adrenoceptor-mediated responses following chronic beta-adrenoceptor stimulation in the rat heart.

1. Noradrenaline and isoprenaline were infused subcutaneously in rats by use of Alzet osmotic minipumps. The effects of catecholamine infusion on ventricular alpha- and beta-adrenoceptor density and also the responses of isolated cardiac tissues were compared with saline infusion. 2. Noradrenaline (1 mg kg-1) or isoprenaline (40 micrograms kg-1) infused for 3 days resulted in a desensitization of beta-adrenoceptor-mediated responses of isolated left atria and papillary muscles. Concentration-response curves to isoprenaline were shifted to the right in left atria whilst maximum responses were reduced in papillary muscles. Right atrial rate responses were not affected by infusions of catecholamines. 3. Infusions of either noradrenaline or isoprenaline resulted in a supersensitivity of alpha-adrenoceptor-mediated responses in isolated papillary muscles with leftward displacements of concentration-response curves to phenylephrine. 4. The density of both ventricular [3H]-dihydroalprenolol and [3H]-prazosin binding sites was reduced following noradrenaline infusion. Isoprenaline infusion reduced only the density of [3H]-dihydroalprenolol binding sites. 5. Noradrenaline infusion therefore 'down-regulates' both alpha- and beta-adrenoceptors in the rat heart but at the same time ventricular alpha-adrenoceptor-mediated responses are enhanced. Isoprenaline similarly enhances responses to phenylephrine and possible mechanisms for this phenomenon are discussed.

Adrenergic beta-Agonists↗
PubMed1994

The effects of aldose reductase inhibition with ponalrestat on changes in vascular function in streptozotocin diabetic rats.

1. The responses of rat isolated aortae to vasoconstrictor and vasodilator agents have been studied in 14-day streptozotocin-diabetic rats. The effects of treatment with the aldose reductase inhibitor, ponalrestat, on these responses have also been investigated. 2. Maximum contractile responses and aortic sensitivity to phenylephrine were significantly enhanced in 14-day diabetic aortae. 3. In contrast, endothelium-dependent relaxations to carbachol were depressed in diabetic rats, whilst endothelium-independent relaxations to forskolin and sodium nitroprusside were unchanged. 4. Pretreatment with ponalrestat (25 mg kg-1, daily) prevented both the enhanced maximum contractile responses to phenylephrine and the depressed endothelium-dependent relaxations to carbachol in aortae from 14-day diabetic rats. Ponalrestat however, had no effect on the reduced phenylephrine EC50 values observed in tissues from diabetic animals. 5. It is concluded that ponalrestat prevents the depression of endothelium-dependent aortic relaxations induced by diabetes of 14 days duration, suggesting that the polyol pathway is involved in these vascular changes. Ponalrestat does not prevent the increase in aortic sensitivity to alpha 1-adrenoceptor agonists.

Aldehyde Reductase↗
PubMed1995

Alpha 1A-adrenoceptor-mediated contractile responses of the human vas deferens.

1. The predominant alpha 1-adrenoceptor mediating contractions of the human vas deferens has been characterised in vitro by use of subtype selective antagonists. 2. Responses of human epididymal vas deferens were obtained to phenylephrine in the presence of amine uptake inhibitors and propranolol. The effects of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, oxymetazoline, WB4101, prazosin and chloroethylclonidine were examined and also the L-type calcium channel blocker, nifedipine. 3. 5-Methylurapidil, WB4101, oxymetazoline and prazosin acted as competitive antagonists of the responses to phenylephrine, yielding pA2 values of 8.8, 9.2, 7.7 and 8.8 respectively. All four antagonists produced Schild plots with slopes similar to unity and maximum responses to phenylephrine were not altered in the presence of any of the antagonists. 4. Tamsulosin (1 nM) caused rightward shifts of phenylephrine concentration-response curves yielding an apparent pKB value of 10.0. However, maximum responses were also reduced by 51% with this concentration of antagonist. 5. Incubation of tissues with chloroethylclonidine (100 microM for 40 min) failed to alter responses significantly but the presence of nifedipine (1 microM) reduced maximum responses to phenylephrine by 32%. 6. The high affinity of 5-methylurapidil, oxymetazoline and WB4101, together with the failure of chloroethylclonidine to antagonize responses, indicate that the predominant alpha 1-adrenoceptor mediating contraction of the human vas deferens has the characteristics previously described for the pharmacologically-defined alpha 1A-adrenoceptor. The data are also consistent with those described for the cloned alpha 1c-adrenoceptor subtype thereby supporting the hypothesis that the two receptors are identical. The human vas deferens therefore represents a readily accessible preparation for functional studies of the human alpha 1A-adrenoceptor.

Adrenergic alpha-Agonists↗
PubMed1996

The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor.

1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a-adrenoceptor or native alpha 1A-adrenoceptor. Since it has previously been shown that the receptor is not the alpha 1B- or alpha 1D-adrenoceptor, the functional alpha 1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the alpha 1-adrenoceptors currently defined by pharmacological means.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

From the inside out: environmental agency views about communications with the public.

Relatively few studies have examined risk communication with the public from the viewpoint of the staff of institutions attempting such communications. This paper reports results of interviews with managers and staff of the New Jersey Department of Environmental Protection, on their programs' current and ideal communications with the public. Q analysis revealed two orthogonal perspectives on current program communications, the Enthused and the Constrained views. The primary focus of their divergence was on the matter of commitment and support for such communications. The Enthused group felt that they had attitudinal support from program culture and managers; the Constrained group focused on the lack of concrete operational support in terms of time, money, and expertise. These differences between the two groups did not appear to be associated with gender, managerial status, education, communication training, or organizational unit. When ideal program communications were discussed, the focus was on the need for all kinds of commitment and support (i.e., culture, managers, time, money, building expertise through training), as well as on more proactive and responsive communication. Both perspectives agreed that communication with the public is essential to their programs' success, trying new ways to communicate is worthwhile, scientific bases for decisions are not compromised by communication, and communication is not delegated to specialists. While varying ideas were held of the public's capacity and interest in communication, citizens were largely not held responsible for communication problems.

Journal Article↗
PubMed1983

Relationship between human T cell functional heterogeneity and human T cell surface molecules.

Our knowledge of human T cell differentiation and function has expotentially increased during recent years. With this growth in knowledge there has been an increase in our appreciation of the complexity of the T-T interactions which initiate and control immune responses. A great deal remains to be learned concerning the mechanisms of these complex cellular interactions. In particular, it will be important to precisely understand the clear heterogeneity of functions within isolated subsets of OKT4+ and OKT8+ T cells. Perhaps, as importantly, it will be necessary to define more clearly the functions of the T4 and T8 molecules as well as the precise function of the other defined glycoproteins on the T cell surface. The evidence is clearly emerging that many of those molecules are not solely markers of unique functional subsets and are intimately involved in the functions of T cells.

Animals↗
PubMed1985

Histopathologic study of changes occurring in eyes with intraocular lens implantation: autopsy eyes, enucleated eyes and corneal buttons.

The clinicopathologic findings in 17 eyes which were surgically enucleated or removed at autopsy as well as the histopathology of 72 corneal buttons removed from eyes with intraocular lenses are described. In four of five autopsy eyes the intraocular lens was well tolerated; however, in all cases, changes related to the pseudophakos were found. In seven of 12 surgically enucleated eyes, postsurgical bacterial or fungal endophthalmitis had developed. On histopathological examination, one eye revealed clinically unsuspected endophthalmitis phacoanaphylactica after extracapsular cataract extraction and intraocular lens implantation. In two cases, choroidal melanoma became evident after cataract extraction and insertion of a pseudophakos. In both cases preoperative ultrasonography was limited to A-scan axial measurements. The 72 corneal buttons were removed from patients with pseudophakic bullous keratopathy; histologically the most striking findings were guttata-like changes in 50% of the specimens and retrocorneal membranes in 13.9% of the specimens.

Aged↗