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Biomedical subjects

J R Docherty

Publications and source records attributed to J R Docherty.

At least 55 records · Page 3Linked to original sources
PubMed1990

The effects of ageing on prejunctional 5-hydroxytryptamine receptors in the rat vas deferens.

The prejunctional inhibitory effects of a series of 5-HT1 receptor agonists were examined against the isometric contraction of epididymal portions of rat vas deferens evoked by single stimulus pulses in the presence of nifedipine (10 mumol/l). The 5-HT1A ligand flesinoxan produced inhibition of contractions which was not inhibited by cyanopindolol or yohimbine. However, the prejunctional inhibitory concentration response curve for the 5-HT1 agonist 5-carboxamidotryptamine (5-CT) was biphasic in tissues from 1.5 month old animals but monophasic in tissues from 24 months animals. Cyanopindolol (1 mumol/l) antagonised the inhibitory effects of 5-CT in tissues from 1.5 and 3 month animals but not in tissues from 8 or 24 months animals. Inhibitory actions of 5-CT were not prevented by pretreating animals with pertussis toxin (6 micrograms/kg i.v.), a dose which abolished the negative inotropic response to acetylcholine in rat left atria. It is concluded that the nerve terminals of vas deferens from 1.5 month old animals contain both 5-HT1B and other as yet unclassified 5-HT1 receptors, but that this 5-HT1B-mediated response is lost in maturation and ageing.

Aging↗
PubMed1990

Contractions to 5-hydroxytryptamine in human coronary artery and human saphenous vein.

Isometric contractions were obtained to 5-hydroxytryptamine receptor agonists in human saphenous vein and human coronary artery. Based on the interaction with the 5-HT2 receptor antagonist ketanserin, both 5-HT1 and 5-HT2 receptors are involved in contractions of human saphenous vein, but the predominant subtype involved in contractions of human coronary artery is the 5-HT1 receptor.

Coronary Vessels↗
PubMed1990

Age-related differences in the depressor responses to sodium nitroprusside and nifedipine in anaesthetized rats.

1. The blood pressure lowering actions of sodium nitroprusside (SNP) and nifedipine were compared in 5-month and 22-month pentobarbitone-anaesthetized Sprague-Dawley rats. 2. Five-month-old rats had significantly higher resting diastolic blood pressure (DBP) than 22-month rats and this may explain why SNP (1-30 micrograms kg-1) produced significantly greater falls of DBP in absolute terms in 5-month animals. 3. The depressor responses to nifedipine were similar in young and old rats, despite differences in resting DBP, suggesting that, in comparison to nifedipine, SNP is less effective at lowering DBP in aged rats.

Aging↗
PubMed1990

Functional evidence for heterogeneity of peripheral prejunctional alpha 2-adrenoceptors.

1. We have examined the potencies of a series of alpha 2-adrenoceptor antagonists in functional studies of prejunctional alpha 2-adrenoceptors in rat atrium and vas deferens, and compared potencies with affinities for the alpha 2A-ligand binding site of human platelet and the alpha 2B-site of rat kidney. 2. Antagonist potency in rat atrium was expressed as an EC30 (concentration producing 30% increase in the stimulation-evoked overflow of tritium in tissues pre-incubated with [3H]-noradrenaline). Antagonist potency in rat vas deferens was expressed as a pA2 or KB at antagonizing the inhibition by the alpha 2-adrenoceptor agonist xylazine of the isometric twitch to a single stimulus, or as an EC30. 3. In ligand binding studies, Ki values were obtained for the displacement by alpha-adrenoceptor antagonists of [3H]-yohimbine binding to human platelet or rat kidney membranes. 4. In functional studies, three antagonists (ARC 239, prazosin and chlorpromazine) distinguished between prejunctional alpha 2-adrenoceptors of rat atrium (EC30) and rat vas deferens (pA2) and showed 49, 12 and 7 times higher potency in rat atrium, respectively. ARC 239 was also 17 times more potent in rat atrium than rat vas deferens when EC30 values were compared. 5. The correlation of affinity for the alpha 2A-site of human platelet was better with prejunctional potency in rat vas deferens than rat atrium. 6. The correlation of affinity for the alpha 2B-site of rat kidney was better with prejunctional potency in rat atrium than rat vas deferens. 7. It is concluded that prejunctional alpha 2-adrenoceptors of rat vas deferens and rat atrium differ, and these receptors may resemble the alpha 2A- and alpha 2B-ligand binding sites, respectively.

Adrenergic alpha-Antagonists↗
PubMed1990

No evidence for differences between pre- and postjunctional alpha 2-adrenoceptors in the periphery.

1. We have compared prejunctional alpha 2-adrenoceptors in rat and guinea-pig vas deferens and rat and guinea-pig atria with postjunctional alpha 2-adrenoceptors in human saphenous vein and human platelets employing the antagonists yohimbine and SK&F 104078 and other alpha 2-adrenoceptor antagonists. 2. Yohimbine was approximately 10 times more potent prejunctionally than SK&F 104078 at antagonizing the inhibition by the alpha 2-adrenoceptor agonist xylazine of stimulation-evoked contractions in rat and guinea-pig vas deferens, and at increasing stimulation-evoked release of tritium in rat and guinea-pig atria pre-incubated with [3H]-noradrenaline. 3. Yohimbine was approximately 10 times more potent postjunctionally than SK&F 104078 at antagonizing contractions to noradrenaline in human saphenous vein and at displacing [3H]-yohimbine binding in human platelet membranes. 4. For the antagonists yohimbine, SK&F 104078, prazosin, phentolamine, CH 38083 and urapidil, there was a significant correlation between prejunctional potency in rat vas deferens atrium and postjunctional potency in human platelet, although the correlation was improved by the omission of prazosin. 5. We have no evidence for differences between functional pre- and postjunctional alpha 2-adrenoceptors in the periphery, although these functional receptors may differ from the ligand binding site in the human platelet.

Adrenergic alpha-Antagonists↗
PubMed1990

No effect of pertussis toxin on peripheral prejunctional alpha 2-adrenoceptor-mediated responses and on endothelium-dependent relaxations in the rat.

1. We have investigated the effects of pertussis toxin treatment on a variety of peripheral tissues in the rat. 2. Incubation with pertussis toxin (1 microgram ml-1) in vitro failed to alter the negative inotropic actions of acetylcholine in rat left atria. 3. Pretreatment with pertussis toxin (6 micrograms kg-1, i.v., 3-4 days) abolished the negative inotropic actions of acetylcholine in rat left atria. 4. Pretreatment with pertussis toxin (40 micrograms kg-1, i.v., 3-4 days) failed to alter the prejunctional inhibitory actions of the alpha 2-adrenoceptor agonist xylazine, either in terms of the isometric contraction to a single stimulus in rat vas deferens or in terms of stimulation-evoked overflow of tritium in atria pre-incubated with [3H]-noradrenaline. 5. Pretreatment with pertussis toxin (6 micrograms kg-1, i.v., 3-4 days) failed to affect, and pertussis toxin (40 micrograms kg-1, i.v., 3-4 days) potentiated endothelium-dependent relaxations of rat aorta to histamine and acetylcholine. 6. It seems unlikely that peripheral prejunctional actions of alpha 2-adrenoceptor agonists or endothelium-dependent relaxations of rat aorta involve pertussis toxin-sensitive G proteins.

Acetylcholine↗
PubMed1989

The effects of ageing on neuronal uptake of noradrenaline in the rat.

We have examined the effects of ageing on the physiological function of the neuronal noradrenaline uptake system by comparing responses to cocaine in young adult (5 month) and aged (22 month) male Sprague-Dawley rats. In rat atria pre-incubated with [3H]-noradrenaline, cocaine (3-30 mumol/l) significantly augmented the 2 Hz stimulation-evoked release of noradrenaline in tissues from young but not from old rats. Cocaine (1 mg/kg) produced a greater increase of the pressor response to noradrenaline in young than in old pithed rats. Cocaine significantly increased the tachycardia to noradrenaline only in young pithed rats, but in old pithed rats the duration of the response to noradrenaline was significantly increased. It is concluded that ageing in the rat is associated with a decreased function of the neuronal noradrenaline uptake system, at least in the cardiovascular system.

Aging↗
PubMed1989

Effects of experimental diabetes on the responsiveness of rat aorta.

1. Vascular responsiveness was examined in aortic ring preparations, with or without endothelium, from rats with experimental diabetes induced by streptozotocin and from vehicle-treated (control) rats. 2. There were no significant differences between diabetic tissues and control tissues in the responsiveness to the vasoconstrictors noradrenaline, 5-hydroxytryptamine and KCl, and to the vasodilators sodium nitroprusside, isoprenaline and acetylcholine. 3. When maximum contractions to vasoconstrictors was expressed relative to tissue weight, maximum contractions were significantly greater in diabetic tissues. 4. When expressed in terms of the KCl contraction, there were no significant differences between diabetic and control tissues in the maximum contraction to vasoconstrictors. 5. These results demonstrate that diabetic-induced changes in vascular responsiveness, if any, do not occur at the receptor level.

Animals↗
PubMed1989

Canine pulmonary artery contains a homogeneous population of alpha-1 adrenoceptors.

We have investigated systemically the hypothesis that there exist subtypes of the alpha-1 adrenoceptor in the canine pulmonary artery. The affinity of the alpha-1 adrenoceptor antagonist, prazosin, was assessed by Schild Regression Analysis against the agonists, phenylephrine, norepinephrine and methoxamine, in rings prepared from canine pulmonary artery using the classical technique in which control and treatment concentration-response curves are obtained in every tissue. This technique allows for appropriate corrections to be made in tissue-dependent differences in agonist potency, time-dependent changes in agonist sensitivity and differences in maximum responses that result from nonspecific effects of agonists occurring at higher concentrations, as was found to be the case for methoxamine. Two cumulative concentration-response curves were constructed for each agonist at 2-hr intervals, with the first (control) concentration-response curve being constructed before the addition of prazosin, and the second concentration-response curve obtained 1 hr after exposure to prazosin. Prazosin had similar pA2 values against phenylephrine (9.56), norepinephrine (9.32) and methoxamine (9.35), with slopes of the Schild Regressions not differing significantly from the theoretical value of unity, suggesting that blockade was competitive in all cases. The results provide no evidence for heterogeneity in alpha-1 adrenoceptors in canine pulmonary artery when assessed using the classical method involving two concentration-response curves in a single tissue and allowing for appropriate corrections in tissue-dependent differences and time-dependent changes in agonist response.

Animals↗
PubMed1989

An investigation of the effects of intravenous injection of the 5-hydroxytryptamine 2 receptor antagonists ketanserin and LY 53857 on blood pressure in anesthetized spontaneously hypertensive rats.

The mode of action of i.v. injected ketanserin, LY 53857 and other 5-hydroxytryptamine (5-HT2) receptor antagonists in lowering blood pressure was examined in anesthetized and pithed spontaneously hypertensive rats (SHR). In pithed SHR, LY 53857 (1 mg kg-1) had no effect on alpha-1 or alpha-2 adrenoceptors, but ketanserin (1 mg kg-1) had some potency as an alpha-1 adrenoceptor antagonist, being approximately 100 times less potent than prazosin. Both ketanserin and LY 53857 (0.01 mg kg-1) markedly antagonized the pressor response to 5-HT. In pentobarbitone-anesthetized SHR, ketanserin and LY 53857 (1 mg kg-1) were equieffective at lowering diastolic blood pressure (DBP) subsequent to prazosin (1 mg kg-1), although ketanserin (1 mg kg-1) was more effective at lowering DBP in the absence of prazosin. The blood pressure lowering effects of LY 53857 were unaffected by the peripherally acting 5-HT2 receptor antagonist BW 501C. Neither LY 53857 nor ketanserin lowered DBP in pithed rats. It is concluded that ketanserin in high doses lowers DBP in anesthetized SHR partly by alpha-1 adrenoceptor blockade, but that ketanserin and LY 53857 in high doses have additional blood pressure lowering properties, unrelated to peripheral 5-HT2 receptor blockade.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1988

The effects of ageing on vascular alpha-adrenoceptors in pithed rat and rat aorta.

In the pithed rat preparation in the absence of captopril, the pressor potency of the alpha 2-adrenoceptor agonist xylazine was significantly reduced in 24 month old rats. This difference between young (3-6 month) and old rats in xylazine potency was eliminated by captopril (5 mg kg-1), which caused a greater shift in xylazine potency in young than in old rats. In the rat isolated aorta, the contractile potency both of the alpha 1-adrenoceptor agonist phenylephrine and of 5-hydroxytryptamine were significantly reduced in 24 month old rats. Hence, both in pithed rats and in the rat isolated aorta, the contractile potency of alpha-adrenoceptor agonists is reduced in aged rats, but the altered responsiveness is not at the level of the alpha-adrenoceptor. In the pithed rat, alpha 2-adrenoceptor responsiveness is reduced with ageing probably due to decreased levels of angiotensin II, and in the rat aorta alpha 1-adrenoceptor responsiveness is reduced with ageing, but since responsiveness to 5-HT is also reduced, this may be a post-receptor change in responsiveness.

Adrenergic alpha-Agonists↗
PubMed1988

Investigations of cardiovascular 5-hydroxytryptamine receptor subtypes in the rat.

Peripheral 5-HT receptor-mediated responses were examined in pithed spontaneously hypertensive rats and normotensive wistar rats. Responses examined were: Pressor and depressor responses, tachycardia and inhibition of stimulation-evoked tachycardia. In pithed spontaneously hypertensive rats, 5-HT, but not the 5-HT1-selective agonist 5-carboxamidotryptamine, produced pressor responses, and these were potently antagonised by the 5-HT2-selective antagonists ketanserin and LY 53857. In pithed spontaneously hypertensive rats, the tachycardia to 5-HT was abolished by a combination of the 5-HT2 receptor antagonist LY 53857 and propranolol, suggesting that the tachycardia is mediated by 5-HT2 receptors and by release of noradrenaline. In pithed spontaneously hypertensive rats, 5-carboxamidotryptamine, 5-HT, and to a lesser extent the 5-HT1 receptor agonist RU 24969, but not the 5-HT1A receptor agonist 8-OH-DPAT, produced depressor responses which were antagonised by methysergide and metitepin, but which do not clearly fit with any of the 5-HT1 ligand binding sites. In pithed normotensive wistar rat, 5-carboxamidotryptamine was approximately 100 times more potent than 5-HT and 8-OH-DPAT at inhibiting the cardio-acceleration produced by single pulse electrical stimulation and this inhibition was antagonised by metitepin, so that the response is mediated by 5-HT1 receptors.

Animals↗
PubMed1988

Evidence that SK & F 104078 does not differentiate between pre- and postjunctional alpha 2-adrenoceptors.

We have investigated the proposed postjunctional selectivity of the alpha 2-adrenoceptor antagonist SK & F 104078 employing the pithed rat, rat isolated atrium and human saphenous vein preparations. In the pithed rat, SK & F 104078 (5 mg kg-1) produced a 20-fold shift in the prejunctional ID50 (concentration of agonist producing 50% inhibition of the cardioacceleration to a single stimulus) and a 3-fold shift in the postjunctional ED50 (concentration producing 50% of maximum rise in diastolic blood pressure) of the alpha 2-adrenoceptor agonist xylazine. However, the alpha 2-adrenoceptor antagonist yohimbine also showed apparent selectivity for prejunctional receptors in the pitched rat. In the rat isolated atrium, yohimbine was approximately 10 times more potent than SK & F 104078 at enhancing the stimulation-evoked release of tritium in tissues preincubated with (3H)-noradrenaline. In the human saphenous vein, yohimbine and SK & F 104078 had pA2 values of 7.40 and 6.33, respectively, against contractions to noradrenaline, so that yohimbine was again approximately ten times more potent than SK & F 104078. In conclusion, SK & F 104078 behaved like yohimbine in its relative potencies at pre- and postjunctional alpha 2-adrenoceptors both in vivo and in vitro, so that we fail to find any selectivity of SK & F 104078 for postjunctional alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1988

Pertussis toxin and pre-junctional alpha 2-adrenoreceptors in rat heart and vas deferens.

1. The effects of pretreatment with pertussis toxin (50-200 micrograms kg-1, i.p.) on the pre-junctional inhibitory actions of the alpha 2-adrenoreceptor agonist xylazine were examined by employing the pithed rat and rat isolated vas deferens. 2. In pithed rats, pertussis toxin attenuated the pressor response to xylazine, but did not alter the pre-junctional cardio-inhibitory actions of xylazine. In epididymal portions of rat vas deferens, pretreatment with pertussis toxin did not alter the pre-junctional inhibitory action of xylazine. 3. These data lend no support for the view that alpha 2-adrenoreceptor-mediated prejunctional inhibition involves inhibition of adenylate cyclase through the Ni regulatory protein, at least in the tissues examined.

Adenylate Cyclase Toxin↗
PubMed1988

No evidence for more than one type of alpha 1-adrenoreceptor in rabbit pulmonary artery.

1. The effects of the alpha-adrenoreceptor antagonists, prazosin and yohimbine, have been examined on the isometric contraction of the rabbit pulmonary artery produced by alpha 1-adrenoreceptor agonists. Cocaine, corticosterone and propranolol were present throughout and either a single or two concentration-response curve method was used. 2. Prazosin and yohimbine competitively antagonized the responses to agonists but did not reveal differences between agonists. 3. Using the single concentration-response curve method, prazosin had pA2 values of 9.06 against clonidine and 8.76 against methoxamine. 4. Using the two concentration-response curve method the absolute pA2 values of prazosin (8.65 against phenylephrine, 8.78 against clonidine) and yohimbine (5.73 against phenylephrine, 5.72 against clonidine), as well as the relative potencies of the two antagonists (prazosin approximately 1000 times more potent than yohimbine), suggest that both agonists act on alpha 1-adrenoreceptors. 5. There is no evidence from this study to support the suggestion that the rabbit pulmonary artery contains two subtypes of alpha 1-adrenoreceptor.

Adrenergic alpha-Antagonists↗
PubMed1988

Adrenoceptor status and cardiovascular function in ageing.

Adrenoceptor function is an important determinant of the physiological control of the circulation and of the response to drugs acting via the sympathetic nervous system and on the vasculature. There is little consistent evidence for an age-dependent change in alpha-adrenoceptor function though the response to various vasoconstrictor agents including alpha 1 agonists has been shown to change with ageing. These changes seem to reflect structural or functional factors and are not specific for receptor types. In the case of beta-adrenoceptor mediated responses there is evidence for both a decrease in response as well as age-related changes in the functioning of various components of the beta-adrenoceptor system, including receptor affinity, which is decreased. It may well be that decreased beta-adrenoceptor function with ageing contributes to altered cardiovascular control and to decreased efficacy of beta-adrenoceptor blocking drugs in elderly hypertensives.

Age Factors↗