Biomedical subjects

J R Docherty

Publications and source records attributed to J R Docherty.

At least 73 records · Page 4Linked to original sources

PubMed1987

Age-related alterations in alpha 1- and beta-adrenoceptors mediated responsiveness of rat aorta.

We have examined the responsiveness of alpha- and beta-adrenoceptors in aortae from 1.5, 3, 6 and 24 month old rats. The isometric contraction to phenylephrine was antagonised competitively by prazosin with a pA2 value of 9.45, suggesting that the receptor is an alpha 1-adrenoceptor. The potency of phenylephrine was significantly reduced in 24 months old as compared with all younger rats combined. The maximum contraction to phenylephrine was unaltered in 24 month old rats. The maximum contraction to potassium chloride was significantly less than that to phenylephrine only in 1.5 months old rats. In tissues contracted by potassium chloride, isoprenaline produced a marked relaxation in 1.5 months old animals, but there was a progressive loss with increasing age of the beta-adrenoceptor-mediated relaxation which was markedly reduced by 6 months and abolished in 24 months old. It is concluded that, in the rat aorta, there is a decrease in alpha 1-adrenoceptor responsiveness in senescence, and a loss of beta-adrenoceptor-mediated responses in maturation.

Aging↗

PubMed1987

Reduction with age in the relaxation to beta-adrenoceptor agonists and other vasodilators in rat aorta.

We have examined the relaxation produced by the beta-adrenoceptor agonists isoprenaline and procaterol, and by sodium nitroprusside, forskolin and isobutylmethylxanthine in KCl (40 mmol/l)-contracted aortae from 6 week, 3 month and 6 month old Sprague-Dawley rats. The maximum relaxation to all agents was greatest in aortae from 6 week old animals. The relaxation to the beta-adrenoceptor agonists was virtually abolished, and the relaxation to the other agents significantly reduced, in aortae from 3 and 6 month old animals. There were no significant differences in the response to any agent between aortae from 3 and 6 month old animals, so that the changes seen occurred in maturation from 6 week to 3 month. The reduced vasodilator response does not occur at the level of the beta-adrenoceptor or adenylate cyclase, since the response to sodium nitroprusside was also affected, but is a general reduction in the ability of the aorta to relax.

Adrenergic beta-Agonists↗

PubMed1987

Difference in the potency of alpha 2-adrenoceptor agonists and antagonists between the pithed rabbit and rat.

The subtypes of alpha-adrenoceptors which mediate pressor responses to sympathomimetic agonists or to nerve stimulation in pithed rabbits have been classified according to the effects of 'selective' antagonists and a comparison has been made, for the alpha 2-subtype, with corresponding responses in the rat. In the rabbit the dose-response curve for phenylephrine was shifted to the right in parallel by prazosin (1 mg kg-1) and was unaffected by rauwolscine (1 mg kg-1). The dose-response curve for noradrenaline was shifted to the right by prazosin (1 mg kg-1) and was shifted to a smaller extent by rauwolscine (1 mg kg-1) or imiloxan (10 mg kg-1). After rauwolscine, prazosin produced a rightward shift larger than when given alone. After prazosin, rauwolscine produced a rightward shift larger than when given alone. The responses to pressor nerve stimulation at low frequencies (less than 1 Hz) could be reduced by prazosin, rauwolscine or imiloxan but those at a higher frequency could be reduced only by prazosin. These results indicate that the responses to noradrenaline or to nerve stimulation are mediated by both alpha 1- and alpha 2-adrenoceptors. Low doses or frequencies have a proportionately greater component which is alpha 2. Responses to noradrenaline after prazosin (1 mg kg-1), were sufficiently sensitive to rauwolscine to be considered as predominantly alpha 2. A comparison was therefore made of such responses in the rat and rabbit. They were produced by a lower dose per unit body weight in the rat whereas this was less marked for the alpha 2-adrenoceptor agonist guanabenz. In the rabbit they were more susceptible to blockade by rauwolscine but were less sensitive to Wy 26703 than in the rat. This demonstrates that the alpha 2-adrenoceptors mediating pressor responses in vivo, like those in other tissues in vitro, are different in rat and rabbit, with regard to antagonists.

Adrenergic alpha-Agonists↗

PubMed1987

Effects of antagonists of 5-hydroxytryptamine on blood pressure in the anesthetised spontaneously hypertensive rat.

In pithed spontaneously hypertensive rats (SHR), the selective 5-HT2-receptor antagonist LY 53857 (1 mg/kg) had no effect on alpha 1- or alpha 2-adrenoceptors, but ketanserin (1 mg/kg) 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) markedly antagonized the pressor response to 5-HT. In anesthetised SHR, both ketanserin and LY 53857 (1 mg/kg) significantly lowered diastolic blood pressure (DBP) alone or subsequent to administration of prazosin (1 mg/kg). In conscious SHR, LY 53857 (1 mg/kg) and ketanserin (0.1 mg/kg) did not significantly affect DBP, but ketanserin (1 mg/kg) significantly lowered DBP. It is concluded that ketanserin lowers DBP in conscious SHR mainly by alpha 1-adrenoceptor blockade, but that in anaesthetised SHR additional actions, possibly 5-HT2 blockade, contribute to the blood pressure lowering effects.

Animals↗

PubMed1986

Alpha-adrenoceptor responsiveness in the aged rat.

The effects of ageing on vascular alpha 1- and alpha 2-adrenoceptors were examined using anaesthetised and pithed young (3-7 months) and old (21-24 months) Sprague-Dawley rats. In pithed animals, the pressor and cardioinhibitory effects of the alpha 2-adrenoceptor agonist xylazine were significantly reduced in old animals (8- and 6-fold shift), but the pressor effects of the alpha 1-adrenoceptor agonist amidephrine were not significantly altered by ageing. In anaesthetised rats, the pressor response to the mixed alpha-adrenoceptor agonist noradrenaline (NA) was not significantly altered, and the pressor potency of the alpha 1-adrenoceptor agonist amidephrine was only slightly reduced (1.7-fold shift) in old animals. In the presence of cocaine (1 mg kg-1) the pressor potency of NA was markedly reduced (13-fold shift) in old animals. In the presence of prazosin (1 mg kg-1) to eliminate alpha 1-adrenoceptor-mediated responses, the pressor potency of NA was markedly reduced in old as animals as compared to young animals (16-fold shift). The neuronal uptake blocker cocaine (1 mg kg-1) significantly potentiated the pressor response to NA only in young. In summary, we have found a reduced alpha 2-adrenoceptor-mediated pressor and cardioinhibitory responsiveness and a reduced neuronal uptake of NA in old animals with little change in alpha 1-adrenoceptor-mediated vascular responsiveness.

Aging↗

PubMed1986

Aging and the cardiovascular system.

What has preceded has been largely a listing of contradictory data: what follows is an attempt to gleam a pattern from all of this. In general, responsiveness is either reduced or unchanged by aging; reduced responsiveness has been demonstrated most frequently for cardiac beta-adrenoreceptors, cardiac muscarinic receptors, vascular beta-adrenoreceptors and vascular alpha 2-adrenoreceptors. A reduced ability of the amine uptake system has been demonstrated in some but not all studies: any reduction in re-uptake would tend to potentiate the effects of NA and counteract the reduced receptor responsiveness (or vice versa). This may explain why the most consistent cardiovascular alteration reported in the elderly is an increased plasma NA. While there are clinical reports that beta-blockers and converting enzyme inhibitors are less effective in elderly hypertensives at lowering blood pressure, this may reflect more the pathological development of hypertension with time rather than a true aging phenomenon. Overall, it appears that resting function of the cardiovascular system is near normal in the aged, but since the mode of control is somewhat altered, in particular with a blunted baroreflex, perturbations in the system produced by drugs may cause a higher incidence of adverse effects.

Aging↗

PubMed1986

Direct cardiac actions of phenylephrine when used in assessment of baroreflex function in the rat.

In pentobarbitone-anaesthetised wistar rats, the baroreflex bradycardia in response to the vasopressor agent phenylephrine was converted to a tachycardia by propranolol. In pithed wistar rats, phenylephrine produced a marked tachycardia which was mediated largely by beta-adrenoreceptors since propranolol markedly antagonised the response. A component of the tachycardia was mediated by alpha 1-adrenoreceptors since the tachycardia to phenylephrine in the presence of propranolol was antagonised by prazosin and mimicked by the alpha 1-adrenoreceptor agonist amidephrine. It is concluded that phenylephrine is not a useful agent for assessment of baroreflex function in the rat due to its marked cardiac stimulant actions.

Animals↗

PubMed1986

Reduced alpha 1-adrenoreceptor mediated responsiveness in vas deferens from spontaneously hypertensive rats.

alpha-adrenoreceptor-mediated responses were investigated in isolated vasa deferentia from spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY) and normotensive rats (NWR). There was no significant difference between NWR, WKY and SHR in the inhibition of the isometric contraction to single pulse field stimulation by the alpha 2-selective agonist xylazine in prostatic portions, nor by xylazine and the alpha 1-selective agonist amidephrine in epididymal portions in the presence of nifedipine to prevent postjunctional actions of alpha 1-selective agonists. There was no significant difference between NWR, WKY and SHR in the potency of amidephrine in causing a postjunctionally mediated potentiation of the isometric contraction to single pulse field stimulation in prostatic portions but the maximum potentiation was significantly reduced in SHR. However contraction by the calcium entry facilitator, Bay K 8644, was not significantly different between NWR, WKY and SHR. The maximum direct contraction to amidephrine, but not to Bay K 8644, was also significantly reduced in SHR. It is concluded that the altered alpha 1-adrenoreceptor-mediated responsiveness in SHR is due not to genetic strain, but is presumably linked to development of hypertension.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1986

An examination of 5-hydroxytryptamine receptors in human saphenous vein.

We have examined the effects of antagonists on the isometric contraction of the human saphenous vein produced by 5-hydroxytryptamine (5-HT). The 5-HT2-antagonist ketanserin (1 microM) had little effect on the lower part of the concentration-response curve to 5-HT, but markedly shifted the upper part of the curve. Yohimbine caused an approximately parallel shift of the concentration-response curve to 5-HT, with a pA2 of 5.48, much lower than its pA2 against noradrenaline in the absence (6.36) or presence (7.06) of cocaine. It is concluded that there are two components to the contractile response to 5-HT in human saphenous vein: at low concentrations 5-HT activates a yohimbine-sensitive receptor, and at higher concentrations 5-HT activates a 5-HT2-receptor.

Adult↗

PubMed1985

An investigation of age-related changes in pre- and postjunctional alpha-adrenoceptors in human saphenous vein.

The responsiveness of prejunctional alpha 2-, postjunctional alpha 1- and postjunctional alpha 2-adrenoceptors was examined in human isolated saphenous veins from male patients in the age range 37-70. There was no age-related alteration in the prejunctional potency of the alpha 2-adrenoceptor agonist xylazine for inhibiting the stimulation-evoked overflow of tritium in tissues preincubated with [3H]noradrenaline. The alpha 2-adrenoceptor antagonist yohimbine (0.01-1 microM) and the alpha 1-adrenoceptor antagonist prazosin (0.1-1 microM) significantly reduced stimulation-evoked contractions in a concentration-dependent manner. There was no significant age-related correlation for the potency of prazosin but there was a significant negative correlation between the potency of yohimbine and age (r = 0.70, n = 11, P less than 0.05), i.e. the potency of yohimbine decreased with increasing age. The decreased postjunctional potency of yohimbine may reflect a loss of alpha 2-adrenoceptors with increasing age.

Adult↗

PubMed1985

Further examination of the inhibitory actions of alpha 1-adrenoceptor agonists in rat vas deferens.

The inhibitory actions of alpha 1-adrenoceptor agonists were examined in the isolated bisected vas deferens of the rat. The calcium entry facilitator Bay K 8644 markedly potentiated the isometric contraction to a single stimulus pulse in epididymal portions of rat vas deferens: subsequent amidephrine produced an inhibition which was antagonised by the alpha 1-adrenoceptor antagonist, prazosin, but not by the alpha 2-adrenoceptor antagonist, yohimbine. The alpha 1-adrenoceptor agonists amidephrine and cirazoline failed to inhibit the transmitter overflow to trains of pulses at a frequency of 2 Hz in epididymal portions, but also failed to abolish the nifedipine-resistant adrenergic contraction to trains of pulses at 2 Hz in epididymal portions. It is concluded that alpha 1-adrenoceptor agonists have inhibitory effects which may be by action at presynaptic alpha 1-adrenoceptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1985

Further examination of the effects of ageing on the adrenoceptor responsiveness of the rat vas deferens.

Age-related changes in presynaptic alpha 2-adrenoceptors were investigated in prostatic and epididymal portions of vasa deferentia from young adult (2-3 months) and old (24-29 months) Sprague-Dawley rats, using the alpha 2-selective agonists xylazine and clonidine. In prostatic portions the inhibitory effects of clonidine against the isometric contractions to single pulse field stimulation were complicated by a postsynaptic action in old animals, but in epididymal portions in the presence of nifedipine both xylazine and clonidine were 3 times less potent in old rats. However, there were no significant differences between young and old in the potency of xylazine at inhibiting the overflow of tritium or the isometric contraction evoked by 5 Hz stimulation for 3 min in tissues pre-incubated with [3H]noradrenaline. It is suggested that there is reduced responsiveness of presynaptic alpha 2-adrenoceptors in the vas deferens of old rats, but that this can only be demonstrated using a sensitive measure of the presynaptic potency of agonists: the isometric contraction to a single stimulus.

Aging↗

PubMed1985

Vascular alpha 2-adrenoceptors can mediate nerve stimulation-evoked contractions.

It is now established that alpha 2-adrenoceptors can be present on vascular smooth muscle as targets for exogenous agonists, but some controversy exists as to whether these vascular alpha 2-receptors may also be the target for neurally released noradrenaline. In human saphenous vein we have found evidence that the alpha 2-antagonist yohimbine in low concentrations (0.01 mumol/l) can significantly inhibit stimulation-evoked contractions, whereas the alpha 1-antagonist prazosin is more than ten times less potent. It is concluded that, at least in some tissues, neuro-effector transmission can be mediated by vascular alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed1985

Ageing and alpha-adrenoceptors.

Ageing changes in alpha-adrenoceptors can be summarized as follows: except in the eye, where there is an apparent increased responsiveness with increasing age in man, peripheral alpha-adrenoceptor responsiveness has generally been found to be either unchanged or reduced with increasing age in animals and man. Even where changes have been found it remains to be clarified whether these changes are selective changes in alpha-receptors or whether they are due to alterations in responsiveness beyond the level of the receptor.

Adrenergic alpha-Agonists↗

PubMed1985

An investigation of alpha-adrenoceptor responsiveness in the vas deferens of spontaneously hypertensive rats.

alpha-Adrenoceptor-mediated responses were investigated in isolated vasa deferentia from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR). There was no significant difference between NWR and SHR in the inhibition of the isometric contraction to single pulse field stimulation by alpha 2-selective agonists in prostatic portions, nor by alpha 2-selective agonists and the alpha 1-selective agonist, amidephrine in epididymal portions in the presence of nifedipine to prevent postjunctional actions of alpha-1-selective agonists. There was no significant difference between NWR and SHR in the potency of amidephrine in causing a postjunctionally mediated potentiation of the isometric contraction to single pulse field stimulation in prostatic portions but the maximum potentiation was significantly reduced in SHR. However, the maximum potentiation of the isometric contraction by the calcium entry facilitator, Bay K 8644, was not significantly different between NWR and SHR. The maximum direct contraction to amidephrine, but not to Bay K 8644, was also significantly reduced in SHR. The irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine was more potent in SHR than NWR in reducing the maximum potentiation by amidephrine of the stimulation-evoked isometric contraction and in reducing the maximum direct contraction to amidephrine. It is concluded that there is a reduced postjunctional alpha 1-mediated responsiveness in the vas deferens of SHR due probably to a reduction in receptor number.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1985

No evidence for differences between pre- and post-junctional alpha 2-adrenoceptors.

We have examined the pre- and post-junctional effects of a series of alpha-adrenoceptor agonists and antagonists at alpha 2-adrenoceptors in the pithed rat preparation and the human isolated saphenous vein. In the pithed rat, there was no difference in relative agonist and antagonist potencies between pre- and post-junctional alpha 2-adrenoceptors but the absolute potencies of antagonists differed: antagonists were more potent prejunctionally. In the human saphenous vein, the alpha 2-adrenoceptor antagonist yohimbine had pre- and post-junctional actions over the same concentration range. We have no evidence to suggest differences between pre- and post-junctional alpha 2-adrenoceptors: differences in absolute antagonist potencies in the pithed rat may be due to non-equilibrium conditions.

Adrenergic alpha-Agonists↗

PubMed1985

Evidence for neuro-effector transmission through postjunctional alpha 2-adrenoceptors in human saphenous vein.

The effects of the alpha 1-adrenoceptor antagonist prazosin and the alpha 2-adrenoceptor antagonist yohimbine were examined against stimulation-evoked contractions in human isolated saphenous veins. The concentration of yohimbine producing 30% inhibition of stimulation-evoked contractions (IC30) was 13.2 nM, whereas the IC30 of prazosin was greater than 250 nM. The inhibition of stimulation-evoked contractions by yohimbine was not prejunctionally mediated since yohimbine (0.01-0.1 microM) significantly potentiated the stimulation-evoked overflow of tritium in tissues pre-incubated with [3H]-noradrenaline. The high potency of yohimbine and the low potency of prazosin indicate that neuro-effector transmission in human saphenous vein is mediated predominantly by postjunctional alpha 2-adrenoceptors.

Adult↗

PubMed1984

An investigation of the actions of the calcium entry facilitator Bay K 8644 on the rat vas deferens.

The pre- and postsynaptic actions of the calcium entry facilitator Bay K 8644 were investigated in the rat isolated vas deferens. Bay K 8644 had no presynaptic effect on adrenergic neurotransmission in the epididymal portion. Bay K 8644 and alpha 1-adrenoceptor agonists potentiated, and the calcium entry blocker nifedipine abolished, the non-adrenergic contraction to a single stimulus in prostatic portions. Bay K 8644 sensitised the prostatic portion to, but did not increase the maximum height of, spontaneous direct contractions produced by alpha-agonists.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗