Lisa Hyland

Age-related alterations in α1- and β-adrenoceptors mediated responsiveness of rat aorta

SummaryWe have examined the responsiveness of α- and β-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 α1-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 β-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 α1-adrenoceptor responsiveness in senescence, and a loss of β-adrenoceptor-mediated responses in maturation.

Evidence for neuro-effector transmission through postjunctional α2-adrenoceptors in human saphenous vein

1 The effects of the α‐adrenoceptor antagonist prazosin and the α2‐adrenoceptor antagonist yohimbine were examined against stimulation‐evoked contractions in human isolated saphenous veins. 2 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. 3 The inhibition of stimulation‐evoked contractions by yohimbine was not prejunctionally mediated since yohimbine (0.01–0.1 μm) significantly potentiated the stimulation‐evoked overflow of tritium in tissues pre‐incubated with [3H]‐noradrenaline. 4 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 α2‐adrenoceptors.

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

1 We have examined the effects of antagonists on the isometric contraction of the human saphenous vein produced by 5‐hydroxytryptamine (5‐HT). 2 The 5‐HT2‐antagonist ketanserin (1 μM) had little effect on the lower part of the concentration‐response curve to 5‐HT, but markedly shifted the upper part of the curve. 3 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. 4 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.

α-adrenoceptor responsiveness in the aged rat

Abstract The effects of ageing on vascular α1- and α2-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 α2-adrenoceptor agonist xylazine were significantly reduced in old animals (8- and 6-fold shift), but the pressor effects of the α1-adrenoceptor agonist amidephrine were not significantly altered by ageing. In anaesthetised rats, the pressor potency of the α1-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 α1-adrenoceptor-mediated responses, the pressor potency of NA was markedly reduced in old 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 α2-adrenoceptor-mediated pressor and cardioinhibitory responsiveness and a reduced neuronal uptake of NA in old animals with little change in α1-adrenoceptor-mediated vascular responsiveness.

An investigation of age-related changes in pre- and postjunctional α-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.

No evidence for differences between pre‐ and post‐junctional α2‐adrenoceptors

1 We have examined the pre‐ and post‐junctional effects of a series of α‐adrenoceptor agonists and antagonists at α2‐adrenoceptors in the pithed rat preparation and the human isolated saphenous vein. 2 In the pithed rat, there was no difference in relative agonist and antagonist potencies between pre‐and post‐junctional α2‐adrenoceptors but the absolute potencies of antagonists differed: antagonists were more potent prejunctionally. 3 In the human saphenous vein, the α2‐adrenoceptor antagonist yohimbine had pre‐ and post‐junctional actions over the same concentration range. 4 We have no evidence to suggest differences between pre‐ and post‐junctional α2‐adrenoceptors: differences in absolute antagonist potencies in the pithed rat may be due to non‐equilibrium conditions.

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.

An investigation of the actions of the calcium entry facilitator bay K 864 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.

Further examination of the inhibitory actions of α1-adrenoceptor agonists in rat vas deferens

Abstract The inhibitory actions of α 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 α 1 -adrenoceptor antagonist, prazosin, but not by the α 2 -adrenoceptor antagonist, yohimbine. The α 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 α 1 -adrenoceptor agonists have inhibitory effects which may be by action at presynaptic α 1 -adrenoceptors.