A hypothesis to explain the presynaptic effects of adrenoceptor antagonists

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1The effects of clonidine, a presumed selective presynaptic x2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. 2 Split left atrial preparations were stimulated transmurally at 2Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. 3 Clonidine inhibited efflux at 3 x 10-8M to 3 x 10 7M by about 30%. Yohimbine, at a concentration (10-6M) which caused a 3 fold increase in the release of 3H-transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. 4 At 10-6M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10-'M), inhibited efflux by over 50%.5 The inhibitory effect of noradrenaline (10-6M) on 3H-transmitter efflux was antagonized by clonidine at 10-6M but not at 10-8M, although neither concentration of clonidine alone inhibited transmitter efflux. 6 The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic M2-adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.

Section: Yohimbine and Clonidinesupporting

confidence: 86%

Clonidine and presynaptic adrenoceptor theory

Kalsner

1985

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“…In addition, however, it has been reported by Lambert, et al (1978) that Yoh antagonizes the contractile action of 5-hydroxytryptamine (5-HT) in the rat fundal strip. Nevertheless, since to our knowledge contraction of uterine muscle by endogenously released 5-HT has not yet been demonstrated, in the present experiments the elevation of uterine activity observed in rats pretreated with Prop and Yoh, may be best explained by the excitatory effect of the endogenously released NA upon a,postjunctional receptors (Kalsner & Quillan, 1984;Langer et al, 1977;1985). This assumption is strengthened by our observation of further augmentation of amplitude of uterine contraction, subsequent to a single PE injection.…”

Section: Discussionsupporting

confidence: 66%

Involvement of α‐adrenoceptors in myometrial responses in the pro‐oestral rat

Acritopoulou-Fourcroy

Marcais-Collado

1988

Myometrial responses to different agents acting on adrenoceptors were examined in vivo in the pro‐oestrous rat. Changes in spontaneous uterine mechanical activity were recorded isometrically and evaluated in terms of amplitude and duration of uterine contractions. Phenylephrine (10 μg kg−1) markedly increased the amplitude and duration of contractions and 40 μg kg−1 gave rise to tetanic contractions. Administration of either nicergoline (400 μg kg−1) or phentolamine (1000 μg kg−1) to phenylephrine‐primed rat uterus reduced the strength of contractions and phentolamine abolished the phenylephrine‐induced uterine contracture. Following blockade of α2‐adrenoceptors by yohimbine (1000 μg kg−1) and β‐adrenoceptors by propranolol (2400 μg kg−1), a single injection of phenylephrine (100 μg kg−1) increased the amplitude of uterine contractions by 30%. Noradrenaline reduced the amplitude of contractions and caused elevation of the baseline level. The response of myometrium to the combination of both propranolol and noradrenaline was the establishment of uterine contracture with subsequent increase of the duration of contractions. These results clearly demonstrate the involvement of α‐adrenoceptors in the myometrial activity of the rat in vivo during pro‐oestrus.

“…had less marked effect on arterial pressure , and unpublished observations). Previously a-adrenoceptor blockade had been observed to increase the rate of sympathetic neurosecretion in mammals (Kalsner & Quillan, 1984;Kirpekar, 1984). Also the sympathomimetic actions of an a-adrenoceptor antagonist, phenoxybenzamine, was shown to increase the rate and force ofcontractions in rat isolated hearts (Chang, 1968).…”

Section: Discussionmentioning

confidence: 99%

“…Conjugates formed with sulphate or glucuronide comprise major fractions of the endogenous catecholamine levels in mammals and birds (Unger et al, 1980;Wang et al, 1983;Davidson et al, 1984;Wilson, 1984). Although controversy attends the control of free catecholamine secretion by a-adrenoceptor mechanisms (Kalsner & Quillan, 1984;Kirpekar, 1984), a-adrenoceptor influences on conjugated catecholamines are unknown. The present experiments extended the study of circulating sulphoconjugated and glucuronoconjugated catecholamines to an amphibian species, observed the effect of the a-adrenoceptor antagonist prazosin on conjugated catecholamines in the circulation, then distinguished the regulation of free catecholamines from that of conjugates.…”

Section: Introductionmentioning

confidence: 99%

Conjugated catecholamines and pressor responses to angiotensin, luteinizing hormone‐releasing hormone and prazosin in conscious toads

Wilson

1985

1 Synthetic angiotensin II (Ang II), mammalian luteinizing hormone-releasing hormone (LHRH) and salmon LHRH (sLHRH) were injected intravenously into conscious, adult toads (Bufo marinus) to elucidate the cardiovascular actions of the hormones. The maximal increases in pulse pressure elicited by the three peptides did not differ from each other but only Ang II increased cardiac frequency. The maximal increases in mean arterial blood pressure (MAP) caused by LHRH and sLHRH were identical, while Ang II caused a 100% greater maximal effect. The median effective doses (ED50) for both Ang II and LHRH were approximately 0.1 nmol kg-' whereas the potency of sLHRH was 10 fold less. Pressor responses to LHRH and sLHRH were blocked completely by (D-pGlu', DPhe2, D-Trp3 6)-LHRH but this antagonist did not inhibit Ang II. 2 Significant proportions of circulating, endogenous dopamine, noradrenaline (NA) and adrenaline (Ad) were found to be sulphoconjugated. Arterial plasma concentration of free NA increased simultaneously with the rise in blood pressure following Ang II injection. The magnitude of the free NA response increased with increasing Ang II dose but even a high dose failed to augment the plasma level of conjugated NA. Ang II did not alter concentrations of free or conjugated dopamine and Ad. 3 Intraarterial injection of an a-adrenoceptor antagonist, prazosin, caused sustained elevation of arterial pressure and free Ad. Subsequently Ang II lowered plasma Ad concentration. Prazosin inhibited the NA response to Ang II yet the pressor effects ofthe x-adrenoceptor antagonist and Ang II were additive. Administration of a P-adrenoceptor antagonist, propranolol, largely reversed the cardiovascular sequelae of x-adrenoceptor blockade. 4 It is concluded, firstly, that the cardiovascular actions of Ang II and LHRH are mediated through different receptors. Secondly, although it had been shown that a-and P-adrenoceptor mechanisms mediate the pressor effect of LHRH, the present experiments showed that mobilization of catecholamines cannot account for the pressor response to Ang II. Thirdly, both free and conjugated catecholamines circulate in toads; however the extent of conjugation can be dissociated from the changes in free NA and Ad induced by Ang II and prazosin.