Presynaptic alpha 2-autoreceptors in mouse atria were characterized in terms of the alpha 2A, alpha 2B, alpha 2C and alpha 2D subtypes. Segments of the atria were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The affinity of up to 16 antagonists for the autoreceptors was assessed as (1) pEC30% values. i.e. concentrations that increased previously autoinhibited release of 3H-noradrenaline (120 pulses, 3 Hz) by 30%, and (2) pKd values against the release-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under conditions of no or little autoinhibition (2 trains of 20 pulses, 50 Hz, train interval 120 s). The pKd values correlated well with the pEC30% values (r = 0.98; P < 0.001; slope of regression line 0.93), indicating that UK 14,304 and released noradrenaline modulated the release of noradrenaline through pharmacologically identical receptors. Comparison with antagonist affinities for (1) prototypic native alpha 2 radioligand binding sites, (2) radioligand binding sites in COS cells transfected with alpha 2 subtype genes, and (3) previously classified presynaptic alpha 2-autoreceptors-all taken from the literature-indicated that the mouse atrial autoreceptors corresponded to the alpha 2D subtype. For example, the pKd values at mouse atrial auto-receptors correlated closely with pKd values at native alpha 2D binding sites in the bovine pineal gland (r = 0.96; P < 0.001); with pKd values at alpha 2D binding sites in COS cells transfected with the rat alpha 2D gene (r = 0.85; P < 0.01); and with pKd values at guinea-pig cerebral and atrial and mouse cerebral alpha 2D-autoreceptors (r = 0.96-0.98; P < 0.001). The antagonist pKd values at mouse atrial autoreceptors correlated less with pKd values at alpha 2A, alpha 2B and alpha 2C sites. It is concluded that the presynaptic alpha 2-autoreceptors in mouse atria are alpha 2D. This identification supports the hypothesis that at least the majority of alpha 2-autoreceptors belong to the alpha 2A/D pair of orthologous alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Electrotonic depolarization of nerve terminals causes a normorphine-resistant release of transmitter.

In the presence of tetrodotoxin (0.5 microM) electrical stimuli of high current strength and long impulse duration evoke the outflow of previously incorporated 3H-noradrenaline from the mouse vas deferens. The mechanism of action is probably an electrotonic depolarization of nerve terminals. The effect of normorphine, calcium and magnesium was compared on transmitter outflow evoked by conducted action potentials and electrotonic depolarization of nerve terminals. It is suggested that in the presence of tetrodotoxin electrical stimulation induces an asynchronous quantal release of transmitter.

Action Potentials↗

PubMedDate not supplied

Conventional radiograms for assessment of salm-calcitonin therapy for bone metastases from breast carcinoma.

The effects of salm-calcitonin on breast cancer osteolytic skeletal metastases have been studied on conventional radiographs. Radiographic criteria for positive response have been defined. It is concluded that radiographs are inadequate for assessing the effects of salm-calcitonin.

Bone Neoplasms↗

PubMedDate not supplied

An examination of pre- and postsynaptic alpha-adrenoceptors in the autoperfused rabbit hindlimb.

Pre- and postsynaptic alpha-adrenoceptors in autoperfused rabbit hindlimbs were examined employing the yohimbine diastereomers rauwolscine and corynanthine, as well as other drugs with varying selectivities for alpha 1-and alpha 2-adrenoceptors. Vasoconstrictor responses were elicited by sympathetic nerve stimulation and by intraarterial injection of agonists. The alpha 2-selective antagonist rauwolscine (10(-7) and 10(-6) M) reduced responses to injected noradrenaline (mixed alpha 1- and alpha 2-agonist) but not to injected phenylephrine (alpha 1-selective agonist); rauwolscine (10(-6) M) actually enhanced nerve-mediated responses. Corynanthine (alpha 1-selective antagonist) was about equipotent against agonist- and nerve-mediated responses. In another series of experiments, rauwolscine (10(-6) M) strongly antagonized the response to xylazine (alpha 2-selective agonist), antagonized the responses to alpha-methylnoradrenaline and noradrenaline (mixed agonists) less strongly, and did not affect the response to phenylephrine, Conversely, prazosin (alpha 1-selective antagonist, 10(-8) M) strongly antagonized phenylephrine, antagonized noradrenaline and alpha-methylnoradrenaline less strongly, and did not antagonize xylazine. Potentiation of neuroeffector responses by rauwolscine demonstrates the operation of an endogenous autoinhibition of noradrenaline release mediated by presynaptic alpha 2-adrenoceptors. However, in comparison with previous in vitro results on rabbit pulmonary artery, the potentiation was small due to the presence of postsynaptic alpha 2-adrenoceptors.

Animals↗

PubMedDate not supplied

Postsynaptic alpha-adrenoceptor subtypes in rabbit blood vessels and rat anococcygeus muscle studied in vitro.

Postsynaptic alpha-adrenoceptor subtypes were investigated in vitro, employing rabbit aorta, pulmonary artery, and portal vein, and rat anococcygeus. Phenylephrine (alpha 1-selective), alpha-methylnoradrenaline (mixed agonist), and xylazine (alpha 2-selective) were used as agonists, and prazosin (alpha 1-selective) and rauwolscine (alpha 2-selective) as antagonists. In all tissues, agonist concentration-response curves were monophasic and their shape was unaltered by either antagonist. In rabbit blood vessels, prazosin was as potent against alpha-methylnoradrenaline as against phenylephrine and was 1,000 times more potent than rauwolscine; xylazine was a partial agonist of low potency. Hence, the postsynaptic receptors of these tissues are alpha 1. In the rat anococcygeus, there was some evidence for an alpha 2-receptor: xylazine was a full and potent agonist, rauwolscine was more potent against xylazine than against alpha-methylnoradrenaline or phenylephrine, and in experiments protecting against irreversible blockade by phenoxybenzamine, xylazine afforded significantly greater protection to alpha-methylnoradrenaline than to phenylephrine. However, prazosin was more potent than rauwolscine against xylazine and was equipotent against all agonists. Hence, although the smooth muscle cells of the rat anococcygeus may contain alpha 2-adrenoceptors, the predominant population is alpha 1.

Animals↗

PubMedDate not supplied

Effects of alpha 1- and alpha 2-adrenoceptor blocking drugs on noradrenaline release rate in anesthetized rabbits.

[3H]noradrenaline was infused intravenously into pentobarbitone-anesthetized rabbits to reach a steady-state plasma (3H]noradrenaline level, from which the noradrenaline plasma clearance was calculated. The plasma level of endogenous noradrenaline was determined simultaneously, and the rate of noradrenaline release was then derived. The effects of a series of selective alpha 1- and alpha 2-adrenoceptor blocking drugs on the noradrenaline release rate and noradrenaline clearance were investigated. Yohimbine (1 mg/kg i.v.), rauwolscine (1 mg/kg i.v.), corynanthine (1 mg/kg i.v.), prazosin (0.3 and 1 mg/kg i.v.), phenoxybenzamine (4 mg/kg i.v.), and sodium nitroprusside (10 micrograms/kg/min i.v.) decreased the plasma noradrenaline clearance. The selective alpha 2-adrenoceptor blocking drugs yohimbine and rauwolscine, as well as phenoxybenzamine, increased the noradrenaline release rate more than equihypotensive doses of the directly acting vasodilators hydralazine and sodium nitroprusside. The selective alpha 1-adrenoceptor blocking drugs prazosin and corynanthine increased the noradrenaline release rate less than equihypotensive doses of the vasodilators. These results suggest that, in vivo, blockade of alpha 2-adrenoceptors results in increased noradrenaline release, probably due to blockade of inhibitory presynaptic alpha 2-adrenoceptors at sympathetic nerve endings. Blockade of alpha 1-adrenoceptors, on the other hand, appears to depress baroreceptor-mediated increases in noradrenaline release in response to a fall in blood pressure.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

Modulation of noradrenaline release in the pithed rabbit: a role for angiotensin II.

This study in the pithed rabbit with electrically stimulated sympathetic outflow (spinal region, T-8; 3 Hz) was conducted to determine the contribution of the renin-angiotensin system to noradrenaline release in vivo. The rate of noradrenaline release (spillover) into the plasma was determined from the endogenous plasma noradrenaline level and the simultaneously determined noradrenaline plasma clearance. In the pithed rabbit, infusion of angiotensin II (0.1 microgram/kg/min i.v.) failed to increase the noradrenaline release rate and only slightly increased blood pressure. On the other hand, the angiotensin-converting enzyme inhibitor captopril (1 mg/kg i.v.) decreased both blood pressure and the noradrenaline release rate. Bilateral nephrectomy was performed to reduce endogenous angiotensin II formation; and in this case, infusion of angiotensin II markedly increased the noradrenaline release rate and blood pressure, whereas captopril had no effect on either parameter. These results suggest that angiotensin II modulates noradrenaline release in vivo through activation of facilitatory prejunctional angiotensin II receptors, and that in the pithed rabbit these receptors are probably maximally activated by endogenously synthesized angiotensin II. The actions of angiotensin II on noradrenaline release open the possibility that increases in blood pressure in the pithed rabbit--by decreasing renin release via intrarenal baroreceptors and hence decreasing angiotensin II formation--may lead to decreased noradrenaline release. This was investigated using phenylephrine (6 micrograms/kg/min i.v.), a selective alpha 1-adrenoceptor agonist, and adrenaline (1 microgram/kg/min i.v.), and alpha 1/alpha 2-agonist. Both drugs increased blood pressure and decreased the noradrenaline release rate. After bilateral nephrectomy, the inhibitory effect of phenylephrine on noradrenaline release was abolished, whereas that of adrenaline was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMedDate not supplied

Dual effect of adrenaline on noradrenaline release in the pithed rabbit.

We examined the effects of adrenaline on the noradrenaline release rate and plasma catecholamine levels in the pithed rabbit with electrically stimulated sympathetic outflow (3 Hz). Adrenaline (0.06 micrograms/kg/min) increased the rate of noradrenaline release into the plasma. This increase was prevented by propranolol (0.2 mg/kg + 0.1 mg/kg/h) and probably involves activation of presynaptic beta-adrenoceptors. A higher dose of adrenaline (1.0 micrograms/kg/min) significantly reduced the noradrenaline release rate. The reduction was "reversed" to a facilitatory effect by phenoxybenzamine (4 mg/kg). Propranolol alone slightly inhibited the noradrenaline release rate. After pretreatment with desipramine (1.0 mg/kg + 0.2 mg/kg/h), the inhibitory effect of propranolol on noradrenaline release was more pronounced and blood pressure was also lowered. However, in rabbits pretreated with captopril (1 mg/kg) in addition to desipramine, the sympathoinhibitory effect of propranolol was not observed. These results suggest that adrenaline can activate either presynaptic beta-adrenoceptors to increase noradrenaline release or, in higher doses, presynaptic alpha-adrenoceptors to inhibit noradrenaline release in vivo. The decrease in the noradrenaline release rate produced by propranolol alone may not be due to blockade of facilitatory presynaptic beta-adrenoceptors, but rather to depression of renin secretion. This would decrease angiotensin II formation and hence decrease the presynaptic release-enhancing effect of angiotensin II.

Angiotensin II↗

PubMedDate not supplied

Bremazocine causes sympatho-inhibition and hypotension in rabbits by activating peripheral kappa-receptors.

We have studied the effects of bremazocine on the peripheral sympathetic nervous system and the arterial blood pressure of pithed rabbits with electrically (2 Hz) stimulated sympathetic outflow, and compared them with the effects of Leu-enkephalin and fentanyl. The 3H-noradrenaline plasma clearance and the plasma concentration of noradrenaline were used to calculate the rate of spillover of endogenous noradrenaline into the plasma; the spillover rate reflects the overall release of noradrenaline from postganglionic sympathetic neurones. Bremazocine (10 and 100 micrograms kg-1, followed by an infusion of 2 and 20 micrograms kg-1 h-1, respectively, i.v.) persistently decreased the noradrenaline spillover rate as well as blood pressure. Both effects were antagonized by naloxone. Leu-enkephalin (70 and 350 micrograms kg-1 min-1 i.v.) caused only transient hypotension. Fentanyl decreased blood pressure only at a very high dose (250 micrograms kg-1, followed by an infusion of 500 micrograms kg-1 h-1 i.v.). The effects of Leu-enkephalin and fentanyl were also antagonized by naloxone. When the blood pressure of pithed rabbits was raised by an intravenous infusion of noradrenaline, rather than by electrical stimulation, bremazocine, Leu-enkephalin, and fentanyl failed to produce hypotension. The results indicate that bremazocine inhibits the release of noradrenaline and, in consequence, lowers arterial pressure by activation of peripheral, probably prejunctional, opioid receptors. The receptors appear to be of the kappa-type.

Analgesics↗