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H Majewski

Publications and source records attributed to H Majewski.

At least 55 records · Page 3Linked to original sources
PubMed1987

Modulation of noradrenaline release in vivo through prejunctional alpha-adrenoceptors.

1. Extensive in vitro studies have suggested that noradrenaline release from sympathetic nerve endings is modulated by alpha 2-adrenoceptors on the terminal varicosities, activation of which by alpha-adrenoceptor agonists or neuronally released noradrenaline leads to inhibition of transmitter release. 2. Studies in intact animals support essentially the physiological operation of this mechanism, whereas human studies have reached mixed conclusions and more information is required.

Animals↗
PubMed1987

Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria.

1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Modulation of neuroeffector transmission.

Local mechanisms that regulate transmitter release at autonomic neuroeffector junctions may be classified into four main types: (a) Automodulation, involving a feedback effect of the transmitter on receptors associated with the prejunctional terminals resulting in a restraint on the facilitation of release that occurs when a train of nerve impulses invades the terminals. Changes in the composition of the transmitter, such as the presence of adrenaline as a cotransmitter together with noradrenaline, can result in increased facilitation of transmission. (b) Transneuronal modulation involving an effect of the transmitter released from terminals of one type on adjacent terminals of another type; thus, noradrenaline release may be inhibited by acetylcholine released from cholinergic nerve terminals adjacent to the noradrenergic terminals. (c) Transjunctional modulation involving a feedback effect on the prejunctional nerve terminals of one or more factors released from effector cells. Such substances include adenyl compounds (adenosine and/or ATP) and metabolites of arachidonic acid. (d) Hormonal modulation involving the action of blood-borne hormones or locally generated hormone-like substances on prejunctional terminals. Some of the substances involved in modulation may act in more than one way; thus, opioids may function as cotransmitters or as hormones, and adenyl compounds may be cotransmitters or be released from effector cells. The effects of exogenous drugs on the substances involved in the modulation of transmission and on the prejunctional receptors for these substances account for many anomalous actions of drugs used or proposed for use in therapeutics.

Acetylcholine↗
PubMed1987

Beta adrenoceptor facilitation of norepinephrine release is not dependent on local angiotensin II formation in the rat isolated kidney.

The aim of the study was to investigate beta adrenoceptor modulation of norepinephrine release from sympathetic nerves in rat isolated kidney. After preincubation with [3H]norepinephrine, the renal nerves were stimulated at 1 Hz. The stimulation induced (S-I) outflow of radioactivity was taken as an index of norepinephrine release. Isoproterenol (0.1 microM) enhanced the S-I outflow of radioactivity. This effect was abolished by the beta-2 adrenoceptor blocking drug ICI 118551 (0.1 microM) but unaltered by the beta-1 adrenoceptor blocking drug atenolol (0.3 microM). In the presence of a high concentration of the angiotensin converting enzyme inhibitor captopril (5 microM), isoproterenol failed to enhance the S-I outflow of radioactivity. However, a lower concentration of captopril (0.1 microM), which totally abolished the facilitatory effect of angiotensin I (0.1 microM) on the S-I outflow of radioactivity, failed to alter the facilitatory effect of isoproterenol. Angiotensin II (0.03 microM) enhanced markedly the S-I outflow of radioactivity and in the presence of the angiotensin II receptor blocking drug saralasin (0.1 microM) this facilitatory effect was reduced markedly. Saralasin did not alter the facilitatory effect of isoproterenol. These results suggest that stimulation of prejunctional beta-2 adrenoceptors on renal sympathetic nerve endings enhances norepinephrine release. This effect is independent of local angiotensin II production and does not involve activation of prejunctional angiotensin II receptors within the rat kidney. However, the inhibitory effect of a high concentration of captopril (5.0 microM) on beta-2 adrenoceptor-mediated facilitation of norepinephrine release remains to be clarified.

Angiotensin II↗
PubMed1986

Adrenaline and stress-induced increases in blood pressure in rats.

Stress was induced by immobilizing the hind limbs of rats for 12 days and housing the rats in individual cages. Control rats were housed in groups without immobilization. Blood pressure and heart rate were measured through an indwelling carotid cannula. After 10 and 12 days of immobilization and isolation, the stressed rats had significantly higher blood pressures (ca. 10 mmHg) and higher cardiac adrenaline levels (ca. 90%). After adrenal medullectomy cardiac adrenaline levels were markedly reduced in both stressed and control rats. Furthermore, the stressing procedure did not cause a rise in blood pressure in adrenal-medullectomized rats. Desipramine HCl (2 mg/kg per day), administered orally to block the neuronal uptake of adrenaline, prevented the elevation in blood pressures and cardiac adrenaline levels. Propranolol HCl (2.8 mg/kg per day), orally, also prevented the rise in blood pressure. The results are consistent with the hypothesis that activation of facilitatory prejunctional beta-adrenoceptors on sympathetic nerves by neuronally-released adrenaline may be responsible for the raised blood pressure.

Adrenal Medulla↗
PubMed1986

Prejunctional beta-adrenoceptors in rabbit pulmonary artery and mouse atria: effect of alpha-adrenoceptor blockade and phosphodiesterase inhibition.

In rabbit isolated pulmonary artery previously incubated with [3H]-noradrenaline, isoprenaline (0.3 microM) had no effect on the stimulation-induced outflow of radioactivity. However, if the phosphodiesterase inhibitor ICI 63,197 (30 microM) or the alpha-adrenoceptor blocker phentolamine (1 microM) was present, then isoprenaline significantly enhanced the stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). ICI 63,197 (30 microM) but not phentolamine significantly enhanced the stimulation-induced outflow of radioactivity. In mouse isolated atria previously incubated with [3H]-noradrenaline and stimulated at a frequency of 10 Hz, isoprenaline had no effect on the stimulation-induced outflow of radioactivity; this is in contrast to its release-enhancing effects at stimulation frequencies of 4 Hz and 2 Hz. The facilitation of stimulation-induced outflow by isoprenaline at 4 Hz was blocked by propranolol (0.08 microM) which, by itself, had no effect on the stimulation-induced outflow. At a stimulation frequency of 2 Hz in mouse atria the facilitatory effect of isoprenaline (0.01 microM) was significantly greater in the presence of ICI 63,197 (30 microM) which, by itself, had no effect on the stimulation-induced outflow. Similarly, the facilitatory effect of isoprenaline was significantly greater in the presence of phentolamine (1 microM) but, in this case, phentolamine significantly enhanced the stimulation-induced outflow. These results suggest that facilitatory prejunctional beta-adrenoceptors are present in both rabbit pulmonary artery and mouse atria. The effects of the phosphodiesterase inhibitor ICI 63,197 suggest that they are linked to adenylate cyclase in both tissues and we propose that the ability of phentolamine to facilitate the release and enhance the effect of isoprenaline may be due to the blockade of alpha-adrenoceptor inhibition of adenylate cyclase. This latter proposition needs further investigation.

Adenylyl Cyclases↗
PubMed1986

Effect of captopril on blood pressure responses to enkephalins in chloralose-anaesthetized rats.

Captopril lowered blood pressure in chloralose-anaesthetized rats and enhanced the depressor responses to metenkephalin and D-Ala-metenkephalinamide to the same extent. Since metenkephalin is a much better substrate than D-Ala-metenkephalinamide for dipeptidylcarboxypeptidase, some mechanism other than inhibition of this enzyme appears to be responsible for the enhancement by captopril of the responses to opioids. When the blood pressure had been lowered by haemorrhage, naloxone was no more effective than saline control in restoring blood pressure. However, when captopril was given after haemorrhage, the blood pressure was further lowered, and then naloxone produced a significant restoration. Hydralazine given after haemorrhage also caused a further lowering of blood pressure, then naloxone produced a lesser restoration of blood pressure than in haemorrhage plus captopril experiments. The results suggest that release of endogenous opioids may contribute to the fall in blood pressure upon bleeding.

Anesthesia↗
PubMed1985

Neuronal and postjunctional components in the blood pressure effects of dopamine and bromocriptine in rabbits.

We have studied the contribution of neuronal and postjunctional dopamine (DA) receptors and of the DA1 and DA2 receptor subtypes to the blood pressure effects of DA and bromocriptine in the rabbit. The norepinephrine release rate, i.e., the rate of entry of endogenous norepinephrine into the plasma, was derived from the plasma level of endogenous norepinephrine and the plasma [3H]norepinephrine clearance. Bromocriptine (40 micrograms kg-1) lowered the norepinephrine release rate and the arterial blood pressure both in anesthetized rabbits and in pithed rabbits with electrically stimulated sympathetic outflow. These effects were antagonized by the selective DA2 antagonist domperidone but not by the selective DA1 antagonist SCH 23390. DA (10-160 micrograms kg-1 min-1) dose-dependently increased the norepinephrine release rate and caused only transient hypotension in anesthetized rabbits. However, after treatment with desipramine, DA did not change the norepinephrine release rate and produced a persistent fall in blood pressure. When DA and domperidone were given simultaneously to desipramine-treated rabbits, the hypotensive effect of DA was unchanged, but now DA increased the norepinephrine release rate. When DA and SCH 23390 were given simultaneously to desipramine-treated rabbits, DA failed to lower blood pressure and decreased the norepinephrine release rate. Propranolol did not change the effects of DA in desipramine-treated rabbits. These results suggest that bromocriptine decreases blood pressure by activating ganglionic and/or prejunctional, inhibitory DA2 receptors in the peripheral sympathetic nervous system. DA also activates these receptors, but in addition releases norepinephrine in the manner of an indirectly acting sympathomimetic amine and activates postjunctional vascular DA1 receptors, and the latter seems to be the main component in DA-induced hypotension.

Anesthesia↗
PubMed1984

Adrenaline mediates a positive feedback loop in noradrenergic transmission: its possible role in development of hypertension.

Adrenaline activates prejunctional beta-adrenoceptors of the beta 2-subtype on sympathetic nerve terminals and enhances noradrenergic transmission. Adrenaline can be incorporated in transmitter stores of noradrenergic nerves and, when released as a cotransmitter, activates the prejunctional beta 2-adrenoceptors, thereby mediating autofacilitation of noradrenergic transmission. Adrenaline released from the adrenal medulla in stress may be incorporated in noradrenergic transmitter stores and reach a sufficient concentration as a cotransmitter to activate the autofacilitatory feedback loop involving prejunctional beta 2-adrenoceptors, resulting in prolongation of the increases in vasomotor tone and cardiac activity that occur acutely: with frequent repetition of stress, there may be progression into a hypertensive state. In accord with this hypothesis, adrenaline administration produces persistent increases in blood pressure in rats, and plasma levels of adrenaline are elevated in a proportion of hypertensive patients; furthermore, repeated stress produces prolonged increases in blood pressure in animals and man.

Animals↗
PubMed1983

Modulation of noradrenaline release in the conscious rabbit through alpha-adrenoceptors.

The effects of selective alpha 1- and alpha 2-adrenoceptor antagonists and agonists on the noradrenaline release rate and plasma catecholamine levels were studied in the conscious rabbit. The selective alpha 2-adrenoceptor blocking drugs yohimbine and rauwolscine (1 mg/kg i.v.) increased the rate of noradrenaline release into the plasma and the plasma noradrenaline and adrenaline levels. This was associated with a rise in blood pressure. The selective alpha 1-blocking drug corynanthine (1 mg/kg i.v.) had no effect. Intravenous infusions of the selective alpha 2-adrenoceptor agonist alpha-methylnoradrenaline (2 micrograms/kg per min) and the alpha 1-agonist phenylephrine (6 micrograms/kg per min) produced equipressor responses. However, only alpha-methylnoradrenaline decreased the noradrenaline release rate and the plasma noradrenaline and adrenaline levels, effects which were blocked by yohimbine. The results are compatible with, but of course do not prove the hypothesis that in the conscious rabbit, noradrenaline release from sympathetic nerves is modulated through presynaptic alpha 2-adrenoceptors. Adrenaline release from the adrenal medulla may also be subject to alpha 2-adrenergic modulation.

Adrenergic alpha-Agonists↗
PubMed1983

Evidence for a physiological role of presynaptic alpha-adrenoceptors: modulation of noradrenaline release in the pithed rabbit.

Rabbits were pithed and the preganglionic nerves at T 8 were stimulated continuously at a frequency of 3 Hz. 3H-noradrenaline was infused to reach a steady-state plasma level, from which the noradrenaline plasma clearance was calculated. The plasma level of endogenous noradrenaline was also determined and the rate of noradrenaline release into the plasma was then derived. The noradrenaline plasma clearance was decreased by guanethidine (7.5 mg/kg), desipramine (1 mg/kg), yohimbine (1 mg/kg) and rauwolscine (1 mg/kg). It was unaffected by corynanthine (1 mg/kg), prazosin (0.1 mg/kg), alpha-methylnoradrenaline (2 micrograms/kg per min) and clonidine (1 micrograms/kg per min). The electrical stimulation resulted in an increase in blood pressure without an increase in heart rate. Both adrenaline and noradrenaline were detected in the plasma. It is likely that the noradrenaline was of neuronal origin as guanethidine decreased its plasma level. The alpha 2-adrenoceptor-selective blocking drugs yohimbine and rauwolscine increased the noradrenaline release rate and only slightly decreased blood pressure. On the other hand, the alpha 1-adrenoceptor-selective blocking drugs corynanthine and prazosin had no effect on the noradrenaline release rate and decreased blood pressure more markedly. The alpha 2-adrenoceptor-selective agonists alpha-methylnoradrenaline and clonidine both decreased the noradrenaline release rate. This effect was blocked by yohimbine, and for the case of clonidine, not blocked by corynanthine. Plasma adrenaline levels were increased by yohimbine and rauwolscine, but not by corynanthine and prazosin. Clonidine reduced the plasma adrenaline level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1983

Modulation of noradrenaline release through activation of presynaptic beta-adrenoreceptors.

On peripheral noradrenergic nerve endings there exist beta-adrenoreceptors activation of which results in an enhanced release of noradrenaline in response to nerve stimulation. These presynapatic beta-adrenoreceptors do not appear to be activated by neuronally-released noradrenaline. However, adrenaline may be a physiological activator during enhanced adrenomedullary secretion. Adrenaline can also be incorporated into the noradrenergic transmitter stores and be released as a co-transmitter. Under these conditions presynaptic beta-adrenoreceptors may be activated by neuronally-released adrenaline, thus forming a 'positive feedback loop'. The release of adrenaline from the adrenal medullae may also be modulated through facilitatory beta-adrenoreceptors, but the release of noradrenaline from noradrenergic nerves in the central nervous system is not. The facilitatory presynaptic beta-adrenoreceptors appear to be in the main of the beta 2-subtype although precise receptor characterization has not been carried out. Increased activation of presynaptic beta-adrenoreceptors by adrenaline may be implicated in the development of essential hypertension. Part of the antihypertensive action of beta-adrenoreceptor blocking drugs may be due to blockade of these facilitatory presynaptic beta-adrenoreceptors.

Adrenal Medulla↗
PubMed1982

Metabolism of endogenous and exogenous noradrenaline in the rabbit perfused heart.

The outflow of noradrenaline, 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxymandelic acid (DOMA) from rabbit perfused hearts was studied by chromatography on alumina followed by high pressure liquid chromatography with electrochemical detection. In the absence of drugs and without nerve stimulation, the outflow of endogenous noradrenaline over a period of 108 min averaged 0.17 pmol X g-1 X min-1 and the outflow of DOPEG 2.1 pmol X g-1 X min-1. The outflow of DOMA was below the detection limit (less than 0.13 pmol X g-1 X min-1). The effect of perfusion with (-)-noradrenaline 0.1, or 10 mumol/l for 18 min was then investigated. As the concentration of nor-adrenaline increased so did the outflow of DOPEG. Moreover, DOMA was found in the venous effluent during and after perfusion with noradrenaline 1 or 10 mumol/l. The increase in the outflow of DOPEG and DOMA was almost abolished when cocaine 10 mumol/l was present during the perfusion with noradrenaline 1 mumol/l. The release of endogenous noradrenaline by sympathetic nerve stimulation or tyramine 10 mumol/l, but not the release evoked by nicotine 30 mumol/l, was accompanied by an increase in the outflow of DOPEG; an outflow of DOMA was not observed. It is concluded that, in the rabbit perfused heart, DOPEG is an important metabolite of endogenous noradrenaline. DOMA is at best a minor product, either when the neurones are at rest or when noradrenaline is released by sympathetic nerve stimulation, nicotine or tyramine. DOMA is formed in detectable amounts when the tissue is exposed to a high concentration of exogenous noradrenaline. Like DOPEG, it is formed intraneuronally. The results confirm and extend those obtained previously on guinea-pig incubated atria. They make it unlikely that, in these tissues at least, DOMA formation is one of the physiological pathways of noradrenaline catabolism.

Animals↗
PubMed1982

The noradrenaline rate in the anaesthetized rabbit: facilitation by adrenaline.

1. 3H-Noradrenaline was infused intravenously into pentobarbitone anaesthetized 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. 2. Pargyline, amezinium, desipramine and guanethidine all reduced the noradrenaline plasma clearance. The noradrenaline release rate was decreased by desipramine, guanethidine and clonidine. 3. Adrenaline (6 nmol/kg i.v. twice) enhanced the noradrenaline release rate by 53%. This effect was apparent after the plasma adrenaline has returned to basal levels. The adrenaline levels in sympathetically innervated tissues were elevated at this time. 4. When the rabbits were pretreated with either propranolol HCl (1 mg/kg i.p.) to block beta-adrenoceptors, or desipramine HCl (1 mg/kg i.v.) to block neuronal uptake, the facilitatory effect of adrenaline was abolished. Noradrenaline (6 nmol/kg i.v. twice) had no effect on the noradrenaline release rate. 5. These findings suggest that if the sympathetic transmitter stores contain sufficient adrenaline neuronally released adrenaline may modulate noradrenaline release in vivo by activating facilitatory presynaptic beta-adrenoceptors.

Anesthesia↗
PubMed1981

An interaction between prejunctional alpha-adrenoceptors and prejunctional beta-adrenoceptors.

The ability os isoprenaline to enhance transmitter release from sympathetic nerves in rat atria incubated with [3H]noradrenaline was assessed under three conditions of prejunctional alpha-adrenoceptor activation: in the presence of phentolamine, in the presence of noradrenaline, and in the absence of either drug. Isoprenaline-induced enhancement of transmitter release was inversely related to the degree of activation of prejunctional alpha-adrenoceptors. Thus there appears to be an interaction between the prejunctional alpha-adrenoceptor inhibitory mechanism and the prejunctional beta-adrenoceptor facilitatory mechanism. In rabbit ear arteries incubated with [3H]noradrenaline, isoprenaline facilitated transmitter release in the presence but not in the absence of phentolamine. Therefore in some tissues it may be necessary to block prejunctional alpha-adrenoceptors before prejunctional beta-adrenoceptors can be demonstrated.

Animals↗