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Biomedical subjects

O A Nedergaard

Publications and source records attributed to O A Nedergaard.

At least 37 records · Page 2Linked to original sources
PubMed1989

Inhibition of 3H-noradrenaline accumulation by dopexamine hydrochloride in the isolated aorta of the rabbit.

The aim of the present work was to study the ability of dopexamine hydrochloride to interfere with the neuronal and extraneuronal uptake mechanisms by investigating the effect of dopexamine hydrochloride on 3H-noradrenaline accumulation by rabbit isolated aorta. Dopexamine hydrochloride (3 x 10(-9) - 10(-5) mol/l) reduced the accumulation of tritium by aorta incubated with 3H-noradrenaline (10(-8) mol/l). The effect of dopexamine was compared to cocaine, dopamine, dobutamine, ADTN [(+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene], ouabain and isoprenaline. Dopexamine hydrochloride (3 x 10(-9)-10(-7) mol/l) caused the same degree of inhibition irrespective of whether corticosterone (4 x 10(-5) mol/l) was present or not. The order of inhibitory potency was: desipramine greater than dopexamine hydrochloride greater than dopamine greater than ADTN greater than or equal to cocaine greater than dobutamine greater than ouabain greater than isoprenaline. In the presence of desipramine (10(-6) mol/l), corticosterone (10(-6)-10(-4) mol/l), but not dopexamine hydrochloride (10(-6) - 10(-4) mol/l), reduced the 3H-accumulation. It is concluded that dopexamine hydrochloride is a potent inhibitor of uptake-1 in rabbit isolated aorta. Dopexamine hydrochloride has no affinity for the uptake-2 mechanism in this tissue.

Adrenergic Agonists↗
PubMed1989

Presynaptic action of adrenaline on adrenoceptors modulating stimulation-evoked 3H-noradrenaline release from rabbit isolated aorta.

The purpose of this investigation was to study the effect of adrenaline on presynaptic adrenoceptors by recording the release of 3H-noradrenaline evoked by electrical-field stimulation. Adrenaline (10(-10)-3 x 10(-9) mol/l) had no effect on the 3H-overflow evoked by stimulation of aorta preloaded with 3H-noradrenaline. At 10(-8) and 3 x 10(-8) mol/l, the 3H-overflow was decreased by up to 47%. The maximum decrease was more marked in the presence of either cocaine (3 x 10(-5) mol/l) plus corticosterone (4 x 10(-5) mol/l), cocaine (3.3 x 10(-6) mol/l) plus normetanephrine (4 x 10(-5) mol/l), or desipramine (10(-6) mol/l) plus normetanephrine (10(-5) mol/l). The relationship between adrenaline-induced decrease and stimulation-frequency was dependent on the experimental design: either the decrease was the same at all frequencies (1-16 Hz) or it was more marked, the lower the frequency (1 greater than 3 greater than 8 Hz). Phentolamine and rauwolscine (both 10(-6) mol/l) antagonized the inhibitory effect of adrenaline (10(-8)-10(-6) mol/l). Phenoxybenzamine (10(-6) mol/l), prevented the inhibitory effect. No enhancing effect of adrenaline (10(-9)-10(-6) mol/l) was observed in the presence of these three alpha-adrenoceptor antagonists. Our results suggest that adrenaline activates inhibitory alpha 2-adrenoceptors, but not facilitatory beta-adrenoceptors on postganglionic sympathetic nerve terminals in rabbit aorta.

Adrenergic alpha-Antagonists↗
PubMed1989

Adrenaline released as a cotransmitter does not enhance stimulation-evoked 3H-noradrenaline release from rabbit isolated aorta.

1. The aim of the present investigation was to examine if adrenaline released as a cotransmitter by field stimulation of sympathetic neurons in rabbit isolated aorta facilitates noradrenaline release by activation of presynaptic beta-adrenoreceptors. 2. Rabbit aortic rings were preincubated with adrenaline (10(-8)-3 x 10(-6) M) or noradrenaline (10(-8)-3 x 10(-6) M) prior to incubation with 3H-noradrenaline (3H-NA; 10(-7) M). Subsequently, the tissues were subjected to repeated electrical-field stimulation. 3. Preincubation of aorta with either adrenaline or noradrenaline did not change the time course of repeated stimulation-evoked 3H-overflow from tissues preloaded with 3H-NA. 4. Propranolol (10(-8)-10(-6) M) did not alter the stimulation-evoked 3H-overflow. 5. Rauwolscine (10(-7)-10(-5) M) enhanced markedly the 3H-overflow evoked by stimulation. In the presence of rauwolscine, propranolol (10(-8)-10(-6) M) and metoprolol (10(-8)-10(-6) M) did not change the 3H-overflow. 6. In experiments using rings of aorta exposed to adrenaline (10(-8) M) for 30 min in the absence of cocaine, stimulation-evoked 3H-overflow was not affected after withdrawal of adrenaline. This was also the case in the presence of propranolol (10(-6) M). 7. We conclude that adrenaline released as a cotransmitter from sympathetic nerve terminals in rabbit aorta does not facilitate noradrenaline release.

Animals↗
PubMed1989

Effect of pinacidil on sympathetic neuroeffector transmission in rabbit blood vessels.

The effects of pinacidil on vascular sympathetic neuroeffector transmission were studied. Pinacidil (3 x 10(-7)-3 x 10(-4) M) inhibited the contractions of rabbit isolated pulmonary artery evoked by nerve stimulation. This was the case both in the absence and presence of cocaine plus corticosterone. The inhibition reached a steady state and was reversible. Pinacidil (10(-5) -3 x 10(-4) M), in the absence or presence of cocaine plus corticosterone, markedly enhanced the 3H-overflow evoked by electrical-field stimulation of the artery preloaded with 3H-noradrenaline (3H-NA). The enhancement was dependent on frequency (1-30 Hz) in a complex manner. Phentolamine (3 x 10(-6) M), but not rauwolscine (10(-6) M) prevented the enhancement. Pinacidil (10(-4) M) did not antagonize the alpha-methylnoradrenaline-induced inhibition of 3H-overflow evoked by stimulation. Pinacidil (10(-5)-3 x 10(-5) M) in a non-competitive manner antagonized the contractions of isolated aorta elicited by noradrenaline (3 x 10(-9)-3 x 10(-5) M), phenylephrine (2 x 10(-8)-3 x 10(-4) M), adrenaline (10(-9)-3 x 10(-5) M), histamine (10(-6) 6 x 10(-4) M), serotonin (10(-8)-10(-4)M), and potassium (10(-3) M). Pinacidil (10(-6)-3 x 10(-4) M) and methacholine (3 x 10(-8)-10(-6) M) relaxed aorta preconstricted with noradrenaline (10(-7) M). The relaxation caused by pinacidil was not dependent on the presence of endothelial cells, while that seen with methacholine was.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of chlorpromazine on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta.

1. The effects of chlorpromazine on sympathetic neuroeffector transmission have been studied in the rabbit isolated pulmonary artery and aorta. 2. Chlorpromazine (10(-8)-10(-5) M), prazosin (10(-9)-10(-7) M) and phentolamine (3 x 10(-8)-3 x 10(-5) M) decreased the contractions of pulmonary artery evoked by electrical field stimulation (150 pulses; 3 Hz). The rank order of inhibitory potency (ID50) was prazosin greater than chlorpromazine greater than phentolamine. 3. Rauwolscine (3 x 10(-9) M-4 x 10(-6) M) enhanced the neurogenic response by up to 201%. However, higher concentrations (6 x 10(-6)-3 x 10(-5) M) reduced the contractions evoked by transmural stimulation. 4. The inhibitory effect of prazosin (10(-6) M) was reversible, while that of chlorpromazine (10(-8) M) was not. 5. Chlorpromazine (10(-8)-10(-4) M), desmethylimipramine (3 x 10(-9)-10(-5) M), cocaine (10(-7)-3 x 10(-4) M) and phentolamine (10(-5)-3 x 10(-4) M) reduced the accumulation of [3H]-noradrenaline ([3H]-NA, 10(-8) M) by aorta. The rank order of inhibitory potency (ID50) was: desmethylimipramine greater than chlorpromazine greater than cocaine greater than phentolamine. Prazosin (10(-7)-10(-5) M) and rauwolscine (10(-8)-10(-4) M) did not reduce [3H]-NA accumulation. 6. Chlorpromazine (10(-8)-10(-6) M) and prazosin (3 x 10(-9)-10(-7) M) antagonized the contractions of aorta evoked by exogenous noradrenaline (10(-9)-3 x 10(-4) M) and phenylephrine (10(-9)-3 x 10(-3) M). The pA2 values for chlorpromazine on the alpha 1-adrenoceptors were 8.24 (noradrenaline) and 8.27 (phenylephrine). The corresponding values for prazosin were 8.64 and 8.57, respectively. 7. It is concluded that chlorpromazine and prazosin are potent inhibitors of postsynaptic alpha 1-adrenoceptors. Chlorpromazine and phentolamine, unlike prazosin and rauwolscine, are also inhibitors of Uptake.

Adrenergic alpha-Antagonists↗
PubMed1988

Frequency-dependence of 3H-noradrenaline release from rabbit pulmonary artery: effect of alpha-adrenoceptor antagonists and inhibitors of transmitter inactivation.

The aim of this study was to examine the modulating role of presynaptic alpha 2-adrenoceptors on transmitter release from vascular sympathetic neurones. This was done by examining the influence of removal of inactivation pathways on the effect of alpha-adrenoceptor antagonists on the release of transmitter from noradrenergic neurones. The rabbit main pulmonary artery preloaded with 3H-noradrenaline (3H-NA) was used. The artery was stimulated with 300 pulses at various frequencies (1, 3, 10 and 30 Hz). Pargyline (3 x 10(-4) M) increased the stimulation-evoked 3H-overflow at 1 and 3 Hz and decreased it at 30 Hz. U-0521 (3',4'-dihydroxy-2-methylpropiophenone; 3 x 10(-6) M) enhanced the overflow at 1 Hz and had no effect at 3-30 Hz. Corticosterone (4 x 10(-5) M) did not alter the stimulation-evoked 3H-overflow at 1-30 Hz. Cocaine (3 x 10(-6) M) enhanced the 3H-overflow slightly at 1-30 Hz. At 3 x 10(-5) M, cocaine enhanced 3H-overflow at 1 Hz and reduced it at 30 Hz. Neither corticosterone (4 x 10(-5) M) nor propranolol (10(-7) M) modified this effect of cocaine. Propranolol (10(-7) M) alone decreased the 3H-overflow at 30 Hz and had no effect at 1-10 Hz. Phenoxybenzamine (10(-6) M) and chlorpromazine (3 x 10(-6) M) potentiated the stimulation-evoked 3H-overflow at 1-30 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1987

Effect of isoprenaline on noradrenaline release from sympathetic neurones in rabbit isolated pulmonary artery.

The aim of the present work was to demonstrate the presence of presynaptic beta-adrenoceptors in the rabbit isolated pulmonary artery by investigating the effect of isoprenaline on 3H-noradrenaline (3H-NA) release evoked by electrical field stimulation. (-)-Isoprenaline (10(-7)-10(-6) mol/l) had no effect on the 3H-overflow evoked by stimulation (3 Hz) of the pulmonary artery preloaded with 3H-NA. At 10(-5) mol/l, (-)-isoprenaline reduced the 3H-overflow by maximally 39%. (-)-Isoprenaline (10(-5) mol/l) caused an inhibition that remained almost constant with time. The same results were obtained with (-)-isoprenaline (10(-7)-3 X 10(-5) mol/l) in the presence of cocaine (3 X 10(-5) mol/l), corticosterone (4 X 10(-5) mol/l), and the catechol-O-methyltransferase inhibitor U-0521 (3',4'-dihydroxy-2-methylpropiophenone) (10(-4) mol/l). In the presence of cocaine plus corticosterone, (-)-isoprenaline (3 X 10(-10)-10(-7) mol/l) had no effect on the 3H-overflow evoked by stimulation at 1 Hz. At 10(-6) mol/l, (-)-isoprenaline slightly reduced the 3H-overflow. At 10 Hz, (-)-isoprenaline (10(-6)-3 X 10(-5) mol/l) decreased the 3H-overflow and had no effect at 10(-7) mol/l. In the presence of either rauwolscine (10(-6) mol/l), phentolamine (10(-6) mol/l) or the phosphodiesterase inhibitor ICI 63,197 (3 X 10(-5) mol/l), (-)-isoprenaline (10(-7)-10(-6) mol/l) did not enhance the stimulation-evoked 3H-overflow. (+/-)-Propranolol (10(-7)-10(-5) mol/l) did not alter the stimulation-evoked 3H-overflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of chlorpromazine on the metabolism of 3H-noradrenaline released from rabbit aorta.

The effect of chlorpromazine on the metabolism of 3H-noradrenaline (3H-NA) released spontaneously or by electrical-field stimulation was studied on the rabbit isolated aorta preloaded with 3H-NA. Chlorpromazine (10(-6) M) neither altered the spontaneous outflow of total tritium nor had any major effect on the distribution of the 3H-outflow on 3H-NA and its 3H-metabolites. Chlorpromazine (10(-6) M) altered the distribution in stimulation-evoked 3H-overflow. Thus, 3H-NA and 3H-NMN were increased, 3H-DOPEG was markedly decreased and 3H-DOMA and 3H-OMDA were unchanged. It is concluded that chlorpromazine is an inhibitor of uptake-1.

Animals↗
PubMed1986

3H-adrenaline release from rabbit isolated aorta by electrical-field stimulation.

The aim of the present work was to study the release of 3H-adrenaline (3H-A) from rabbit isolated aorta. This release was compared with that of 3H-noradrenaline (3H-NA). The stimulation-evoked 3H-overflow from aorta preloaded with 3H-A decreased with repeated stimulation (S1-S3). In contrast, prestimulation enhanced subsequent stimulation-evoked 3H-overflows. For both 3H-amines, the 3H-overflow increased concomitantly to the same degree with the number of pulses (30-1000) at 3 Hz. The time course of 3H-overflows with either 3H-A or 3H-NA was compared. In the case of 3H-A, the 3H-overflow increased with time, while for 3H-NA the 3H-overflow remained unchanged both at 3 and 10 Hz. The stimulation-evoked 3H-overflow from rings preloaded with either 3H-amine was the same at frequencies from 1 to 10 Hz, whereas at 30 Hz the 3H-overflow derived from 3H-A was higher than that using 3H-NA. An analysis of the quantitative aspects of individual stimulation-evoked 3H-overflows showed that the fractional profile did not differ using either amine. In both cases, at least 96% of the 3H-overflow evoked by stimulation at 3 or 10 Hz was contained in the initial four 2-min. fractions. The ratio between stimulation-evoked 3H-overflow and spontaneous 3H-outflow was the same for both amines at 3 Hz, while the ratio was higher for 3H-NA at 10 Hz. Rauwolscine (10(-6) M) enhanced the 3H-overflow 6-fold, while (-)-propranolol (10(-7) M) had no effect at 3 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Dual inhibitory action of ATP on adrenergic neuroeffector transmission in rabbit pulmonary artery.

The aim of this study was to determine whether the inhibitory action of ATP on sympathetic neuroeffector transmission in the isolated pulmonary artery is due to ATP itself or one of its dephosphorylated breakdown products, ADP, AMP or adenosine. Furthermore, the mechanism of the inhibitory action was investigated. ATP (10(-6)-3 X 10(-4) M), the degradation-resistant ATP-analogue, beta, gamma-methylene-5'-triphosphate (10(-5)-3 X 10(-4) M), ADP (10(-6)-3 X 10(-4) M), AMP (10(-5)-3 X 10(-4) M), adenosine (10(-5)-3 X 10(-4) M) and 2-chloroadenosine (10(-7)-3 X 10(-4) M) reduced the contractions evoked by field-stimulation. This was also the case for prostaglandin E2 (3 X 10(-9)-3 X 10(-7) M), while prostaglandin F2 alpha (1.4 X 10(-8) M) slightly augmented the neurogenic response. The time course of the inhibitory effect of purinergic compounds on the stimulation evoked contractions was studied. In the case of ATP and ADP the inhibition was biphasic: an initial marked block (1 min. after drug addition) which in the continued presence of either compound recovered partially 10 min. later and then remained almost constant for another 90 min. The other purinergic agents caused a monophasic reduction. In the presence of indomethacin (5 X 10(-5) M), ATP and ADP also reduced the neurogenic contractions in a monophasic manner. Indomethacin did not alter the beta, gamma-methylene-5'-triphosphate-induced inhibition. Dilazep (3 X 10(-6) M) plus deoxycoformycin (3.6 X 10(-6) M), augmented the inhibitory effect of ATP. In contrast, theophylline (5 X 10(-5) M) did not alter the effect of ATP. The inhibitory effect of ATP (10(-4) M) on stimulation-evoked contractions was inversely proportional to the extracellular Ca2+ concentration (0.3-5.2 mM) and to frequency of stimulation (3-15 Hz). These results suggest that ATP initially causes a presynaptic inhibition of noradrenaline release evoked by field-stimulation. This phase I block is probably mainly due to an ADP-mediated short-lasting release of prostaglandins of the E type. The continuous inhibition (phase II) is probably due to ATP and its metabolites, possibly mainly adenosine. The phase II inhibition may possibly involve a decreased entry of Ca2+ into adrenergic nerve terminals during depolarization.

Adenosine↗
PubMed1985

Accumulation of 3H-adrenaline by rabbit aorta.

The accumulation of (-)-3H-adrenaline (3H-A) by rabbit isolated aorta was studied. In all experiments, monoamine oxidase and catechol-O-methyltransferase were inhibited by treatment with pargyline and 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), respectively. The relationship between the accumulation of 3H derived from 3H-A (10(-8) M) and the duration of incubation (0-3 h) was linear. The 3H-accumulation after 3 h incubation was 22.5 ml X g-1. In reserpine-treated tissue, the 3H-accumulation levelled off after 30 min and was 8.5 ml X g-1 after 3 h. The concentration of 3H-A or (-)-3H-noradrenaline (3H-NA) and the 3H-accumulation (ml X g-1) were inversely related. At 10(-8) M, the 1-hour accumulation of 3H derived from 3H-A and 3H-NA was 7.8 and 15.2 ml X g-1, respectively. With increasing concentrations (3 X 10(-8)-10(-4) M), the accumulation values approached each other. At 10(-4) M, the accumulation was 2.3 and 2.8 ml X g-1 for 3H-A and 3H-NA, respectively. The accumulation of 3H derived from 3H-A (10(-8)-10(-4) M) by reserpine-treated tissue also showed an inverse relationship with concentration: 5.4 ml X g-1 (10(-8) M) and 2.6 ml X g-1 (10(-4) M). The accumulation of 3H derived from 3H-A (10(-8) M; 1 h) was dependent on the bath temperature (1-37 degrees C). The accumulation increased continuously from 1.1 ml X g-1 (1 degree C) to 11.1 ml X g-1 (37 degrees C). Storage of tissue (0-5 days in salt solution without equilibration with 95% O2/5% CO2; 4 degrees C) did not affect the accumulation of 3H derived from 3H-A (10(-8) M; 1 h). Thereafter (7-14 days), the accumulation decreased. The inhibitory potency (IC50;-log M) of desimipramine, cocaine, (-)-propranolol, (-)-isoprenaline, and (+/-)-normetanephrine on accumulation of 3H derived from 3H-A (10(-8) M; 1 h) was found to be 8.26; 6.50; 5.48, 4.88, and 4.02, respectively. The maximal degree of inhibition was almost the same for these drugs, while that of clonidine and corticosterone was 50 and 20%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Acid-base interactions with noradrenaline-induced contractile response of the rabbit isolated aorta.

The effect of acidosis and alkalosis on vascular smooth muscle contractions evoked by noradrenaline was studied. Helical strips of rabbit aorta were mounted for isometric tension recording. Acidosis (pH 7.24-6.51) was obtained by either increasing the PCO2 (hypercapnic) and/or lowering the HCO3-concentration (hypobicarbonatic). Acidosis shifted the noradrenaline concentration-response curve to the right in a competitive manner. The maximal developed tension was unchanged at pH 7.24-6.90 and decreased by 30% at pH 6.51. Alkalosis (pH 7.61-8.04) did not alter noradrenaline-evoked contractions. The results suggest that hydrogen ions during acidosis (pH less than 7.40) but not during alkalosis (pH greater than 7.40) exert alpha-adrenoceptor blocking properties.

Acid-Base Equilibrium↗
PubMed1981

Inhibition of adrenergic neuroeffector transmission in rabbit pulmonary artery and aorta by adenosine and adenine nucleotides.

The effect of adenosine and adenine nucleotides on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta was studied. Adenosine (10(-5)-3 x 10(-4)M) decreased the contractile response of pulmonary artery and aorta evoked by electrical-field stimulation. The decrease was reversible. No tachyphylaxis developed. Inhibition of either adenosine deaminase by deoxycoformycin (3.6 x 10(-6)M) or of adenosine transport by dilazep (3 x 10(-6)M) did not alter the inhibitory effect of adenosine on the neurogenic contractions in the pulmonary artery. However, deoxycoformycin plus dilazep markedly enhanced the inhibitory effect of adenosine. The calcium antagonists nifedipine (1.5 x 10(-8)M) and nimodipine (1.3 x 10(-8)M) had no effect on the adenosine-induced inhibition. This was also the case with theophylline (5 x 10(-5)M), atropine (10(-7)M), and the prostaglandin synthetase inhibitors indomethacin (5 x 10(-5)M and suprofen (3 x 10(-5)M). The contractile response of the pulmonary artery elicited by exogenous (-)-noradrenaline (NA; 10(-9)-3 x 10(-4)M) was essentially not altered by adenosine (10(-5)-3 x 10(-4)M). Adenosine (10(-4)M) did not alter the spontaneous 3H-outflow from rabbit aorta preloaded with 3H-(-)-noradrenaline (3H-NA). Adenosine (10(-5)-3 x 10(-4)M), ADP (10(-4)M), ATP (10(-5)M), and inosine (10(-4)M) diminished the overflow of tritium from pulmonary artery and aorta preloaded with 3H-NA. The spontaneous outflow of tritium from aorta preloaded with 3H-NA consisted of 3H-NA (17%), 3H-dihydroxyphenylglycol (3H-DOPEG; 30%), 3H-dihydroxymandelic acid (3H-DOMA, 4%), 3H-O-methylated and deaminated metabolites (3H-OMDA; 42%), and 3H-normethanephrine (3H-NMN; 2%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-DOPEG and 2H-NMN, decreased 3H-NA, and did not alter 3H-DOMA and 3H-OMDA. The stimulation-evoked overflow of tritium for aorta preloaded with 3H-NA consisted of 3H-NA (31%), 3H-DOPEG (18%), 3H-DOMA (2%), 3H-ONDA (46%), and 3H-NMN (3%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-NA and 3H-DOPEG, decreased 3H-OMDA and did not alter 3H-DOMA and 3H-NMN. Adeosine (10(-6)-10(-4)M) did not alter the accumulation of 3H-NA (10(-8)M) by aorta. It is concluded that adenosine inhibits vascular sympathetic neuroeffector transmission by diminishing the release of transmitter from the nerve terminals.

Adenine Nucleotides↗
PubMed1981

Dual effect of the muscarinic agonist McN-A-343 on vascular neuroeffector transmission.

The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10(-6) - 3 x 10(-5) M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10(-4) -3 x 10(-4)M) inhibited them. McN-A-343 (10(-4)M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 x 10(-5)M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10(-5) - 10(-4)M), hexamethonium (10(-5) M), atropine (3 x 10(-7) M), suprofen (10(-5) M), and 4-aminopyridine did not alter the effect of McN-A-343 (1-(-4)M). Cocaine (3 x 10(-5)M) and (+)-amphetamine (10(-5) M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 x 10(-5) M). Atropine (3 x 10(-7) M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10(-4) M) caused a partial and transitory reversal. On the aorta McN-A-343 (10(-4)M) did not alter the contractile concentration-response curve of (-)-noradrenaline (10(-9) - 3 x 10(-4)M), while that of serotonin (10(-8) - 3 x 10(-5)M) was moved to the right in a competitive manner. McN-A-343 (10(-4)M) did not alter the contractions evoked by noradrenaline (10(-7) M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10(-4)M) slightly antagonized the contractions caused by tyramine (10(-6) - 10(-3) M) and carbachol (10(-6) - 10(-3) M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗