Jørgen Schrold

The mechanism of action of nicotine on vascular adrenergic neuroeffector transmission.

The aim of this study was to determine the site and mechanism of action of nicotine on sympathetic neuroeffector transmission in the isolated pulmonary artery of the rabbit. Nicotine and cocaine potentiated the constrictor response elicited by electrical-field stimulation of postganglionic adrenergic neurones. The potentiation was reversible and in the case of nicotine, no tachyphylaxis developed. The nicotine-induced potentiation was characterized by a rapid onset and an initial, transitory peak, while the enhancement caused by cocaine progressed more slowly and was monophasic. Hexamethonium and (+)-tubocurarine prevented the potentiation caused by nicotine. Nicotine did not prevent the adrenergic neurone blocking effect of bretylium on the response to field stimulation. Nicotine increased the stimulation-induced outflow of tritium from pulmonary artery preloaded with 3H-(--)-noradrenaline. Contractions of the artery elicited by tyramine were enhanced by pargyline, unaltered by nicotine and blocked by cocaine. Nicotine did not alter the concentration--response curve of exogenous (--)-noradrenaline while cocaine moved it to the left. The accumulation of 3H-(--)-noradrenaline by rabbit isolated aorta was not altered by nicotine, hexamethonium and (+)-tubocurarine. The accumulation of 3H-nicotine by the aorta was much lower than that seen with 3H-(--)-noradrenaline. The disposition of the 3H-nicotine accumulation into adventitia and media was concentration-independent. These results suggest (1) that nicotine potentiates the neurogenic vasoconstriction response in part by increasing the stimulation-induced release of transmitter from adrenergic neurone terminals; (2) that the site of the nicotinic receptors mediating this action is located on the outer surface of the neurones; and (3) that the potentiation is not due to blockade of noradrenaline re-uptake.

Effect of Atropine on Vascular Adrenergic Neuroeffector Transmission

Atropine, homatropine, scopolamine, procaine, lidocaine and phentolamine inhibited the contractile response of rabbit isolated pulmonary artery elicited by electrical-field stimulation. Methylatropine had no effect. The inhibition induced by atropine (2 x 10(-6)-2 x 10(-4) M) had a rapid onset of action and then remained almost constant. The inhibition was slowly reversible. The potency of atropine as an inhibitor of responses to field stimulation was very much less than the potency of phentolamine. The inhibition was not antagonized by cocaine or (+)-amphetamine. Atropine (3 x 10(-5) and 3 x 10(-4) M) enhanced the electrical-field-stimulation-induced outflow of tritium from the pulmonary artery preloaded with 3H-(-)-noradrenaline. In contrast, atropine in a concentration-dependent manner either had no effect or slightly decreased the tyramine-induced outflow of tritium. Atropine reduced the contractile response of the pulmonary artery evoked by tyramine. Atropine (10(-4) and 3 x 10(-4) M) and phentolamine inhibited the arterial contractions elicited by exogenous (-)-noradrenaline in an apparently competitive manner. The contractions of rabbit isolated aorta elicited by (-)-noradrenaline, serotonin and histamine were inhibited by atropine (10(-5) and 10(-4) M). Atropine was very much less potent in antagonizing noradrenaline, histamine and serotonin than in antagonizing acetylcholine. tthe inhibotory potency of atropine, procaine and lidocaine on the accumulation of 3H-(-)-noradrenaline by rabbit aorta in vitro was much less than that of cocaine. The relationship between the aortic concentration of 3H-atropine and in vitro accumulation was almost linear. The accumulation was slightly higher at 37 degrees C than at 1 degree C. The results suggest that atropine blocks alpha-adrenoceptors, both presynaptically at the adrenergic neurone terminals and postsynaptically at the smooth muscle. In addition, atropine may possibly act in a nonspecific manner at postsynaptic sites.

3H-noradrenaline outflow induced from isolated adventitia and intima-media of rabbit aorta by electrical field stimulation

Electrical field stimulation of the isolated adventitial and intima-medial layers of rabbit aorta preloaded with 3H-noradrenaline elicited a 3H outflow. The initial 3H outflow from adventitia was independent of external Ca2+ concentration. Each of the subsequent 3H outflows was mainly Ca2+ sensitive. All stimulation-induced 3H outflows from media were Ca2+ insensitive. It is concluded that the isolated adventitia is a suitable preparation to outflow from aorta is of neuronal and extraneuronal origin.

Presynaptic Muscarinic and α-Adrenergic Receptor Blocking Effect of Atropine on the Noradrenergic Neurones of the Rabbit Pulmonary Artery

The effect of atropine on the electrical-field stimulation-evoked overflow of tritium from isolated rabbit pulmonary arteries preincubated with 3H-noradrenaline was studied. Atropine (10(-4) M) and phentolamine (10(-6) M) increased stimulation-induced overfoow of tritium. Clonidine (10(-6) to 10(-5) M) and acetylcholine (10(-6) M) diminished the stimulation-evoked overflow of tritium. After the overflow had been raised by either atropine (10(-4) M) or phentolamine (10(-6) M), clonidine (10(-6) M) decreased the overflow below control values. Clonidine (10(-5) M) prevented the enhancement of tritium overflow evoked by atropine (10(-4) M). A lower concentration of clonidine (10(-6) M) only caused a partial prevention. Enhancement of the overflow by phentolamine (10(-6) and 3 X 10(-5) M) was not altered by atropine (10(-4) M). Atropine (10(-7) M), in a concentration which was without any effect on the stimulation-induced tritium overflow, prevented the reduction evoked by acetylcholine (10(-6) M). It is concluded that atropine in a low concentration blocks presynaptic inhibitory muscarinic receptors; at higher concentrations it blocks in addition presynaptic alpha-adrenoceptors.

Effect of Tropolone on Vascular Sympathetic Neuroeffector Transmission

After a latency period the catechol- O -methyltransferase inhibitor tropolone blocked increasingly the contractile response of rabbit isolated pulmonary artery elicited by electrical-