Pharmacological actions of substance P in the rat vas deferens.

SP produces two different muscular responses in the isolated vas deferens of the rat. 1) A myotropic, post-synaptic effect that results from stimulation of one subtype of SP receptor, located on the membrane of the smooth muscle (NK-3 receptor). 2) A neurogenic effect at the pre-synaptic level that results from stimulation of another subtype of SP receptor, located on the nerve terminals (NK-1 receptor).

Evidence that dopamine is acting at alpha-adrenoceptors of the rat vas deferens.

In the rat vas deferens, a vast number of experiments have shown that the alpha-adrenoceptors present are of two types: alpha 1 and alpha 2. This series of experiments with the isolated rat vas deferens was designed to probe by pharmacological means, the nature of the responses elicited by neurogenic transmural stimulation and also those responses evoked by exogenous NE and DA. The methodology required the production of chemical denervation, neurotransmitter depletion, and the use of specific adrenoceptor blockers. The results obtained with the blocking agents, yohimbine or prazosin versus NE and DA, were pA2 values that were virtually interchangeable. The effects of chemical alteration with 6-OH-DA or reserpine point to a certain similarity and interdependence of the mechanism of action for the two neurotransmitters. Therefore, it is suggested that these two transmitters act at the same receptor site or share a common receptive microenvironment in the rat vas deferens.

Pre- and post-synaptic muscarinic receptors of the rat vas deferens: an update.

The pre- and post-synaptic muscarinic receptors of the rat vas deferens are not M1 since the M1-selective antagonist pirenzepine (PZ) has low affinity for both. On this basis both the pre- and post-synaptic actions of ACh in this preparation seem to be mediated via M2-like muscarinic receptors. The following experimental observations reveal that both responses are mediated by pharmacologically distinct muscarinic receptors. The rank order of potency displayed by 3 muscarinic antagonists (Atropine, N-methyl-scopolamine [NMS] and PZ) at each of these sites is different. Atropine and PZ are selective blockers of the post-synaptic smooth muscle muscarinic receptor. NMS is a selective antagonist of the pre-synaptic muscarinic receptor that facilitates norepinephrine's release. Finally, PZ and NMS are non-competitive and competitive antagonists, post- and pre-synaptically, respectively. The results suggest that the post-synaptic smooth muscle muscarinic receptor belongs to the M2B (or M3) subtypes. The pre-synaptic muscarinic receptor belongs to the M2A (or M2) subtypes or to a subclass of the M2B (or M3) muscarinic receptor subtypes.

Pre and post-synaptic muscarinic receptors of the rat vas deferens: an update

Los receptores muscarínicos pre- y post sinápticos del vas deferens de la rata no son M1 ya que el antagonista muscarínico M1-selectivo pirenzepina (PZ) posee baja afinidad por ambos. Basándonos en este hecho las dos acciones de ACh, pre-0y post-sinápticas, en esta preparación parecen ser mediadas por receptores muscarínicos parecidos al subtipo M2. La siguiente serie de observaciones experimentales revelan que ambas respuestas son mediadas por receptores muscarínicos farmacológicamente distintos. El rango de orden de potencia desplegado por 3 antagonistas muscarínicos (Atropina, N-metil-escopolamina [NMS] y PZ) en cada uno de estos lugares son diferentes. Atropina y PZ son bloqueadores selectivos del receptor muscarínico presente en músculo liso. NMS es un antagonista selectivo del receptor pre-sináptico muscarínico que facilita la liberación de norepinefrina. Por último, PZ y NMS despliegan un antagonismo diferencial, siendo competitivos y no-competitivos pre- y post-sinápticamente, respectivamente. Los resultados sugieren que el receptor muscarínico post-sináptico presente en el músculo liso pertenece a los subtipos M2B (oM3). El receptor pre-sináptico pertenece a los subtipos M2A (o M2) o a una subclase de los receptores muscarínicos M2B (o M3)

Neuromodulatory actions of substance P on the muscarinic receptors of the vas deferens of the rat.

The response of post-synaptic neurokinin receptors to SP were not changed by pirenzepine or N-methyl-scopolamine. Atropine led to a slight increase in the EC50 of SP for its post-synaptic neurokinin (NK-A) receptor. In the presence of neostigmine no changes in the Emax and EC50 values of SP for its post- and pre-synaptic receptor site were observed. Only the muscarinic receptor site were observed. Only the muscarinic receptor antagonists, atropine and NMS, elicited statistically significant increases in the Emax of SP at its presynaptic receptor (NK-A). Addition of 7.4-740 nM SP resulted in a decrease in the EC50 and Emax values of ACh for its post-synaptic muscarinic receptor (M1). Conversely, 740 nM SP produced an increase in the EC50 and Emax values of ACh at its pre-synaptic muscarinic receptor (M2). Concentrations of 7.4 and 74 nM SP did not produce statistically significant changes in the Emax of ACh for its pre-synaptic M2 receptor.

Selective antagonism by pirenzepine and N-methyl-scopolamine on muscarinic receptor subtypes of the rat vas deferens.

1. The effects of pirenzepine and N-methyl-scopolamine on the responses to ACh in the isolated rat vas deferens were studied. 2. Pirenzepine was inactive at the M2-ACh receptor. 3. N-methyl-scopolamine was a competitive antagonist (pA2 = 8.76) at M2-ACh receptor, alone or in the presence of pirenzepine. 4. Pirenzepine and N-methyl-scopolamine were both non-competitive antagonists at M1-ACh receptor. 5. The mixture of pirenzepine and N-methyl-scopolamine did not alter the type of antagonism demonstrated by each drug at the M1-ACh receptor.

Effects of haloperidol on neurotransmitter activity in the rat vas deferens.

1. The effects of haloperidol on the responses of the isolated rat vasa deferentia to catecholamines and ACh were studied. 2. Haloperidol produced a competitive antagonism to responses elicited by NA and DA in the vas deferens. 3. The M1 and M2 muscarinic responses to ACh of the vas deferens were potentiated by this neuroleptic. 4. The AChE activity of the vas deferens was significantly depressed by pretreatment with haloperidol. 5. The ability of haloperidol to lower AChE activity was compared with that of neostigmine and it may be due to a similar molecular mechanism. 6. The present results suggest that haloperidol has anti-AChE properties that may be responsible for the potentiation of the responses to ACh. 7. The study indicates that haloperidol has a wider range of pharmacological actions than previously reported.

Effects of clonixin, a non-steroidal analgesic, on the neurotransmission of the vas deferens of the rat.

1. The effect of C1X on the responses to TNS, ACh and NE in the isolated rat vas deferens was studied. 2. C1X produced a significant reduction of muscular twitch induced by TNS. 3. The M1-ACh response was significantly increased by this non-steroidal analgesic. 4. The M2-ACh response was not changed by pre-treatment with C1X. 5. The alpha 1-NE response was not altered by C1X. 6. The alpha 2-NE response was potentiated by pre-treatment with C1X. 7. The findings suggest that C1X beside its ability to block the release of NE, has some common pharmacological properties, close to those of a "calcium modulator".

Castration and tolerance induces changes in the levels of the activity of acetylcholinesterase in the isolated vas deferens of the rat.

Changes in the activity of acetylcholinesterase (AChE) of the isolated vas deferens from normal, castrated, morphine and ethanol-tolerant rats were studied. Three days after the termination of treatment with morphine and on the last day of treatment with ethanol, a significant inhibition of the activity of AChE was detected. This reduction in the enzymatic activity persisted in morphine-tolerant rats for 15 days, but not for 30 days, at which time the levels of AChE were determined to be normal. However, in ethanol-tolerant rats, there were no significant changes found at days 15 or 30. The activity of AChE was decreased significantly in castrated rats, but this effect was reversed by treatment with testosterone. During withdrawal from morphine or ethanol, the levels of AChE were significantly increased. The results indicate that morphine and ethanol may be inducing changes in the feedback mechanism which regulates the levels of AChE at post-synaptic sites, and these changes could play an important role in the development of tolerance to morphine and to ethanol.

Mixed actions of hemicholinium at autonomic receptor sites of the rat vas deferens.

1. The effects of hemicholinium (HC-3) on several autonomic agents in the isolated rat vas deferens were investigated. 2. HC-3 reduced slightly the effects of NE and DA. 3. The responses by cholinergic agents on the M1-ACh receptors were not modified, however HC-3 reduced, significantly, the responses on the M2-ACh receptors. 4. These results suggest that HC-3 besides its anticholinergic properties possesses ability to interact with adrenoceptors in the isolated rat vas deferens.

Ontogenesis of autonomic receptors and AChE activity in the rat vas deferens.

The study was undertaken to obtain some information about the development of the autonomic receptors and the AChE activity in the rat vas deferens. The results suggest that the adrenoceptors were fully developed at birth. The M1-ACh receptors were developed before the M2-ACh receptors. The AChE activity developed before the ACh muscarinic receptors of the rat vas deferens.

Presynaptic regulation by ACh of the NE mediated responses in the rat vas deferens.

In the isolated electrically stimulated vas deferens preparation the effect of exogenous acetylcholine (ACh) was studied. It was possible to differentiate two separate sites for the action of ACh. A postsynaptic effect (M1) which is revealed as a sudden decrease in the basal tension of the muscular twitch, antagonized competitively by atropine (pA2 = 8.44 +/- 0.79), potentiated at a ratio of 10.24 by neostigmine, and not altered by hexamethonium, yohimbine, clonidine, theophylline or prazosin. Treatment with reserpine or 6-OH-DA induced a supersensitivity of this effect. The second action is a presynaptic effect (M2), which is manifested by a rapid increase in the muscular twitch, is dose-dependent to ACh, and is potentiated significantly by reserpine, neostigmine and clonidine. This latter effect was not modified by atropine, hexamethonium, yohimbine, prazosin or theophylline. The normal efficacy of ACh is 185 times greater in presynaptic over postsynaptic receptors. The increase in the twitch is not considered to be by the release of endogenous ACh or ATP. The evidence presented here indicates that the presynaptic effect of ACh (M2) is due to participation of alpha 2-adrenoceptors in enhancement of the release of norepinephrine (NE) from the nerve terminals.

Testosterone and tolerance in rat vas deferens.

Testosterone is able to inhibit the development of tolerance in the smooth muscle of the rat vas deferens. Cycloheximide and actinomycin D also inhibit the tolerance to morphine and ethanol in smooth muscle of rat vas deferens. The toxic effect of cycloheximide and actinomycin D do not play roles in the inhibition of tolerance. The physiological responses of vas deferens to norepinephrine are not altered by cycloheximide and actinomycin D.

Effect of certain drugs in perfused human placenta XII: autacoid antagonism by phenothiazines.

The effects of chlorpromazine, prochlorperazine, and trifluoperazine on the pressor actions of serotonin, angiotensin, and bradykinin in the perfused vessels of full-term human placentas were investigated. A significant inhibition of the effect of serotonin was observed with trifluoperazine and chlorpromazine but not with prochlorperazine. The inhibition is attributed to the ability of phenothiazines to cause adrenergic blockade. Because both bradykinin and angiotensin could not be consistently antagonized, it is concluded that they must act primarily via musculotropic mechanisms and only secondarily by stimulation of adrenergic receptors.