Mechanism of action of B-HT 933 (azepexole) in rat vas deferens and guinea-pig ileum

The mechanism of action of B-HT 933 (azepexole) was studied on the rat vas deferens and myenteric plexus-longitudinal muscle (MP-LM) of the guinea-pig ileum. The drug caused a concentration-dependent inhibition of the twitch response in both preparations. The maximal inhibition in both preparations was 80-90%. B-HT 933 did not affect the cumulative dose-response curves of the vas deferens and of MP-LM to noradrenaline (NA) and acetylcholine (Ach) respectively. Yohimbine antagonized in a competitive way the twitch inhibitory effect of B-HT 933 on vas deferens and on MP-LM; the pA2 values were 8.62 and 8.5, respectively. The twitch inhibitory effects of B-HT 933 were not antagonized by propranolol. The results suggest that the action of B-HT 933 is mediated by stimulation of presynaptic alpha 2-receptors.     

A STUDY OF STIMULATION-EVOKED ACTIVATION OF α2-ADRENOCEPTORS IN THE RAT ISOLATED VAS DEFERENS

Experiments were performed with prostatic and epididymal segments of rat vas deferens to determine whether alpha 2-adrenoceptors in this organ were activated during field stimulation of sympathetic terminals with short trains of pulses applied at low frequencies. In prostatic segments the magnitude of twitches evoked by trains of ten field pulses at 1 or 2 Hz declined after 2-3 s of stimulation. In contrast, facilitation of twitches and fusion of contractions occurred when similar stimulation was applied to epididymal segments. In prostatic segments from rats treated with reserpine (2.5 mg/kg i.p.) 24 h previously, there was no decline in the magnitude of twitches produced by successive impulses in a train of stimulating pulses. In epididymal segments from reserpine-treated rats facilitation of twitches in response to successive impulses in each train still occurred. In prostatic segments cocaine (5 and 10 mumol/l) enhanced twitch fade with stimulation at 1 and 2 Hz without altering the time for onset of this effect. In epididymal segments cocaine led to enhancement and prolongation of contractile responses. In prostatic segments yohimbine (0.01-0.06 mumol/l) reduced or reversed the effect of cocaine in enhancing twitch fade. In preparations where the reversal of the effect of cocaine by yohimbine was incomplete, subsequent addition of phentolamine (1 mumol/l) produced complete reversal. In epididymal segments yohimbine (0.01 mumol/l) produced a further enhancement in the twitch responses to stimulation at 1 and 2 Hz. Subsequent addition of phentolamine (1 mumol/l) reversed the facilitatory effects of cocaine and yohimbine. Propranolol (10 mumol/l) was without effect upon responses to stimulation in either segment of rat vasa deferentia. These experiments indicate that noradrenaline, released by short trains of impulses applied at low frequency to hypogastric nerve terminals activates prejunctional alpha 2-adrenoceptors in the prostatic segment of the vas deferens. In the epididymal portion the effects arising from activation of prejunctional alpha 2-adrenoceptors are outweighed by the consequences of activation of extrajunctional alpha 1-adrenoceptors located on longitudinally arranged muscle.     

Evidence for heterogeneity of prejunctional alpha-2-adrenoceptors.

The interactions between SK&F 104078 and several selective alpha 2-adrenoceptor agonists at pre- and postjunctional alpha 2-adrenoceptors were investigated in order to assess the previously reported selectivity of SK&F 104078 for postjunctional alpha 2-adrenoceptors and to determine whether or not SK&F 104078 could uncover subtypes of alpha 2-adrenoceptors located prejunctionally as has also been suggested. The alpha 2-adrenoceptor agonists, UK 14,304, xylazine, B-HT 933, B-HT 920, clonidine and M-7, produced concentration-dependent prejunctional alpha 2-adrenoceptor-mediated inhibition of neurogenic responses in the guinea pig atrium and rat vas deferens and produced postjunctional alpha 2-adrenoceptor-mediated contraction of the canine saphenous vein. The alpha 2-adrenoceptor antagonist, rauwolscine, blocked all the agonists at both pre- and postjunctional alpha 2-adrenoceptors without demonstrating preference for any agonist or any synaptic location of alpha 2-adrenoceptors. In marked contrast, SK&F 104078 produced equivalent antagonism of all agonists in the canine saphenous vein but had no significant effect against the same agonists in the guinea pig atrium, suggesting a high degree of selectivity for postjunctional alpha 2-adrenoceptors in these test systems, consistent with our previous observations. In the rat vas deferens, however, SK&F 104078 significantly antagonized the prejunctional alpha 2-adrenoceptor-mediated effects of clonidine and M-7 but did not block the responses to UK 14,304, xylazine, B-HT 933 and B-HT 920. These results indicate that the prejunctional alpha 2-adrenoceptor antagonist effects of SK&F 104078 are tissue and agonist dependent, and that there may be at least two subtypes of prejunctional alpha 2-adrenoceptors that can be discriminated with SK&F 104078 but not with rauwolscine. Both subtypes of prejunctional alpha 2-adrenoceptors may be present in the rat vas deferens, while only the SK&F-104078-insensitive subtype is present in the guinea pig atrium.     

Alpha 2-adrenoceptor blocking profile of SK&F 104078: further evidence for receptor subtypes.

1. The ability of the putative, selective post-junctional alpha 2-adrenoceptor antagonist, SK&F 104078 to antagonize the effects of structurally-diverse agonists at pre-junctional alpha 2-adrenoceptors in the guinea-pig ileum and rat vas deferens in vitro and in the rat heart in vivo, and at post-junctional alpha 2-adrenoceptors in the rabbit ear vein in vitro, was examined. Results obtained with SK&F 104078 were compared with those obtained with yohimbine. 2. Xylazine and B-HT933 each caused a concentration-dependent inhibition of the field-stimulation-evoked twitch responses of the guinea-pig ileum and rat vas deferens. SK&F 104078 did not antagonize either agonist in the guinea-pig ileum and exerted only minimal blocking activity against xylazine in the rat vas deferens. In contrast, SK&F 104078 competitively antagonized B-HT933 in the rat vas deferens (pA2 = 6.45). Yohimbine competitively antagonized both agonists in each tissue (pA2 values ranged between 7.46 and 7.88). 3. In the pithed rat xylazine and B-HT933, injected intravenously, caused a dose-dependent reduction in the tachycardia elicited by stimulation of the cardiac preganglionic sympathetic nerves. SK&F 104078 (10 mg kg-1, i.v.) caused a 20-30 fold rightward displacement of the dose-response curve to xylazine, but did not affect responses to B-HT933. Yohimbine (1 mg kg-1, i.v.) antagonized both agonists to a similar degree. 4. In the rabbit ear vein xylazine, B-HT933, noradrenaline and UK 14304 elicted vasoconstrictor responses. Prazosin was without effect, but in contrast, SK&F 104078 was a competitive antagonist of each of the agonists (pA2 values ranged between 6.63 and 6.72).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cannabinoid receptor activation on rabbit bisected vas deferens strips

1. In the present study, the effects of anandamide and WIN 55,212-2, cannabinoid receptor agonists, were investigated on electrical field stimulation (EFS)-induced biphasic twitch responses obtained from the epididymal and prostatic portions of rabbit vas deferens strips. 2. Anandamide and WIN 55,212-2 dose-dependently inhibited both the first and second phases of the EFS-induced twitch responses recorded from epididymal and prostatic portions of the vas deferens over the concentration range 10(-9) to 3 x 10(-6) mol/L. 3. The cannabinoid CB1 receptor antagonist AM 251 (10(-6) mol/L) and the cannabinoid CB2 receptor antagonist AM 630 (10(-6) mol/L) had no effect on the inhibitory action of anandamide on the biphasic twitch responses in the prostatic and epididymal portions of the rabbit vas deferens. 4. In both the prostatic and epididymal portions of the rabbit vas deferens, AM 251 significantly, but not completely, reversed the inhibitory effect of WIN 55,212-2 on the first phase of the twitch response. In contrast, AM 630 did not have any effect on the inhibitory action of WIN 55,212-2 in the rabbit vas deferens strips. 5. The inhibitory effects of anandamide or WIN 55,212-2 on EFS-induced twitch responses of both the prostatic and epididymal portions of the rabbit vas deferens were not altered in the presence of 10(-5) mol/L naloxone. 6. These results suggest that cannabinoid receptors may have a modulatory role in the regulation of sympathetic transmission in the rabbit vas deferens. However, further investigation is required to characterize the receptors involved.     

Effects of prostaglandin E2 on fast and slow components of the response of the rat vas deferens to field stimulation

1 The response of the rat vas deferens to field stimulation with single pulses is biphasic. The first, rapid component of the response is dominant at the prostatic end and is thought by some to be mediated by non-adrenergic, non-cholinergic neurotransmission. The second, slower component predominates at the epididymal end and has the usual properties associated with adrenergic responses. 2 Prostaglandin E2 (PGE2, 10(-8) to 10(-5) mol/l) inhibited the 'fast component' responses elicited by field stimulation of the prostatic vas from reserpine-treated rats. The prostaglandin was more potent in the presence of 1.25 than 2.5 mmol/lCa2+. 3 PGE2 (10(-7) to 10(-5) mol/l) had similar effects on prostatic preparations from normal rats, but was less active on these. 4 PGE2 (10(-9) to 10(-5)mol/l) did not inhibit the 'slow component' responses resulting from field stimulation of the epididymal vas but rather, at the two highest concentrations used (5 x 10(-6) and 10(-5) mol/l), potentiated them. These high concentrations of the prostaglandin also potentiated the contractions of the epididymal vas elicited by exogenous noradrenaline. 5 These effects of PGE2 on the two components of the response of the rat vas deferens are not as might be expected from its inhibitory effects on the 'typical' adrenergic neurotransmission in several other sympathetically-innervated tissues.     

Effects of alpha,beta-methylene ATP on potentiation of contractions to field stimulation of rat vas deferens by carbachol

Carbachol (0.1-300 mumol/L) potentiated contractions to field stimulation (0.1 Hz, 1 ms, supramaximal V) in the rat epididymal and prostatic vas deferens. Desensitization of P2-purinoceptors by exposure to alpha,beta-methylene ATP (30 mumol/L) markedly reduced (greater than 80%) the potentiating effect of carbachol in the prostatic vas deferens but only moderately reduced (about 20%) the maximal stimulated response to carbachol in the epididymal segment. The presence of prazosin (10 mumol/L) and yohimbine (10 mumol/L), being selective alpha 1- and alpha 2-adrenoceptor antagonists, did not modify the attenuation of carbachol potentiation caused by alpha,beta-methylene ATP treatment. At 0.1 mmol/L, alpha,beta-methylene ATP had no significant effect on the binding of [3H]QNB to muscarinic cholinergic receptors. It is concluded that carbachol may potentiate the contractions to field stimulation in the prostatic vas deferens via an enhancement of purinergic neurotransmission. The molecular mechanism of carbachol potentiation in the epididymal vas deferens remains to be established.     

Alpha 2-adrenoceptor-mediated contractions in the rabbit aorta treated with BAY K 8644.

We tested the effect of the selective alpha 2-adrenoceptor agonists B-HT 920 and B-HT 933 on the rabbit aorta. These drugs had weak contractile effects in the tissue, which were inhibited by the selective alpha 1-adrenoceptor antagonist prazosin (10(-5) M). Their contractile effects were potentiated by the Ca2+ channel facilitator BAY K 8644 (10(-6) M). The selective alpha 2-adrenoceptor antagonist yohimbine (10(-5) M) reduced the contractions elicited by B-HT 920 and B-HT 933 in the presence of BAY K 8644 (10(-6) M), but did not alter the control effect of these drugs. In the rabbit aorta, the contractile effect of B-HT 920 and B-HT 933 in the presence of BAY K 8644 (10(-6) M) was partly caused by alpha 1-adrenoceptor stimulation, because prazosin (10(-5) M) relaxed the contractions elicited under these conditions. In the aorta preincubated with BAY K 8644 (10(-6) M) and prazosin (10(-5) M), B-HT 920 (3 x 10(-4) M) elicited non-sustained phasic contractions (1-5 g), which were probably due to alpha 2-adrenoceptor stimulation, as they were inhibited by yohimbine (10(-5) M). In similar experiments B-HT 933 (3 x 10(-4) M) caused inconsistent and slight contractions (< 0.5 g developed tension).     

Prazosin selectively inhibits the responses to field stimulation in the rat vas deferens

The effects of prazosin on contractile responses of the epididymal and prostatic halves of the rat vas deferens have been studied. In the epididymal half responses to acetylcholine were not altered by hexamethonium, 100 microM, but were inhibited by atropine, 10 nM. Prazosin, 100 nM, had no effect on maximal or submaximal responses to acetylcholine or methacholine. In the presence of cocaine, 10 microM, prazosin 10 and 100 nM, reduced the magnitude of the maximal twitch and sustained responses to field stimulation in the epididymal and prostatic halves of the vas deferens. Submaximal responses at all frequencies of stimulation and to exogenously applied noradrenaline were also inhibited by prazosin. Thus all responses to field stimulation of the epididymal and prostatic halves of the vas deferens are susceptible to selective alpha 1-adrenoceptor blockade with low concentrations of prazosin.     

Potentiation of purinergic transmission by angiotensin in prostatic rat vas deferens.

1. Angiotensin II (AII) elicited only a minute, if any, direct contractile response in smooth muscle cells of prostatic rat vas deferens, but it potentiated contractile responses to field stimulation. 2. Angiotensin-potentiated contractile response to field stimulation was concentration-dependent, and the order of potency was AII > AIII approximately AI. The EC50 of AII was 8.11 +/- 2.79 nM. 3. AII did not modify the contractile response of exogenous noradrenaline (NA) on non-stimulated prostatic vas deferens. Furthermore, the concentration-response curve for AII-potentiated contractile responses to field stimulation in reserpine-treated rats did not significantly differ from the control group. 4. Desensitization of purinoceptors with 30 microM alpha, beta-methylene-ATP almost completely abolished the potentiation of the contractile response to field stimulation by AII. 5. The response to AII in the prostatic rat vas deferens was blocked by the AT1 selective antagonist losartan, but not by the AT2 selective antagonist CGP 42112. Losartan acted as a competitive antagonist with a pA2 value of 8.75. 6. In conclusion, AII potentiated purinergic transmission in the prostatic rat vas deferens via the AT1 receptor.     

Inhibition of field stimulation-induced contractions of rabbit vas deferens by muscarinic receptor agonists: selectivity of McN-A-343 for M1 receptors

Inhibition of the field stimulation-induced twitch responses of the rabbit vas deferens by the muscarinic receptor agonist, McN-A-343, has been attributed to presynaptic muscarinic receptors of the M1 subtype located on noradrenergic nerve terminals. Stimulation of these receptors causes inhibition of transmitter release and inhibition of the contractile response. However, the selectivity of McN-A-343 for M1 receptors has been questioned and this throws doubt on whether the prejunctional receptors of the rabbit vas deferens are of the M1 subtype. In this study we have undertaken a comprehensive re-evaluation of the inhibition of prostatic and epididymal portions of the rabbit isolated field-stimulated vas deferens by several agonists, including McN-A-343, and quantified the antagonism by M1-selective antagonists, pirenzepine and telenzepine. Prostatic and epididymal portions of vasa deferentia from New Zealand White rabbits were immersed in a low Ca2+ Krebs solution at 32+/-0.5 degrees C gassed with 5% CO2 in oxygen. Yohimbine (1.0mM) was present throughout to block prejunctional alpha2-adrenoceptors. Field stimulation was applied by repeated application of single pulses (30 V, 0.05 Hz, 0.5 ms) and isometric contractions recorded. Carbachol and oxotremorine initially potentiated the epididymal contractions but at higher concentrations there was inhibition. In the prostatic portion, oxotremorine only inhibited. McN-A-343 produced inhibitory responses only in both epididymal and prostatic portions. Pirenzepine shifted the concentration-response curves forthe inhibitory responses to oxotremorine to the right. However, the potentiation of the twitches also became more apparent with the lower concentrations of oxotremorine. Schild plots for the antagonism by pirenzepine yielded pA2 values of 7.96+/-0.004 and 7.7+/-0.02 for the epididymal and prostatic portions, respectively. The concentration-response curves for the inhibition of twitches by McN-A-343 were displaced to the right in a parallel manner by pirenzepine in both prostatic and epididymal portions with no potentiation of the twitches. The Schild plot for this antagonism generated pA2 values of 7.68+/-0.01 and 8.07+/-0.01, respectively. Telenzepine caused parallel shifts of the McN-A-343 concentration-response curves to the right in prostatic portions, the pA2 value being 8.70+/-0.13. Telenzepine (10(-7) M) abolished the inhibitory effect of carbachol to reveal only concentration-dependent potentiation of the contractions. The Schild plot for antagonism of this contractile effect yielded a pA2 value (7.07+/-0.09) that was significantly less by almost two orders of magnitude (1.70) than the value for the antagonism by telenzepine of the McN-A-343-induced inhibitory response. The pA2 values of pirenzepine and telenzepine against the inhibitory responses of the rabbit vas deferens are consistent with the involvement of M1 receptors. This leads to the conclusion that McN-A-343 causes inhibition through this receptor type. The doubts concerning the selectivity of McN-A-343 for M1 receptors are therefore unfounded. The fact that McN-A-343 does not display a selective binding profile suggests that its selectivity does not arise from affinity differences but probably resides in its intrinsic efficacy.     

Adrenergic and purinergic components in bisected vas deferens from spontaneously hypertensive rats

1. Purinergic and adrenergic components of the contractile response to electrical field stimulation (EFS) have been investigated in epididymal and prostatic portions of Wystar Kyoto (WKY) and spontaneously hypertensive rat (SHR) vas deferens. 2. In both halves of SHR and WKY vas deferens, EFS (40 V, 0.5 ms for 30 s, 0.5-32 Hz) evoked frequency-related contractions. The neurogenic responses were biphasic, consisting of a rapid non-adrenergic response, dominant in the prostatic portion, followed by a slow tonic adrenergic component, dominant in the epididymal half. 3. Phasic and tonic components of the frequency-response curves evoked by EFS were significantly higher in the epididymal but not in the prostatic portion of vas deferens from SHR compared to WKY rats. 4. The alpha1-adrenoceptor antagonist prazosin (0.1 microM) was more effective against both components of the contractile response in the epididymal end of SHR than in WKY rats. 5. Inhibition by alpha, beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP 3 and 30 microM) was higher in both components of the contractile responses in WKY preparations than in SHR. 6. Combined alpha1-adrenoceptor and P2x-purinoceptor antagonism virtually abolished the EFS-evoked contractile response in both strains. The degree of inhibition by prazosin (0.1 microM) after P2x-purinoceptor blockade was higher in SHR than in WKY rats. 7. These results demonstrate a modification in the purinergic and noradrenergic contribution to neurogenic responses in SHR and WKY animals besides a co-participation of ATP and noradrenaline in both contractile components of the response to EFS.     

Verapamil enhances the non-adrenergic twitch response of rat vas deferens

Verapamil (3 X 10(-6)-3 X 10(-5) M) enhanced the twitch contractions of the epididymal and prostatic portions of vas deferens stimulated at 0.1 Hz. This verapamil effect was essentially similar to those of diltiazem, D-600 and Bay K 8644. However, when stimulation at 2 Hz was used verapamil (3 X 10(-5) M) attenuated the contractions of the epididymal portion by half but still augmented those of the prostatic portion. Verapamil enhanced the reserpine- and prazosin-resistant component of the stimulation-induced contractions of both portions of the vas deferens. Yohimbine augmented the twitch response but attenuated the verapamil-augmented response. Verapamil did not augment norepinephrine- or tyramine-induced contractions whereas it augmented ATP-induced contractions of the prostatic portion but not of the epididymal portion. Verapamil increased the stimulation-evoked 3H-efflux from the vas deferens labelled with [3H]norepinephrine. It is suggested that verapamil augments non-adrenergic responses of both portions of the vas deferens by acting as a Ca agonist on the prejunctional site to increase the release of co-transmitter, or by acting on the postjunctional site to enhance the action of the substance released. Its effect in augmenting norepinephrine release is concluded not to contribute to the potentiating action.     

A comparison of the effects of oxodipine and nifedipine on rat vas deferens

The effects of oxodipine, a new dihydropyridine, were studied and compared with those of nifedipine in the complete vasa deferentia and in the prostatic and epididymal halves of the rat vas deferens. Oxodipine and nifedipine, 10(-9) -10(-6)M, produced a dose-dependent inhibition of the contractile responses induced by single pulse stimulation, noradrenaline (3 x 10(-5)M) and high-K (50 mM). The inhibitory effects of oxodipine were significantly reduced in high Ca media. From these experiments it is concluded that oxodipine, like nifedipine, produced a similar and potent inhibitory effect of the contractile responses induced in the rat vas deferens.     

The distribution of adrenoceptors and other drug receptors between the two ends of the rat vas deferens as revealed by selective agonists and antagonists.

1. The effects of adrenoceptor agonists and other agonists on the contractile responses of the prostatic and epididymal portions of the rat isolated vas deferens to single pulse field stimulation were investigated. 2. alpha-Adrenoceptor agonists produced prejunctional alpha 2-mediated inhibition and post-junctional alpha 1-mediated potentiation of the nerve-induced responses. Guanabenz and xylazine produced mainly inhibitory effects, xylazine being 10 times less potent. Clonidine and oxymetazoline produced inhibition with similar potency to guanabenz but at higher concentrations excitatory effects were present, particularly in the epididymal portion. Phenylephrine produced only potentiation of the nerve-induced response in both portions. Potentiation of nerve-induced responses was a more sensitive and quantitative index of excitation than was direct contraction of the tissue. 3. Isoprenaline and salbutamol both gave beta 2-mediated inhibition of the nerve-induced responses in both portions of tissue. At least part of the effect was post-junctional since phenylephrine contractions were inhibited. Isoprenaline also produced a post-junctional alpha 1-mediated excitation. 4. Noradrenaline produced effects qualitatively similar to those of the other alpha-adrenoceptor agonists, inhibition and excitation predominating in the prostatic and epididymal ends respectively. 5. Morphine produced inhibition in the mouse but not in the rat vas deferens. In rat vas, however, enkephalin analogues produced pre-junctional inhibition of responses in both portions which could be partly reversed by naloxone; restoration of the adrenergic component was more complete. Rat anococcygeus showed no equivalent effect. 6. Adenosine 5'-triphosphate (ATP) inhibited nerve-induced responses in each portion with a greater effect on the prostatic portion.     

Effects of St-587 on the alpha-adrenoceptors in the bisected rat vas deferens

The effects of the alpha-adrenoceptor agonist St-587 have been studied on the twitch responses induced by field stimulation in the prostatic portion of rat vas deferens. Moreover the drug's influence on the unstimulated prostatic and epididymal halves of rat vas deferens has also been determined. Alone and after addition of yohimbine (0.3 microM) it enhanced in a concentration-dependent manner the twitch responses in the prostatic half. Prazosin competitively antagonized (pA2 = 8.41 +/- 0.03) this effect. The enhancing effect of St-587 was not reduced in reserpinized animals. These results suggest that post-synaptic alpha 1-adrenoceptors are involved in the potentiation of twitch responses induced by St-587. When alpha 1-adrenoceptors were blocked by prazosin (0.1 microM), St-587 partially inhibited the twitch responses of the prostatic portion of rat vas deferens (Emax = 49.5 +/- 3.5%). Yohimbine completely reversed the inhibitory effects of both St-587 and clonidine. Furthermore St-587 antagonized the inhibitory effects of clonidine on twitch responses. Thus it appears that St-587 also behaves as a partial agonist of presynaptic alpha 2-adrenoceptors in this portion of rat vas deferens, but it did not induce contractions in the unstimulated prostatic half of the vas deferens. However, it competitively antagonized the alpha 1-adrenoceptor agonist phenylephrine by acting as an antagonist of prostatic postsynaptic alpha 1 adrenoceptors. These alpha 1-adrenoceptors are probably different from those that mediate the twitch enhancing response to St-587 in that portion. On the other hand, St-587 was a partial agonist of alpha 1-adrenoceptors in the epididymal half.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of alpha 1-adrenoceptor subtypes in tension response of human prostate to electrical field stimulation.

1. The effects of various alpha 1-adrenoceptor antagonists and nifedipine on tension responses of human prostate to electrical field stimulation were evaluated in this study. 2. Prazosin (3 x 10(-10) to 10(-8) M) and 5-methyl-urapidil (10(-9) to 3 x 10(-8) M) blocked concentration-dependently the tension responses to electrical field stimulation and completely abolished them in the maximal concentrations (10(-8) M and 3 x 10(-8) M, respectively); in contrast, chloroethylclonidine (CEC), in the maximal concentration of 100 microM, blocked these effects by only 50%. 3. The contractile responses of rat vas deferens and spleen to exogenously-applied alpha 1-adrenoceptor agonists were competitively inhibited by prazosin and 5-methyl-urapidil; in addition, the pA2 values were calculated and the relative potencies with reference to prazosin were obtained. The relative potency of 5-methyl-urapidil in human prostate (0.105) was close to that in rat vas deferens (0.257), which contains primarily putative alpha 1A-adrenoceptors. However, it was much more than that in rat spleen (0.011), which contains primarily putative alpha 1B-adrenoceptors. 4. Nifedipine (10(-8) to 10(-6) M) inhibited concentration-dependently the contractile responses to electrical field stimulation in human prostate; in addition, the inhibition percentages were similar to those to exogenously-applied noradrenaline in rat vas deferens. In contrast, CEC (10 microM), which almost flattened the concentration-response curve of the rat spleen to phenylephrine, only partially inhibited (by 33.1%) the nerve-mediated contraction of human prostate. 5. The involvement of prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of human prostate was also examined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related change in serotonin-mediated prejunctional inhibition of rat vas deferens

The effect of age on the serotonin (5-HT)-induced prejunctional inhibition of twitch contractions induced in rat vas deferens by single-pulse field stimulation at 0.1 Hz was studied. The inhibitory effect of 5-HT gradually decreased with increasing age of the rats (4–15 weeks old) and was no longer detectable in preparations from rats over 15 weeks old. Moreover, on a further increase in age to 45 weeks, 5-HT conversely enhanced the twitch response of the vas deferens. The 5-HT₂ antagonists ketanserin and mianserin potentiated the 5-HT-induced inhibition of contractions of the vas deferens of young rats (8–15 weeks old), and attenuated the amplifying effect of 5-HT on the responses of preparations from old rats (95 weeks old). Thus unmasking of the inhibition depended on the age of rats. This change occurred earlier in life in the prostatic portion of the vas deferens than in the epididymal portion. A functional decrease in 5-HT-mediated prejunctional inhibition and the resultant increase in amplification of the twitch response by 5-HT are probably responsible for the age-related decrease in prejunctional inhibition.     

Relationship between alpha 2-adrenoceptor occupancy and response for B-HT 933 in canine saphenous vein

The relationship between alpha 2-adrenoceptor occupancy and contractile response for B-HT 933 was investigated in canine saphenous vein. B-HT 933 produced a concentration-dependent, alpha 2-adrenoceptor mediated contractile response in canine saphenous vein with an ED50 of 0.65 microM. The dissociation constant (KA) of B-HT 933 was calculated to be 5 microM. The relationship between alpha 2-adrenoceptor occupancy and contractile response for B-HT 933 in canine saphenous vein was hyperbolic, typical of full agonists or agonists with high intrinsic efficacies. B-HT 933 produced a half-maximal response in canine saphenous vein at only 11% alpha 2-adrenoceptor occupancy, with a maximal response being obtained with 40-60% alpha 2-adrenoceptor occupancy. We conclude that the selective alpha 2-adrenoceptor agonist, B-HT 933, has high efficacy at alpha 2-adrenoceptors, such that a significant alpha 2-adrenoceptor reserve, or spare alpha 2-adrenoceptors, exists for this compound in canine saphenous vein.