Chronic clonidine treatment and its termination: effects on penile erection and ejaculation in the dog.

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 micrograms/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p.). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.     

Adrenoceptor mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys.

The purpose of the current experiment was to study the role of various adrenoceptor subtypes in the cardiovascular response to cocaine in conscious squirrel monkeys. A variety of adrenoceptor antagonists were administered i.v. prior to the administration of 0.3 mg/kg cocaine (i.v.). Cocaine alone produced an increase in both blood pressure and heart rate. The non-selective alpha adrenoceptor antagonist phentolamine produced a dose-dependent antagonism of the pressor effect of cocaine, as did the alpha-1 selective antagonist prazosin. The alpha-2 selective antagonist yohimbine had no effect on the pressor effect of cocaine. The non-selective beta antagonist propranolol enhanced the pressor effect of cocaine as did the beta-1 selective antagonist atenolol. However, the effect of atenolol was not dose-dependent. The beta-2 selective antagonist ICI 118,551 and labetalol, which blocks both alpha and beta adrenoceptors, did not alter the pressor effect of cocaine. Propranolol, atenolol, and labetalol all antagonized the tachycardiac effect of cocaine in a dose-dependent manner, while the beta-2 antagonist ICI 118,551 did not. Phentolamine, prazosin and yohimbine also reduced the tachycardiac effect of cocaine, although these effects were dose-dependent only for yohimbine, which also significantly elevated baseline heart rate. These results indicate that alpha-1 adrenoceptor mechanisms mediate the pressor effect of cocaine, while beta-1 adrenoceptor mechanisms are involved in the tachycardiac effect of cocaine in squirrel monkeys. Propranolol potentiated cocaine's pressor effect through beta-2 independent mechanisms. Thus, neither alpha-2 nor beta-2 adrenoceptor mechanisms appear to be involved in cocaine's cardiovascular effects.     

Involvement of the opioid system in the central antisecretory action of alpha-2 adrenoceptor agonists in rat

The aim of the present study was to analyse the role of the central alpha-2 adrenoceptors in the regulation of gastric acid secretion in pylorus ligated rats. It was found that the intracerebroventricularly (icv.) injected presynaptic alpha-2 adrenoceptor agonist clonidine and the alpha-2A adrenoceptor subtype selective stimulant oxymetazoline exerted a dose dependent inhibition on gastric acid secretion. The antisecretory ED(50) values for clonidine and oxymetazoline were 20 and 7.5 nmol/rat icv., respectively. The antisecretory effect of these compounds was antagonised by the presynaptic adrenoceptor antagonist yohimbine (50 nmol/rat icv.) indicating that the action is mediated through central presynaptic alpha-2 adrenoceptors. Moreover, naloxone (50 nmol/rat icv.)--non-selective opioid antagonist--and naltrindole (0.5 nmol/rat icv.)--delta-opioid receptor selective antagonist--also decreased the antisecretory effect of clonidine and oxymetazoline suggesting that the endogenous opioid system is likely to be involved in the central antisecretory action of alpha-2 adrenoceptor stimulants.     

Role of beta-1 and beta-2 adrenoceptors in isoproterenol-induced renin release in conscious dogs.

The present experiments were designed to classify the ß-adrenoceptors pertaining to the renin release induced by isoproterenol in conscious dog. Atenolol (ß-1 adrenoceptor antagonist), in oral dose of 6 mg/kg, produced a significant inhibition of renin release caused by isoproterenol. This dose of atenolol suppressed effectively the tachycardia of isoproterenol. On the other hand, the renin release produced by isoproterenol was not modified significantly by a ß-2 adrenoceptor antagonist, IPS-339, at a oral dose of 3 mg/kg which fully antagonized hypotensive response to isoproterenol. These results strongly suggest that the renin release induced by isoproterenol is largely due to stimulation of ß-1 type adrenoceptors.     

Effects of alpha-2 adrenoreceptor blockade by yohimbine on the hormonal response to hypoglycaemic stress in normal man

In order to evaluate the effect of alpha-2 adrenoreceptor blockade on the ACTH response to insulin-induced hypoglycaemia, six normal men were studied with and without yohimbine (30 mg p.o.) premedication. Despite a similar hypoglycaemic stimulus and significant suppression of the growth hormone response (P less than 0.05), no change was observed in basal or stimulated plasma ACTH, cortisol, arginine vasopressin (AVP) or prolactin responses following yohimbine. We conclude that alpha-2 adrenoceptor blockade with yohimbine does not significantly affect the ACTH response to hypoglycaemia in man.     

Adrenergic stimulation of inositol-phosphate production in a genital tract smooth muscle cell line

Catecholamines are important in the modulation of smooth muscle contractile activity; this study was undertaken to evaluate adrenoceptor stimulation of intracellular inositol-phosphate production in a genital tract smooth muscle myocyte. DDT1 MF-2 smooth muscle myocytes, derived from a hamster ductus deferens leiomyosarcoma, were loaded with 3H-inositol, incubated in 10 mM LiCl, then stimulated with adrenergic agonists with and without antagonists. Subsequently, the inositol phosphates were isolated by anion-exchange chromatography. In the presence of norepinephrine (NE), inositol trisphosphate (IP3) was produced by 30 s and peaked at 2 min; inositol 1-phosphate was also apparent by 30 s, and continued to increase over 15 min. Clonidine (an alpha-2 agonist), isoproterenol, and NE in the presence of phentolamine or prazosin (an alpha-1 antagonist) failed to increase IP3. In contrast, NE in the presence of yohimbine (an alpha-2 antagonist) or propranolol stimulated IP3 production to levels comparable to that stimulated by NE alone. These studies provide evidence that inositol phosphate production is involved in alpha-1 adrenergic signal transduction in DDT1 MF-2 myocyte.     

Effects of progesterone blockade over cocaine-induced genital reflexes of paradoxical sleep-deprived male rats

Paradoxical sleep deprivation (PSD) enhances cocaine-induced genital reflexes (penile erection [PE] and ejaculation [EJ]) in male rats and induces a significant increase in progesterone concentration. As progesterone treatment facilitates PE in PSD castrated rats, we may speculate that progesterone appears to be a relevant hormonal factor eliciting genital reflexes in PSD males. In order to expand the latter finding, different doses of antiprogestin mifepristone (vehicle, 2.5, 5, 10, and 20 mg/kg, s.c.) were administered to PSD rats at the end of a 4-day period of PSD 1 h prior to cocaine administration (7 mg/kg, i.p.) and placed in observation cages for the evaluation of genital reflexes. Pretreatment with vehicle induced PE in all rats and this effect was significantly reduced by mifepristone at 5 to 20 mg/kg doses that lowered the proportion to 40% of the rats. The frequency of PE was also significantly reduced for all doses used. There were no significant differences between vehicle and mifepristone in EJ behavior. As for hormone concentrations, mifepristone reduced progesterone concentrations at the 5-20 mg/kg doses compared to vehicle group. At 20 mg/kg, it also elevated testosterone concentrations. In addition, mifepristone administration induced a significant decrease in the duration of PS episodes at all doses. These data suggest that progesterone exerts an essential role in erectile response induced by cocaine in PSD male rats.     

DA-8159 has erectile potentials much longer than the plasma half-life in a conscious rabbit model

DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.     

L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: possible role of an alpha-2-adrenergic mechanism.

Dopaminergic agents ameliorate experimentally induced gastroduodenal mucosal injury, but there is no information about their effect on small intestinal mucosa. We studied the effect of L-dopa and related substances on indomethacin-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after refeeding fasted rats. Total ulcer area was measured 24 hrs after indomethacin administration. L-dopa, 5 mg/kg given in two divided doses 5 h apart, starting 30 minutes before administration of indomethacin, was found to protect the small bowel mucosa against indomethacin- induced damage (ulcer area 122 +/- 5.5 vs 224.2 +/- 5.4 mm2, mean +/- SEM, p less than 0.006). Administration of 5 mg/kg haloperidol, a dopa antagonist, did not abolish the protective effect of L-dopa. On the other hand, yohimbine, an alpha-2-adrenoreceptor antagonist, almost completely abolished the protective effect (180.4 +/- 5.3 vs 122 +/- 5.5, p less than 0.004). Clonidine 20 micrograms/kg, an alpha-2-adrenoreceptor agonist, closely mimicked the protective effect of L-dopa (141.5 +/- 10.9 vs 224.2 +/- 5.4, p less than 0.006). All drugs were give i.p. in two divided doses, at the same schedule as described for L-dopa. The results demonstrate that L-dopa has a protective effect on indomethacin-induced small bowel injury in the rat. The protective effect is probably mediated through stimulation of alpha-2-adrenoreceptors.     

Alpha-2 adrenergic and opioid receptor-mediated gastroprotection.

Clonidine inhibited the development of gastric mucosal lesions induced by either acidified ethanol or indomethacin. The ED50 values were: 7.1 and 5.2 microg x kg(-1) orally, respectively. The gastroprotective effect was antagonised by the pre-synaptic alpha-2 antagonist yohimbine, the more selective alpha-2 antagonist Ch-38083 and the pre-synaptic alpha-2B antagonist prazosin. Moreover, the non-selective opioid receptor antagonist naloxone, the delta receptor selective naltrindole also reversed the clonidine-induced mucosal protective action. Clonidine was also effective following intracerebroventricular administration with the ED50 of 37 ng/rat against ethanol-induced mucosal damage. Our results suggest that: 1) the gastroprotective effect of clonidine is likely to be mediated by alpha-2B adrenoceptor subtype; 2) there is an interaction between pre-synaptic alpha-2 adrenoceptors and opioid system; and 3) clonidine can induce gastroprotection by central mechanism.     

Reversal of ketamine/xylazine anesthesia in the rabbit with yohimbine

Ketamine and xylazine used in combination have been shown to be effective, easily administered, cost efficient agents for surgical anesthesia in the rabbit. The effect of xylazine on the central nervous system has been shown to be mediated through alpha-2 adrenergic receptors. Yohimbine, an alpha-2 adrenergic antagonist has been shown to reverse xylazine induced depression and partially antagonize ketamine in other species. We evaluated the antagonistic effect of yohimbine on ketamine/xylazine anesthesia in the rabbit. Six New Zealand White rabbits were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (10 mg/kg) to establish baseline parameters including respiratory rate, heart rate, and palpebral, pedal and postural reflex activity. Fourteen days later each rabbit was subjected to the same anesthetic regimen followed 30 minutes later by the intravenous administration of yohimbine (0.2 mg/kg). The duration of anesthesia estimated by the time elapsed between the loss and return of the palpebral reflex was reduced in the yohimbine treated trial (means = 29.7 +/- 1.9 minutes) compared to the control trial (means = 67.0 +/- 13.5 minutes). The palpebral reflex returned within 5 minutes following yohimbine treatment. Our results indicated that yohimbine is an effective antagonist of ketamine/xylazine anesthesia in the rabbit. Yohimbine decreases anesthetic duration after intravenous administration and also may aid in the control of undesirable anesthetic effects and overdosage.     

D2-dopamine receptor and alpha2-adrenoreceptor-mediated analgesic response of quercetin

Quercetin, a bioflavonoid (100-300 mg/kg) produced dose dependent increase in tail-flick latency, the analgesic effect being sensitive to reversal by naloxone (1 mg/kg). Prior treatment with haloperidol (1 mg/kg), D1/D2 receptor antagonist haloperidol, sulpiride (50 mg/kg), a selective D2 receptor antagonist, yohimbine (5 mg/kg), a alpha2-adrenoreceptor antagonist but not by SCH 23390 a, selective D1 receptor antagonist blocked this response. Apomorphine (1 mg/kg) a mixed D1/D2 dopamine receptor agonist, and quinpirole (0.5 mg/kg), a selective D2 receptor agonist also produced antinociception, that was reversed by haloperidol (1 mg/kg), sulpiride (50 mg/kg), but not by yohimbine (5 mg/kg). The antinociceptive action of quercetin (200 mg/kg) was potentiated by D2 agonist quinpirole (0.2 mg/kg). Dopamine D1 receptor agonist SKF38393 (10 and 15 mg/kg) failed to alter the antinociceptive effect of quercetin (200 mg/kg). Quercetin (200 mg/kg) reversed reserpine (2 mg/kg-4 hr) induced hyperalgesia, which was reversed by sulpiride but not by yohimbine. Thus, a role of dopamine D2 and alpha2-adrenoreceptors is postulated in the antinociceptive action of quercetin.     

Nature of alpha receptors implicated in the hypertensive effect of high doses of isoprenaline in dogs and rats

Isoproterenol injected intravenously in dogs (3 mg/kg-1) and rats (5 mg/kg-1) induced an increase in blood pressure. After alpha 1 blockade (by AR-C 239, 0.1 mg . kg-1 i.v.) or alpha 2 blockade (by yohimbine, 1 mg/kg-1 i.v.) isoproterenol, as adrenaline, again induced an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2 adrenoceptor blocking agent after an alpha 1 adrenoceptor blocking agent, and vice versa. These results are compatible with stimulation by high doses of isoproterenol of both alpha 1 and alpha 2 adrenoceptors to produce increase in blood pressure.     

Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently.     

Ketamine-xylazine anesthesia in red-tailed hawks with antagonism by yohimbine

Five red-tailed hawks (Buteo jamaicensis) were anesthetized at weekly intervals with intravenous ketamine hydrochloride (KET, 4.4 mg/kg) and xylazine hydrochloride (XYL, 2.2 mg/kg). Twenty min after anesthesia, yohimbine hydrochloride (YOH, 0.05, 0.10, 0.20 and 0.40 mg/kg) or a control was administered. All doses of YOH significantly reduced the head-up times (F = 20.84, df = 1,24, P less than 0.0001) and the standing times (F = 12.30, df = 1,24, P less than 0.0001), compared to the control group. The heart and respiratory rates following YOH (all doses) were significantly greater (P less than 0.01) than the anesthetized rates, but were comparable to the rates observed in restrained, unanesthetized hawks. Yohimbine did not appear to have any significant effect on body temperature. Based upon administration of 4.4 mg/kg KET and 2.2 mg/kg XYL, a dose of 0.10 mg/kg YOH was recommended to achieve antagonism without causing profound cardiovascular or respiratory changes.     

Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: implications for copulation.

Dopamine D1 and D2 receptors may synergize with or oppose each other's effects. We suggest that stimulation of D1 and D2 receptors in the medial preoptic area (MPOA) of male rats have opposing effects on genital reflexes. In Experiment 1 a D1 agonist injected into the MPOA increased the number of ex copula erections but decreased the number of seminal emissions. In Experiment 2 a D1 antagonist had the opposite effects (decreased erections and increased seminal emissions), as had a D2 agonist previously. We also suggest that D1 and D2 mechanisms in the MPOA have different thresholds of activation. In Experiment 3 a low dose of the mixed D1/D2 agonist apomorphine increased erections and anteroflexions, an effect blocked by the D1 antagonist. In Experiments 3 and 4 a high dose of apomorphine increased seminal emissions, an effect blocked by the D2 antagonist. Thus, low levels of dopaminergic stimulation may facilitate erections and anteroflexions (controlled by the parasympathetic system and striated muscles) via D1 receptors; higher or more prolonged stimulation may shift to seminal emission (controlled by the sympathetic system) via D2 receptors. This may explain the progression from erectile to ejaculatory mechanisms during copulation.     

Ejaculations induced by p-chloroamphetamine (PCA) in rats, hamsters and mice.

The ejaculatory response induced by p-chloroamphetamine (PCA) in male rats, hamsters and mice was observed during 2 hours after the injection. The animals were treated intraperitoneally with PCA at doses ranging from 0.78125 to 160 mg/kg. The ED50 (effective dose in 50% of animals) values of PCA for the initiation of ejaculation in rats and hamsters were 1.3397 (1.0732-1.6725) and 0.1105 (0.0802-0.1522) mg/kg, respectively. On the other hand, no ejaculation was observed in any mice at any doses examined. So we concluded that there are species differences in the ejaculatory response, induced by PCA, among rats, hamsters and mice.     

Alpha-adrenergic stimulation of phosphatidylinositol synthesis in human platelets as an alpha-2 effect secondary to platelet aggregation

Epinephrine and adenosine diphosphate (ADP) stimulated 3H-glycerol uptake into phosphatidylinositol of human platelets. Yohimbine, an alpha-2 adrenoceptor antagonist, markedly reduced epinephrine-stimulated 3H-glycerol uptake into phosphatidylinositol; while prazosin, an alpha-1 antagonist, was without effect. Likewise, yohimbine, but not prazosin, blocked epinephrine-induced platelet aggregation. Furthermore, clonidine, a specific agonist for alpha-2 adrenoceptors, stimulated incorporation of 3H-glycerol into phosphatidylinositol and promoted platelet aggregation in the presence of low concentrations of ADP. These studies indicate that the effects of epinephrine on platelet aggregation and phosphatidylinositol synthesis are mediated through alpha-2 adrenoceptors. Further, since the stimulation of phosphatidylinositol synthesis seen with epinephrine was also observed with ADP, this suggests that the increased 3H-glycerol labeling is an indirect result of platelet aggregation.     

Factors affecting angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (AII) to the rat has previously been shown to induce a dose-dependent, hypothermic response manifested by a fall in colonic temperature (CT), a decrease in heat production and an increase in tail skin temperature (TST). The factors mediating AII-induced hypothermia and their site of action were the subjects of the present investigation. To this end, intracerebroventricular administration of 1 microgram of AII induced a 0.4 degrees C reduction in CT and a 2.4 degrees C increase in TST. In contrast, SC administration of 200 micrograms angiotensin III/kg induced a slight increase in CT but had no affect on TST. Pretreatment with the AII-receptor antagonist, saralasin, at either 1 or 10 micrograms/kg, SC did not affect either the fall in CT or the increase in TST induced by administration of 200 micrograms AII/kg, SC. However, the administration of 100 micrograms saralasin/kg, SC attenuated both the fall in CT and the increase in TST induced by either 100 or 200 micrograms AII/kg. Since both the presynaptic alpha adrenoceptor agonist, clonidine, and the opioid antagonist, naloxone, modulate the pressor and dipsogenic responses to AII, their effects on AII-induced hypothermia were tested. Both clonidine (25 micrograms/kg, SC) and naloxone (1 mg/kg, IP) enhanced the fall in CT. Clonidine lengthened the duration of the increase in TST while naloxone had no effect. Pretreatment with the presynaptic adrenoceptor antagonist, yohimbine (300 micrograms/kg, SC), did not alter the hypothermic response to administration of AII. To determine whether vasodilation of the tail of the rat was mediated by AII-induced prostaglandin release, indomethacin (4 and 6 mg/kg) was administered.(ABSTRACT TRUNCATED AT 250 WORDS)