Adrenergic Receptor Antagonist Prazosin Research Articles

IS THERE BEHAVIORAL EVIDENCE FOR CONSTITUTIVE ACTIVITY AT 5‐HT2A RECEPTORS?

There are several demonstrations of constitutive receptor activity whereby receptor signaling occurs in the absence of ligand binding. Under such conditions, drugs can increase (agonist), decrease (inverse agonist), or have no effect (neutral antagonist) on receptor signaling. To test whether drug discrimination can be used to study these three different drug actions, separate groups of rats (n=8/group) were trained to discriminate between saline and either an agonist (1‐(2,5‐dimethoxy‐4‐methylphenyl)‐2‐aminopropane [DOM], 0.56 mg/kg), an inverse agonist (MDL100907, 0.1 mg/kg), or a neutral antagonist (ketanserin, 1.0 mg/kg) at serotonin (5‐HT)2A receptors, the primary site of action for many hallucinogens. Stimulus control was adequate for testing in all three groups after an average of 33‐35 training sessions. The discriminative stimulus effects of DOM were attenuated by MDL100907 and by ketanserin and the discriminative stimulus effects of MDL100907 and ketanserin were attenuated by DOM. Neither MDL100907 nor ketanserin occasioned DOM‐lever responding and DOM did not occasion MDL100907‐ or ketanserin‐lever responding. Ketanserin occasioned >90% MDL100907‐lever responding whereas MDL100907 occasioned only 50% ketanserin‐lever responding. However, the combination of MDL100907 and the alpha2 adrenergic receptor antagonist prazosin occasioned >90% ketanserin‐lever responding, suggesting that the ketanserin discriminative stimulus comprises 5‐HT and alpha2 adrenergic components. That a ketanserin discrimination was established indicates that it is not acting as a neutral antagonist at 5‐HT2A receptors, that constitutive activity is not significant under these conditions, or that it has effects by antagonism of endogenous 5‐HT. Depletion of 5‐HT in these rats failed to provide convincing evidence for constitutive activity at 5‐HT2A receptors. CPF is supported by a Senior Scientist Award (DA17918).

Enhanced α1 adrenergic sensitivity in sensorimotor gating deficits in neonatal ventral hippocampus-lesioned rats

Neonatal ventral hippocampus (nVH) lesion in rats is a widely used animal model of schizophrenia due to the predominantly post-pubertal emergence of many schizophrenia-like behaviours. Our previous studies have shown increased ligand binding of alpha1 adrenergic receptors (AR) in the frontal cortex of post-pubertal, but not pre-pubertal, nVH-lesioned rats, compared to sham-lesioned control rats. Moreover, pretreatment with the alpha1 adrenergic receptor antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. This led to our hypothesis that nVH lesions may lead to post-pubertal hyperactivity of alpha1 adrenergic receptors. In order to test the functional relevance of alpha1 adrenergic hyperactivity to schizophrenia-like behaviours of nVH-lesioned animals, we conducted prepulse inhibition (PPI) studies in post-pubertal (postnatal days 56-120) sham and lesioned animals in response to systemic injections of alpha1 adrenergic receptor antagonist and agonist, prazosin and cirazoline, respectively. Our results show that PPI deficits in nVH-lesioned animals were reversed with prazosin treatment, without a significant effect on PPI in sham animals. Further, at various doses, cirazoline had a significantly greater PPI disruptive effect in nVH-lesioned animals than in sham animals. Together, these results suggest that nVH-lesioned animals show a hyperactive alpha1 adrenergic receptor system that may mediate sensorimotor gating abnormalities reported in these animals.

Possible involvement of supraspinal opioid and GABA receptors in CDP-choline-induced antinociception in acute pain models in rats

Cytidine-5'-diphosphate choline (CDP-choline; citicoline) is an essential endogenous compound normally produced by the organism and is a source of cytidine and choline. Our recent studies on acute pain models demonstrate that intracerebroventricularly administered CDP-choline produces antinociception via supraspinal alpha-7 nicotinic acetylcholine receptors-mediated mechanism in rats. However, it remains to be elucidated which other supraspinal mechanisms are involved in the antinociceptive effect of CDP-choline. In this study, we investigated the role of the supraspinal opioidergic, GABAergic, alpha-adrenergic and serotonergic receptors in CDP-choline-induced antinociception. The antinociceptive effect of CDP-choline was evoked by the intracerebroventricular (i.c.v.) administration. Two different pain models were utilized: thermal paw withdrawal test and mechanical paw pressure test. The i.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 micromol) produced dose-dependent antinociception. Non-specific opioid receptor antagonist naloxone (10 microg; i.c.v.) and GABA(B) receptor antagonist CGP-35348 (20 microg; i.c.v.) pretreatments inhibited the antinociceptive effects of CDP-choline (1.0 micromol; i.c.v.). In contrast, the alpha-1 adrenergic receptor antagonist prazosin (20 microg; i.c.v.), alpha-2 adrenergic receptor antagonist yohimbine (30 microg; i.c.v.) and non-specific serotonin receptor antagonist methysergide (20 microg; i.c.v.) pretreatments had no effect on CDP-choline-induced antinociception in the thermal paw withdrawal test and in the mechanical paw pressure test. Therefore, it can be postulated that i.c.v. administered CDP-choline exerts antinociceptive effect mediated by supraspinal opioid and GABA(B) receptors in acute pain models. Furthermore, supraspinal alpha-adrenergic and serotonergic receptors do not appear to be involved in the antinociceptive effect of CDP-choline.

Clozapine Blocks D-Amphetamine-Induced Excitation of Dopamine Neurons in the Ventral Tegmental Area

Current antipsychotic drugs are thought to inhibit central dopamine (DA) transmission by blocking DA receptors. Here, we provide evidence that the atypical antipsychotic drug clozapine may produce part of its effect by inhibiting a subset of excitatory inputs to DA neurons. Thus, in chloral hydrate-anesthetized rats, systemic administration of D-amphetamine produced two opposing effects on DA neurons in the ventral tegmental area. Under control conditions, D-amphetamine inhibited the firing of the cell through D2-like receptors. When D2-like receptors were blocked by raclopride, D-amphetamine excited DA neurons, instead of producing no effect. The excitation, expressed as an increase in firing rate and a slow oscillation in firing pattern, was suppressed by the adrenergic alpha1 receptor antagonist prazosin, suggesting an involvement of alpha1 receptors. In rats pretreated with the typical antipsychotic drug haloperidol, D-amphetamine also excited DA neurons. However, when given after clozapine, D-amphetamine produced no significant effects. The failure of D-amphetamine to produce an excitation is not due to an incomplete blockade of D2-like receptors by clozapine because co-treatment with clozapine and raclopride also failed to enable the excitatory effect of D-amphetamine. The suggestion that clozapine inhibits the excitatory effect of D-amphetamine is further supported by the finding that clozapine, given after D-amphetamine, reliably reversed D-amphetamine-induced excitation in raclopride-treated rats. Thus, different from raclopride and haloperidol, clozapine may inhibit DA transmission through two additive mechanisms: blockade of DA receptors and inhibition of an amphetamine-sensitive, excitatory pathway that innervates DA neurons.

The α2C-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder

Drugs that modify noradrenergic transmission such as atomoxetine and clonidine are increasingly prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). However, the therapeutic targets of these compounds are unknown. Norepinephrine is also implicated in the hyperactivity exhibited by coloboma mice. To identify the receptor subtypes that regulate the hyperactivity, coloboma mice were systematically challenged with adrenergic drugs. The beta-adrenergic receptor antagonist propranolol and the alpha(1)-adrenergic receptor antagonist prazosin each had little effect on the hyperactivity. Conversely, the alpha(2)-adrenergic receptor antagonist yohimbine reduced the activity of coloboma mice but not control mice. Subtype-selective blockade of alpha(2C)-, but not alpha(2A)- or alpha(2B)-adrenergic receptors, ameliorated hyperactivity of coloboma mice without affecting activity of control mice, suggesting that alpha(2C)-adrenergic receptors mediate the hyperactivity. Localized in the basal ganglia, alpha(2C)-adrenergic receptors are in a prime position to impact locomotor activity and are, therefore, potential targets of pharmacotherapy for ADHD.

Role of NMDA receptor subtypes in the induction of catalepsy and increase in Fos protein expression after administration of haloperidol

The increase of Fos expression in the striatum induced by haloperidol, an antagonist of the dopamine D 2 receptor, might be related to the activation of glutamatergic neurotransmission, especially that of N-methyl- d-aspartate (NMDA) receptors. In this study, using behavioral and immunohistochemical techniques, we examined the effects of a noncompetitive NMDA antagonist, (+)-MK-801, and an NMDA receptor NR2B subunit antagonist, ifenprodil, on catalepsy, an extrapyramidal symptom; in this context, we also considered the expression of Fos protein in the forebrain after the administration of haloperidol. Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg). Furthermore, pretreatment with (+)-MK-801 (0.2 mg/kg) significantly attenuated the induction of Fos-immunoreactive (IR) cells in the dorsomedial, dorsolateral, and ventrolateral striatum, but not in the shell region of the nucleus accumbens after the administration of haloperidol, whereas pretreatment with ifenprodil (10 mg/kg) significantly attenuated the induction of Fos-IR cells in all of these areas. It is known that ifenprodil binds σ receptors and α-1 adrenergic receptors with high affinity. Pretreatment with the σ receptor antagonist BD-1407 (3 mg/kg) or the α-1 adrenergic receptor antagonist prazosin (3 mg/kg) affected neither catalepsy nor the expression of Fos-IR cells after the administration of haloperidol. However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol. These results suggest that the NMDA receptor antagonists attenuated the induction of catalepsy and Fos-IR cells in forebrain after the administration of haloperidol. It was also suggested that haloperidol-induced expression of Fos-IR cells in the shell region of the nucleus accumbens might be differentially regulated by NMDA receptor subunits. Therefore, it appears that selective antagonists for the NR2B subunit of the NMDA receptor (e.g., CP-101,606) might be useful drugs for the treatment of extrapyramidal side effects (EPS) associated with the chronic use of typical antipsychotics such as haloperidol.

The fenfluramine metabolite (+)-norfenfluramine is vasoactive.

The anorexigen (+)-fenfluramine was used for treatment of obesity until the association of use with valvular heart disease and primary pulmonary hypertension. (+)-Fenfluramine has been found in Chinese and Korean slimming pills. The hepatic metabolite of (+)-fenfluramine, (+)-norfenfluramine, has affinity for 5-hydroxytryptamine (5-HT)(2A) and 5-HT(2B) receptors. We tested the hypothesis that (+)-norfenfluramine contracts arterial smooth muscle in a 5-HT receptor-dependent manner and acts as a pressor in the conscious rat. Isometric contraction experiments showed that (+)-norfenfluramine (10 nM, 100 microM) but not (+)-fenfluramine nor the isomer (-)-norfenfluramine caused concentration-dependent contraction in arteries [-log EC(50) (moles per liter), thoracic aorta = 5.77 +/- 0.09; renal artery = 6.29 +/- 0.02; mesenteric resistance artery = 5.70 +/- 0.06]. Contraction was dependent on the 5-HT(2A) receptor because ketanserin (10 nM) rightward shifted (+)-norfenfluramine response curves (aorta = 16-fold, renal artery = 26-fold, and resistance artery = >100-fold). Dependence on activation of 5-HT(2A) receptors and independence of (+)-norfenfluramine-induced contraction from stimulation of alpha-adrenergic receptors and the sympathetic nervous system was validated by demonstrating 1) unchanged contraction to (+)-norfenfluramine in arteries from chemically denervated rats; 2) a minimal effect of the alpha(1)-adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT(2) receptor antagonist without alpha-receptor affinity. (+)-Norfenfluramine (10-300 microg/kg i.v.) caused a dose-dependent increase in mean arterial blood pressure in conscious rats, the maximum of which could be virtually abolished by ketanserin (3 mg/kg i.v.) but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for the first time that (+)-norfenfluramine is vasoactive and has the potential to increase blood pressure.

Noradrenergic modulation of ephedrine-induced hypophagia.

The hypophagic action of the sympathomimetic amine ephedrine (EPH) in the rat may reflect actions on central dopaminergic (DA) and noradrenergic (NE) systems. EPH indirectly facilitates DA and NE activity and acts as a partial agonist at alpha(1)-adrenergic receptors. Two approaches were used to assess the possible contribution of NE and DA pathways to EPH-induced hypophagia. In the first, regression analyses of published archival data were computed to characterize the relation between the hypophagic potency values of (-)-(EPH) and related sympathomimetic drugs, including (+)-amphetamine, aminorex, mazindol, and phentermine (data derived from Blosser JC et al., 1987) and the most potent action of these drugs on facilitating NE activity or DA activity in rat brain (data derived from Rothman RB et al., 2001). In the NE analyses, the ED(50) values for these drugs for the inhibition of eating in rats were significantly related (r = 0.91, P = 0.03) to the potency of each drug in facilitating NE activity (either release or inhibition of [(3)H]NE reuptake), whereas in the DA analyses the correlation between ED(50) values and DA activity for these drugs was also significant (r = 0.98, P = 0.003). The regression analyses are thus supportive of a role for NE or DA in the hypophagic capacity of EPH. Although an earlier study noted that administration of the putative DA antagonist pimozide in rats attenuated EPH hypophagia, pimozide exerts similar potency in antagonizing DA receptors and alpha(1)-adrenergic receptors. To clarify the role of alpha(1)-adrenoceptors in EPH-induced hypophagia, adult male rats were pretreated with the alpha(1)-adrenergic receptor antagonist prazosin (0.0.5 and 2 mg/kg) prior to the administration of (-)-EPH (0, 5, 10, or 20 mg/kg, IP). Prazosin pretreatment at 2.0 mg/kg significantly attenuated the hypophagia, but not the hypodipsia, induced by administration of 10 mg/kg and by 20 mg/kg (-)-EPH. Collectively, these results confirm a critical contribution of of alpha(1)-adrenoceptors to the hypophagic action of (-)-EPH in rats.

Host brain regulation of dopaminergic grafts function: role of the serotonergic and noradrenergic systems in amphetamine-induced responses.

The indirect dopaminergic (DA) agonist amphetamine has frequently been used to study functional responses of DA grafted neurons. However, it is not known if striatal responses, primarily related to DA release by the grafted neurons, are modulated by the host striatal afferents. We investigated the changes in amphetamine-induced rotational behavior and striatal expression of Fos in DA-denervated and grafted rats subjected to serotonergic denervation and/or treatment with the alpha(1)-adrenergic receptor antagonist Prazosin. Acute serotonergic lesions with p-chlorophenylalanine suppressed the expression of Fos induced by 1 mg/kg of amphetamine in both the grafted and the contralateral striatum. Chronic serotonergic denervation with 5,7-dihydroxytryptamine induced a significant reduction in Fos expression in both the grafted and nongrafted striata and a nonsignificant reduction in the contraversive rotation. In DA-innervated striata, Prazosin significantly reduced the expression of Fos but only in the presence of serotonergic innervation. However, Prazosin did not decrease the expression of Fos induced by grafts located in striata not subjected to serotonergic denervation. The present results suggest functional integration of transplanted DA neurons and major host striatal afferent systems, particularly the serotonergic system, in modulating responses of the host striatal neurons. However, indirect effects exerted by the noradrenergic system on the normal striatum were not observed in the DA-denervated and grafted striata.

Central α2 adrenergic receptors and cholinergic-induced salivation in rats

Salivation induced by intraperitoneal (i.p.) injections of pilocarpine (cholinergic agonist) is reduced by intracerebroventricular (i.c.v.) injections of moxonidine ( α 2 adrenergic and imidazoline receptor agonist). In the present study, we investigated the involvement of central α 2 adrenergic receptors in the inhibitory effect of i.c.v. moxonidine on i.p. pilocarpine-induced salivation. Male Holtzman rats with stainless steel cannula implanted into the lateral ventricle (LV) were used. Saliva was collected using pre-weighted small cotton balls inserted into the animal’s mouth under ketamine (100 mg kg −1) anesthesia. Salivation was induced by i.p. injection of pilocarpine (4 μmol kg −1). Pilocarpine-induced salivation was reduced by i.c.v. injection of moxonidine (10 nmol) and enhanced by i.c.v. injections of either RX 821002 (160 nmol) or yohimbine (320 nmol). The inhibitory effect of i.c.v. moxonidine on pilocarpine-induced salivation was abolished by prior i.c.v. injections of the α 2 adrenergic receptor antagonists, RX 821002 (160 nmol) or yohimbine (160 and 320 nmol). The α 1 adrenergic receptor antagonist prazosin (320 nmol) injected i.c.v. did not change the effect of moxonidine on pilocarpine-induced salivation. The results suggest that moxonidine acts on central α 2 adrenergic receptors to inhibit pilocarpine-induced salivation, and that this salivation is tonically inhibited by central α 2 adrenergic receptors.

M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague–Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague–Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the α1 adrenergic receptor antagonist prazosin. Furthermore, the α1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the α1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague–Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. [Neuropsychopharmacology 20:311–321, 1999]

Role of G proteins in alpha1-adrenergic inhibition of the beta-adrenergically activated chloride current in cardiac myocytes.

alpha1-Adrenergic receptor stimulation can inhibit the Cl- current activated by beta-adrenergic receptor agonists in guinea-pig ventricular myocytes. We investigated the role of G proteins in mediating this type of alpha-adrenergic response. The combined alpha- and beta-adrenergic agonist norepinephrine (NE) activated the Cl- current with an EC50 value of 53 nM. Preincubation of myocytes with PTX decreased the EC50 value for NE activation of the Cl- current to 5.9 nM, and addition of the alpha1-adrenergic receptor antagonist prazosin did not cause any further change in sensitivity to NE. These results suggest that the alpha1-adrenergic inhibition of beta-adrenergic responses is mediated through a PTX-sensitive G protein. However, PTX pretreatment also increased the sensitivity of the Cl- current to the selective beta-adrenergic agonist isoproterenol (Iso), which indicates that the PTX treatment increases the sensitivity to beta-adrenergic stimulation alone and that this could account for the PTX-induced change in sensitivity to NE. Consistent with this idea, the selective alpha1-adrenergic receptor agonist methoxamine was still able to inhibit the Cl- current activated by Iso in PTX-treated myocytes. However, the sensitivity to methoxamine was significantly decreased. In control cells, the Cl- current activated by 30 nM Iso was inhibited by methoxamine with an EC50 value of 8.3 microM, but in PTX-treated cells, the EC50 value was 284 microM. The EC50 for methoxamine inhibition was similarly increased when the Cl- current was activated by 300 nM Iso. These data suggest that the effects of PTX on alpha1-adrenergic responses can actually be explained by changes in the sensitivity to beta-adrenergic stimulation. To verify the role for a G protein in mediating the inhibitory alpha1-adrenergic response, we examined the effect of methoxamine on the Cl- current activated in cells dialyzed with the nonhydrolyzable GTP analogue guanosine-5'-O-(3-thio)triphosphate. Pre-exposure to methoxamine resulted in an attenuated response upon subsequent exposure to Iso alone. We conclude that alpha1-adrenergic inhibition of beta-adrenergic responses is mediated by a G protein-dependent mechanism that appears to be PTX-insensitive.

Inhibition of Central Sympathetic and Somatic Outflow to the Lower Urinary Tract of the Cat by the Alpha sub 1 Adrenergic Receptor Antagonist Prazosin

Selective alpha sub 1 adrenergic receptor antagonists are used to reduce the dynamic component of urethral obstruction in patients with benign prostatic hyperplasia. Their effectiveness is presumed to result from blockade of alpha 1 adrenergic receptors within the prostatic smooth muscle. However, a reduction in central sympathetic tone to the prostate might also contribute to their effectiveness. The present experiments examined the effects of the selective alpha 1 adrenergic receptor antagonist prazosin on sympathetic activity recorded from the hypogastric nerve in chloralose-anesthetized cats. For comparison, the effects of prazosin were also examined on somatic activity recorded from the pudendal nerve. When the urinary bladder was empty, prazosin reduced spontaneous activity recorded from the hypogastric nerve (to 65 percent of control) and reduced evoked reflex activity recorded from the hypogastric nerve (to 44 percent of control) and the pudendal nerve (to 48 percent of control). Interestingly, when the urinary bladder was filled, the inhibitory effects of prazosin on the pelvic to hypogastric reflex were overcome. These experiments indicate that central noradrenergic neurons mediate a tonic facilitation of sympathetic and somatic activity to pelvic viscera via activation of alpha sub 1 adrenergic receptors. Thus, alpha 1 adrenergic receptor antagonists may reduce the dynamic component of urethral outlet obstruction in patients with benign prostatic hyperplasia through dual mechanisms: first, through a blockade of alpha 1 adrenergic receptors on the prostatic smooth muscle itself and, second, by reducing the activity of the sympathetic neurons that innervate the prostate. Additional therapeutic relief may be provided through reduction of somatic neural activity to the external urethral sphincter, which might also reduce outlet resistance and improve flow.

Inhibition of Central Sympathetic and Somatic Outflow to the Lower Urinary Tract of the Cat by the Alpha sub 1 Adrenergic Receptor Antagonist Prazosin

Inhibition of Central Sympathetic and Somatic Outflow to the Lower Urinary Tract of the Cat by the Alpha sub 1 Adrenergic Receptor Antagonist Prazosin

Suppression of luteinizing hormone release by the α1-adrenergic receptor antagonist prazosin in the ovariectomized female rhesus monkey.

The effects of adrenergic antagonists on LH release were examined in ovariectomized female rhesus monkeys implanted with indwelling jugular catheters. While the α2-adrenergic antagonist rauwolscine and the vehicle were without effect, the α1-antagonist prazosin suppressed LH release. In 5 of the 8 monkeys tested, LH pulses were completely arrested; in the remaining 3 monkeys, small LH pulses were detectable after the administration of 0.2 mg/kg prazosin. In a second series of experiments, the effects of three different doses of prazosin were examined. Doses of 0.1 mg/kg and 0.4 mg/kg suppressed LH release in a manner indistinguishable from that of the 0.2 mg/kg dose. Finally, the ability of the pituitary to respond to a bolus of LHRH during the prazosin-induced suppression was tested. In all 6 animals, the injection of LHRH during the time when LH was suppressed by prazosin resulted in a marked increase in LH release. These results indicate 1) that α1-adrenergic receptors but not α2 receptors are important for pulsatile LH secretion, 2) that varying the dose of prazosin administered does not alter the effect of the drug or LH release within the range of doses tested, and 3) the pituitary is able to respond to LHRH with an increase in LH release during the prazosin-induced suppression period.

Cardiovascular profile and hypotensive mechanism of ketanserin in the rabbit.

Using the radioactive microsphere technique, we studied the systemic and regional hemodynamic effects of ketanserin in conscious renal hypertensive rabbits. To characterize the hypotensive mechanism of the compound, we evaluated its antagonism toward 5-hydroxytryptamine2 and alpha 1-adrenergic receptors at hypotensive doses and compared the cardiovascular profile of ketanserin with that of the alpha 1-selective adrenergic receptor antagonist prazosin. Ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) produced a biphasic effect on the arterial blood pressure. A short, pronounced fall in blood pressure accompanied by tachycardia preceded a more moderate and longer lasting dose-related hypotensive effect. The presence of adequate autonomic nervous system activity seems to be required for the prolonged hypotensive action of ketanserin because, in animals pretreated with hexamethonium (30 mg/kg), the blood pressure, after an initial decrease, returned to baseline values within a few minutes after each ketanserin dose. Ketanserin inhibited the pressor responses produced by 5-hydroxytryptamine (10, 30, and 100 micrograms/kg i.v.) and phenylephrine (3, 10, and 30 micrograms/kg i.v.), which indicates that, at hypotensive doses, the compound antagonized both 5-hydroxytryptamine2 receptors and alpha 1-adrenergic receptors. At doses that caused a comparable degree of alpha 1-adrenergic receptor blockade, ketanserin (0.1, 0.3, and 1.0 mg/kg i.v.) as well as prazosin (0.01, 0.03, and 0.10 mg/kg i.v.) decreased the blood pressure as a result of a reduction in total peripheral resistance. While cardiac output increased, especially at the lower doses of ketanserin, a moderate decrease in this variable contributed to the hypotensive effect of the highest dose of prazosin. Both compounds decreased the vascular resistance in the kidneys, gastrointestinal tract, and bones, whereas that in the skin and skeletal muscles was not significantly altered. In contrast to prazosin, ketanserin also caused vasodilatation in the coronary and cerebral vascular beds.(ABSTRACT TRUNCATED AT 250 WORDS)