Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys

• 1.1. The effects of barnidipine, a new dihydropyridine Ca²⁺ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys.
• 2.2. Barnidipine (0.3–3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr.
• 3.3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph.
• 4.4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration.
• 5.5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

     

A cardiovascular monitoring system used in conscious cynomolgus monkeys for regulatory safety pharmacology. Part 2: Pharmacological validation

INTRODUCTION: This project addresses the validation study design of a test system using a telemetered non-human primate model for cardiovascular safety pharmacology evaluation. METHODS: In addition to non-pharmacological validation including installation and operation qualifications, performance qualification (locomotor activity and cardiovascular evaluations) was completed on free-moving cynomolgus monkeys by quantifying the degree of cardiovascular response measured by the telemetric device to various positive control drugs following their intravenous administration. Remifentanil (0.0005, 0.001, 0.002, 0.004, 0.008 and 0.016 mg/kg) was given to induce bradycardia and hypotension. Medetomidine (0.04 mg/kg) was used to induce an initial phase of hypertension followed by hypotension and bradycardia. Esmolol (0.5, 1.0 and 2.0 mg/kg) was used to induce bradycardia. Dopamine (0.002, 0.008, 0.01, 0.02, 0.03 and 0.05 mg/kg/min) was infused over 30 min to induce an increase in arterial and pulse pressures and tachycardia. Amiodarone (0.4, 0.8 and 1.6 mg/kg/min) was infused over 10 min to induce QT interval prolongation. Potassium chloride (0.08 mEq/kg/min) was infused for periods of less than 30 min to induce electrocardiographic (EKG) changes characteristic of hyperkalemia. Reliability was evaluated over 60 days. RESULTS: Monitoring with a reference methodology and the telemetry system was important in order to evaluate precision and accuracy of the test system. Positive control drugs produced a wide range of cardiovascular effects with different amplitudes, which were useful in identification of the limits of the test system. DISCUSSION: Reference monitoring methods and selection of a battery of positive control drugs are important to ensure proper test system validation. Drugs inducing not only QT prolongation but also positive and negative chronotropic effects, positive and negative systemic arterial pressure changes and ECG morphology alterations were useful to identify test system limitations during performance qualification. ECG data processing at significantly elevated heart rates revealed that a trained observer should review all cardiac cycles evaluated by computer.     

Behavioral effects of D-Ala2-beta-endorphin in squirrel monkeys.

The effects of D-Ala2-beta-endorphin administered either intravenously (IV) or intracisternally (IC) in squirrel monkeys were tested using a number of behavioral measures: general activity, eating, social behavior, aggression/distress, analgesia, and startle/escape. There were 10 groups (N = 5) consisting of 4 dose levels administered IC (0.4, 40, 400 microgram/kg) and 6 dose levels injected IV (0, 4, 40, 80, 400, 800 microgram/kg). Every monkey was tested with all tasks on each of 5 identical repeated trials, one pre-injection baseline trial and 4 post-injection trials. After IC administration, the 2 largest doses exerted toxic effects, which were partially reversed with naloxone, producing in 2 cases muscular rigidity and profound sedation. The smaller 4 microgram/kg dose produced significant decreases in activity over trials but increased reactivity to noxious stimulation after the initial post-injection trial. With IV injection reliable changes in activity and approach to food were found. The results demonstrate significant behavioral effects of an endorphin analog in the squirrel monkeys after both central and peripheral injection.     

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.     

Reinforcing effects of smoked methamphetamine in rhesus monkeys

Rationale The occurrence of methamphetamine (METH) use by the smoking route is increasing. A nonhuman primate model for examining the reinforcing effects of smoked METH would be valuable for testing potential interventions for treating METH abuse disorders.Objective The purpose of the present study was to examine the reinforcing effects of smoked METH in monkeys.Materials and methods Four rhesus monkeys were trained to smoke cocaine (COC) under a chain fixed-ratio (FR) 64 lever press, FR 5 inhalation schedule of reinforcement. Upon observing stable levels of self-administration, METH was substituted for COC and a dose-response function for METH (0.08–0.8 mg/kg) was determined. Subsequently, the number of deliveries of COC (1 mg/kg), and 0.2 and 0.8 mg/kg METH were examined across increasing response requirements.Results METH was dose-dependently self-administered. Higher doses of METH (0.2, 0.4, and 0.8 mg/kg) produced asymptotic levels of responding that were slightly lower than those obtained with 1 mg/kg COC. Numbers of deliveries of COC and METH decreased as response requirement increased. METH, however, maintained fewer deliveries than 1 mg/kg COC at most response requirements.Conclusions METH is readily self-administered by smoking in rhesus monkeys when substituted for COC. METH may have a lower reinforcing strength than COC, but further research is needed to fully characterize its relative reinforcing strength.An erratum to this article can be found at     

Central cardiovascular effects of acetylcholine in the conscious dog.

1. The effects of central cholinomimetic drugs on cardiovascular and vasoactive hormonal responses (blood pressure, heart rate, catecholamines, vasopressin, atrial natriuretic factor, neuropeptide Y plasma levels and plasma renin activity) were investigated in conscious Beagle dogs. For this purpose a catheter was chronically implanted into each dog's cisterna magna to allow repeated central injections in the awake animals. 2. Intracisternal acetylcholine (20 micrograms kg-1) significantly increased systolic and diastolic blood pressure. These changes were accompanied by an initial short term tachycardia followed by a long lasting bradycardia. Intracisternal acetylcholine also increased noradrenaline, adrenaline and vasopressin plasma levels, decreased plasma renin activity but did not modify plasma levels of neuropeptide Y and atrial natriuretic factor. 3. The effects of acetylcholine were completely abolished by pretreatment with intracisternal injection of the muscarinic antagonist, atropine (5 micrograms kg-1) but not by the intracisternal injection of the nicotinic antagonist, mecamylamine (25 micrograms kg-1). 4. The present results demonstrate that there are qualitative and quantitative differences between the central cardiovascular effects of acetylcholine in conscious dogs compared to what we previously reported, using a comparable protocol, in anaesthetized dogs. Under both conditions, we observed a central cholinergically mediated increase in blood pressure secondary to an increase in sympathetic tone and vasopressin release but these responses were shorter (less than 10 min) in the conscious dogs than in anaesthetized dogs (more than 10 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys.

Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an alpha(2)-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct alpha(2)-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1-0.56 mg/kg, i.m.) or RS-79948 (0.01-0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the alpha(2)-adrenoceptor agonist clonidine (0.1-0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of alpha(2)-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.     

The effects of methamphetamine on fine motor control in rhesus monkeys.

Six rhesus monkeys were trained to extend their arms through a tube to press a lever with between 25 and 40 g of force for 3 or 5 sec. Responding was maintained by the delivery of 1.5 cc of water. Stimulus lights indicated whether the exerted force was below 25 g. between 25 and 40 g (i.e., correct) or above 40 g. Sessions were terminated after 50 water deliveries or 30 min had elapsed. Performance was well-maintained in all monkeys. Allowing the animals access to water prior to the session had no effect on performance. Discontinuing sessions for two weeks disrupted some aspects of performance but responding improved within 5 sessions. Single injections of methamphetamine (0.06-0.5 mg/kg) were given IM 20 min prior to the session. The highest dose of 0.5 mg/kg totally eliminated responding. Lower doses decreased rate of responding somewhat and increased phasic activity (i.e., tremors) in a dose-dependent manner. The procedure seems ideally suited for investigating the effects of psychotropic drugs on fine motor control in rhesus monkeys.     

Cardiovascular effects of intracerebroventricular norepinephrine in conscious and anaesthetized monkeys.

Norepinephrine, infused into the third cerebral ventricle of 7 restrained, unanaesthetized rhesus monkeys, evoked dose-related increases in systemic arterial pressure at each of three different (30 sec, 5 min or 1 hr) infusion times and rates. Anaesthetic doses of sodium pentobarbital blocked, but did not reverse, the presser response. A series of 6-hydroxydopamine injections (31 mg over an 11-day period) given centrally to 3 monkeys led to a steady reduction of basal blood pressures and pulse rates (?18 and ?16 mm Hg systolic and diastolic and ?34 beats/min during the second week after the last injection) and blocked the effects of centrally, but not intravenously, administered norepine- phrine. The monkeys had intense sympathomimetic response to the initial injection of 1 mg of 6-hydroxydopamine, but became progressively tachyphylactic to subsequent higher doses. The results suggest that noradrenergic nerves near the lateral and third ventricles of primates play an important role in controlling both acute and chronic levels of systemic arterial blood pressure.     

Discriminative stimulus effects of inhaled cocaine in squirrel monkeys

Squirrel monkeys (N=4) were trained with food reinforcement to press one of two levers after administration of IV cocaine (0.3 or 1.0 mg/kg) or the other lever after saline. After training, IV cocaine (0.03–3.0 mg/kg) produced dose-related increases in the percentage of responses on the cocaine lever (ED₅₀=0.15 mg/kg). Cocaine delivered IM also produced dose-related increases in cocaine-appropriate responding (ED₅₀=0.32 mg/kg), but was approximately half as potent as IV cocaine. Similar relative potency relations were obtained for decreases in response rates produced by cocaine. Prior to some sessions subjects were placed in a Plexiglas^® chamber and exposed for 60 s to cocaine vapor created with an ultrasonic nebulizer. Exposure to vapor from cocaine solutions (1.0–30.0 mg/ml) produced concentration-dependent increases in cocaine-appropriate responding and decreases in response rates. Exposure to vapor from a 30 mg/ml concentration produced virtually exclusive cocaine-appropriate responding. Concentration-effect curves for inhaled cocaine were similar to dose-effect curves obtained when cocaine was administered by the other routes. The time course of the minimally effective concentration of inhaled cocaine was compared to that of the minimally effective doses of systemically administered cocaine. Inhaled cocaine had a duration of action longer than IV cocaine. The results indicate that inhaled cocaine vapor has effects qualitatively similar to those of IV cocaine, and may have a duration of action longer than that of an IV cocaine dose producing a similar degree of drug-appropriate responding.     

Physostigmine-insensitive behavioral excitatory effects of atropine in squirrel monkeys

Lever press responses of squirrel monkeys were maintained under a multiple schedule in which the first response after 3 min produced either food or electric shock depending on the prevailing stimulus. Atropine sulfate (0.3-3 mg/kg, IM) given immediately before experimental sessions disrupted the temporal pattern of responding and produced dose-related decrease in rates of food- and shock-maintained responding. Increases in responding occurred when 1 mg/kg atropine was given 1 to 12 hr prior to experimental sessions. A maximal increase of 200% of control rates was seen following the 2-hr pretreatment. Qualitatively similar effects were obtained with scopolamine suggesting that the time-dependent increases may be a general consequence of muscarinic receptor blockade. Response patterning changes and response rate increases were also produced by coadministration of atropine and physostigmine both given immediately before the session. Increases in rates of responding have also been observed previously after administration of atropine with rate-decreasing doses of the direct-acting muscarinic agonist oxotremorine. Physostigmine did not reverse the rate increases or the alteration in temporal patterning produced by the 2-hr atropine pretreatment; rate decreases induced by immediate pretreatment with atropine were blocked by physostigmine. Thus, the response rate-decreasing effects of atropine were distinct from its rate-increasing effects. Whereas the rate-decreasing effects of atropine appear to involve muscarinic receptors, increases in responding may not. Such nonmuscarinic behavioral excitatory actions of atropine may be expressed when the muscarinic-related decreases are blocked by physostigmine or oxotremorine, or when the decreases are overridden by excessive nonmuscarinic stimulation, perhaps triggered by time-dependent changes in acetylcholine turnover associated with atropine.     

Behavioral effects of chronically administered cocaine in squirrel monkeys

Cocaine (0.1 or 0.3 mg/kg/h) was infused continuously from osmotic minipumps during 14-day periods in three squirrel monkeys trained under a fixed-interval schedule of stimulus-shock termination. Chronic exposure to 0.1 mg/kg/h cocaine increased response rates during control sessions for two subjects, and rates returned to pre-infusion levels after the osmotic minipumps were removed. During chronic administration with 0.3 mg/kg/h cocaine, tolerance developed to the gross behavioral effects observed initially in all subjects and to the rate-suppressing effects observed in one subject. Using a cumulative-dosing procedure, cocaine was administered IV acutely once per week before, during and after each chronic administration with cocaine. The acute effects of cocaine on schedule-controlled responding before chronic administration and during chronic exposure to 0.1 and 0.3 mg/kg/h cocaine were similar, providing no evidence of sensitization or tolerance.Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1985     

Discriminative stimulus effects of intravenous nicotine in squirrel monkeys

Three squirrel monkeys were trained to emit one response after IV administration of nicotine (0.1 or 0.18 mg/kg depending on the subject) and a different response after IV administration of saline. Subjects emitted nicotine-appropriate responses with substitutions of higher doses, but only emitted saline-appropriate responses after substitutions of lower doses. Discrimination performance was then maintained at 0.1 mg/kg of nicotine in all subjects. Neither morphine nor cocaine substituted for the effects of nicotine in any subjects across a range of doses up to those that suppressed responding. Ethyl-beta-carboline-3-carboxylate, an inverse agonist at the benzodiazepine receptor, substituted or partially substituted for nicotine in both subjects in which it was studied.     

Serotonergic modulation of the discriminative-stimulus effects of cocaine in squirrel monkeys

 In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03–1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipa- zine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT₂-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys. Received: 15 May 1996 / Final version: 14 February 1997     

Distinctive behavioral effects of the pyrazoloquinoline CGS 8216 in squirrel monkeys

The behavioral effects of the pyrazoloquinoline CGS 8216 were studied in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of food presentation. Dose-effect curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the FI schedule. CGS 8216 (0.1-3.0 mg/kg) produced dose-related decreases in the rate of FI responding. In comparison, diazepam (0.1-3.0 mg/kg) had biphasic effects under identical conditions: intermediate doses increased the rate, whereas high doses decreased the rate of FI responding. Pretreatment with the benzodiazepine antagonist Ro 15-1788 (3.0 or 5.6 mg/kg) attenuated the decreases in response rate normally produced by high doses of CGS 8216. The behavioral effects of CGS 8216 were not altered systematically by pretreatment with either diazepam (0.3-3.0 mg/kg) or the alpha 2-adrenergic agonist clonidine (0.01-0.03 mg/kg). The results suggest that CGS 8216 has benzodiazepine inverse agonist effects on schedule-controlled behavior of squirrel monkeys. CGS 8216 can, however, be distinguished from inverse agonists of the beta-carboline type on the basis of its effects in the presence of diazepam or clonidine.     

Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Mu and delta opioid receptors modulate the reinforcing effects of ethanol, however, their role in the subjective effects of ethanol is not well understood. This study evaluated the contribution of mu and delta opioid receptors to the subjective effects of ethanol using drug discrimination procedures. Monkeys were trained to discriminate ethanol from saline under a schedule of food delivery. In tests, ethanol engendered increases in drug-lever responding, reaching a maximum of > 80%. The mu opioid receptor agonists fentanyl and buprenorphine and the delta opioid receptor agonists SNC 80 and SNC 162 did not substitute for the discriminative stimulus effects of ethanol. As pretreatments, the full agonists fentanyl and SNC 80 enhanced the effects of low doses of ethanol and fentanyl attenuated the effects of the ethanol training dose. Although the possibility of pharmacological antagonism of the effects of ethanol cannot be ruled out, a more likely alternative is that the diminished effects of ethanol were due to perceptual masking of the ethanol stimulus. In contrast, the partial agonists buprenorphine and SNC 162 did not alter ethanol's effects. Finally, the discriminative stimulus effects of ethanol were attenuated following administration of presumably mu-selective doses of the antagonist naltrexone, but not after administration of the delta opioid receptor antagonist naltrindole. The ability of naltrexone to block the discriminative stimulus effects of ethanol likely reflects its capacity to attenuate ethanol-induced increases in endogenous opioids, in particular beta-endorphin, because attenuation of the ethanol stimulus was not accompanied by significant suppression of response rate.     

Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms

RATIONALE AND OBJECTIVES: Opioid agonists frequently have been reported to share discriminative stimulus (DS) effects with cocaine; however, the pharmacological basis of these shared effects is not understood completely. The present study assessed the ability of heroin and its deacetylated metabolites, 6-monoacetylmorphine (6-MAM) and morphine, to engender cocaine-like DS effects and investigated the role of opioid receptor subtypes in modulating these DS effects. METHODS: Squirrel monkeys were trained to discriminate 0.3 mg/kg cocaine (i.m.) from vehicle under a 10-response fixed-ratio schedule of food reinforcement, and responding on the drug lever was assessed after varying i.m. doses of heroin, 6-MAM, and morphine. The potential role of opioid receptor mechanisms in modulating the cocaine-like DS effects of heroin and its metabolites was assessed with the mixed mu/kappa opioid antagonist naltrexone, the delta-selective antagonist naltrindole, and the kappa-selective antagonist nor-binaltorphimine. RESULTS: Heroin, 6-MAM, and morphine engendered dose-related increases in responding on the cocaine lever in three of four monkeys. Naltrexone shifted the dose-response functions for heroin and its metabolites to the right, and in vivo apparent pA2 analyses revealed that naltrexone antagonized the effects of the opioids in a manner consistent with mu receptor antagonism (apparent pA2 values ranging from 8.20 to 8.47). Naltrindole only minimally altered the dose-response functions of heroin, 6-MAM, and morphine, whereas nor-binaltorphimine did not block the cocaine-like DS effects of the three opioid agonists, suggesting that neither delta nor kappa receptors played a prominent role in the cocaine-like DS effects of heroin and its metabolites. CONCLUSIONS: These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.     

Central noradrenergic mechanisms and the cardiovascular effects of intracerebroventricular (+)- and (−)-propranolol in the conscious rabbit

Intracerebroventricular (?)-propranolol in the conscious rabbit produced a transient increase in mean arterial pressure followed by a prolonged depressor response. Pretreatment with intracisternal 6-hydroxydopamine diminished the rise in mean arterial pressure and abolished the late fall. Intravenous infusion of (+)-propranolol also produced a depressor response which could be attenuated by 6-hydroxydopamine pretreatment. The role of central noradrenergic neurones in these responses was further studied using the (+)-isomer which produces only the early pressor effect. Depletion of central noradrenaline by intracerebroventricular reserpine, blockade of Uptake₁ by intracerebroventricular desmethylimipramine and antagonism of alpha-adrenoceptor function by intracerebroventricular yohimbine reduced or abolished the pressor response and tachycardia following centrally administered (+)-propranolol. An increase in mean arterial pressure and heart rate was also observed when a second dose of (+)-propranolol was given 30 min after an initial intracerebroventricular injection of the drug. Central injection of desmethylimipramine also produced an increase in mean arterial pressure.These studies suggest that propranolol is taken up into central noradrenergic neurones via the Uptake₁ mechanism and causes the release of endogenous noradrenaline which exerts a pressor effect. These noradrenergic neurones may also mediate the late hypotensive response produced by the (?)-isomer.