Non-selective Beta-adrenoceptor Antagonist Research Articles

β‐ADRENOCEPTOR MEDIATED SECRETION OF ACTIVE AND INACTIVE RENIN IN CONSCIOUS SHEEP

1. Beta-adrenoceptor linked regulation of plasma active and inactive renin was investigated in sheep with indwelling artery, vein and bladder catheters. Concurrent changes in renal function were also monitored. 2. The beta-adrenoceptor agonist isoprenaline (bolus intravenous (i.v.) dose 0.5 mg/kg, 0.05 microgram/kg per min) increased plasma active renin concentration within 15 min and reached a plateau increase of 306%. Initially plasma inactive renin remained unchanged but after 105 min it decreased. 3. The non-selective beta-adrenoceptor antagonist propranolol (bolus i.v. dose 4 mg/kg, 40 micrograms/kg per min) did not significantly alter basal plasma active renin but selectively reduced inactive renin. The absence of any change in active renin may reflect the relatively low level of stress-induced sympathetic activation in these conscious animals compared to equivalent studies carried out on human subjects. 4. Using the same dose schedules, propranolol completely blocked the isoprenaline-induced increases in plasma active renin secretion even though it had no effect on the basal active renin levels. 5. The selective beta 1-adrenoceptor antagonist atenolol (bolus i.v. dose 5 mg/kg) decreased basal plasma active renin by 24% (+ 135 min) but reduced plasma inactive renin by 75% compared to control. 6. Therefore, both a beta-adrenoceptor agonist (isoprenaline) and two beta-adrenoceptor antagonists (propranolol and atenolol) decreased plasma inactive renin concentration in conscious sheep. 7. These results are discussed in relation to the accompanying changes in arterial blood pressure and aspects of renal function.

Role of adrenoceptors in vitro and in vivo in the effects of lithium on blood glucose levels and insulin secretion in the rat

1. Pretreatment of rats with the non-selective alpha-adrenoceptor antagonist dihydroergotamine counteracts the inhibition of glucose-induced insulin secretion caused by lithium both in vitro and in vivo. The present study was therefore carried out to specify further which type of adrenoceptor is involved in lithium-induced hyperglycaemia and inhibition of insulin secretion. 2. The lithium-induced effects were reversibly blocked by pretreatment of rats with the alpha 2-adrenoceptor antagonist yohimbine or a combination of yohimbine and the non-selective beta-receptor antagonist propranolol, whereas the alpha 1-receptor antagonist prazosin and propranolol alone were ineffective in blocking these effects. 3. These findings suggest that the effects of lithium on plasma glucose and insulin levels are mediated mainly by the stimulation of alpha 2-adrenoceptors.

Effect of calcium and beta‐adrenoceptor antagonists on beta‐ adrenoceptor density and Gs alpha expression in human atria.

In 21 patients undergoing open heart surgery the effects of the beta-adrenoceptor antagonists propranolol and sotalol and the calcium antagonist nifedipine (alone or in combination) on right atrial beta-adrenoceptor density and G protein expression were studied. The non-selective beta-adrenoceptor antagonists increased both right atrial beta 1- and beta 2-adrenoceptor density; this increase was not affected by nifedipine. There was no correlation between beta-adrenoceptor density and expression of the G protein subunit Gs alpha suggesting independent regulation of the gene expression for G proteins and their coupled receptors.

Further Evidence of Interaction Between Vasodilator β2- and Vasoconstrictor α2-Adrenoceptor–Mediated Responses in Maintaining Vascular Tone in Anesthetized Rats

The importance of the interaction of alpha- and beta-adrenoceptors in maintaining vascular tone in rats was studied. This interaction after clenbuterol (CLEN) treatment indicates an important contribution of the circulating epinephrine (EPI) levels. In urethane-anesthetized rats, the beta 2-adrenoceptor antagonist ICI 118.551 was more effective in antagonizing isoproterenol-induced hypotension (mainly beta 2-mediated) than tachycardia (mainly beta 1-mediated). Intravenous (i.v.) administration of the alpha 2-adrenoceptor agonist clonidine (CLO) induced an initial pressor response followed by a more prolonged hypotension and bradycardia. The initial hypertensive effect was potentiated by previous acute administration of ICI 118.551 as well as by the nonselective beta-adrenoceptor antagonist propranolol, but not by metoprolol, a more selective beta 1-blocker. Fourteen days of administration of the beta 2-adrenoceptor agonist CLEN [0.3 mg/kg, subcutaneously (s.c.) twice daily], a treatment that induces desensitization of beta 2-mediated vasodilation, increased the pressor response induced by CLO, an effect that was not observed in pentobarbital-anesthetized rats. In any case, neither beta-blockers nor CLEN treatment affects the hypotension and bradycardia induced by CLO. Mean blood pressure (BP) of CLEN-treated rats was increased under urethane anesthesia but not under pentobarbital anesthesia. Catecholamine levels (principally EPI) were higher in urethane-anesthetized rats. These results provide further evidence of a functional interaction between alpha 2- and beta 2-adrenoceptor-mediated responses in rat vasculature and suggest that vasodilator beta 2-adrenoceptors might contribute to the determination of peripheral vascular tone when circulating EPI is substantially elevated.

Enhanced Presynaptic β2 Adrenoceptor–Mediated Facilitation of the Pressor Responses in the Prehypertensive SHR

The effects of beta-adrenoceptor agonists and antagonists on pressor responses of the isolated perfused mesenteric arteries to periarterial nerve stimulation (PNS) in the prehypertensive 4-week-old spontaneously hypertensive rat (SHR) and the age-matched Wistar Kyoto rats (WKY) were examined. The systolic arterial blood pressure (SBP) of SHR and WKY were not significantly different at this young age. The pressor responses of the mesenteric arteries to PNS at various stimulating frequencies, however, were significantly greater in SHR than WKY. Cocaine, isoproterenol (a nonselective beta-adrenoceptor agonist) and salbutamol (a selective beta 2-adrenoceptor agonist) significantly enhanced the pressor responses to PNS in SHR and WKY, with significantly greater increase in SHR than WKY. The nonselective beta-adrenoceptor antagonist (propranolol) and the selective beta 2-adrenoceptor antagonist (ICI 118,551) significantly inhibited the pressor response to PNS in SHR without affecting that in WKY. The selective beta 1-adrenoceptor antagonist (practolol) was without effect on the PNS-induced pressor responses in both SHR and WKY. These results demonstrate that the presynaptic beta 2-adrenoceptor-mediated facilitation of neurogenic pressor response in mesenteric arteries already are enhanced in 4-week-old SHR. In view of the higher concentration of circulating epinephrine (Epi) in prehypertensive SHR, the enhanced facilitatory modulation via presynaptic beta 2-adrenoceptors in prehypertensive SHR may be involved in development of hypertension.

Adrenaline-induced enhancement of the blood pressure response to sympathetic nerve stimulation in adrenal demedullated pithed rats

The influence of the prejunctional beta-adrenoceptor-mediated control mechanism of noradrenaline release on the cardiovascular response to preganglionic nerve stimulation (PNS) and the role of adrenaline as endogenous activator of this facilitatory mechanism were studied in pithed rats. The increases in mean arterial blood pressure and heart rate responses to eight PNS (0.8 Hz, 1 ms, 75 V, for 20 s at 12 min intervals) were measured in control, adrenal demedullated and sham-operated pithed rats, respectively. Repeated stimuli of the sympathetic outflow elicited similar blood pressure responses in control and sham-operated rats, whereas the blood pressure responses were attenuated in adrenal demedullated rats. Administration of the non-selective beta-adrenoceptor antagonist propranolol (5 mg x kg-1, i.v.) decreased the blood pressure response in control, but not in adrenal demedullated rats. The increase in heart rate during PNS was abolished in both groups after administration of propranolol. Infusion of adrenaline (0.06 microgram x kg-1 x min-1) increased the circulation levels of adrenaline from 0.4 nmol x l-1 to 4.8 nmol x l-1, but did not modify the blood pressure response to PNS in control rats. In adrenal demedullated rats, however, the blood pressure response to PNS was enhanced during as well as after the infusion of adrenaline. This facilitatory effect of adrenaline on the blood pressure response in adrenal demedullated rats was blocked by pretreatment with propranolol (5 mg x kg-1, i.v.). Taken together the present findings give further support to the hypothesis that neuronal adrenaline of adrenal medullary origin is the endogenous agonist at prejunctional beta-adrenoceptors mediating a facilitation of neuronal noradrenaline release.

In vivo studies on the function of cardiac -adrenoceptors in man

The original Lands classification considered cardiac beta-adrenoceptors to be predominantly beta 1 in type and to respond to both noradrenaline and adrenaline. Radioligand binding studies subsequently identified substantial numbers of beta 2-adrenoceptors in cardiac tissue. Studies in man employing intensive exercise, isoprenaline testing and a variety of selective and non-selective beta-adrenoceptor antagonists would now suggest that under certain circumstances these receptors may be functionally active. Severe exercise, as a sympathetic stimulus, is associated with high circulating noradrenaline concentrations, and appears to produce tachycardia predominantly by cardiac beta 1-adrenoceptor activity. In contrast, isoprenaline testing increases heart rate by a number of mechanisms: it stimulates beta 1-adrenoceptor activity in the sinoatrial node; it may result in reflex vagal withdrawal; and it appears to stimulate cardiac beta 2-adrenoceptors directly. In addition, isoprenaline also facilitates noradrenaline release by presynaptic beta 2-adrenoceptors. Thus the effects of isoprenaline would appear to mimic stress in man with the subsequent release of adrenaline from the adrenal medulla and its complex interaction directly and indirectly with both cardiac beta 1 and beta 2-adrenoceptors. These differing circumstances may also influence the relative efficacy of beta 1-selective and non-selective beta-adrenoceptor agonists and antagonists.

Coexistence and localization of 1- and 2-adrenoceptors in the human heart

Quantitative autoradiography was used to determine the location and density of beta 1- and beta 2-adrenoceptors in the right atrium (RA), left ventricular free wall (LVFW), right ventricular free wall (RVFW), interventricular septum (IVS), right atrium from an area near the atrioventricular node (RAAV) and cardiac nerves (N) taken from a patient with end-stage cardiac failure. The densities of beta-adrenoceptors detected by the non-selective beta-adrenoceptor antagonist radioligand (-)-[125I] cyanopindolol (50pM) were 4.93 (N), 10.6 (RVFW), 12.2 (RA), 12.4 (IVS), 15.8 (LVFW) and 18.7 fmol (mg protein)-1 (RAAV). The proportion of beta 2-adrenoceptors ranged from 19.5% (RAAV) to 95% (N). RA taken from patients with ischaemic heart disease had a higher density of beta-adrenoceptors (29.3 fmol (mg protein)-1). The results suggest that both beta 1- and beta 2-adrenoceptors are down-regulated in patients with end-stage cardiac failure. Positive inotropic responses were established to (-)-isoprenaline, RO363 (beta 1-selective), procaterol (beta 2-selective) and dopexamine in the absence or presence of the antagonist CGP 20712A (beta 1-selective) or ICI 118,551 (beta 2-selective) in electrically driven human right atrial appendage strips. RO363 and procaterol were nearly full agonists in this preparation and produced their responses through activation of beta 1- or beta 2-adrenoceptors, while dopexamine was a partial agonist which produced its inotropic responses through activation of both receptor subtypes. These studies demonstrate the presence and location of beta 1- and beta 2-adrenoceptors in the human heart.

Subtype-selective up-regulation of human saphenous vein \2-adrenoceptors by chronic \-adrenoceptor antagonist treatment

To study beta-adrenoceptor antagonist-induced changes in human vascular beta-adrenoceptors, we determined the effects of chronic treatment with different beta-adrenoceptor antagonists without intrinsic sympathomimetic activity (ISA) on beta 2-adrenoceptor density (assessed by (-)-[125I]-iodopindolol binding) in human saphenous vein membranes obtained from patients undergoing coronary artery bypass grafting. In patients chronically treated with the non-selective beta-adrenoceptor antagonists propranolol or sotalol, the density of saphenous vein beta 2-adrenoceptors was significantly higher than in control (i.e. patients not treated with beta-adrenoceptor antagonists), whereas in patients chronically treated with the selective beta 1-adrenoceptor antagonists metoprolol or bisoprolol it was not different from control. It is concluded that beta-adrenoceptor antagonists without ISA increase human saphenous vein beta 2-adrenoceptors in a subtype-selective fashion.

Propranolol antagonizes hypotension induced by α-blockers but not by sodium nitroprusside or methacholine

A pressor response has been observed with propranolol, a nonselective beta-adrenoceptor antagonist, in animals given a nonselective alpha-adrenoceptor antagonist. This study investigates whether a pressor response to propranolol occurs in conscious unrestrained rats following a hypotensive response induced by phentolamine (nonselective alpha-antagonist), prazosin (selective alpha 1-antagonist) and (or) rauwolscine (selective alpha 2-antagonist), sodium nitroprusside (smooth muscle relaxant), or methacholine (muscarinic agonist). The rats were subjected to a continuous infusion of a hypotensive agent or normal saline followed by i.v. injection of propranolol. The infusion of phentolamine significantly decreased mean arterial pressure (MAP). Subsequent injection of propranolol restored MAP to the control level. Prazosin and rauwolscine each caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a significant decrease in MAP. Subsequent injection of propranolol caused a large pressor response which increased MAP to 20% above control MAP prior to the administration of drugs. Nitroprusside or methacholine each caused a significant decrease in MAP, but the hypotension was not antagonized by propranolol. The concurrent infusions of a low dose of nitroprusside and prazosin caused a significant decrease in MAP which was reversed by propranolol. The infusion of saline did not alter MAP, and propranolol did not cause a pressor response. It is concluded that propranolol antagonizes the hypotensive effect of an alpha-blocker but not that of sodium nitroprusside or methacholine. Our results suggest the presence of a specific interaction between alpha- and beta-antagonists.

Involvement of central alpha- and beta-adrenoceptors in the pressor response to electrical stimulation of the rostral ventrolateral medulla in rats.

1. Electrical stimulation of the C1 area of the rostral ventrolateral medulla in rats elicits an increase in mean arterial pressure (MAP). 2. This increase in MAP is attenuated by intra-hypothalamic and intracisternal administration of the non-selective beta-adrenoceptor antagonist (+/-)-propranolol and the beta 2-selective antagonist ICI 118551. 3. The selective beta 1-antagonist atenolol and (+)-propranolol, which is inactive on beta-adrenoceptors, did not alter the increase in MAP produced by stimulation of the C1 area. 4. The alpha 2-adrenoceptor antagonist idazoxan enhanced the effects of C1 stimulation on MAP when administered either into the posterior hypothalamus or intracisternally. 5. The results indicate that beta 2- and alpha 2-receptors both have a role in the mediation of the rise in MAP during stimulation of the C1 area and that the receptors involved are located both within the hypothalamus and the spinal cord.

Presynaptic beta 2-adrenoceptors on the sympathetic nerve fibres of the human saphenous vein: no evidence for involvement in adrenaline-mediated positive feedback loop regulating noradrenergic transmission.

Spirally cut strips of human saphenous veins preincubated with 3H-noradrenaline were superfused in the presence of corticosterone and, unless stated otherwise, of cocaine or desipramine. Tritium overflow was stimulated electrically (2 Hz). Adrenaline (in the presence of rauwolscine), isoprenaline and the preferential beta 2-adrenoceptor agonist procaterol concentration-dependently increased the electrically evoked tritium overflow. Prenalterol, a beta-adrenoceptor agonist with moderate preference for beta 1-adrenoceptors, was ineffective. The concentration-response curve of isoprenaline was shifted to the right by the nonselective beta-adrenoceptor antagonist propranolol and by the preferential beta 2-adrenoceptor antagonist ICI 118,551, but was not affected by the beta 1-selective antagonist atenolol. In experiments on strips preexposed to adrenaline 10 nmol/l (i.e. a concentration higher than that which normally occurs in vivo) for 32 min in the absence of cocaine or desipramine, the electrically evoked 3H overflow was not affected 12 and 44 min after withdrawal of adrenaline, irrespective of whether propranolol was absent or present in the superfusion fluid. In veins incubated with 3H-adrenaline, a considerable amount of the radioactivity was accumulated. During subsequent superfusion with 3H-adrenaline-free solution, electrical stimulation induced tritium overflow in a tetrodotoxin-sensitive manner. Propranolol failed to modify the evoked tritium overflow. It is concluded that the sympathetic nerve fibres of the human saphenous vein are endowed with facilitatory presynaptic beta 2-adrenoceptors. These receptors do not seem to play a substantial role in a local adrenaline (previously taken up)-mediated positive feedback loop regulating noradrenergic transmission, at least under the present in vitro conditions.

Pharmacological characterization of human ciliary muscle adrenoceptors in vitro

The in vitro pharmacological characteristics of adrenoceptors of the human ciliary muscle were investigated. Tissue was obtained from 30 eyes used previously for corneal transplantations which had been enucleated 6-24 hr after death. Experiments were performed within 2 days of enucleation. Strips of the meridional and circular portion of the ciliary muscle were attached to a tension gauge in an organ bath and the effect of drugs added to the perfusion medium was monitored isometrically. The muscle was precontracted with physostigmine (10(-5) M) and acetylcholine (10(-5) M). The non-selective beta adrenoceptor agonist isoproterenol (10(-6)-10(-3) M) caused a dose-related relaxation of the ciliary muscle, an effect which was completely inhibited by the non-selective beta adrenoceptor antagonist timolol (10(-5) M), while the beta 1 adrenoceptor antagonist betaxolol (10(-5) M) had no effect. The beta 2 adrenoceptor agonist salbutamol (10(-6)-10(-3) M) produced a dose-related relaxation of the ciliary muscle, an effect which was completely blocked by the beta 2 adrenoceptor antagonist L1 32-468 (10(-5) M). The non-selective alpha adrenoceptor agonist noradrenaline (10(-6)-10(-3) M) also caused a dose-related relaxation of the ciliary muscle. The non-selective alpha adrenoceptor antagonists phentolamine (10(-5) M) and thymoxamine (10(-5) M) and the alpha 1 adrenoceptor antagonist prazosin (10(-5) M) partially blocked the response to noradrenaline, while the alpha 2 adrenoceptor antagonist idazoxan (10(-5) M) and timolol (10(-5) M) had no effect. The alpha 1 adrenoceptor agonist phenylephrine (5 X 10(-6)-5 X 10(-3) M) caused a dose-dependent relaxation in five out of 12 isoproterenol-sensitive muscle strips. Further, it was not possible to block the phenylephrine-induced relaxation with thymoxamine (10(-5) M). The alpha 2 adrenoceptor agonist clonidine (10(-6)-10(-3) M) had no effect. No qualitative difference between drug effects on the meridional and circular ciliary muscles was observed. We conclude from these data that beta 2, and most probably alpha 1, adrenoceptors are present on both the meridional and circular portions of the ciliary muscle of the human eye.

Whole-body composition in patients with angina pectoris receiving long-term treatment with the nonselective beta-receptor blocking drug nadolol.

Nadolol is a nonselective beta-adrenergic receptor antagonist used on a long-term basis for therapy of angina and hypertension. It has been reported to increase renal blood flow in humans. Theoretically, this could lead to an increase in glomerular filtration rate and improved renal sodium handling. The present study was designed to test whether patients receiving long-term nadolol therapy exhibited changes in whole-body composition that might arise as a consequence. Nine nadolol recipients with angina were followed for up to one year, and serial assessments were made of glomerular filtration rates and whole-body composition using in vivo neutron activation analysis to assess nitrogen, oxygen, sodium, potassium, chlorine, phosphorous, and calcium. No significant changes in these elements were observed. We conclude that any effect of nadolol on renal blood flow in short-term studies is not associated with significant changes in body composition measured over a period of one year.

ChemInform Abstract: Indole‐Phenol Bioisosterism. Synthesis and Antihypertensive Activity of a Pyrrolo Analogue of Labetalol.

AbstractDas Pyrrolo‐Analogon (XIa) des Labetalols (XII) wird ausgehend vom N‐Acetylindolin (I) entsprechend dem Formelschema in einer vielstufigen Reaktionssequenz hergestellt.

Indole-phenol bioisosterism. Synthesis and antihypertensive activity of a pyrrolo analogue of labetalol.

The synthesis of 5-[hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1H-indole-7- carboxamide, 5, a pyrrolo analogue of labetalol, is described. Compound 5 was found to reduce blood pressure in spontaneously hypertensive rats with an ED50 of 5 mg/kg po, without causing any decrease in heart rate. Isolated tissue studies with 5 shows that it is a nonselective beta-adrenoceptor antagonist and that it is a weaker alpha-adrenoceptor antagonist with a relative selectivity for alpha 1-receptors. Additionally, the compound displayed significant beta-adrenoceptor intrinsic sympathomimetic activity. Evidence is presented that the beta-adrenoceptor antagonist and agonist properties of 5 are mediated via hydrogen-bond formation with the receptor.

Beta-adrenoceptor antagonists (non-selective as well as beta 1-selective) with partial agonistic activity decrease beta 2-adrenoceptor density in human lymphocytes. Evidence for a beta 2-agonistic component of the partial agonistic activity.

In the present study the effects of pindolol [non-selective beta-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on beta 2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the beta 1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA. Administration of pindolol (2 X 5 mg/day) caused an about 25% decrease in lymphocyte beta 2-adrenoceptor density after 2 days; during treatment beta 2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte beta 2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte beta 2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3 X 40 mg/day) indicating that the PAA of pindolol is the cause of its beta-adrenoceptor decreasing effect. Administration of the non-selective beta-adrenoceptor antagonist bopindolol (1 X 2 mg/day) with PAA caused decreases in lymphocyte beta 2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 mumol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the beta-adrenoceptor antagonist-induced decrease in beta-adrenoceptor density is accompanied by a loss in beta-adrenoceptor function.(ABSTRACT TRUNCATED AT 250 WORDS)

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Effect of Propranolol, Alprenolol, Pindolol, and Bopindolol on β2-Adrenoceptor Density in Human Lymphocytes

Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound effects." To investigate the position of the new nonselective beta-adrenoceptor antagonist bopindolol [with moderate intrinsic sympathomimetic activity (ISA)], this drug was compared with propranolol (no ISA), alprenolol (weak ISA), and pindolol (marked ISA). The effects on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]iodocyanopindolol (ICYP) binding--were investigated in healthy volunteers aged 23-35 years. None of the test drugs changed the affinity of ICYP for beta 2 adrenoceptors. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; during treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol, beta 2-adrenoceptor density declined slowly, being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h, though heart rate was significantly increased. Alprenolol treatment (4 X 100 mg/day) did not significantly affect beta 2-adrenoceptor density. Pindolol treatment (2 X 5 mg/day) caused a 50% decrease of beta 2-adrenoceptor density after 2 days, which remained reduced during treatment. After withdrawal, beta 2-adrenoceptor density was still significantly diminished after 4 days. During and after treatment heart rate was not affected. Bopindolol treatment (2 mg/day) caused a 40% decrease of beta 2-adrenoceptor density after 2 days, which remained reduced during treatment. After withdrawal, beta 2-adrenoceptor density was still significantly diminished after 4 days. During and after treatment heart rate was not affected. It is concluded that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blockade of beta 1- but not of beta 2-adrenergic receptors replicates propranolol's suppression of the cerebral spread of an engram in mice.

Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal area induce amnesia of aversive maze-learning in mice for 3 days after training but are ineffective 6 or more days after training. At these later times, additional puromycin sites covering widespread forebrain areas are necessary to induce amnesia, a result that we attribute to the cerebral spread of the engram during the 6-day period. We have reported that blockade of about 60% of cerebral beta-adrenergic receptors by a single, subcutaneous injection of (-)-propranolol, a nonselective beta-receptor antagonist, inhibited engram spread for 60-90 days, at which time engram spread spontaneously occurred. In the present experiments using single doses of antagonists that appeared to block 60% of beta 2- or beta 1-adrenergic receptors, it was found that the selective beta 2 antagonist ICI 118,551 was without effect on engram spread, whereas the selective beta 1 antagonist betaxolol inhibited the spread for at least 3 months. Propranolol's effect consequently appears to be accounted for by its blockade of beta 1 receptors.