Central beta 1-adrenergic receptors are involved in CRF-induced defensive withdrawal

Previous studies indicated that peripheral administration of propranolol, a nonselective beta-adrenergic antagonist, attenuated ICV CRF-induced suppression of a conditioned emotional response and defensive withdrawal behavior in rats, suggesting the involvement of a beta-adrenergic receptor in the CRF-induced behavioral changes. The present study was carried out to determine whether central or peripheral beta-adrenergic receptors are involved in CRF-induced defensive withdrawal behavior, and which subtype of beta-adrenergic receptor is involved. l-Propranolol (2.5 mg/kg IP) significantly reversed CRF-induced defensive withdrawal behavior. CGP-12177 (1 mg/kg IP), a beta-adrenergic antagonist with predominant effects on peripheral beta-adrenergic receptors, and ICI 118,551 (0.5 mg/kg IP), a selective beta 2-adrenergic antagonist, had no significant effects on CRF-induced defensive withdrawal. When administered ICV, two selective beta 1-adrenergic antagonists, CGP-20712A (10 micrograms) and atenolol (100 micrograms), significantly antagonized CRF-induced defensive withdrawal. Our results suggest that a central beta 1-adrenergic receptor is involved in CRF-induced defensive withdrawal in rats.     

Effect of beta-adrenergic antagonists on the spontaneous appetite for NaCl solution in rats

Chronic dietary administration of the beta-adrenergic antagonist, propranolol (1.6-2.0 g/kg), to both male and female rats induced an appetite for 0.25 M NaCl solution when the rats were offered a choice between distilled water and salt solution to drink. Treatment was also accompanied by a significant reduction in both water and food intakes. In addition, increases in intake of NaCl solution during treatment with propranolol were correlated significantly with increases in urinary sodium output. To test for completeness of beta-adrenergic blockade, treated and control rats in the first study were administered isoproterenol (25 micrograms/kg b.w., SC) acutely and given only water to drink. The increased 1 hr water intake characteristically accompanying acute administration of isoproterenol was blocked completely by propranolol. Additional experiments were carried out with butoxamine, a selective beta 2-adrenoceptor antagonist, (1.5 and 3.0 g/kg of food) to determine its effect on intake of 0.25 M NaCl solution. Butoxamine failed to produce a significant effect on salt appetite. The results indicate that chronic treatment with propranolol, but not butoxamine, induces an appetite for NaCl solution. They further suggest, but do not prove, that beta 1-adrenoceptors may be involved in the appetite for NaCl solutions in rats.     

On the mechanism of serotonin-induced dipsogenesis in the rat

Subcutaneous administration of l-5-hydroxytryptophan (5-HTP), the precursor of serotonin, to female rats induces copious drinking accompanied by activation of the renin-angiotensin system. Neither a reduction in blood pressure nor body temperature accompanied administration of 5-HTP. The objective of the present study was to determine whether serotonin-induced dipsogenesis, like that of 5-HTP, is mediated via the renin-angiotensin system. Serotonin (2 mg/kg, SC)-induced drinking was inhibited by the dopaminergic antagonist, haloperidol (150 micrograms/kg, IP), which also inhibits angiotensin II-induced drinking. Both captopril (35 mg/kg, IP), an angiotensin converting enzyme inhibitor, and propranolol (6 mg/kg, IP), a beta-adrenergic antagonist, blocked serotonin-induced dipsogenesis. The alpha 2-adrenergic agonist, clonidine (6.25 micrograms/kg, SC), which suppresses renin release from the kidney, attenuated serotonin-induced water intake. The dipsogenic responses to submaximal concentrations of both serotonin (1 mg/kg, SC) and isoproterenol (8 micrograms/kg, SC) were additive rather than interactive suggesting that similar pathways mediate both responses. The serotonergic receptor antagonist, methysergide (3 mg/kg, IP), inhibited serotonin-induced drinking but had no effect on isoproterenol (25 micrograms/kg, SC)-induced dipsogenesis. However, neither serotonin (2 mg/kg, SC) nor isoproterenol (25 micrograms/kg, SC)-induced drinking was inhibited by cinanserin (25 micrograms/kg, IP). These data indicate that serotonin induces drinking in rats via the renin-angiotensin system. However, the results of the studies using methysergide suggest that serotonin appears to act at a point prior to activation of beta-adrenoceptors in the pathway leading to release of renin from the kidneys.     

L-5-hydroxytryptophan-induced drinking in rats: Possible mechanisms for induction

Administration of L-5-hydroxytryptophan (25 mg/kg body weight, SC) to female rats resulted in copious drinking. The dipsogenic response to administration of L-5-hydroxytryptophan (5-HTP) was blocked by propranolol (6 mg/kg body weight, IP), a β-adrenergic antagonist, and captopril (35 mg/kg body weight, IP), an angiotensin converting enzyme inhibitor. In addition, clonidine (12.5 and 25 μg/kg body weight, IP), a central α-adrenergic agonist known to inhibit renin release, attenuated drinking during 1, 2 and 3 hours after 5-HTP was administered. These results suggest that 5-HTP-induced drinking is mediated by way of the renin-angiotensin system. Haloperidol (150 μg/kg body weight, IP), a dopaminergic antagonist, also attenuated the dipsogenic response to administration of 5-HTP. In addition, incremental reductions in 5-HTP-induced drinking with increasing doses of spiperone (37.5 to 150 μg/kg body weight, IP), a more potent dopaminergic antagonist, were demonstrated. Thus, the dipsogenic response to administration of 5-HTP to rats is dependent on both the renin-angiotensin system and an intact dopaminergic pathway.     

Bethanechol-induced water intake in rats: possible mechanisms of induction

Acute administration of the parasympathomimetic agent, bethanechol, at 2, 4, 8 and 12 mg/kg body wt, IP, induced drinking and increased urine output of rats in a dose-dependent fashion. The first significant increases in both water intake and urine output above that of controls occurred when 4 mg/kg was administered. The drinking and increased urine output in response to administration of 8 mg bethanechol/kg was inhibited by atropine sulfate (3 and 6 mg/kg, IP). In addition, the beta-adrenergic antagonist, propranolol (6 mg/kg, IP, administered 30 min prior to treatment with bethanechol), inhibited bethanechol (8 mg/kg, IP)-induced drinking. Urine output, however, was unaffected by propranolol. Further, the angiotensin I converting enzyme inhibitor, captopril, inhibited significantly the drinking response, but not the increased urine output, accompanying administration of bethanechol (8 mg/kg). The effect of bethanechol and the beta-adrenergic agonist, isoproterenol (25 micrograms/kg) separately and in combination, on water intake was also studied. Both compounds increased water intake but they exerted no interactive effect when administered simultaneously. Administration of bethanechol (8 mg/kg) to conscious rats was also accompanied by a significant reduction in both mean blood pressure and heart rate that reached minimal levels within 10 min after treatment. Both responses had returned to control level by one hr after treatment. These results suggest that bethanechol induces drinking in rats by way of the renin-angiotensin system.     

Effects of four beta-adrenergic receptor antagonists on male rat sexual behavior

Antihypertensive medication has been reported to cause serious sexual side effects in men. Frequently mentioned as causing sexual dysfunction are beta-adrenergic receptor antagonists. The purpose of this study was to examine in detail the effects of beta blockers on adult male rat sexual behavior. Thirty minutes following a single subcutaneous injection of propranolol, pindolol, atenolol or labetalol, mating tests were conducted. The mixed beta 1- and beta 2-adrenergic antagonists, propranolol and pindolol, profoundly inhibited male sexual behavior. At the 5 and 10 mg/kg doses, propranolol inhibited ejaculatory behavior to the extent that only 9.1 and 8.3% respectively showed the behavior while pindolol reduced this behavior to 36.4% (16 mg/kg). These drugs also adversely affected various parameters of behavior in a dose-dependent manner. The selective beta 1 antagonist, atenolol, had only minor effects and labetalol even less so at the doses tested. It was suggested that the strongly inhibitory effects of propranolol and pindolol on male rat sex behavior may well be due to their 5-HT1A antagonistic binding properties rather than their beta-antagonistic properties.     

Involvement of beta2-adrenergic and mu-opioid receptors in antinociception produced by intracerebroventricular administration of alpha,beta-methylene-ATP

The present study examined what kind of receptors are involved in the antinociception produced by intracerebroventricular (i.c.v.) administration of a,beta-methylene-ATP using antagonists at adrenergic, serotonin or opioid receptors. Antinociceptive effect of alpha,beta-methylene-ATP (10 nmol/rat) was significantly attenuated by subcutaneous pretreatment with propranolol and naloxone, but not phentolamine or methysergide, at a dose of 10 mg/kg. I.c.v. pretreatment with propranolol (100 nmol/rat), butoxamine (100 nmol/rat), ICI-I 18,551 (100 nmol/rat) and naloxone (30 nmol/rat) significantly attenuated the antinociceptive effect of alpha,beta-methylene-ATP. However, i.c.v. pretreatment with atenolol (100 nmol/rat), naltrindole (30 nmol/rat) or nor-binaltorphimine (30 nmol/rat) did not show any significant effects. These results suggest that supraspinal beta2-adrenergic and mu-opioid receptors are involved in the antinociceptive effect of i.c.v. administered alpha,beta-methylene-ATP.     

Effects of the beta-2 adrenergic agonist zinterol on DRL behavior and locomotor activity

The purpose of the present study was to assess the behavioral effects of the beta adrenergic agonist zinterol and to determine whether its actions were mediated by beta adrenergic receptors. Zinterol reduced response rate and increased reinforcement rate of rats under a differential-reinforcement-of-low-rate schedule in a dose-dependent manner; significant decreases in response rate and increases in reinforcement rate were observed at doses of 0.1–1 mg/kg. The effect of 0.3 mg/kg zinterol on this behavior was blocked by pretreatment with the beta adrenergic antagonist propranolol. Zinterol also reduced locomotor activity in a dose-dependent manner; significant reductions were observed at doses of 0.3–10 mg/kg. Similarly, the effect of 1 mg/kg zinterol on locomotor activity was antagonized by propranolol. These effects of zinterol were similar to those of other beta adrenergic agonists as well as those of antidepressant drugs. Although the site of action (central versus peripheral) of zinterol was not determined in the present study, an experiment was carried out to determine if zinterol could act centrally after peripheral administration. The ability of repeated, systemic administration of zinterol to reduce the density of beta adrenergic receptors in cerebral cortex and cerebellum was determined. Repeated treatment with a high dose of zinterol (10 mg/kg, IP) reduced the density of beta adrenergic receptors in these brain regions, suggesting that, at least under certain conditions, systemically administered zinterol did have access to the central nervous system.     

Exercise-induced increase in plasma arachidonic acid and thromboxane B2 in healthy men: effect of beta-adrenergic blockade

We examined the effects of beta-blockade with the nonselective antagonist propranolol, the cardioselective antagonist atenolol, and the cardioselective antagonist with partial agonist activity, practolol, on the levels of free arachidonic acid (AA), thromboxane B2 (TxB2), prostaglandin (PG) E2, and 6-keto-PGF1 alpha in plasma, and TxB2 production by platelets during clotting in six normal subjects during submaximal dynamic exercise. The drugs were given intravenously in equipotent increasing doses before the exercise test. Exercise induced a clear increase in AA, TxB2, and 6-keto-PGF1 alpha in plasma. During the first 60 min of exercise all three beta-blockers decreased the plasma levels of AA and TxB2. Propranolol (0.19 mg/kg) was slightly more effective than atenolol (0.19 mg/kg) or practolol (0.64 mg/kg); however, at exhaustion, propranolol was markedly more effective than the other two blockers. Plasma 6-keto-PGF1 alpha and PGE2 levels were less affected by beta-blockade during exercise, and no significant effect was seen on TxB2 formation by platelets. The plasma 6-keto-PGF1 alpha/TxB2 ratio was markedly higher after propranolol treatment than after treatment with the other two blockers during the exercise period. These results suggest that the capability of a nonselective blocker to inhibit both beta 1- and beta 2-adrenergic receptors may be of advantage because of the more effective inhibition of thromboxane formation than with a cardioselective blocker, especially when the sympathetic tone is markedly increased.     

β-adrenergic antagonists attenuate withdrawal anxiety in cocaine-and morphine-dependent rats

Rats were treated chronically with either cocaine (20 mg/kg/day, 14 days), morphine (incrementing doses of 10 mg/kg/day to 80 mg/kg, 11 days) or saline. During morphine or cocaine abstinence (48 h), dependent rats showed increased anxiety-like behavior in a conditioned defensive burying paradigm as evidenced by significantly shorter latencies to begin burying as well as a 4-fold increase in burying duration relative to salinetreated animals. This withdrawal-induced increase in burying behavior was blocked by pretreatment with either the -adrenergic antagonist propranolol (5 mg/kg) or the lipophobic selective ₁-antagonist, atenolol (5 mg/kg). These results are consistent with the possibility that activation of peripheral ₁ receptors may substantially contribute to withdrawal-induced anxiety and that -adrenergic antagonists could be useful in treating in cocaine and morphine dependent addicts.     

Effect of chronic treatment with estrogen on the dipsogenic response of rats to angiotensin

Female rats treated with estradiol benzoate for 23 weeks at doses of 25 and 44 μg/kg/day had an attenuated drinking response to peripheral administration of graded doses of angiotensin I and angiotensin II. No significant difference between the responses of the two estrogen-treated groups was observed, suggesting that maximal attenuation had been attained with the lower dose. Angiotensin II (50, 100 and 200 μg/kg, IP) increased urine output and urinary sodium excretion rate in a graded fashion with increasing doses in both control and estrogen-treated rats. However, the latter had a somewhat greater response. Administration of angiotensin I (50, 100 and 200 μg/kg, SC) had a similar, but less consistent, effect on urine output and urinary sodium excretion rate in both control and estrogen-treated groups. The attenuated drinking response of estrogen-treated rats to angiotensin I and angiotensin II suggests either that administered angiotensin failed to gain access to the brain or that central receptors mediating thirst are less sensitive in estrogen-treated rats. The present studies fail to distinguish between these possibilities.     

Observations on the mechanism underlying the differences in exercise and isoprenaline tachycardia after cardioselective and non-selective beta-adrenoceptor antagonists

1 Differences in ability to attenuate isoprenaline tachycardia between the cardioselective beta-adrenoceptor antagonist atenolol and the non-selective drug propranolol, when administered in equivalent anti-exercise tachycardia oral doses, were measured in four normal volunteers. 2 Propranolol at all dose comparisons showed a greater potency in antagonism of isoprenaline tachycardia than atenolol; this ranged from 6 at the lowest doses (40 and 50 mg respectively) to 13 at the highest doses (320 and 400 mg respectively). 3 After doses of each drug which produced equal inhibition of exercise tachycardia, isoprenaline induced a greater increase in heart rate and greater decrease in diastolic blood pressure after pre-treatment with atenolol than after propranolol. 4 The contribution of this isoprenaline induced vasodilatation to the reduced tachycardia response, 1 h after 25 mg oral atenolol, was measured in the same four subjects by correction of the hypotension with an intravenous angiotensin infusion. Reversal by angiotensin of the 17 mm Hg average fall in diastolic blood pressure during the sustained isoprenaline infusion did not reduce the tachycardia. 5 The hypotension that results from isoprenaline stimulation of unblocked vasodilator beta 2-adrenoceptors in normal subjects pre-treated with atenolol appears to make a negligible contribution to the tachycardia response and does not explain the different abilities of cardioselective and non-selective beta-adrenoceptor blocking drugs to antagonise isoprenaline tachycardia. Our results are compatible with the presence of beta 2-adrenoceptors in human atria.     

Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat

Effects of the new cardiotonic and selective beta 1-adrenergic agonist TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, on circulating concentrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg (ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective beta-adrenergic antagonist) and practolol (a selective beta 1-adrenergic antagonist). The non-selective beta-adrenergic agonist isoproterenol and the selective beta 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective beta 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.     

In vivo evidence that isoproterenol may increase heart rate in the rat by mechanisms in addition to activation of cardiac beta(1)- or beta(2)-adrenoceptors

This study demonstrates that the tachycardia produced by systemic injections of the beta-adrenoceptor agonist, isoproterenol (10 microg/kg, i.v.), in conscious rats were not reduced after injection of the selective beta(1)-adrenoceptor antagonist, atenolol (1 mg/kg, i.v.), or after subsequent injection of the beta(1,2)-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.). The hypotensive responses produced by isoproterenol were slightly diminished by atenolol and markedly diminished by propranolol. The tachycardia produced by catecholamines released for cardiac sympathetic nerve terminals were blocked by atenolol. These results suggest that the hypotensive actions of a 10 microg/kg dose of isoproterenol are mediated by activation of beta(1,2)-adrenoceptors whereas the increases in heart rate may be due to activation of another type of beta-adrenoceptor in cardiac pacemaker cells.     

The importance of choice of agonist in studies designed to predict β 2:β 1 adrenoceptor selectivity of antagonists from pA2 values on guinea-pig trachea and atria

1. pA2 values have been obtained for propranolol, butoxamine, H35/25 and atenolol on guinea-pig isolated trachea and atria (rate) using noredrenaline (beta 1-selective), isoprenaline (non-selective) and fenoterol (beta 2-selective) as agonists. 2. pA2 values varied with the agonist used on trachea but not on atria and, therefore, trachea : atria selectivity values varied with the agonist used. 3. It is suggested that the best estimate of the selectivity of an antagonist between beta 2- and beta 1-adrenoceptors is obtained by comparing its pA2 value obtained on trachea using a beta 2-selective agonist with that obtained on atria using a beta 1-selective agonist. The reasons for this are discussed. 4. The quantitative values for beta 2 : beta 1 selectivity obtained using the above pA2 values were butoxamine 17.0 H35/25 13.5, propranolol 2.75 and atenolol 0.036, i.e. butoxamine and H35/25 were beta 2-selective, propranolol was non-selective and atenolol was beta 1-selective. 5. The results support the hypotheses that guinea-pig trachea contains a mixture of beta 1- and beta 2-adrenoceptors and that guinea-pig atria contain only beta 1-adrenoceptors.     

Influence of beta-adrenoceptor agonists and antagonists on baclofen-induced memory impairment in mice

Post-training administration of different doses of baclofen (a GABAB agonist) has been shown to impair memory retention, in a step-down passive avoidance test in mice. We have studied the effects of beta-adrenergic agonists and antagonists on baclofen-induced memory impairment in mice. Dobutamine (a beta 1-agonist) or salbutamol (a beta 2-agonist) reversed the memory impairment induced by baclofen without exhibiting intrinsic actions on memory when administered alone. The administration of atenolol (a beta 1-antagonist) or propranolol (a beta-antagonist) produced a memory impairment. When co-administered with baclofen, both atenolol and propranolol exacerbated the memory impairment induced by the GABAB agonist. It is concluded that beta-adrenergic mechanisms may be involved in the modulation of memory via GABAB receptors.     

Continued pharmacologic analysis of consummatory behavior in the albino rat

In continuation of the pharmacological analysis of consummatory behavior in the albino rat, it was established that the mechanisms of the response to peripherally injected serotonin, namely copious drinking and simultaneous inhibition of the urine flow, is closely related to that of the β-adrenergic agonist isoproterenol.In 23-hr food deprived rats, peripheral serotonin (1.0 mg/kg, s.c.) like isoproterenol (0.1 mg/kg, s.c.), caused a more than 50% inhibition of the one hour food intake, which like the drinking was obviated by propranolol and enhanced by tolazoline. In contrast, the almost equipotent anorexic effect of peripheral d-amphetamine (0.5 mg/kg, s.c.) remained unaltered by the same α- and β-adrenergic blockade. Direct application to the perifornical hypothalamus of isoproterenol (30 μg) or serotonin (18 μg) elicited highly significant inhibition of the food intake, which was likewise obviated by central pretreatment with propranolol and enhanced by tolazoline. The close similarity of effects upon eating behavior obtained with the peripheral and central route of administration are interpreted as evidence for the existence of β-adrenergically coded satiety circuits.The central dipsogenic activity of angiotensin II was inhibited by pretreatment of the intracerebral site with tolazoline but not by phenoxybenzamine, phentolamine, propranolol or atropine, whereas chlorpromazine produced exaggeration of water intake. Peripheral administration of atropine (5 mg/kg, s.c.), on the other hand, dramatically reduced the intracerebral dipsogenic activity of angiotensin II, whereas methylatropine was without effect, suggesting that cholinergically coded circuits are involved in the mediation of angiotensin-induced drinking.Since peripheral atropine (5 mg/kg, s.c.) had no effect on drinking elicited by peripheral isoproterenol, it is concluded that angiotensin does not constitute the final mediator in the brain of thirst evoked by systemic β-adrenergic activation.     

Anterior hypothalamic beta-adrenergic activity in the maintenance of hypertension in aortic coarctated rats.

The aim of this work was to demonstrate an alteration of the anterior hypothalamic catecholaminergic system in aortic coarctated (ACo) rats by the perfusion of beta-adrenergic antagonist and the microinfusion of beta-adrenergic agonist. Wistar urethane-chloralose anesthetized rats were used. The carotid artery was cannulated for blood pressure recording and changes in blood pressure were measured. A concentric microdialysis probe was inserted in the anterior hypothalamus. Metoprolol (a beta(1)-adrenoceptor antagonist) perfusion (6 microg ml(-1)) reduced the mean arterial pressure (MAP) in the ACo rats but not in sham operated (SO) animals. The anterior hypothalamic infusion of non-specific beta-adrenergic agonist isoproterenol induced a dose-dependent decrease of blood pressure in both experimental groups, but the depressor response was significantly lower in ACo rats. The pretreatment with atenolol, a selective beta(1)-adrenoceptor antagonist, increased the depressor effect of isoproterenol in ACo rats, but not in SO rats. On the other hand, the hypotensive action of isoproterenol was significantly diminished after the administration of non-specific beta-adrenoceptor antagonist propranolol in SO and ACo rats. The anterior hypothalamic infusion of clenbuterol, a selective beta(2)-adrenergic agonist, induced a dose-dependent decrease of blood pressure in both experimental groups. The depressor response to clenbuterol (1 nmol) was significantly lower in ACo rats than in SO rats.In summary, this study provides the evidence that there is a beta(1)-adrenergic compromise in anaesthetized ACo rats and this compromise may be involved in the maintenance of hypertension. On the other hand, this study also suggests the existence of pressor beta(1)-adrenoceptors in the anterior hypothalamic area of ACo rats but not in SO rats. We also found a diminished depressor beta(2)-adrenergic activity in ACo rats.     

Disease-drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

Inflammatory conditions reduce clearance, hence increase plasma concentration of drugs such as propranolol that are efficiently cleared by the liver. The therapeutic consequences of this increased plasma drug concentration is mainly unknown. However, for sotalol, another beta-adrenergic antagonist, inflammation causes reduced potency. Sotalol, however, is renally cleared; hence, its clearance is unaffected by inflammation. We examined if the inflammation-induced increased plasma propranolol concentration compensates for the reduced responsiveness. A modified lead I ECG was used to record PR interval and heart rate (HR). ECG was monitored following oral administration of 3, 5, 10, 15, 20, 25, and 30 mg/kg propranolol to both control and adjuvant arthritis (AA) rats. To confirm altered pharmacokinetics, single 25 mg/kg doses of propranolol were administered to both AA and control rats, with an inserted cannula in their right jugular vein for serial blood sampling. As expected, AA caused a significant reduction in the propranolol oral clearance and subsequently substantial increases in plasma total and unbound drug concentration. Interestingly, however, despite the elevated propranolol concentrations, the effect on HR remained unchanged and the prolongation of PR interval was significantly reduced in AA compared with control rats. The reduced sensitivity to propranolol in AA rats is suggestive of altered beta-adrenergic receptors function.     

Effects of full and partial beta-adrenergic agonists and antagonists on human lung adenylate cyclase

The beta-adrenergic stimulation of adenylate cyclase in membranes from human lung was compared to that of adenylate cyclase in membranes with a majority of beta 2-adrenergic receptors (from rat lung) and in membranes with a homogeneous population of beta 2-adrenergic receptors (from rat erythrocytes and reticulocytes). In terms of adenylate cyclase stimulation, three full agonists (isoproterenol, epinephrine and norepinephrine), four partial agonists (procaterol, salbutamol, fenoterol and zinterol), and four antagonists (propranolol, metoprolol, atenolol and practolol) were tested. The potency (Kact or Ki) of the eleven beta-adrenergic agents, and the Hill coefficient (of 1) for the four antagonists tested indicated that the activation of human lung adenylate cyclase occurred through receptors of the beta 2-subtype only. Partial beta-adrenergic agonists were efficiently discriminated by the human lung preparation, as shown by distinct intrinsic activities. The mediocre efficacy and the relatively low potency of all beta-adrenergic agonists on adenylate cyclase suggested a relatively low density of beta 2-adrenergic receptors, as compared to the enzyme density.