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PubMed1982

Cardiac hyper- and hyporesponsiveness after pindolol withdrawal.

Abrupt withdrawal of some beta-adrenergic blockers has resulted in clinical syndromes suggestive of adrenergic hypersensitivity that may be due to an adaptive increase in cardiac beta-receptor responsiveness. it was postulated that the partial agonist activity of pindolol might limit enhanced responsiveness of cardiac beta receptors and prevent or diminish withdrawal manifestations. Pindolol was given to 10 hypertensive patients in doses of 10 mg b.i.d. for at least 4 wk, then abruptly replaced with placebo for 20 days. Cardiac chronotropic responsiveness to isoproterenol was decreased on pindolol and gradually returned to normal over 10 to 20 days with no evidence of enhanced responsiveness. In contrast, both resting and exercise heart rate showed rebound increase in responsiveness between the second to sixth day after pindolol (P less than 0.05). Resting and exercise blood pressures gradually rose to stable values without rebound. Plasma norepinephrine and epinephrine and serum thyroxine and triiodothyronine did not change. These data show that abrupt withdrawal of pindolol after long-term dosing leads to transient cardiac hyperresponsiveness of resting and exercise heart rate at the same time as persistent cardiac hyporesponsiveness to isoproterenol. These opposite effects of pindolol on subsets of cardiac beta-adrenergic chronotropic receptors.

Adult↗
PubMed2000

Effects of chronic fluoxetine treatment in the presence and absence of (+/-)pindolol: a microdialysis study.

Using in vivo microdialysis in the frontal cortex of the freely moving rat we evaluated the effects of chronic treatment with the serotonin specific reuptake inhibitor (SSRI) fluoxetine in the presence and absence of the 5-HT(1A)/beta-adrenergic antagonist (+/-)pindolol. Chronic vehicle treated animals produced no significant response to a challenge with fluoxetine (10 mg kg(-1)) on day 8 and 15. Alternatively, a significant (P<0.05) decrease in extracellular 5-HT was observed in control animals upon challenge with the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.03 and 0.1 mg kg(-1)). Conversely, animals treated with fluoxetine (10 mg kg(-1) o.d.) for 7 and 14 days produced a significant (P<0.05) 2 fold increase in extracellular 5-HT when challenged with fluoxetine (10 mg kg(-1)) on day 8 and 15. Moreover, no significant decrease in extracellular 5-HT was observed upon challenge with either dose of 8-OH-DPAT. Animals chronically treated with (+/-)pindolol (10 or 20 mg kg(-1) b.i.d.) produced a significant dose-related increase in extracellular 5-HT upon challenge with fluoxetine on day 15 only. Furthermore, both doses produced a significantly blunted response to the low dose challenge of 8-OH-DPAT (0.03 mg kg(-1)). In addition, 20 mg kg(-1) (+/-)pindolol treated animals also had no response to the higher 0.1 mg kg(-1) dose of 8-OH-DPAT. Animals treated for 14 days with a combination of (+/-)pindolol (10 or 20 mg kg(-1)) and fluoxetine were not significantly different from vehicle treated animals when challenged with fluoxetine or 8-OH-DPAT. Taken together it would therefore appear that although (+/-)pindolol alone has sufficient intrinsic activity to produce a desensitization of the 5-HT(1A) receptor, when given in combination with fluoxetine it is able to prevent the desensitization induced by not only fluoxetine but also itself. This may suggest that the clinical augmentation of antidepressant action by pindolol, when co-administered with a SSRI, is via antagonism of the 5-HT(1A) receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1980

A comparison of the acute haemodynamic effects of propranolol and pindolol at rest and during supine exercise in man.

1. Dose-response curves for heart rate, cardiac output, arterial blood pressure and pulmonary artery pressure were obtained in 16 male patients after intravenous administration of three increasing doses of pindolol, propranolol or placebo. All patients had an uncomplicated acute myocardial infarction 6-8 months earlier. 2. The dose-response curves were obtained at rest and during repeated bouts of supine bicycle exercise. The cumulative dose amounted to 0.024 mg/kg body weight for pindolol and to 0.192 mg/kg body weight for propranolol. 3. At rest propranolol significantly reduced heart rate and cardiac output by 12% and 15% respectively. Arterial mean blood pressure was reduced by 9.2 mmHg. Mean pulmonary artery pressure increased significantly by 2 mmHg. Statistically significant changes in these variables were not seen after pindolol or placebo. 4. During exercise pindolol and propranolol both reduced cardiac output, heart rate and arterial blood pressure to the same extent. After propranolol mean pulmonary artery pressure was increased significantly by 3.6 mmHg. Pindolol and placebo did not change pulmonary artery pressure significantly. 5. The study suggests that pindolol may offer haemodynamic advantages over beta-receptor-blocking agents without intrinsic sympathomimetic activity during low activity of the sympathetic nervous system, and may be preferable in situations where the beta-receptor-blocking effect is required only during physical or psychic stress.

Adult↗
PubMed1981

Metoprolol and pindolol in hypertension: different effects on peripheral haemodynamics.

1. Thirty-six patients with essential hypertension, were randomly allocated to double-blind treatment with either metoprolol (100--200 mg/day) or pindolol (5--10 mg/day). The effects upon blood pressure and peripheral blood flow were determined. Both drugs reduced blood pressure significantly. 2. Heart rate was significantly reduced by metoprolol but not by pindolol. 3. Vascular resistance at maximal dilatation was not changed by either pindolol. 4. At rest, pindolol reduced vascular resistance in the calf by 14% (P less than 0.05) but metoprolol tended to increase the resistance slightly. The difference in effect was also significant (P less than 0.005). 5. During leg muscle work there were no changes in vascular resistance in the forearm with either compound. 6. We conclude that pindolol appears to reduce blood pressure at least partly through vascular mechanisms, in contrast to metoprolol. The response to sympathetic stimulation induced by physical exercise does not differ between metoprolol- and pindolol-treated patients.

Double-Blind Method↗
PubMed1986

Intrinsic sympathomimetic activity (ISA) of pindolol in patients with sinus node dysfunction.

The effects of pindolol treatment on mean heart rate (MHR) and the number of paced heart beats were investigated in a group of 12 patients, with frequency programmable pacemakers implanted to control symptomatic bradyarrhythmias resulting from sinus node dysfunction. In a randomized double blind cross over experiment the patients were treated with pindolol (5 mg t.i.d.) or with placebo. Before the study the pacemaker was programmed to its lowest frequency in the demand mode. In the pretreatment period and after 2 weeks treatment with either pindolol or placebo a 24-hour ambulatory ECG was recorded. MHR during the night (24.00-8.00) was slightly but significantly increased by pindolol treatment by 6.0% when compared to placebo (P less than 0.05). There was no difference in the daytime MHR during either treatment period. During pindolol treatment the number of paced beats was reduced in 8/12 patients and in 4 of these the reduction exceeded 98%. In 2 patients the number of paced beats increased. The results indicate that in some patients with sinus node dysfunction pindolol can effectively reduce the number of paced beats thereby preserving the atrial contribution to pump function.

Adult↗
PubMed1998

Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study.

This double-blind, controlled study was undertaken to investigate whether the addition of pindolol could improve the therapeutic response to fluvoxamine of depressed patients with psychotic features. After a 1-week placebo run-in period, 72 patients received fluvoxamine 300 mg/day in combination with placebo or pindolol 7.5 mg/day. At study completion, 28 (80%) of 35 patients treated with fluvoxamine plus placebo and 29 (80.5%) of 36 patients treated with fluvoxamine plus pindolol were categorized as responders (reduction of their score on the 21-item Hamilton Rating Scale for Depression to 8 or less and on the Dimension for the Delusional Experience Rating Scale to 0). In the third and fourth weeks, the response rates were significantly superior in the fluvoxamine plus pindolol group (p = 0.0001, p = 0.023, respectively). Treatment response seemed to be unrelated to the demographic and the clinical characteristics recorded. No significant difference was found comparing plasma levels of fluvoxamine between groups, thus excluding a pharmacokinetic interaction. Other than mild nausea and sedation in a few patients, treatments were well tolerated. No medically significant adverse events occurred. Depressed patients with psychotic features who were administered pindolol experienced a more rapid improvement during fluvoxamine treatment. Thus, the combination of fluvoxamine with pindolol may be a useful pharmacologic strategy in the treatment of this disorder. A rapid clinical response in such patients is of relevance in clinical practice as well as in economic fields, given the direct and indirect costs of depression.

Adolescent↗
PubMed1999

Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance.

The aims of this study were to examine whether pindolol, a serotonin (5-hydroxytryptamine [5-HT])-1A receptor antagonist, and mianserin, a 5-HT2A/C and alpha2-adrenoceptor (alpha2-AR) antagonist, may augment the clinical efficacy of fluoxetine, a selective serotonin reuptake inhibitor, and shorten the latency of onset of antidepressive activity in the treatment of major and treatment-resistant depression (TRD). Ten days after admission to the hospital, 31 major depressed patients were randomly assigned using a double-blind, controlled design to receive fluoxetine 20 mg daily, fluoxetine 20 mg daily plus pindolol 7.5 mg daily, or fluoxetine 20 mg plus mianserin 30 mg daily for 5 weeks. The 17-item Hamilton Rating Scale for Depression (HAM-D) score was the primary outcome measure. Analysis of efficacy was conducted according to the intent-to-treat analysis principle considering the change from baseline to endpoint. It was found that fluoxetine plus pindolol and fluoxetine plus mianserin were significantly more effective than fluoxetine alone. Using an outcome measure of 50% reduction in the HAM-D, a 60% response rate was found in patients treated with either fluoxetine plus pindolol or fluoxetine plus mianserin compared with a 9% response rate in patients treated with fluoxetine alone. The HAM-D score 1 week after starting fluoxetine plus mianserin decreased more than 4 points and was significantly greater than that obtained by fluoxetine alone. The results suggest that pindolol and mianserin augment the efficacy of fluoxetine in the treatment of TRD and that mianserin, but not pindolol, may significantly shorten the latency of onset of antidepressive action when combined with fluoxetine.

Adult↗
PubMed2001

Augmentation of fluoxetine's antidepressant action by pindolol: analysis of clinical, pharmacokinetic, and methodologic factors.

In a controlled trial, the beta-adrenoceptor/5-hydroxytryptamine-1A (5-HT1A) receptor antagonist pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (> or = 50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus pindolol (N = 55) and 29 days for fluoxetine plus placebo (N = 56) (p = 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of pindolol remained stable between 3 days (first blood sampling) and 6 weeks. Mean values were approximately 26 nM, a concentration higher than the Ki of (-)pindolol for human 5-HT1A autoreceptors (11 nM). Plasma fluoxetine and norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p = 0.043), but there was no significant relationship to the clinical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained response between both groups would have also been detected (1) in a 2-week trial, (2) without a placebo lead-in phase, and (3) with less frequent visits. However, the use of "response" instead of "sustained response" as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p = 0.08 instead of p = 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data of all sustained responders (N = 27) in the fluoxetine-plus-placebo group with the first 27 responders in the fluoxetine-plus-pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively; p = 0.0002). This indicates that the faster response in the fluoxetine-plus-pindolol group is not a result of the greater proportion of responders.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Effect of intravenous and oral pindolol on exercise tolerance and electrocardiographic changes in angina pectoris.

The effects of intravenous (0.4 mg) and oral pindolol (5 mg, t.i.d.) on exercise tolerance and electrocardiographic ST-segment changes were investigated in 20 patients with documented coronary artery disease (16 males and 4 females; mean age, 56.7 years). A randomized double-blind crossover design was used, and graded submaximal exercise was performed on a bicycle ergometer. Pindolol significantly decreased heart rate at rest, and during and after exercise. The time intervals before the appearance of ST depression, before anginal pain, and before the cessation of work were significantly increased after beta-adrenergic blockade, and work tolerance was enhanced, both indicating that pindolol is an effective antianginal agent. Angina appeared at a lower heart rate after pindolol. Anginal pain and cessation of work were associated with significantly less ST-segment depression after pindolol, suggesting that the relation between ST depression and myocardial ischemia is altered by beta-adrenergic blockade. The appearance and disappearance of ST-segment changes correlated closely with heart rate during placebo and pindolol treatment. Heart rate thus seems to be a major determinant of ST-segment depression during and after exercise in coronary artery disease.

Administration, Oral↗
PubMedDate not supplied

Effects of chronic antihypertensive treatment with acebutolol and pindolol on blood pressures, plasma catecholamines, and oxygen uptake at rest and during submaximal and maximal exercise.

The effects of 4-week periods of treatment, with equivalent doses of acebutolol (500 mg daily) and pindolol (15 mg daily), on plasma noradrenaline, adrenaline, and dopamine, and oxygen uptake at rest, during submaximal steady-state exercise and maximal exercise, and 5 min after exercise, were studied in 11 moderately hypertensive men aged 26-40 years, using a single, crossover design. The two agents had similar effects on heart rate and arterial pressures. Neither the noradrenaline nor the dopamine response to exercise was affected by acebutolol or pindolol. However, 5 min after exercise, nor adrenaline was significantly lower after pindolol. Plasma adrenaline concentration was significantly raised only by pindolol during maximal exercise (from 3.9 +/- 2.3 to 5.0 +/- 3.3 nmol/L, p less than 0.05). Neither oxygen uptake, nor ventilation during steady-state exercise were significantly different from control conditions. Maximal oxygen uptake tended to be slightly lower after acebutolol (5%), and distinctly lower after pindolol (14%). The maximal oxygen pulse was significantly increased only after acebutolol. The absence of a noradrenaline enhancement during the action of pindolol and acebutolol suggests that the increased plasma noradrenaline levels observed after some Beta-receptor blockers during work, do not reflect a compensatory response to lower blood pressure or restricted physical work capacity. The differential effects of Beta-receptor blockers appear to be due to differences in their pharmacological properties.

Acebutolol↗
PubMed1987

Antihypertensive and hormonal responses to beta-blockade with intrinsic sympathomimetic activity: pindolol versus epanolol.

After a 2-week placebo period, 30 men, aged 60 years (mean), with mild or moderate hypertension were randomly assigned to one of three treatment groups: pindolol, 10 mg b.i.d.; epanolol, 200 mg b.i.d.; and epanolol, 400 mg q.d. At the end of the placebo period and of 4 weeks of active treatment, heart rate, blood pressure, plasma renin activity (PRA), and nonepinephrine (NE) concentration of subgroups of subjects, were measured during isoproterenol infusion (30 ng/kg.min-1 for 15 min) and submaximal ergometric exercise (89 W, mean). Sitting heart rates were reduced with 200 mg b.i.d. epanolol (p less than 0.01) but unchanged with pindolol and 400 mg q.d. epanolol. Reductions of systolic and diastolic blood pressures occurred in all treatment groups but were most pronounced with pindolol. Isoproterenol-induced cardioacceleration and rise in PRA and plasma NE concentration were abolished by pindolol but only attenuated by epanolol. Pindolol also abolished the isoproterenol-induced reduction in diastolic blood pressure; epanolol had no effect on it. The hemodynamic and hormonal responses to exercise were attenuated by pindolol and epanolol in proportion to their beta-blocking activities. In the doses used, epanolol had moderate beta 1-selective blocking action. The intrinsic sympathomimetic activity of epanolol is dose dependent.

Adrenergic beta-Antagonists↗
PubMed1976

beta-Adrenoceptor blocking activity and duration of action of pindolol and propranolol in healthy volunteers.

The beta-adrenoceptor blocking activities of pindolol and propranolol have been investigated in healthy male volunteers. Pindolol was about forty times more potent than propranolol in reducing isoprenaline-induced tachycardia. Pindolol (5 mg) and propranolol (u99 mg) were approximately equiactive in reducing exercise-induced tachycardia, 2 h after oral administration. The duration of action of pindolol is significantly longer than that of propranolol; 24 h after pindolol (kmg), 36+/-5% of the masimum effect were still present, and after propranolol (100 mg) 16+/-4% remained. Despite the long duration of action of pindolol, there was no evidence for cumulation during oral administration of 5 mg t.d.s. for 5 days.

Adult↗
PubMed1982

Pindolol--the pharmacology of a partial agonist.

1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs.

Animals↗
PubMed1982

Effects of age and smoking on the pharmacokinetics of pindolol and propranolol.

1 Pharmacokinetic investigations were carried out in a group of 32 ambulant normal male volunteers in order to determine the effect of age and smoking on steady-state plasma levels of pindolol and propranolol. There were four groups of 8: young non-smokers (YNS), young smokers (YS), old non-smokers (ONS) and old smokers (OS). Each subject received, in a randomized cross-over sequence, 5 mg pindolol and 80 mg propranolol three times daily for 2 days with an interval of at least 14 days between the two treatment periods. 2 Neither age nor smoking was shown to have any influence on the time to reach a peak plasma level after pindolol or propranolol. Age, on the other hand, significantly increased the peak plasma levels and the areas under the plasma concentration time curves, and decreased the elimination rate constants, the differences between the age groups being more pronounced for propranolol than for pindolol. No effect of smoking on these parameters was observed. 3 Differences were found between pindolol and propranolol in respect of time to reach a peak plasma level, peak plasma levels and area under the plasma concentration time curves in the groups ONS and YS when related to the YNS control group. Changes observed (with the exception of the time to reach a peak level) tended to be less for pindolol and were considered to be of little clinical relevance.

Adult↗
PubMed1983

Comparison of the effect of pindolol and propranolol on heart rate after acute and chronic administration.

1 The present study compared the effects in healthy volunteers of the acute and chronic administration of placebo, pindolol and propranolol to see if the partial agonist activity of pindolol was reduced by the beta-adrenoceptor blocking activity of pindolol on chronic administration. 2 Five subjects received in random order for 8 days placebo, propranolol 160 mg and pindolol 10 mg; on days 1 and 8 treatments were given twice at 0 and 2 h. Heart rate in supine position and at end of exercise was recorded before dosing and at 2 and 4 h post-dosing on days 1 and 8. 3 Propranolol and pindolol reduced exercise heart rate to the same extent on days 1 and 8. 4 Propranolol reduced supine heart rate more than pindolol on days 1 and 8 but the difference was only significant on day 8.

Adult↗
PubMed1985

Comparison of the haemodynamic effects of bucindolol, propranolol and pindolol in healthy volunteers.

The effects of single oral doses of bucindolol (50, 100, 200 and 400 mg), pindolol (10 mg), propranolol (160 mg) and placebo on arterial pressure and heart rate in the supine and standing positions and exercise heart rate were compared in 12 healthy male volunteers. Supine heart rate was significantly greater after all four doses of bucindolol and pindolol in comparison to propranolol. Bucindolol had no significant effect on standing heart rate which was significantly reduced by pindolol and propranolol. Bucindolol, pindolol and propranolol significantly reduced an exercise tachycardia for at least 24 h after drug administration. Supine systolic pressure was not affected by any treatment but supine diastolic pressure was significantly reduced by bucindolol (200 and 400 mg) and by pindolol. All doses of bucindolol, propranolol and pindolol significantly reduced standing systolic blood pressure. There was a significant linear trend for reductions in standing systolic blood pressure and increasing doses of bucindolol. Standing diastolic blood pressure was significantly reduced by bucindolol 200 and 400 mg. Faintness and light headedness occurred in 6 of 12 subjects after 200 mg bucindolol and in 8 of 10 subjects after 400 bucindolol. After bucindolol, analysis of plasma samples demonstrated the presence of bucindolol, 5-hydroxy and 6-hydroxy bucindolol and indolyl-t-butylamine. These observations indicate that in man, bucindolol is a beta-adrenoceptor blocking drug with hypotensive activity and probably partial agonist activity. It is unlikely that the hypotensive effects result from blockade of beta-adrenoceptors or from the drug's partial agonist activity.

Adrenergic beta-Antagonists↗
PubMed1987

Is the ISA of pindolol beta 2-adrenoceptor selective?

1. Pindolol is a beta-adrenoceptor blocking drug with ISA (also called partial agonist activity). This means that in addition to blocking the effects of beta-adrenoceptor agonists, it produces some stimulation of beta-adrenoceptors. 2. In vitro studies with pindolol show that its maximum stimulant action is similar to that of isoprenaline in tissues possessing mainly beta 2-adrenoceptors, but is negligible in tissues possessing mainly beta 1-adrenoceptors. This suggests selective stimulation of beta 2-adrenoceptors. 3. In man the arteriodilator effects observed after intra-arterially infused pindolol at concentrations within the same range as those producing an antihypertensive effect also suggest a stimulant action on vascular beta 2-adrenoceptors. 4. The fact that pindolol prevents the reduction of resting heart rate and cardiac output observed after drugs lacking ISA at first sight suggests stimulation of cardiac beta 1-adrenoceptors. However, human atria possess not only beta 1- but also beta 2-adrenoceptors, stimulation of which would produce the same effect. 5. Although all beta-adrenoceptor antagonists lower blood pressure, recent experiments have shown that those agents with combined beta 1-adrenoceptor blocking activity and ISA at those receptors are less effective. This observation lends weight to the thesis that pindolol does not stimulate beta 1-adrenoceptors since it lowers blood pressure as effectively as drugs lacking ISA. 6. The evidence available therefore suggests that although pindolol blocks both beta 1- and beta 2-subtypes, it selectively stimulates beta 2-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1992

Down-regulation of beta-adrenergic receptors by pindolol in Gs alpha-transfected S49 cyc- murine lymphoma cells.

The role of the alpha subunit of the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase (GS alpha) in the down-regulation of beta-adrenergic receptors by pindolol was studied in S49 cyc- cells (normally GS alpha-deficient) transfected to express functional recombinant rat GS alpha. An inducible cell line (S49 GS alpha IND) was derived from S49 cyc- cells transfected with a vector containing the full-length coding sequence of GS alpha under the inducible control of the mouse mammary tumor virus long-terminal repeat promoter. GS alpha was not detectable in S49 GS alpha IND cells by immunoblot or by ADP-ribosylation in the presence of cholera toxin and [alpha-32P]NAD. When cells were grown in 100 nM dexamethasone, isoproterenol-stimulated cyclic AMP accumulation increased within 3 h. After 15 h, GS alpha was present at a level 40-50% of that found in S49 wild-type (WT) cells as measured either by immunoblot analysis or by [alpha-32P]ADP-ribosylation. Membranes prepared from GS alpha IND cells grown in the presence of dexamethasone bound agonist with high affinity, and this binding was sensitive to guanine nucleotides. A second vector, DzbGS alpha +, contained the coding sequence of GS alpha under the constitutive regulatory control of the SV40 early promoter. This vector was introduced into cyc- cells, and the resulting cells, S49 GS alpha CST cells, expressed GS alpha at a level comparable to that found in S49 WT cells as measured by immunoblot analysis. Isoproterenol-stimulated cyclic AMP accumulation in S49 GS alpha CST cells was at least as great as in S49 WT cells. When cells were grown in the presence of dexamethasone, exposure to 50 nM pindolol for 12 h down-regulated the density of beta-adrenergic receptors in S49 WT cells to 60% of that in cells grown in the absence of pindolol, but pindolol had no effect on the density of receptors on cyc- or GS alpha IND cells. When GS alpha CST cells were exposed to 50 nM pindolol for 12 h, the density of beta-adrenergic receptors was down-regulated by the same amount as in S49 WT cells. These results suggest that GS alpha is necessary to restore the ability of pindolol to down-regulate beta-adrenergic receptors in S49 cyc- cells and that the protein must be expressed at a level comparable to that found in S49 WT cells.

Adenylyl Cyclases↗