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PubMed1976

Depressed myocardial function in the goat at high altitude.

To determine if depressed myocardial function contributes to the reported decrease in cardiac performance at high altitude, six chronically instrumented, unsedated goats were studied before, during, and after 2-wk exposure to hypobaric hypoxia (PaO2 44 mmHg). Undistorted ventricular pressure wave form was obtained from a miniature transducer implanted in the left ventricular cavity. The relationship between (dP/dt)/28P and P was extrapolated to obtain Vmax as an index of myocardial function. With beta sympathetic blockade (practolol) and pacing to reproduce heart rates, Vmax was uniformly and significantly depressed (P less than 0.01) during chronic hypoxia, and returned to control values following descent to low altitude. Likewise, stroke volume following saline infusion was decreased at high altitude and returned to control values following descent. Acute relief of hypoxia at high altitude by administration of 100% oxygen by mask did not reverse the depressed Vmax. These findings indicate that chronic hypobaric hypoxia produces a depression of myocardial function which is reversible by chronic but not acute relief of hypoxia.

Adaptation, Physiological↗
PubMed1998

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats.

Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-receptor desensitization. The mechanisms involved in this desensitization were evaluated in 32 male Wistar rats kept in a hypobaric pressure chamber (PO2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions, plasma norepinephrine (NE) levels were higher (2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2.2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measured by [3H]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [3H]mazindol in vitro binding showed a decrease in uptake-1 carrier protein density by 38% in the RV and by 41% in the LV. In vitro binding assays with [3H]CGP-12177 indicate beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta1-subtype fraction (competition binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decrease in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV and 42% decrease in the LV), and forskolin (39% decrease in the RV and 41% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gialpha2 in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenergic function. The myocardial desensitization associated with both a reduction in externalized beta1-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system.

Adenylyl Cyclases↗
PubMed1988

Mechanism of action of the anti-shock effect of CCK-8: influence of CCK antagonists and of sympatholytic drugs.

In an experimental model of haemorrhagic shock that causes 100% mortality in rats within 30 min, the intravenous bolus injection (20 micrograms/kg) of sulfated cholecystokinin octapeptide (CCK-8) induces a prompt and sustained rise in blood pressure and pulse amplitude, all treated animals still surviving at the end of the experiment (2 h). This effect of CCK-8 is completely blocked by reserpine (5 mg/kg i.p.), significantly antagonized by prazosin (0.1 mg/kg i.v.) and yohimbine (1 mg/kg i.v.), and unaffected by practolol (15 mg/kg i.v.) and proglumide (0.2 mg/kg i.v.); it is completely antagonized by the intravenous (0.01-0.05 mg/kg), but not by the intracerebroventricular (0.002 mg/kg) injection of the 'peripheral' CCK antagonist, L-364,718. The present data indicate that the cardiovascular effects of CCK-8 in haemorrhagic shock involve peripheral CCK receptors, and require the functional integrity of the sympathetic nervous system.

Animals↗
PubMed1981

Adverse reactions of the skin to metoprolol and other beta-adrenoreceptor-blocking agents.

Oral provocation tests revealed the relation between long-term oral use of metoprolol and development of psoriasiform and/or eczematous skin lesions in 3 patients. The clinical and histopathological findings in 1 case are described more in detail and are discussed. The data in the recent literature, with respect to side effects of skin due to different beta-blocking agents, are summarized. In addition, some aspects dealing with possible mechanism in the side effects of beta-blocking agents are briefly discussed. Since beta-blocking agents may cause similar side effects, as described during practolol treatment, on should still be alert to this possibility during long-term treatment with (new) beta-blocking agents, which may allow us to prevent serious damage that might occur in different organs.

Adrenergic beta-Antagonists↗
PubMed2002

Norepinephrine elicits beta2-receptor-mediated dilation of isolated human coronary arterioles.

BACKGROUND: The exact role of adrenoceptors in norepinephrine (NE)-mediated regulation of the human coronary circulation has yet to be elucidated. Thus, the goals of this study were to characterize the adrenoceptors involved in the responses to NE in isolated human coronary arterioles and small arteries. METHODS AND RESULTS: Arterioles (n=39) and small arteries from the left ventricle of explanted human hearts were isolated and cannulated. Vessels from the hearts of 21 patients were studied: 15 males and 6 females, aged 0.5 to 63 years. Nineteen patients were considered to be New York Heart Association class 4. All hearts exhibited hypertrophy (190+/-20%). The passive diameter of arterioles was 167+/-8 microm (range 97 to 323 microm). NE (10(-7) to 3x10(- 7) mol/L) elicited concentration-dependent dilations (47+/-4 microm) that were unaffected by endothelium removal, N(omega)-nitro-L-arginine (10(- 4) mol/L, an NO synthase inhibitor), or practolol (10(-6) mol/L, a beta1-receptor blocker). However, administration of propranolol (10(-5) mol/L, a combined beta1- and beta2-blocker) or butoxamine (10(-6) mol/L, a beta2-receptor blocker) completely eliminated the NE-induced dilation. Constrictions to NE (2 of 39 vessels) were inhibited by prazosin (10(-6) mol/L, an alpha1-receptor blocker). Methoxamine (10(-9) to 10(-5) mol/L, an alpha1-agonist) had no effect, whereas U44619, a thromboxane mimetic, elicited dose-dependent constriction of vessels. CONCLUSIONS: Our data indicate that isolated human coronary arterioles and small arteries dilate to NE via beta2-receptors on smooth muscle. These findings are important to our understanding of the mechanisms action of NE in the human coronary circulation.

Adolescent↗
PubMed1976

Normal myocardial contractile state in the presence of quinidine.

Since quinidine is one of the few agents available to treat and prevent ventricular arrhythmias in ambulatory patients, its hemodynamic effects have been reevaluated. When given in therapeutic doses to anesthetized mongrel dogs, quinidine significantly reduced heart rate, aortic pressure and flow, but it did not significantly change the first derivative of the left ventricular pressure curve (left ventricular dp/dt) in nine dogs. A subsequent group of dogs was studied after vagotomy and practolol administration to block cardiac reflexes. This group showed significant reductions in heart rate, aortic pressure and left ventricular dp/dt, with the latter returning to predrug control values when preload, afterload and heart rate were maintained constant. These studies suggest that quinidine does not directly affect myocardial contractility when given in therapeutic doses. Furthermore, the reduction in heart rate in these animals provides support for a direct depressant effect of quinidine on the sinus node. The adverse effects of quinidine on cardiac function previously reported may be due to the use of toxic doses or are secondary to quinidine peripheral circulatory effects, rather than due to a direct reduction in cardiac contractile state.

Animals↗
PubMed1986

Enhancement by norepinephrine of automaticity in sheep cardiac Purkinje fibers exposed to hypoxic glucose-free Tyrode's solution: a role for alpha-adrenoceptors?

A period of drive in the presence of norepinephrine (NE) may be followed by the induction or acceleration of spontaneous activity. Experiments were carried out in sheep cardiac Purkinje fibers to determine whether the effects of NE on automaticity were modified during superfusion with hypoxic glucose-free Tyrode's solution and to assess the possible contribution of alpha-adrenergic influences on automaticity under these conditions. The following results were obtained: Low concentrations of NE (10(-7) and 3 X 10(-7)M) were able to induce automaticity after a period of drive in normal oxygenated (97% O2, 3% CO2) Tyrode's solution. Superfusion with hypoxic (97% N2, 3% CO2) glucose-free Tyrode's solution enhanced NE-induced automaticity. Practolol, in concentrations able to block the effects of NE in normal oxygenated solution, did not counteract the effects of NE in hypoxic glucose-free solution. Yohimbine, but not prazosin, antagonized the effects of NE in hypoxic glucose-free solution. At the same concentration, yohimbine did not affect transmembrane potentials or automaticity induced by isoproterenol. It is concluded that alpha-adrenergic responsiveness appears to be enhanced during superfusion in vitro with hypoxic glucose-free solution, and that alpha-adrenoceptors belonging to the alpha 2-subtype in sheep cardiac Purkinje fibers might influence abnormal automaticity, possibly through an effect on oscillatory potentials.

Animals↗
PubMedDate not supplied

Acute vasodilator action of pindolol in humans.

The local hemodynamic effect of pindolol, a nonselective beta-blocker with intrinsic sympathomimetic activity, was investigated in 17 healthy volunteers. Changes in forearm blood flow (FBF) in response to infusion of drugs into the brachial artery were measured by plethysmography. Pindolol increased FBF dose dependently to a maximal value of 62 +/- 8% (mean +/- SEM, p less than 0.001) without inducing changes in heart rate or blood pressure. For a single dose of pindolol the maximal effect on FBF was seen after approximately 4 minutes of infusion, and this effect persisted for at least 12 minutes after the infusion. The pindolol-induced increase in FBF was reduced by concomitant infusion of propranolol (p less than 0.001). Intra-arterial infusion of practolol did not influence FBF. No significant influence of pindolol was found on the vasoconstriction induced by the alpha 1-adrenergic receptor agonist methoxamine, the alpha 2-adrenergic receptor agonist BHT-933, or angiotensin II. Measurement of plasma pindolol concentrations in the venous effluent of the forearm suggested that vasodilatation occurred at drug levels within the therapeutic range. These results indicate that the beta-blocker pindolol has vasodilatory properties owing to stimulation of vascular beta 2-adrenergic receptors and that this effect may be of therapeutic relevance.

Adult↗
PubMed1983

Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Graded doses of norepinephrine and methoxamine were given to rabbits over a standard 90-minute infusion period to assess their potential for inducing myocardial injury. Lesions of myofiber necrosis and leukocytic infiltration were graded semiquantitatively in animals killed 2 days later. A close correlation was found between the dose of norepinephrine and the histological score (r = 0.912, P less than 0.001). Mean arterial pressure rose from 100 mm Hg to a maximum of 129 mm Hg, and averaged 115 mm Hg during infusion of 2 micrograms/min per kg. However, heart rate fell from 287 beats/min to average 208 beats/min. The pressure-rate product, an index of metabolic demand, showed no significant change and did not differ from saline-infused controls. Beta-adrenergic blockade with practolol (4 mg/kg) or propranolol (1 mg/kg) failed to significantly reduce cardiac injury with norepinephrine. However, alpha-adrenoceptor blockade with phentolamine (10 mg), alone or in combination with either of the beta-antagonists, markedly reduced lesion formation as reflected by the histological score (P less than 0.02). Administration of the alpha-agonist methoxamine produced dose-related increases in the intensity of myocardial injury (r = 0.938, P less than 0.01), morphologically identical with those resulting from norepinephrine. Hemodynamic changes also were comparable. Phentolamine markedly reduced methoxamine injury. It may be concluded from these studies that norepinephrine cardiomyopathy results in large part from activation of the alpha-adrenergic system in the rabbit model. Ischemia or a supply-demand mismatch are unlikely mechanisms. We speculate that alterations in myofiber Ca++ translocation, uptake, and binding induced by alpha 1-receptor activation may contribute to membrane damage.

Adrenergic alpha-Antagonists↗
PubMed1983

Coexistence of beta 1- and beta 2-adrenoceptors in human right atrium. Direct identification by (+/-)-[125I]iodocyanopindolol binding.

The highly specific beta-adrenoceptor radioligand, (+/-)-[125I]iodocyanopindolol, has been used to subclassify beta-adrenoceptors in membranes from human right atrial appendage obtained during open heart surgery. Binding of (+/-)-[125I]iodocyanopindolol was saturable (Bmax = 86.4 +/- 7.4 fmol (+/-)-[125I]iodocyanopindolol bound/mg protein, n = 4), of high affinity (KD = 53 +/- 6 pM, n = 4), rapid, reversible, and stereospecific. The relative potencies of isoprenaline, adrenaline, and noradrenaline for inhibition of (+/-)-[125I]iodocyanopindolol binding and activation of adenylate cyclase were 1:10:10, indicating a population composed mainly of beta 1-adrenoceptors. Inhibition of (+/-)-[125I]iodocyanopindolol binding by beta 1- (practolol, metoprolol, betaxolol) and beta 2- (IPS 339, ICI 118,551, zinterol, procaterol) selective drugs, however, resulted in biphasic displacement curves with slope factors (nH, pseudo Hill coefficients) significantly less than 1.0. Nonlinear regression analysis of these curves revealed a beta 1: beta 2 ratio of 80:20 in human right atrial appendage. Nonselective beta-adrenergic drugs (propranolol, isoprenaline, and adrenaline), on the contrary, inhibited binding with monophasic displacement curves and nH = 1.0. Binding of agonists to the beta-adrenoceptors in human right atrial appendage seems to be regulated by guanyl nucleotides. In the absence of GTP, isoprenaline binds to high and low affinity state of the beta-adrenoceptors. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous one of low affinity. It is concluded that, in human right atria, beta 1- and beta 2-adrenoceptors coexist; however, beta 1-adrenoceptors predominate. The physiological function of beta 2-adrenoceptors in human right atrium remains to be elucidated.

Adenylyl Cyclases↗
PubMed1988

Hemodynamic and neural mechanisms of action of thyrotropin-releasing hormone in the rat.

The mechanisms mediating the effects of thyrotropin-releasing hormone (TRH) on the cardiovascular system were studied in the conscious rat. Intracerebroventricular (i.c.v.) injection of TRH (8 pmol-80 nmol/kg) induced dose-dependent increases in mean arterial pressure, heart rate, and cardiac index. Hindquarter blood flow increased due to vasodilation, while an increase in renal and mesenteric vascular resistance caused a decrease in blood flow in the respective organs. The plasma levels of norepinephrine and epinephrine were increased by TRH, while there was no change in plasma renin activity or vasopressin. The cardiovascular actions of i.c.v. TRH were not influenced by blockade of the renin-angiotensin system or vasopressin receptors. The ganglion blocker chlorisondamine and the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine (2 mg/kg i.v.) abolished the increase in blood pressure and mesenteric vasoconstriction after i.c.v. TRH. Propranolol (2 mg/kg i.v.) blocked the TRH-induced increase in cardiac index, heart rate, and hindquarter blood flow. The hindquarter vasodilation induced by TRH was also blocked by the selective beta 2-adrenoceptor antagonist ICI 188,551 (1 or 2 mg/kg i.v.), while the beta 1-adrenoceptor blocker practolol (10 mg/kg i.v.) had no effect on the hindquarter vasodilation produced by TRH but totally blocked the increase in cardiac index. In adrenal demedullated rats, the systemic hemodynamic effects of i.c.v. TRH were diminished along with the decrease in renal blood flow and increase in renal vascular resistance; however, the increase in hindquarter blood flow was attenuated only in adrenal demedullated rats pretreated with the sympathetic blocker bretylium. The renal vasoconstriction induced by i.c.v. TRH was not abolished by renal denervation. In sinoaortic debuffered rats, the pressor, tachycardic, and mesenteric vasoconstrictor responses to centrally administered TRH were significantly potentiated. Taken together, these data suggest that the putative neurotransmitter TRH may play a role in central regulation of cardiac functions and organ blood flow distribution through both the sympathetic nerves and the adrenal medulla. A pivotal role for beta 2-adrenoceptors in mediation of hindquarter vasodilation is also demonstrated.

Adrenalectomy↗
PubMed1993

Feedforward control of coronary blood flow via coronary beta-receptor stimulation.

It is usually assumed that the increase in coronary blood flow observed with norepinephrine occurs through local metabolic vasodilation secondary to cardiac beta-receptor activation. However, direct feedforward beta-receptor-mediated coronary vasodilation is also a possibility. In dogs with alpha-receptor blockade, the left circumflex artery was perfused at constant pressure. The vasodilator effect of intracoronary norepinephrine injections was determined during prolonged diastoles to avoid the chronotropic and intropic effects of norepinephrine. Norepinephrine caused a dose-dependent increase in coronary blood flow that was attenuated by both the selective beta 1-antagonist practolol and the selective beta 2-antagonist ICI 118,551. These data indicate that norepinephrine activates beta 1- and beta 2-receptors in coronary resistance vessels to cause vasodilation independent of inotropic and chronotropic effects. The physiological significance of coronary beta-receptor-mediated vasodilation was investigated in the beating heart. The coronary blood flow response and coronary venous oxygen tension response were compared when myocardial oxygen consumption was increased over the same range by one of three positive inotropic interventions: (1) norepinephrine, (2) paired-pulse stimulation, or (3) norepinephrine after alpha-blockade. During norepinephrine infusion (intervention 1), coronary venous oxygen tension decreased, indicating that the match between myocardial oxygen consumption and oxygen delivery is not maintained when coronary blood flow is controlled by alpha- and beta-receptors in addition to local metabolic factors. Paired-pulse stimulation (intervention 2) also resulted in a decrease in coronary venous oxygen tension, demonstrating that the balance between oxygen consumption and delivery is not maintained when blood flow is controlled by local metabolic factors alone. However, when coronary beta-receptor-mediated vasodilation was unmasked by alpha-blockade, norepinephrine infusion (intervention 3) produced no change in coronary venous oxygen tension. Therefore, coronary beta-receptor vasodilation helps maintain the balance between flow and metabolism in a feedforward manner in the beating heart.

Animals↗
PubMed1974

Effects of dobutamine on left ventricular performance, coronary dynamics, and distribution of cardiac output in conscious dogs.

The effects of dobutamine ([+/-]-4-[2-[[3-(p-hydroxyphenyl)-1-methyl propyl] amino] ethyl] pyrocatechol hydrochloride), a new synthetic cardioactive sympathomimetic amine, were examined on direct and continuous measurements of left ventricular (LV) diameter (D), pressures (P), velocity of shortening (V), dP/dt, dP/dt/P, arterial pressure, cardiac output, and regional blood flows in the left circumflex coronary, mesenteric, renal, and iliac beds in healthy, conscious dogs. At the highest dose of dobutamine examined, 40 mug/kg/min, the drug increased dP/dt/P from 65+/-3 to 128+/-4 s(-1) and isolength velocity from 72+/-4 to 120+/-7 mm/s without affecting LV end diastolic D significantly. Mean arterial P rose from 92+/-2 to 104+/-3 mm Hg and heart rate from 78+/-3 to 111+/-7 beats/min, while LV end systolic D fell from 24.1+/-1.4 to 19.9+/-1.8 mm, reflecting a rise in stroke volume from 30+/-4 to 42+/-3 ml. Cardiac output rose from 2.41+/-0.23 to 4.35+/-0.28 liter/min, while calculated total peripheral resistance declined from 0.042+/-0.005 to 0.028+/-0.003 mm Hg/ml/min. The greatest increases in flow and decreases in calculated resistance occurred in the iliac and coronary beds, and the least occurred in the renal bed. Propranolol blocked the inotropic and beta(2) dilator responses while vasoconstricting effects mediated by alpha adrenergic stimulation remained in each of the beds studied. When dobutamine was infused after a combination of practolol and phentolamine, dilatation occurred in each of the beds studied. These observations indicate that dobutamine is a potent positive inotropic agent with relatively slight effects on preload, afterload, or heart rate, and thus may be a potentially useful clinical agent. The one property of this drug which is not ideal is its tendency to cause a redistribution of cardiac output favoring the muscular beds at the expense of the kidney and visceral beds.

Animals↗
PubMed1989

Adverse effects of the use of unusual phenethylamine compounds sold as illicit amphetamine.

A 40-year-old man, who had regularly taken illicit amphetamine by intra-nasal inhalation for several years without ill effects, was admitted to hospital with signs of massive adrenergic overstimulation shortly after inhaling material which he had purchased in the belief that it was amphetamine. The administration of the beta-blocker practolol produced a paradoxical increase in blood pressure. After his discharge from hospital he suffered disabling feelings of anxiety for several weeks. Analysis of a sample of the material showed it to contain p-methyl amphetamine and N, p-dimethyl amphetamine.

Adult↗
PubMed1986

Adverse reactions in ten years' general practice, computer analysed.

A total of 167 264 symptoms were recorded in numerical shorthand during a ten years period in a general practice. Computer analysis yielded 1535 adverse reactions with the drug prescribed. Especially prominent were reactions from three antibiotics (13% of all reported reactions), most of which were alimentary symptoms. Ampicillin also induced rashes reported at a rate of 5.2 per thousand prescriptions. Reactions to an oral contraceptive (Minovlar) were the most frequent to a single named drug, being 25.9% of prescriptions for that drug. A worldwide total of around one trillion symptoms seems likely before AD 2000. Computers could be used to detect the unpredictable side effects, as with practolol. Various 'costs' involved are noted, together with wider questions.

Ampicillin↗
PubMed1988

Detecting adverse reactions to drugs.

1. Present attitudes to drug safety have been shaped largely by a series of disasters. 2. In 1937 about 107 people in the USA died of poisoning by diethylene glycol used as a vehicle for sulphanilamide which led to the requirement that all formulations must be licensed by the FDA before marketing. 3. Up to 1960 the rate of production of new drugs outstripped the ability to introduce them safely. In Germany, thalidomide, an effective sedative, had been introduced in 1956 but it was not until 1961, when an estimated 10,000 babies worldwide had been born with birth deformities, that the teratogenicity of this compound was recognized. 4. Further legislation soon followed, both reducing the number and lengthening the time required to introduce a new drug onto the market. However, problems were encountered with practolol in the 1970s and with benoxaprofen in the 1980s, the latter highlighting the need to make special provision for drug use in the elderly. 5. As to the future, more attention will be paid to the special needs of children and to the possible effects of genetic differences in metabolism.

Abnormalities, Drug-Induced↗
PubMed1977

The influence of propranolol on the thyrotropin receptor.

Propranolol, a beta adrenergic blocking drug, is known to inhibit the thyrotropin (TSH) stimulation of adenosine-3',5'-monophosphate (cyclic AMP production in thyroid membranes but the mechansim of this inhibitory action is known. We have therefore investigated the influence of propranolol on the binding of 125I-labelled TSH to human thyroid membranes. Both d- and l-propranolol were found to enhance the binding of 125I-labelled TSH to thyroid membranes. The amount of label bound increased from about 30% in the absence of propranolol to about 60% in the presence of 3.3 x 10(-3)M propranolol. Scatchard analysis of the binding data indicated that propranolol increased the association constant of the thyrotropin-thyrotropin receptor interaction. Practolol, lithium carbonate, methimazole, and somatostatin had no effect on thyrotropin binding. This effect of propranolol appeared to be due to a direct reversible action of propranolol on the thyroid membranes and could be attributed to the membrane-disrupting properties of the drug rather than its beta-blocking activity. The increased TSH receptor occupancy which resulted from the increased association constant of the TSH-thyroid membrane interaction corresponded with a decrease in TSH-stimulated cyclic AMP formation. These data could indicate that propranolol reduced the efficiency of the receptor-adenylyl cyclase coupling system.

Cell Membrane↗
PubMed1981

Stimulation of beta 2-adrenergic responsiveness by follicle-stimulating hormone in rat granulosa cells in vitro and in vivo.

The development of adrenergic responsiveness in ovarian granulosa cells cultured in the presence of androstenedione was investigated. Progesterone production by granulosa cells obtained from immature hypophysectomized diethylstilbestrol-treated rats was stimulated by FSH, but was only minimally affected by various adrenergic agents. In contrast, FSH treatment for 2 days in vivo or in vitro resulted in an increase in the adrenergic responsiveness of granulosa cells. Subsequent treatment with (-)epinephrine, (-)norepinephrine, or (-)isoproterenol (a potent beta-adrenergic agonist) resulted in time- and dose-dependent increases in progesterone production. The adrenergic agents enhanced the effects of hCG and PRL with respect to progesterone production, but were without effect on estrogen production or the maintenance of LH/hCG receptors in FSH-primed granulosa cells. A selective beta 2-adrenergic agonist (terbutaline) stimulated progesterone production in FSH-treated granulosa cells, whereas a beta 1-agonist (dobutamine) was 10,000-fold less effective. Furthermore, progesterone production induced by (-)epinephrine was blocked by a selective beta 2-antagonist (IPS 339), but the beta 1-antagonist (practolol) was 7,000-fold less effective. These results suggest that FSH treatment in vivo and in vitro increases beta 2-adrenergic responsiveness in ovarian granulosa cells and that this functional responsiveness is coupled to progesterone, but not to estrogen, biosynthesis.

Adrenergic beta-Agonists↗