Number Of Beta-adrenergic Receptors Research Articles

The relationship between adrenaline and beta 2‐adrenoceptors on human lymphocytes.

To study the relation between plasma adrenaline (AD) and noradrenaline (NA) and the beta 2-adrenoceptor number (Bmax) on lymphocytes these variables were measured in the following three groups: a) In 67 normotensive volunteers after a rest period of at least 15 min. b) In 10 essential hypertensive (HT) and 10 age and sex matched normotensive (NT) subjects before and after a standardized bicycle exercise test (BE). c) In 10 bilaterally adrenalectomized females (AF) and 10 healthy age matched females (NF) before and after a mental arithmetic test (MA). Significant correlations were found between AD and Bmax in NT (r = 0.30, P = 0.015) and between the proportional increase in AD and the proportional increase in Bmax after BE (r = 0.60, P less than 0.005). The MA induced elevation of Bmax was blunted after adrenalectomy. All these findings point to a relation between AD and beta 2-adrenoceptor regulation.

Sodium intake modulates the development of cardiac hypertrophy in two-kidney, one clip rats.

Sodium homeostasis exerts a powerful influence on the cardiovascular system in normotensive and hypertensive animals. Previous studies indicate that factors other than blood pressure can influence cardiac hypertrophy. In the present experiments, we evaluated the effects of different sodium diets in the two-kidney, one clip hypertension model in the rat. After the renal artery had been clipped, the rats received a normal sodium (177 meq/kg), high sodium (517 meq/kg), and low sodium (7 meq/kg) diet during 4 weeks. The final blood pressure was almost the same in the three groups (normal sodium 170 +/- 12 mm Hg; low sodium 168 +/- 4 mm Hg; and high sodium 162 +/- 7 mm Hg). Sodium restriction significantly reduced the development of cardiac hypertrophy as compared with rats on normal or high sodium diets. Thus, ventricular weight and ventricular weight/body weight ratio were significantly higher in rats subjected to a normal or high sodium diet (p less than 0.01). The hypertrophied hearts of rats on normal and high sodium diets showed a larger increase in the number of cardiac beta-adrenergic receptors than those observed in hearts from low sodium diet, clipped rats. These results show that sodium modulates the development of cardiac hypertrophy in two-kidney, one clip hypertensive rats. Similarly, the cardiac beta-adrenergic receptors appear to be influenced by dietary sodium intake. A possible role of the sympathetic nervous system is suggested.

Circadian variations of adrenergic receptors in the mammalian pineal gland: A review

Pineal adrenergic receptor numbers show circadian variations in both rat and Syrian hamster. In the rat pineal beta-adrenergic receptor density reaches peak values either late in the light phase or at middark; the differences in the circadian phase seem related to the light:dark cycle to which the animals are exposed. No circadian rhythm of pineal alpha-adrenergic receptors is documented in intact rats. In the Syrian hamster pineal beta-adrenergic receptor density is high throughout the light phase and drops to minimal values at the time of the nocturnal peak of melatonin production. The circadian rhythm of pineal alpha-adrenergic receptor numbers runs parallel to the beta-adrenergic receptor variation, but is less pronounced. In the rat, pineal melatonin production is rapidly induced by beta-adrenergic agonists at any time during a 24-hour period, even when the pinealocyte beta-adrenergic receptor number is lowest (early in the light phase). In contrast, the Syrian hamster pineal seems most responsive to beta-adrenergic agonists in the late night while being less responsive during the day when beta-adrenergic receptor density is high. Interestingly, the human pineal gland is also not especially responsive to adrenergic stimulation during the light phase, possibly making the Syrian hamster pineal a better model than the rat pineal for determining neural/pineal interactions in humans. Comparison of the circadian variations in pineal adrenergic receptors leads to the conclusion that the functional differences between rat and hamster pineal are probably not explicable in terms of the adrenergic receptors, but are caused most likely by (a) intracellular mechanism(s) beyond the adrenergic receptors.

Alterations of neuroreceptors in nasal hyperreactivity.

Cholinergic and adrenergic abnormalities have been observed in nasal allergy and may be due to changes in pharmacological characteristics of neuroreceptors. Radioligand receptor binding studies demonstrated no significant changes in affinities or densities of alpha-adrenoceptors, a decreased number of beta-adrenoceptors and a decreased affinity combined with a decreased number of muscarinic acetylcholine receptors.

Effects of insulin on human beta‐adrenoceptors.

The effect of insulin on beta-adrenoceptor stimulation and binding in mononuclear leucocytes from healthy subjects was studied. After 1 min exposure to insulin, the sensitivity and maximum response to (-)-isoprenaline and the number of beta-adrenoceptors increased. After 35 min exposure to insulin, the sensitivity and maximal response to (-)-isoprenaline stimulation were lower than the pretreatment values. The beta-adrenoceptor density was similar to the control value after 35 min exposure to insulin. The present observations may account for some of the cardiovascular effects of insulin.

Beta‐adrenoceptor control of immune function in congestive heart failure.

1. We have determined the number of beta-adrenoceptors and the isoprenaline-stimulated cAMP generation in lymphocyte subsets. The in vitro beta-adrenergic sensitivity was greatest in Tsuppressor/cytotoxic- and natural killer cells and smallest in Thelper- and B-cells. B lymphocytes appear to have a poor receptor coupling to adenylate cyclase as they have many beta-adrenoceptors but generate only little cAMP in response to isoprenaline. 2. A 7 day treatment of healthy volunteers with terbutaline decreased the number of circulating cells in those lymphocyte subsets with a high in vitro sensitivity to beta-adrenoceptor stimulation (i.e. Tsuppressor/cytotoxic- and natural killer cells) but not in those with a poor in vitro sensitivity (i.e. Thelper- and B-lymphocytes). 3. Similar alterations of circulating lymphocyte subsets were found in patients with congestive heart failure (CHF). These alterations were not related to the aetiology of CHF but to its severity and could be correlated with plasma catecholamine levels. 4. We conclude that prolonged exposure to beta-adrenoceptor agonists or enhanced sympathetic activity can decrease the number of circulating lymphocytes with an increase in the Thelper-/Tsuppressor/cytotoxic-cell ratio.

Differential regulation of human cardiac beta‐adrenergic and muscarinic receptors by chronic beta‐adrenoceptor antagonist treatment.

In patients undergoing coronary artery bypass grafting chronic beta 1-adrenoceptor antagonist treatment increased right atrial beta 1-adrenoceptor number, did not affect beta 2-adrenoceptor number and decreased muscarinic M2-receptor number. Concomitantly, the M2-receptor-mediated negative inotropic effect of carbachol was reduced, while the beta 1-adrenoceptor-mediated positive inotropic effect of noradrenaline was not altered. The beta 2- adrenoceptor mediated positive inotropic effect of procaterol, however, was markedly enhanced. We conclude that chronic beta 1-adrenoceptor antagonist treatment increases beta 1-adrenoceptor number, sensitizes beta 2-adrenoceptor function and desensitizes M2-receptor function in the human heart.

Lung beta-adrenoceptor number is increased in children with secondary pulmonary hypertension

Lung beta-adrenoceptor number is increased in children with secondary pulmonary hypertension

Membrane proteins of the myocytes in cardiac overload.

1. Hypertrophy of the cardiac myocytes resulting from a mechanical overload may be responsible for major membraneous modifications, either at the sarcolemmal or at the sarcoplasmic level. In this study several sarcolemmal markers such as beta-adrenoceptors, muscarinic receptors or (Na+, K+)-ATPase were investigated in an experimental model of cardiac hypertrophy, the chronic aortic stenosis in adult rats. 2. Left ventricular beta-adrenoceptor density (expressed in fmol mg-1 protein) was decreased in the aortic stenosis group by about 30%; however, when expressed in number of receptors per cardiac cell beta-adrenoceptor number in the hypertrophied myocytes was unchanged. 3. Similarly, the number of muscarinic receptors in the hypertrophied cells, expressed as number of receptors per cardiac cell, was unchanged. 4. The number of (Na+, K+)-ATPase molecules with high affinity for ouabain was markedly increased in the hypertrophied myocytes, while those with low affinity for ouabain were not. 5. These results indicate the necessity in chronic hypertrophy to calculate receptors not only in density (fmol mg-1 protein) but also in number per cardiac cell. The unchanged number of beta-adrenergic and muscarinic receptors present on the hypertrophied myocytes suggests a non-regulation for the genes coding for these receptors.

Increased bumber of bata-adrenoceptors in cultured heart cells after propranolol withdrawal.

We have studied the effects of propranolol on the number and function of beta-adrenoceptors of cultured heart cells from mice. After 24 hrs in culture, heart cells were incubated for 48 hrs with either standard medium or medium containing propranolol. After a washing period of 30 min, beta-adrenoceptors were measured with a receptor binding assay. The dissociation constant (Kd) did not differ between control and cultured heart cells pretreated with propranolol. By contrast, the maximum number of binding sites (Bmax) was 2.5 times higher in propranolol-pretreated than control cultured heart cells. The increase in the rate of beating and the elevation of cyclic AMP content induced by 10(-5) M isoproterenol were significantly higher for cultured cells pretreated with propranolol than for control cells. These results indicate a correlation between an increased number of beta-adrenoceptors and increased physiological responses of cultured heart cells after propranolol withdrawal.

Effects of propranolol on, and noradrenergic correlates of, the response to nonreward

Rats were rewarded by food for running in a straight runway with short (15 sec) intertrial intervals. On the final day, animals were subjected to either 14 extinction trials or 14 rewarded trials. During acquisition, half of each group had been injected once daily for 15 days with propranolol (5 mg/kg IP), the remainder with saline vehicle. All animals were killed immediately after the final trial and the cerebral cortex taken for noradrenaline assay and radioligand binding to beta- and alpha 2-adrenoceptors. Propranolol increased running times early in extinction; this effect was replicated in a second experiment. Neither the drug injections nor the extinction procedure affected neurochemical measures. However, the rate of extinction correlated positively with both beta- and alpha 2-adrenoceptor number. Although consistent with the theory that beta-adrenoceptors are involved in adaptation to stress, these results differ from our previous findings. The relationship between beta-adrenoceptor number and the response to stress may depend on the severity of the stress.

The beta-adrenergic system in man: Physiological and pathophysiological response: Regulation of receptor density and functioning

Catecholamines play an essential role in the activation of the cardiovascular system and in the regulation of energy metabolism in a variety of physiological conditions. Many of these effects are mediated through beta-adrenoceptors located on cell membranes. Binding of catecholamines to beta-adrenoceptor increases the concentration of intracellular cyclic AMP which in turn activates protein kinase A. This enzyme phosphorylates a number of other intracellular enzymes influencing cell metabolism and functions. The primary structures of the receptor and its topography in the cell membrane as well as its binding domains have been partially clarified. In studies of the human beta-adrenergic receptors blood lymphocytes have mostly been used as model cells. These cells carry receptors of mainly the beta 2-subtype. The adequacy of this model system has been demonstrated in several studies. In clinical work receptor assays have had limited use until now. However, studies on the pathophysiology of the adrenergic system in several diseases have revealed that receptor alterations may constitute an important factor in the disease process. Measurements of adrenergic receptors may also have increasing usefulness in determining optimal drug concentrations. Our own studies have primarily focused on physiological adjustments in the beta-adrenergic system during acute or prolonged physical exercise as well as receptor changes in heart failure, muscle diseases and the alcohol withdrawal syndrome. We have also explored receptor dynamics during therapy with beta-blocking agents. These studies, briefly reviewed in this communication, have led to the following conclusions: (1) High aerobic capacity is associated with an increased density and ability of lymphocytic beta-adrenoceptors to respond to catecholamines. (2) Both short-and long-term physical exercise induce a rapid up-regulation and more effective functioning of lymphocytic beta-adrenoceptors. (3) Administration of beta-blocking drugs is associated with a subnormal exercise-induced up-regulation and decreased functioning of the lymphocytic beta-adrenoceptors. (4) The exercise-provoked up-regulation and improved functioning of beta-adrenoceptors is blunted in heart failure patients. (5) Patients with Duchenne-type of muscular dystrophy have a reduced number of lymphocytic beta-adrenoceptors. (6) In chronic alcoholics the lymphocytic beta-adrenoceptor level is subnormal but during abrupt ethanol withdrawal a rapid increase in the number and functioning of the receptors to a normal level takes place. This sequence of events may lead to a condition of relative adrenergic hypersensitivity.

The Role of Catecholamines in Ischemia

In myocardial ischemia, sympathetic activity of the heart is closely connected with the progression of cell injury and the incidence of malignant arrhythmias. Adrenergic stimulation of the ischemic myocardium is due to increased local norepinephrine concentrations in the heart, whereas the plasma catecholamine levels are of minor relevance. During the first few minutes of ischemia. efferent sympathetic nerves are activated. Excessive accumulation of norepinephrine, however, is prevented since adenosine, formed in the ischemic myocardium, suppresses exocytotic norepinephrine release, and released norepinephrine is rapidly removed as long as catecholamine reuptake is functional. With progression of ischemia to more than 10 min, the myocardium is no longer protected against excess catecholamine accumulation in the interstitial space because local metabolic release mechanisms become increasingly important. This release, which is independent of central sympathetic activity and extracellular calcium, occurs in two steps: first, norepinephrine escapes from its intracellular storage vesicles and accumulates in the cytoplasma of the neuron; in a second, rate-limiting step, norepinephrine is transported across the plasma membrane into the interstitial space, using the neuronal uptake carrier in reverse of its normal transport direction. Studies using acute and chronic sympathetic denervation and antiadrenergic agents demonstrate that this local metabolic, rather than centrally induced, norepinephrine release is critically involved in the progression of ischemic cell damage and the occurrence of ventricullar fibrillation in early ischemia. As a consequence of local metabolic catecholamine release, extracellular norepinephrine reaches 1,000 times the normal plasma concentration within 20 min of ischemia. Myocardial ischemia results in a temporary supersensitivity to catecholamines of the myocytes. This is due to a twofold increase in alpha1- and a 30% increase of beta-adrenergic receptor number at the cell surface. The sensitization of adenylate cyclase during the first 20 min of total ischemia is followed by a rapid inactivation of the enzyme that also includes the coupling protein Gs. The deleterious combination of extremely high norepinephrine concentrations with an at least temporarily enhanced responsiveness of the tissue to catecholamines is thought to accelerate the propagation of the wavefront of irreversible cell damage in the ischemic myocardium. Moreover, the inhomogenous distribution of catecholamine excess within the heart is considered to promote malignant arrhythmias by unmasking and enhancing electrophysiological disturbances in early ischemia.

Hormonal Regulation of β-Adrenergic Receptors in the Rat Mammary Gland during the Estrous Cycle and Lactation: Role of Sex Steroids and Prolactin

To gain further knowledge on the role of ovarian hormones in the regulation of mammary beta-adrenergic receptors, virgin animals were killed during the various phases of the estrous cycle as well as after ovariectomy and treatment with sex steroid. beta-Adrenergic receptor levels fluctuate in the rat mammary gland during the estrous cycle, with higher receptor numbers during the proestrous and estrous phases of the cycle. Ovariectomy caused an almost 50% loss of beta-adrenergic receptor concentration in the mammary gland of virgin rats. Treatment of ovariectomized animals with 17 beta-estradiol or progesterone alone or in combination for 3 weeks induced a marked increase in beta-adrenergic receptor concentration, while administration of the androgen dihydrotestosterone did not modify mammary beta-adrenergic binding sites. While levels of beta-adrenergic receptors in control lactating animals (10 days of lactation) were elevated, chronic treatment with the dopaminergic-mimetic agent 2 alpha-bromoergocryptine (CB-154; for 7 days) reduced beta-adrenergic receptor concentration. Castration of lactating animals decreased beta-adrenergic receptor number to approximately 30% of the value in intact controls, while combined withdrawal of circulating ovarian hormones and inhibition of plasma PRL levels caused an almost complete inhibition of beta-adrenergic receptor concentration. Scatchard analysis of the binding data revealed that the observed alterations in beta-adrenergic receptors resulted from changes in the number of beta-adrenergic binding sites, with no change in binding affinities. The present findings indicate that the beta-adrenergic receptor population of the rat mammary gland is under the control of ovarian hormones and PRL and suggest that circulating or locally released catecholamines could interact with sex steroids and PRL in the regulation of mammary gland growth, differentiation, and activity.

Viral Pneumonia Attenuates Adenylate Cyclase But Not Beta-Adrenergic Receptors in Murine Lung

Respiratory infections provoke increased airway reactivity in both asthmatic and otherwise healthy subjects in part through impaired beta-adrenergic relaxation of bronchial and tracheal muscle. The precise mechanism remains obscure, but some studies report a decrease in the number of beta-adrenergic receptors. The present study was designed to assess the effect of viral respiratory infection with influenza A on lung beta-adrenergic receptors and adenylate cyclase activation in mice under two separate protocols. First, to determine whether changes are due to a local or systemic effect, we compared mice with influenza infections limited to the upper respiratory tract to mice with infection of the total respiratory tract. Four days after upper respiratory tract infection there were no changes in either isoproterenol- or NaF-stimulated adenylate cyclase activity. In contrast, there was an 82% decrease in isoproterenol- and a 25% decrease in NaF-stimulated adenylate cyclase activity on the fourth day after total respiratory tract infection. There were no changes in beta-adrenergic receptors or receptor coupling to adenylate cyclase with either type of infection. Our second protocol compared acutely infected mice to postrecovery mice. Twelve days after infection the virus was no longer present in the lungs, and adenylate cyclase activity was restored to normal. These data suggest that viral respiratory infection may impair airway function through attenuation of receptor and postreceptor activation of adenylate cyclase activity.

Adrenergic Receptors in Aging and Alzheimer's Disease: Increased β2‐Receptors in Prefrontal Cortex and Hippocampus

Loss of pigmented noradrenergic locus ceruleus neurons occurs in Alzheimer's disease (AD) and, to a lesser extent, in aging. We studied beta-adrenergic receptors and their subtypes, beta 1 and beta 2, by the specific binding of 125I-pindolol to particulate membrane preparations from prefrontal cortex, hippocampus, putamen, and cerebellum and to sections from frontal cortex by in vitro autoradiography. In prefrontal cortex from controls, numbers of total beta- and beta 2-adrenoceptors did not significantly correlate with age, but number of beta 1-adrenoceptors showed a weak but significant negative correlation. Binding in tissue particulate preparations to total beta-receptors did not reveal significant differences in samples from prefrontal cortex between AD subjects and age-matched controls. However, beta 1-adrenoceptors were decreased and beta 2-adrenoceptors were increased in number by approximately 30-50% in AD subjects. Thus, the relative ratio of beta 1-/beta 2-receptors was decreased in AD. Binding by in vitro receptor autoradiography performed in a subset of samples of frontal cortex also showed beta 2-adrenoceptors, and less consistently total beta- and beta 1-receptors, to be increased significantly in number in cortical laminae II, III, IV, and V of tissue sections from AD subjects. In these subjects, number of locus ceruleus cells and norepinephrine concentrations in putamen and frontal cortex were markedly reduced compared with values in controls. In the hippocampus, total beta- and both beta 2- and beta 1-adrenoceptors were increased in number in AD. In contrast, in the putamen, where beta 1-receptors predominate, total beta- and beta 1-receptors were significantly decreased in number with no consistent change in content of beta 2-receptors in AD. There were no significant changes in the cerebellum. Specific pindolol binding was not affected by interval between death and sampling of tissue at autopsy. Our results indicate selective changes in number of beta-receptors in AD. These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.

Positive inotropic stimulation in the normal and insufficient human myocardium

Cardiac alpha- and beta-adrenoceptors and the positive inotropic effects of several adenylate cyclase dependent and independent agents have been measured in papillary muscle strips from patients without, as well as with moderate and severe heart failure. The number of beta-adrenoceptors was found to be decreased depending on the degree of heart failure. This does not apply to alpha-adrenoceptors, which remain unchanged. The antagonist affinity of adrenoceptors for the different ligands did not change in heart failure. Maximal increases in force of contraction were measured after raising Ca++ up to 15 mM in the muscle strips. In healthy human myocardium, isoprenaline, dobutamine, IBMX or cardiac glycosides increase force of contraction to the same maximal values as Ca++ does. However, in cardiac tissue from heart failure patients, positive inotropic agents which increase intracellular cAMP or are cAMP-dependent are less effective than Ca++. Furthermore, the results seem to indicate a homologous (agonist specific) downregulation of receptors in moderate heart failure and a heterologous downregulation in severe heart failure. Thus, many well known positive inotropic drugs lose their effectiveness just when they are needed most: in severe heart failure.

Distribution and subtype determination of?-receptors in the spinal cord of the adult rat

1. We determined the number of beta-receptors in the whole spinal cord of the adult rat and in the cervical, thoracal, and lumbal/sacral parts. 2. The undivided spinal cord contains 47 +/- 10 fmol/mg beta-receptors (KD = 2066 +/- 982 pmol/liter), and the cervical part of the spinal cord contains 53 +/- 8 fmol/mg protein (KD = 3224 +/- 1775 pmol/liter). The thoracal part shows 40 +/- 1 fmol/mg protein (KD = 3229 +/- 104 pmol/liter), and the lumbal/sacral spinal cord contains 48 +/- 8 fmol/mg protein (KD = 3610 +/- 1610 pmol/liter). 3. Competitive inhibition studies with l-practolol, dl-atenolol, and ICI 118,551 were performed and we calculated by a computer program in the whole spinal cord the following ratio of beta-receptor subtypes: 80 +/- 5% Beta 1-receptors and 20 +/- 5% beta 2-receptors. 4. The basal and (-)-isoproterenol- and NaF-stimulated activity of adenylate cyclase was highest in the cervical part of the spinal cord and equally distributed between the thoracal and the lumbal/sacral parts. 5. The whole synaptosomal protein of the cervical part of the spinal cord contained 132 +/- 20 fmol, the thoracal part 117 +/- 3 fmol, and the lumbal/sacral part 133 +/- 22 fmol.

Altered adrenoceptor responsiveness during adrenaline infusion but not during mental stress: differences between receptor subtypes and tissues.

1. Effects of 3 h infusions of adrenaline (0.4 nmol kg-1 min-1) or placebo and of mental stress evoked by a colour word test (CWT) on adrenergic receptor function were investigated in healthy men. Responses of heart rate, blood pressure, plasma catecholamines, plasma cyclic AMP and plasma free fatty acids (FFA) were evaluated during infusions and CWT. In vitro beta 2-adrenoceptor numbers [( 125I]-HYP binding) and function (isoprenaline induced cyclic AMP accumulation) were studied on lymphocytes in all experiments. alpha 2-adrenoceptor binding [( 3H]-yohimbine and adrenaline) to intact platelets was evaluated in the infusion experiments only. 2. Placebo infusion evoked no major alterations of any parameter. 3. Adrenaline infusion raised venous plasma adrenaline levels to 4-5 nmol l-1, increased heart rate by 14 +/- 3 beats min-1 and plasma cyclic AMP by 17 +/- 3 nmol l-1, and decreased diastolic blood pressure by 15 +/- 5 mm Hg. These responses persisted throughout the infusion. Plasma FFA levels, on the other hand, increased at 30 min of infusion (from 236 +/- 44 to 717 +/- 92 mumol l-1) and returned to basal levels after 3 h of infusion. 4. In vitro, lymphocytes showed increased beta 2-responsiveness after 30 min of adrenaline infusion (delta cyclic AMP increased from 1.86 +/- 0.24 to 3.06 +/- 0.58 pmol/10(6) cells), but a decreased response (0.47 +/- 0.10 pmol/10(6) cells) after 3 h of infusion. [125I]-HYP binding to lymphocyte membranes showed a three-fold increase of Bmax at 30 min of adrenaline infusion followed by a return to basal values after 3 h of infusion. [125I]-HYP binding reflected the functional responsiveness of the lymphocytes in vitro poorly. alpha 2-adrenoceptors on platelets were not altered with regard to Bmax or Kd for [3H]-yohimbine binding or Ki for adrenaline displacement of [3H]-yohimbine binding. 5. CWT evoked marked circulatory changes, a four-fold increase in plasma adrenaline and a 60% increase in beta 2-adrenoceptor binding sites without changes in functional responsiveness of the lymphocytes. 6. We conclude that exposure to high physiological levels of adrenaline in vivo alters lymphocyte beta-adrenoceptor responsiveness in a biphasic manner, with an early increase followed by a later decrease, but that most beta-adrenoceptor mediated responses to adrenaline in vivo remain intact. Lymphocyte alterations may reflect recruitment of cells into the circulation during sympathoadrenal stimulation. Platelet alpha 2-adrenoceptors are apparently not easily subjected to agonist induced dynamic receptor regulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperthyroid adult rat cardiomyocytes. I. Nucleotide content, beta- and alpha-adrenoreceptors, and cAMP production

Ventricular myocytes isolated from the hypertrophied hearts of thyrotoxic adult rats have an increase in mean protein content per myocyte (6.3 +/- 0.2 vs. 4.4 +/- 0.2 ng) compared with euthyroid cells. Viability and adenine nucleotide profiles are similar in both populations, but NAD content of the hyperthyroid myocytes is depressed (4.9 +/- 0.2 vs. 5.5 +/- 0.2 nmol/mg for controls) and UTP is higher (1.2 +/- 0.09 vs. 0.9 +/- 0.04 nmol/mg). Binding of (-)-[125I]iodocyanopindolol to intact hyperthyroid myocytes is increased by 42% compared with controls, with no change in the dissociation constant (Kd). This elevation in beta-receptor number is correlated to enhanced beta-agonist-induced adenosine 3',5'-cyclic monophosphate (cAMP) production. The half-maximal effective concentration (EC50) for the euthyroid isoproterenol dose-response curve is 2.14 x 10(-7) M but is decreased to 2.51 x 10(-8) M in hyperthyroid cardiac cells. Basal adenylate cyclase activity is apparently not affected by thyroid hormones, since basal cAMP levels for both groups are identical (5 pmol/mg) and both rise roughly twofold in the presence of a phosphodiesterase inhibitor. Forskolin-induced cAMP production and cAMP-specific phosphodiesterase activity are similar as well. In contrast to beta-adrenergic response, there are no significant differences in alpha 1-antagonist [3H]prazosin binding parameters between hyperthyroid and euthyroid cardiomyocytes.