Number Of Β-adrenergic Receptors Research Articles

β-adrenergic ([ 3H] CGP-12177) receptors are elevated in slices of soleus muscle from CHF 147 dystrophic hamsters

We have utilized a muscle slice technique to compare the ontogeny of cell surface β-adrenergic receptor binding in soleus and extensor digitorum longus (EDL) muscles of male Golden Syrian (GS) and Canadian Hybrid Farms 147 (CHF 147) dystrophic hamsters. Binding of the β-adrenergic antagonist, [ 3H] CGP-12177 (CGP), to GS muscle slices was reversible, saturable, stereospecific and of high affinity. B max was higher in the soleus (2.57±.12 fmol/mg wet wt) than in the EDL (1.61±.17 fmol/mg wet wt) of adult animals while affinities were similar (0.35 ±.06 and 0.24 ±.04 nM respectively). No differences in binding characteristics were seen in EDL of GS compared to CHF 147 animals. In soleus slices frm GS hamsters, B max was highest at 16 days of age (5.72 ± 0.26 fmol/mg), decreased between 16 and 29 days and remained constant until 300 days (2.51 ± 0.52 fmol/mg). In dystrophic soleus slices, B max was also higher at 16 days than at any other age but receptor number decreased gradually, remaining higher than in GS until 90 days of age (p< 0.05). The failure of β-adrenergic receptor number to decrease at a normal rate may be implicated in the pathogenesis of hamster polymyopathy.

Mechanism of action of prostaglandin F 2α-induced luteolysis: evidence for a rapid effect on the guanine nucleotide binding regulatory component of adenylate cyclase in rat luteal tissue

The initial events in prostaglandin F 2α-(PGF 2α)-induced luteolysis were studied in pregnant mare serum gonadotropin/human chorionic gonadotropin-(PMSG/hCG)-treated rats with luteinized ovaries. Injection with a potent PGF 2α analog (cloprostenol, 5 μg/ml) induced functional luteolysis, as assessed by plasma levels of progesterone and 20α-dihydroprogesterone. At 0.5 and 3 h after cloprostenol administration the luteolytic effect was also evident as a reduced response of luteal adenylate cyclase to all stimulatory agents tested, LH, isoproterenol, fluoride, guanylylimidodiphosphate and forskolin. 24 h after cloprostenol the response to all agents, except to LH, had returned to normal. This general and transient block of the luteal adenylate cyclase system indicates that a common factor, possibly the stimulatory guanine nucleotide binding protein (N s), is involved in the mechanism of action of PGF 2α. To test this hypothesis, we measured the functional coupling of the N s protein to the β-adrenergic receptor in luteal membranes. Binding competition curves showed a marked shift to the right in membranes prepared from rats injected with cloprostenol 0.5 and 3 h before membrane preparation, while at 24 h after cloprostenol the shift had disappeared. The total number of β-adrenergic receptors was, however, not affected by the cloprostenol treatment. Computer analysis of the data indicates that, at 0.5 and 3 h after cloprostenol treatment, there was a reduced number of high affinity binding sites, 38 and 41%, respectively, compared to 53% for control membranes. The cellular mechanism for this action of PGF 2α on the N s protein remains to be elucidated.

Induction of functional β-adrenergic receptors in rat aortic smooth muscle cells by sodium butyrate

Rat aortic smooth muscle cells in culture (A-10; ATCC CRL 1476) exhibited low levels of β-adrenergic receptors as determined by specific binding of [125I]cyanopindolol ([125I]CYP) and marginal stimulation of adenylate cyclase in plasma membranes by (−)isoproterenol. When these cells were exposed to 5 mM sodium butyrate, the number of β-adrenergic receptors and the β-agonist-stimulated adenylate cyclase activity increased markedly. However, basal, GTP, Gpp(NH)p, and fluoride-stimulated activities did not change. The induction of β-adrenergic receptors and β-agonist stimulated adenylate cyclase activity was time- and dose-dependent, and was relatively specific for sodium butyrate. Propionate and valerate were less effective than butyrate, while isobutyrate, succinate, and malonate were ineffective. The induction involved RNA and protein synthesis because induction was prevented by treatment with cycloheximide, puromycin, and actinomycin D. Butyrate did not cause a general increase in cell surface receptors, because the number of vasopressin receptors did not change. The sustained presence of butyrate appeared to be necessary for the maintenance of the induced β-receptors. When butyrate was removed, receptor number and β-agonist-stimulated adenylate cyclase activity were decreased by 90% over 24 hr. We conclude that the poor response of rat aortic smooth muscle cell plasma membranes to β-adrenergic agonists is due to the presence of a low number of β-adrenergic receptors. Butyrate markedly increased the number of β-receptors which resulted in a proportional increase in β-agonist-stimulated adenylate cyclase activity. The increase in receptor number was dependent on RNA and protein synthesis. Butyrate treatment did not affect the activity of the cyclase unit and the efficiency of coupling between the receptors and the guanine nucleotide regulatory protein, Ns.

Adaptive regulation of beta-adrenergic receptors in children with insulin dependent diabetes mellitus.

The beta-adrenergic receptors were investigated in partially purified mononucleal leukocytes (MNL) plasma membranes from 18 patients with IDDM in pediatric period, 9 healthy children and 8 normal adults. The decreased beta-adrenergic receptor number was seen in patients with IDDM (Bmax = 27.6 +/- 8.3 fM (125I) IHYP/mg protein) compared with normal children (Bmax = 40.4 +/- 10.4 fM (125I) IHYP/mg protein) and normal adults (Bmax = 36.9 +/- 6 fM (125I) IHYP/mg protein). MNL beta-receptor binding affinities (apparent Kd = 109.8 +/- 26.1 pM in IDDM, 102.8 +/- 46.6 pM in normal children, 130.0 +/- 43.1 pM in normal adults) did not differ. We divided the patients with IDDM into two groups based on their level of blood glycosylated hemoglobin (HbA1) when samples were taken. Group A IDDM (consisted of 9 diabetic patients with below 10% of HbA1) had markedly decreased beta-receptor numbers compared with group B IDDM (consisted of 9 diabetic patients with more than 10% of HbA1), whereas Kd was not significantly different. Also, there was negative correlation between Bmax and level of blood sugar or HbA1 in IDDM. This is the first report concerning the beta-adrenergic receptor in IDDM in pediatric period. We suggest that decreased Bmax in group B is a homeostatic response to restore the poorly-controlled hyperglycemic state to normoglycemia because the group B patients had high level of HbA1 and blood sugar.

Induction of desensitization by phorbol ester to β-adrenergic agonist stimulation in adenylate cyclase system of rat reticulocytes

Treatment of rat reticulocytes with a phorbol ester, tetradecanoyl phorbol acetate (TPA), resulted in the desensitization of adenylate cyclase to the β-adrenergic agonist stimulation depending on the dose and period of the TPA treatment. Treatment of the reticulocytes with TPA caused approximately 40% reduction in the stimulation by β-adrenergic agonists of adenylate cyclase activity, whereas the treatment had little effect on the basal activity and the activation by fluoride and guanine nucleotide of the enzyme system. No change in the number of β-adrenergic receptors was observed after the TPA treatment. Treatment with 1-oleoyl-2-acetyl-glycerol (OAG), an activator of protein kinase C, also caused the desensitization of reticulocyte adenylate cyclase to isoproterenol. On the other hand, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C, prevented the desensitization induced by TPA. These results suggest the involvement of protein kinase C in a process of desensitization of adenylate cyclase system to β-adrenergic agonists in rat reticulocytes.

Elevated level of β-adrenergic receptors in hepatocytes from regenerating rat liver: Time study of [ 125I]iodocyanopindolol binding following partial hepatectomy and its relationship to catecholamine-sensitive adenylate cyclase

Hepatocytes from regenerating rat liver show an enhanced epinephrine-sensitive adenylate cyclase activity and cAMP response, which may be involved in triggering of the cell proliferation. We have determined adrenergic receptors and adenylate cyclase activity in hepatocytes isolated at various time points after partial hepatectomy. The number of β-adrenergic receptors, measured by binding of [ 125I]iodocyanopindolol ([ 125I]CYP) to a particulate fraction prepared from isolated hepatocytes, increased rapidly after partial hepatectomy as compared with sham-operated or untreated controls. The maximal increase, which was observed at 48 h, was between 5- and 6-fold (from ~1 800 to ~ 10 500 sites per cell). Thereafter, the number of β-adrenergic receptors decreased gradually. Competition experiments indicated β 2-type receptors. Parallelism was found between the change in the number of β 2-adrenergic receptors and the isoproterenol-responsive adenylate cyclase activity. The number of α 1-adrenergic receptors, determined by binding of [ 3H]prazosin, was transiently lowered by about 35% at 18–24 h, with no significant change in K d . Although the results of this study do not exclude the possibility of post-receptor events, they suggest that the increased number of β 2-adrenergic receptors is a major factor responsible for the enhanced catecholamine-responsive adenylate cyclase activity in regenerating liver.

Beta-adrenergic responses in drug-free subjects with asthma

Young atopic subjects with asthma who had taken no medication for 30 days and had normal pulmonary function were compared to atopic and nonatopic control subjects in several measures of β-adrenergic response. Subjects with asthma required a larger dose of infused isoproterenol (14.3 ± 3.9 ng/kg/min) to increase pulse pressure by a target >22 mm Hg than nonatopic control subjects (8.7 ± 3.3 ng/kg/min). Asymptomatic atopic control subjects had intermediate sensitivity (12.0 ± 6.0 ng/kg/min) (F = 3.67; p < 0.05). At the dose of infused isoproterenol producing the target pulse pressure response, the increase in low frequency (1 to 8 cycles per minute) heart rate variability was less in subjects with asthma (107 ± 34% increase in normal subjects versus 9 ± 21 % increase in subjects with asthma; p < 0.05). In addition, subjects with the least β-adrenergic responsiveness had the most reactive airways. Airway reactivity (assessed by the provocative concentration of methacholine causing a 20% fall in FEV 1) correlated with both the dose of isoproterenol required for the target pulse pressure response (R s = - 0.46; p < 0.05) and the isoproterenol-induced increase in low-frequency heart-rate variability (R s = 0.47; p < 0.05). In contrast, in lymphocytes and granulocytes from these same subjects, the cAMP response to isoproterenol and β-adrenergic receptor number were identical in normal subjects and subjects with asthma and unrelated to airway reactivity or to cardiovascular β-adrenergic responses. Thus, different results for β-adrenergic responsiveness in subjects with asthma are obtained in different tests in the same subjects.

DSP4-induced noradrenergic lesions increase β-adrenergic receptors and hippocampal electrophysiological responsiveness

Following profound (>90%) depletions of norepinephrine (NE) by the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), the numbers of β-adrenergic receptors were significantly increased (20–25%) in rat hippocampal and somatosensory cortical membrane; however, the numbers of α 1-adrenergic receptors and the affinities of both types of receptors were unaffected. This selective up-regulation of β-adrenergic receptors was evident 1 week after DSP4 administration and was maintained for at least 2 more weeks. In electrphysiological experiments in the hippocampal slice preparation, responses to threshold as well as maximal concentrations of isoproterenol were enhanced 150% and 33%, respectively, in the DSP4-lesioned animals. The results demonstrate that nearly complete depletion of brain NE produced by administration of DSP4, like that produced by 6-hydroxydopamine, results in increased numbers of β- but not α-adrenergic receptors, and suggest that the density of the former are regulated by afferent noradrenergic fibers. Furthermore, the functional significance of the increased number of hippocampal β-adrenergic receptors is directly manifested in a greater electrophysiological responsiveness to an exogenously administered β-adrenergic receptor agonist.

Endogenous noradrenaline masks beta-adrenergic receptors in rat heart membranes via tight agonist binding

The tight binding of noradrenaline (NA) to β-adrenergic receptors was studied in membranes from the left ventricular myocardium of the rat. Addition of GTP (0.1 mM) to membrane preparations from control rats (NA concentration 8.5 ± 2.1 nM) caused a 4–35% (N = 8) increase (P < 0.01) in the number of specific binding sites of [ 125I](−)pindolol. In contrast, addition of GTP did not cause any changes in the number of β-adrenergic receptors in heart membranes from reserpinized animals (NA concentration < 0.1 nM). In heart membranes from reserpinized animals, preincubation with NA (followed by washing) revealed a time- and concentration-dependent decrease with a maximum of 35–40% in the [ 125I](−)pindolol-binding sites. This agonist-mediated decrease in the number of receptors was prevented if GTP was also present in the NA-preincubation medium. It is concluded that NA can undergo tight binding to β-adrenergic receptors in rat heart membranes. The heart-membrane preparations contain endogenous NA which, via tight agonist binding, is responsible for masking part of the β-adrenergic receptor population.

Cholesterol modulation of β-adrenergic receptor characteristics

Cholesterol, a major structural component of plasma membranes, has a profound influence on cell surface receptor characteristics and on adenylate cyclase activity. β-Adrenergic receptor number, adenylate cyclase activity, and receptor-cyclase coupling were assessed in rat lung membranes following preincubation with cholesteryl hemisuccinate. β-Adrenergic receptor number increased by 50% without a change in antagonist affinity. However, β-adrenergic receptor affinity for isoproterenol increased 2-fold as a result of an increase in the affinity of the isoproterenol high-affinity binding site. This increase in agonist affinity did not potentiate hormone-stimulated adenylate cyclase activity, which decreased 3-fold following cholesterol incorporation. However, the ratio of isoproterenol to GTP-stimulated activity was unchanged with cholesterol. Stimulation distal to the receptor by GTP, NaF, GppNHp, Mn 2+ and forskolin also demonstrated 50–80% reduced enzyme activity following cholesterol incorporation. These data suggest that membrane cholesterol incorporation decreases catalytic unit activity without affecting transduction of the hormone signal.

Autoradiographic quantitation of β-adrenergic receptors on neural cells in primary cultures. II. Comparison of receptors on various types of immunocytochemically identified cells

We have developed a microcomputer-based video method to quantify neurotransmitter receptors on single, immunocytochemically labeled cultured cells. This method has been applied to determine whether β-adrenergic receptors are more numerous on neurons, astroglia, oligodendroglia or fibroblasts in primary neural cell cultures, and to assess the heterogeneity of receptor expression within a single cell type. Dissociated cells from perinatal rat cerebral cortex were grown in very sparse cultures on polylysine-coated glass slides. The cultured cells were fixed and permeated, then stained with fluorescently labeled immunocytochemical markers for astroglia (glial fibrillary acidic protein), fibroblasts (fibronectin), oligodendroglia (galactocerebroside) or neurons (A2B5). β-Adrenergic receptors were labeled with [ 125I]pindolol or [ 125I]cyanopindolol, and dry-mount autoradiography was carried out on the fixed cells. Cells were identified according to their morphology and cell-type specific staining, then autoradiographic grains associated with the defined cells were visualized by reflected polarized light microscopy and counted with a microcomputer-based video digitizing system. Using this technique, we have determined that fibroblasts have less than 15% of the number of β-adrenergic receptors expressed by polygonal astroglia, whereas oligodendroglia and neurons had no detectable binding of 125I-labelled ligands. This suggests that in these mixed neural cell cultures, the great majority of β-adrenergic receptors are associated with astroglia. Furthermore, we determined that process-bearing astroglia have less than 5% of the number of β-adrenergic receptors expressed by polygonal astroglia. Since process-bearing astroglia are thought to be derived from polygonal astroglia, these results suggest that the β-adrenergic receptor is lost from this population of astroglia during development. This method provides a novel approach to the problem of measuring cell-type specific, membrane-associated receptors on individual, well-characterized cells in mixed primary neural cultures.

β-Adrenergic-receptor and adenylate cyclase properties in pregnant and nonpregnant guinea pig myometrium

Stimulation of myometrial β-adrenergic receptors by agonists results in myometrial relaxation through adenylate cyclase-dependent mechanisms. Their activity is modulated by local or systemic estrogen-progesterone milieu. During pregnancy, guinea pigs demonstrate an ovarioplacental shift for progesterone production at ⩽0.35 gestation and a gradual increase in estrogen levels. To investigate whether these changes affect myometrial β-adrenergic-receptor and adenylate cyclase properties, we directly characterized β-adrenergic receptors and adenylate cyclase in myometrial plasma membranes from time-dated pregnant (term 65 days), postpartum, and nonpregnant virgin guinea pigs by well-established in vitro methods. In all animals, there appeared to be a high-affinity, low-capacity, single class of binding sites with pharmacologic specificities consistent with the β2-adrenergic-receptor subtype. The dissociation constants of these β-adrenergic receptors were significantly decreased in pregnant animals at approximately ⩾0.80 gestation when compared to pregnant animals at 0.35 to 0.40 gestation, nonpregnant animals, and postpartum animals. Moreover, the total number of β-adrenergic receptors was significantly higher at ⩾0.80 gestation than in the other groups. Basal adenylate cyclase activity increased in animals from 0.35 to ⩾0.8 gestation and was higher than that of postpartum animals and nonpregnant animals. The degree of adenylate cyclase stimulation by (−)isoproterenol was higher at term than at an earlier point in gestation or in nonpregnant and postpartum animals. These results indicate that, with advancing gestation in pregnant animals, there is an up-regulation of β-adrenergic-receptor and adenylate cyclase function.

Progesterone in rat brain: Modulation of β-adrenergic receptor activity

Cytosolic proteins binding specifically the progesterone analogue 3H R5020 can be detected in various areas of the central nervous system (CNS) of rat. Our study demonstrates that the concentration of progesterone receptors in the brain of adult, ovariectomized, female rats is maximal in frontal cortex and midbrain and lowest in the cerebellum. Short term administration of the hormone does not alter the β-adrenergic receptor system, while a prolonged administration of progesterone results in an up-regulation of 3H-DHA binding in the frontal cortex. Such increase in binding activity is due to an increased number of β-adrenergic receptors. Furthermore, high doses of progesterone can also increase the number of β-adrenergic binding sites in an “in vitro” system where brain slices are incubated for few hours in a physiological medium.

The influence of the sympathetic nervous system on the development of β-adrenergic receptors in the rat submandibular salivary gland

During the development of the rat submandibular gland (SMG) there is a clearly-defined sequence in the maturation of the β-adrenergic receptor/adenylate cyclase-linked stimulus-secretion coupling system. The sympathetic nervous system does not become functionally linked to the exocrine process in the SMG until approximately six days after birth. The temporal correlation of the ingrowth of catecholamine-containing nerve processes, the appearance of β-adrenergic receptors and the functional coupling of the stimulus-secretion system suggested the possibility of a cause and effect relationship between the appearance of the catecholamine-containing nerves in the gland and the maturational increase in the number of β-adrenergic receptors. Chemical sympathectomy in neonates did not effect the time of appearance or the number of β-adrenergic receptors seen in the developing gland. However, chronic isoproterenol treatment resulted in accelerated maturation of the gland with a concomitant premature appearance of the β-receptors. These data suggest that the increase in the number of β-adrenergic receptors which normally occurs in the developing gland at 5–6 days after birth is a specifically-programmed step closely associated with the degree of maturation attained by the cells and is independent from the ingrowth of catecholamine-containing nerves.

Association of sequestered beta-adrenergic receptors with the plasma membrane: A novel mechanism for receptor down regulation

Chronic exposure of frog erythrocytes to β-adrenergic agonists leads to desensitization of the responsiveness of adenylate cyclase to isoproterenol and is accompanied by “down-regulation”, a decrease in the number of β-adrenergic receptors on the cell surface. When frog erythrocyte plasma membranes are prepared by osmotic lysis of cells, the receptors lost from the cell surface during desensitization can be recovered in a “light membrane fraction”, obtained by centrifuging the cell cytosol at 158,000 × g for 1 hr. These receptors are sequestered away from the plasma membrane fraction which contains the adenylate cyclase and the guanine nucleotide regulatory protein. If desensitized frog erythrocytes are disrupted by gentler freeze/-thaw procedures, however, the sequestered β-adrenergic receptors can be demonstrated to be physically associated with the plasma membrane. Typically, plasma membranes prepared in this fashion do not demonstrate a significant down regulation despite attenuation of isoproterenol-stimulated adenylate cyclase activity. Under these conditions, β-adrenergic receptors from control and desensitized preparations co-migrate on sucrose density gradients in exactly the same place as the plasma membrane marker, adenylate cyclase. In contrast, when membranes from osmotically lysed desensitized cells are fractionated on sucrose gradients the down regulated receptors are sequestered in a light membrane fraction which barely enters the gradient and which is physically separated from adenylate cyclase activity. The data are consistent with a novel mechanism of receptor down-regulation which appears to involve the sequestration of the β-adrenergic receptors away from the cell surface into a membrane compartment which remains physically associated with the plasma membrane.

Alteration of the pattern of β-adrenergic desensitization in cultured L 6E 9 muscle cells infected with Trypanosoma cruzi

L 6E 9 myoblasts infected with Trypanosoma cruzi undergo desensitization to β-adrenergic catecholamines in a manner distinct from uninfected control myoblasts. Following incubation of intact cells with isoproterenol for 2h, homogenates prepared from differentiated, high density uninfected L 6E 9 cells retain isoproterenol-dependent adenylate cyclase activity. In addition, previous exposure to isoproterenol is accompanied by a decrease in the number of β-adrenergic receptors. Homogenates of high density L 6E 9 cells infected with T. cruzi retain their adenylate cyclase responsivity to isoproterenol but demonstrate a marked decrease in β-adrenergic receptors. Following desensitization infected cell homogenates lose their responsiveness to isoproterenol and demonstrate a more marked decrease in β-receptors. There does not appear to be any effect of T. cruzi infection on affinity of β-adrenergic agonists for the β-receptor or on changes in agonist affinity associated with desensitization. Infection of low density undifferentiated cells results in no apparent change in adenylate cyclase activity or in β-receptors. Their behavior in the setting of desensitization — decreased whole cell cyclic AMP, decreased adenylate cyclase, unchanged β-receptors — is also not affected by infection. The pattern of desensitization to β-adrenergic agonists in high density infected cells shares several properties with the pattern of desensitization in low density uninfected cells, suggesting that infection may be associated with part of the more primitive cellular response pattern.

The regulation of adenylate cyclase in adipocyte plasma membrane from genetically obese (ob/ob) mice.

Adenylate cyclase activity was determined using a purified plasma membrane fraction prepared from isolated adipocytes by a Percoll gradient centrifugation procedure. The activation of adenylate cyclase by isoprenaline was reduced by approximately 50% in membranes from obese mice, although no reduction in the sensitivity of the response was apparent. Basal and fluoride- and 5'-guanylyl-imidodiphosphate-stimulated activities were similar in both groups. However, two defects in the obese system were identified which suggested that an alteration in the properties of the regulatory protein may account for the impaired hormonal activation. The specific binding of 3H-dihydroalprenolol to membranes from obese animals also was decreased, suggesting a reduction in the number of beta-adrenergic receptors.

Desensitization of beta-adrenergic receptors by pheochromocytoma.

Prolonged stimulation of cells by beta-adrenergic receptor agonists may lead to diminished responsiveness of the cells to subsequent activation by catecholamines. This phenomenon has been termed desensitization; the mechanism(s) for desensitization may involve an apparent loss in the number of beta-adrenergic receptors or an alteration in receptor-effector coupling. We have examined the consequences of prolonged stimulation of beta-adrenergic receptors in an interesting rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and plasma norepinephrine concentrations approximately 40-fold greater than controls. beta-Adrenergic receptors were quantitated in several tissues from controls and rats with transplanted pheochromocytoma using the beta-adrenergic receptor antagonist [125I]iodocyanopindolol. Down-regulation of beta 1-receptors was found in heart tissue (22.8 vs. 13.6 fmol/mg protein; P less than 0.001) and adipocytes (29,400 vs. 2,800 sites/cell; P less than 0.001). Also, maximal isoproterenol-stimulated cAMP accumulation in isolated adipocytes was diminished in pheochromocytomic animals (13.1 vs. 4.9 pmol cAMP/10(5) cells/min; P less than 0.05). Interestingly, there was no change in beta-receptors in lung and mesenteric artery, which predominantly contain beta 2-receptors. Furthermore, the competition curves of isoproterenol in the heart membranes from control and pheochromocytomic rats in the absence and presence of guanylylimidodiphosphate indicated uncoupling of the beta-adrenergic receptors in pheochromocytomic animals. Rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying the in vivo development of desensitization.

β-adrenergic receptors in brain microvessels of diabetic rats

A significant decrease in the number of β-adrenergic receptors was observed in cerebral microvessels of fatty (fa/fa) and streptozotocin-induced diabetic rats, without receptor affinity changes. These results suggest that alterations of central adrenergic regulation of small vessels may be involved in brain microvasculature disturbances that occur with diabetes.

Effects of elevated prolactin and its normalization on thyroid hormone, cardiac β-adrenoreceptor number and β-adrenergic responsiveness

Subcutaneous inoculation of the prolactin secreting MtTW15 adenoma in male Wistar Furth rats for 4 weeks produced a significant increase in serum prolactin and a corresponding decrease in peripheral β-adrenergic responsiveness. Both the isoproterenol induced drink and heart rate responses used to assess the β-adrenergic responsiveness were significantly reduced in the hyperprolactinemic rat. Serum T 3 and T 4 levels were measured as was cardiac β-adrenergic receptor number to ascertain if an alteration of thyroid hormone and a resultant decrease in β-adrenergic receptor number was responsible for the attenuated β-adrenergic responsiveness. Serum T 4 was significantly reduced in the hyperprolactinemic group (1.9 ± 0.3 μg%) as compared to the control group (6.4 ± 0.5 μg%). However there was no significant difference in serum T 3 or in cardiac β-adrenergic receptor number between the two groups. Removal of the MtTW15 adenoma resulted in a normalization of serum prolactin, T 4, and in the responsiveness of the peripheral β-adrenergic system within 4–6 weeks. These results indicate that the attenuated β-adrenergic responsiveness associated with hyperprolactinemia is reversible and not dependent on a reduction in β-adrenergic receptor number.