The SAGA continues: expanding the cellular role of a transcriptional co-activator complex.

Throughout the last decade, great advances have been made in our understanding of how DNA-templated cellular processes occur in the native chromatin environment. Proteins that regulate transcription, replication, DNA repair, mitosis and other processes must be targeted to specific regions of the genome and granted access to DNA, which is normally tightly packaged in the higher-order chromatin structure of eukaryotic nuclei. Massive multiprotein complexes have been discovered, which facilitate access to DNA and recruitment of downstream effectors through three distinct mechanisms: chemical modification of histone amino-acid residues, ATP-dependent chromatin remodeling and histone exchange. The yeast Spt-Ada-Gcn5-Acetyl transferase (SAGA) transcriptional co-activator complex regulates numerous cellular processes through coordination of multiple histone post-translational modifications. SAGA is known to generate and interact with a number of histone modifications, including acetylation, methylation, ubiquitylation and phosphorylation. Although best characterized for its role in regulating transcriptional activation, SAGA is also required for optimal transcription elongation, mRNA export and perhaps nucleotide excision repair. Here, we discuss findings from recent years that have elucidated the function of this 1.8-MDa complex in multiple cellular processes, and how misregulation of the homologous complexes in humans may ultimately play a role in development of disease.

Reducing black/white disparity: changes in injury mortality in the 15-24 year age group, United States, 1999-2005.

In 1999, the injury death rate for black males aged 15-24 in the USA was 80% greater than for white males: 148.5 vs 82.5/100,000, a difference of 66/100,000. Injury-specific changes between 1999 and 2005 in death rates for the 15-24 age group and in racial disparity were analysed using data from CDC's WISQARS. The gap between black and white all-injury death rates in males was reduced by 24%, to a difference of 50/100,000, largely because of greater decreases in the rates for motor vehicle crashes and firearm suicide in young black men than young white men, and large increases in suicide by suffocation and unintentional poisoning in the latter. Among females, despite a reduction in the black/white gap in firearm homicide rates, the gap between the races in total injury rates changed from a small black excess to a higher rate in young white women, which was due primarily to greater increases in these white women than black women in unintentional poisoning and suicide by suffocation, and greater decreases in black women than white women in firearm suicide.

Road-traffic deaths in China, 1985-2005: threat and opportunity.

OBJECTIVE: To examine recent trends and geographic variations in road-traffic deaths in China. DESIGN: A longitudinal descriptive analysis of national and provincial data on road-traffic deaths, examining recent trends and geographic variations. SETTING: China, 1985-2005. DATA SOURCES: The Transportation and communications yearbook of China (1986-2006) and the National statistics yearbook of China (1996-2006). MAIN OUTCOME MEASURES: The percentage change in death rates per 100,000 population was used to examine the trend. Epi Info was used to map the geographic distribution of road-traffic death rates and the increases in rates. Correlation coefficients were calculated between per capita gross regional product, road quality, and the number of motor vehicles in the 31 provinces, to help understand the geographic variations in road-traffic mortality at the provincial level in China. RESULTS: The road-traffic death rate increased by 95%, from 3.9/100,000 persons in 1985 to 7.6/100,000 persons in 2005. High death rates and the greatest increases in death rates occurred in both developed provinces in the southeast and underdeveloped northern and western provinces. Xizang/Tibet, Qinghai, and Xinjiang, with the lowest population density, had the highest death rates per 100 vehicles. CONCLUSIONS: China's government should introduce and support measures to prevent road-traffic injuries. Developed and underdeveloped provinces in China should both be considered when road-traffic policy and interventions are developed.

Injury control: an opportunity for China.

Injury control is an important health issue in China, but has been less well explored than in other countries. To encourage health policy makers to give greater attention to injury control, this report highlights the great damage caused by injuries and the neglected status of injury control in China. China's situation and the experiences and lessons from industrialized countries, especially the USA, are summarized. Finally, two opportunities to improve injury control in China are identified: establishment of a mechanism for multi-department coordination and collaboration; and improvement of injury data surveillance.

Long-term changes in glutamatergic synaptic transmission in phenylketonuria.

The cellular mechanisms that underlie impaired brain function during phenylketonuria (PKU), the most common biochemical cause of mental retardation in humans, remain unclear. Acute application of L-Phe at concentrations observed in the PKU brain depresses glutamatergic synaptic transmission but does not affect GABA receptor activity in cultured neurons. If these depressant effects of L-Phe take place in the PKU brain, then chronic impairment of the glutamate system, which may contribute to impaired brain function, could be detected as changes in postsynaptic glutamate receptors. This hypothesis was tested by using a combination of liquid chromatography-mass spectrometry, patch-clamp, radioligand binding and western blot approaches in forebrain tissue from heterozygous and homozygous (PKU) Pah(enu2) mice. Brain concentrations of L-Phe were nearly six-fold greater in PKU mice (863.12 +/- 17.96 micromol/kg) than in their heterozygous counterparts (149.32 +/- 10.23 micromol/kg). This concentration is significantly higher than the K(B) of 573 microM for L-Phe to compete for N-methyl-D-aspartate (NMDA) receptors. Receptor binding experiments with [3H]MK-801 showed significant up-regulation of NMDA receptor density in PKU mice. Consistent with the depressant effects of L-Phe, expression of NMDA receptor NR2A and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor Glu1 and Glu2/3 subunits was significantly increased, whereas expression of the NR2B subunit was decreased. There was no change in GABA alpha1 subunit expression. Given the role of the glutamatergic system in brain development and function, these changes may, at least in part, explain the brain disorders associated with PKU.

Phase I study of high-dose piroxantrone with granulocyte colony-stimulating factor.

PURPOSE: We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone. PATIENTS AND METHODS: Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2. RESULTS: Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild. CONCLUSION: The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines.

Age-related reductions in rat atrial high affinity choline uptake, ACh synthesis, and ACh release. A brief note.

We have developed a rat atrial mince preparation that can take up choline, acetylate it, and then release acetylcholine in a depolarization-dependent manner. We demonstrate that aging appears to reduce the functional cholinergic activity in this tissue, which may be important for understanding how senescence alters the regulation of cardiac activity.

Substituted 1,3-dipropylxanthines as irreversible antagonists of A1 adenosine receptors.

This report describes the synthesis of 29 xanthines containing a chemoreactive chloroaryl, beta-chloroethylamino, alpha,beta-unsaturated carbonyl, bromoacetyl, 3-(fluorosulfonyl)benzoyl, or 4-(fluorosulfonyl)benzoyl group as part of an exocyclic 1-, 3-, or 8-substituent. The xanthines inhibited the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to the A1 adenosine receptor (A1AR) of DDT1 MF2 cells at IC50s in the low-nanomolar to low-micromolar range. Seven of the 29 analogues irreversibly inhibited the binding of [3H]CPX without changing the KD of that ligand; five were 1,3-dipropylxanthines having the following reactive groups as 8-substituents: (bromoacetamido)methyl (24), (bromoacetamido)ethyl (25), (bromoacetamido)propyl (26), [4-(fluorosulfonyl)benzamido]methyl (33) or 3-[[4-(fluorosulfonyl)benzoyl]oxy]cyclopentyl (42). Both 8-cyclopentyl-3-[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (53) and 8-cyclopentyl-1,3-bis[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]xanthine (55) inhibited [3H]CPX binding irreversibly. Five of the ligands, including 26, 33 (IC50 = 49 microM), and 53 (IC50 = 9 microM), antagonized the binding of [3H]NECA to the A2aAR of PC12 cells, but unlike binding to the A1AR, binding to the A2aAR was completely reversible. The potency of 33 (IC50 = 2 microM, 72% loss of CPX binding at 1 microM) and 53 (IC50 = 0.01 microM, 74% loss of CPX binding at 0.05 microM) and their selectivity for the A1AR suggest that those two ligands may be useful in studies of the structure and function of that receptor.

Fluorosulfonyl-substituted xanthines as selective irreversible antagonists for the A(1)-adenosine receptor.

FSCPX (1) has been reported to be a potent, selective, and irreversible antagonist for the A(1)-adenosine receptor (AR). To obtain an irreversible A(1)AR antagonist with potentially better stability and to further elucidate the effects of linker structure on the pharmacological characteristics, several new analogues were targeted in which the labile ester linkage of 1 was replaced by more stable functionalities. In particular, alkyl and amide linkers between the xanthine pharmacophore and the reactive 4-fluorosulfonylphenyl group were explored. The data showed that the chemical composition of the linker affects the affinity and apparent irreversible binding to the A(1)AR. Overall, compound 23b appeared to have the most advantageous characteristics as a potential irreversible ligand for the A(1)AR. These include relatively high affinity for the A(1)AR as compared to the A(2A)AR, concentration-dependent and selective apparent irreversible binding to the A(1)AR, and ease of removal of unbound ligand from biological membranes. These properties indicate that 23b has the potential to be a useful tool for further study of the structure and function of the A(1)AR.

Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbonyl)]-xanthine.

The individual enantiomers 8 and 12 of the potent and highly selective racemic A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine (ENX, 4) were synthesized utilizing asymmetric Diels-Alder cycloadditions for the construction of the norbornane moieties. The absolute configuration of 12 was determined by X-ray crystallography of the 4-bromobenzoate 14, which was derived from the bridged secondary alcohol 13. The latter was obtained from 12 by an acid-catalyzed intramolecular rearrangement. The binding affinities of the enantiomers 8 and 12 and the racemate 4 at guinea pig, rat, and cloned human A1- and A2a-adenosine receptor subtypes were determined. The S-enantiomer 12 (CVT-124) appears to be one of the more potent and clearly the most A1-selective antagonist reported to date, with K1 values of 0.67 and 0.45 nM, respectively, at the rat and cloned human A1-receptors and with 1800-fold (rat) and 2400-fold (human) subtype selectivity. Both enantiomers, administered intravenously to saline-loaded rats, induced diuresis via antagonism of renal A1-adenosine receptors.

Carbostyril derivatives having potent beta-adrenergic agonist properties.

Derivatives carrying a substituent in the para position of the phenyl group of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] carbostyril (10) were prepared and their effects on beta-adrenoceptors evaluated in vitro. Unsubstituted compound 10, iodo 11, amino 12, and bromoacetamido 13 derivatives (all racemic) bound to the receptor with 15-100-fold lower dissociation constants than that of (-)-isoproterenol. All the above compounds stimulated adenylate cyclase more potently than (-)-isoproterenol. The intrinsic activities of compounds 10 and 12 were equal to that of (-)-isoproterenol. The intrinsic activities of compounds 11 and 13 were 1.3 and 1.2 times that of (-)-isoproterenol, respectively. Treatment of membrane preparations with bromoacetamido derivative 13 resulted in an irreversible loss of binding sites, and thus, 13 seems to be an alkylating affinity label for beta-adrenoceptors.

Motor vehicle occupant deaths in young children.

Motor vehicle occupant deaths of US children aged 0 to 12 years were analyzed. Surprisingly, the death rate is highest for children less than 6 months old: 9.0/100,000, dropping to 4.5/100,000 for 1-year-olds and about 3/100,000 for children aged 6 to 12. The second and third months of age are a period of especially high risk. More attention should therefore be focused on protecting infants from injury and death resulting from motor vehicle crashes.

Frequency of painless myocardial ischemia during exercise tolerance testing in patients with and without diabetes mellitus.

To evaluate the frequency of painless myocardial ischemia, all patients with positive exercise tolerance test responses (at least 2 mm of ST depression) from 1983 to 1985 were examined. Of the 211 patients with exercise-induced ischemia, 101 (48%) did not have pain during the ischemic period; 26 (12%) had diabetes mellitus, 24 of whom (92%) had type II diabetes mellitus. Lack of pain was not correlated with age, gender, history of cigarette smoking, systemic hypertension, past acute myocardial infarction, coronary artery bypass grafting, use of beta-blocking or calcium-channel blocking drugs, number of narrowed coronary arteries or average calculated ejection fraction at cardiac catheterization. Patients with painless myocardial ischemia were less often taking nitrates (39% vs 55%, p less than 0.05) and reported prior episodes of chest pain less often (50% vs 82%, p less than 0.01) than control subjects. There was no difference in the frequency of painless myocardial ischemia between patients with and without diabetes mellitus (54% vs 47%). Duration of exercise was shorter in patients with diabetes mellitus and in patients who had pain with myocardial ischemia. No significant difference in age, gender, use of nitrates, beta-blocking or calcium-channel blocking drugs, history of myocardial infarction, angina pectoris or cigarette smoking was found between diabetic and nondiabetic patients. Systemic hypertension was more common in diabetic patients. Thus, painless myocardial ischemia is common in our patients with positive exercise tolerance test responses, but its frequency is similar in diabetic and nondiabetic patients.

Cardiac beta-adrenoceptors during normal growth of male and female rats.

1 A binding assay involving (-)-[3H]dihydroalprenolol (DHA) and KCl-washed cardiac membranes were used to assess the numbers and affinities of beta-adrenoceptors in hearts from male and female rats varying in age from about 2 weeks to 18 months. 2 Although female rats grow more slowly and attain lower adult weights than male rats, heart weights increased in approximate proportion to body weight with little sex difference. 3 As heart weight increased about three fold, beta-receptors increased three fold. Since the number of myocardial cells is believed to be nearly constant during postnatal growth, the numbers of receptors/cell presumably increases similarly. 4 As heart weight increased, the number of beta-receptors per g of tissue decreased according to the equation: total pmol/g = 4.33 - 1.43 x heart weight, equally in males and females. 5 Dissociation constants for DHA (2 to 4 nM) remained the same, and equal, in male and female rats during their growth. 6 An excellent correlation was found between the decline in beta-receptors/g tissue during growth and the decline in the area of the external sarcolemma/g tissue. The data suggest that the number of receptors per unit area remains constant during growth, and thus that cell surface area is a major factor determining normal numbers of receptors per cardiocyte.

Effect of propranolol on beta-adrenoceptors in rat hearts.

The question of whether the chronic administration of propranolol modifies the numbers or properties of cardiac beta-adrenoceptors was examined because of many reports suggestive of cardiac hypersensitivity following the withdrawal of beta-antagonists. In three studies, rats were given (+/-)-propranolol, 30 mg/day, orally or intraperitoneally, for 1 to 7 weeks. The numbers and affinities of specific binding sites for radioactive dihydroalprenolol in whole hearts from 60 control and 75 test animals were found to be the same. Thus catecholamine deprivation does not exert an important regulatory effect on most beta-receptors in the heart, as it does in the brain.

Differential A(1)-adenosine receptor reserve for inhibition of cyclic AMP accumulation and G-protein activation in DDT(1) MF-2 cells.

1. The A(1)-adenosine receptor (A(1)AdoR) reserve for N(6)-cyclopentyladenosine (CPA) mediated inhibition of (-)isoprenaline stimulated cyclic AMP accumulation and stimulation of [(35)S]-guanosine-5'-O-(thiotriphosphate) (GTPgammaS) binding, a measure of guanine nucleotide binding protein (G-protein) activation, was determined in DDT(1) MF-2 cells. 2. Inactivation of the A(1)AdoRs with the chemoreactive ligand 8-cyclopentyl-3-[3-[[4-(fluorosulphonyl)benzoyl]oxy]propyl]-1-p ropylx anthine (FSCPX) caused a progressive rightward shift of the concentration-response curves for CPA to inhibit cyclic AMP accumulation, with a maximum of 10 fold increase in the EC(50) value. In contrast, inactivation of A(1)AdoR's caused only a 1.7 fold rightward shift in the CPA concentration-response for stimulation of [(35)S]-GTPgammaS binding. 3. The A(1)AdoR occupancy-response relationship for CPA inhibition of cyclic AMP accumulation was hyperbolic with 43% receptor occupancy required to elicit the maximal response, i.e. a 57% A(1)AdoR reserve. In contrast, the A(1)AdoR occupancy-response relationship for CPA mediated stimulation of [(35)S]-GTPgammaS binding was linear indicating little or no receptor reserve for G-protein activation. The relationship between CPA stimulation of [(35)S]-GTPgammaS binding and cyclic AMP inhibition was also hyperbolic with 44% G-protein activation sufficient to cause maximal inhibition. 4. The data suggest that the A(1)AdoR reserve for CPA mediated inhibition of cyclic AMP accumulation occurs at the level of G-protein interaction with adenylyl cyclase. However, each A(1)AdoR appears to activate a constant fraction of the total G-protein population suggesting signal amplification at the receptor-G-protein level which may also contribute to the receptor reserve for CPA.

Distribution and function of beta-adrenoceptors in different chambers of the canine heart.

1 An improved binding assay involving (-)-[(3)H]-dihydroalprenolol (DHA) and KCl-washed cardiac membranes was developed to study beta-adrenoceptors in the canine heart quantitatively.2 Receptor numbers varied from 3.8 to 7.1 pmol/g fresh tissue, showing a steady increase from left atrium --> right atrium --> right ventricle --> interventricular septum --> left ventricle. With one minor exception, the same pattern was found for adenylate cyclase activity and Na(+), K(+)-activated ATPase activity.3 The binding of DHA was inhibited in the expected manner by beta-adrenoceptor agonists and antagonists, and was stereospecific, in confirmation of previous studies. Dissociation constants determined from Scatchard analyses included DHA: 2.5 nM; (-)adrenaline: 230 nM; (-)noradrenaline: 1167 nM. Kinetic analyses of the binding of DHA yielded a K(D) of about 4 nM.4 The distribution of beta-receptors is closely related to that of blood flow and the arrival plus retention of a circulating catecholamine, but is markedly different from that of endogenous noradrenaline, and thus adrenergic nerve terminals. Most receptors thus appear not at synapses but diffusely localized where they can react with circulating adrenaline.5 Evidence is discussed that beta-receptors at synapses respond primarily to neural noradrenaline, less to circulating adrenaline, and hardly at all to circulating noradrenaline; responses mediate increased cardiac output during exercise. In contrast most cardiac beta-receptors appear to respond only to adrenaline, and to be used, except at times of severe circulatory stress, during psychological stress.

Irreversible binding of a carbostyril-based agonist and antagonist to the beta-adrenoceptor in DDT1 MF-2 cells and rat aorta.

1. The chemoreactive ligands 5(2-(((1'-(4'-isothiocyanatophenylamino)thiocarbonyl)-amino) -2-methylpropyl)amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (DCITC) and 8-hydroxy-5(2-(((1'-(4'-isothiocyanatophenylamino)thiocarbonyl+ ++)amino)-2-methylprop-2-yl)amino-1-hydroxyethyl)-carbostyril++ + (HCITC) were synthesized and shown to be potent irreversible antagonist and agonist ligands, respectively, for the beta-adrenoceptor in DDT1 MF-2 (DDT) cells and the rat isolated aorta. 2. In DDT cell membranes DCITC and HCITC inhibited (-)[125I]-iodocyanopindolol (CYP) binding to the beta-adrenoceptor with IC50 values of 1.1 and 18 nM, respectively. (-)-Isoprenaline inhibited [125I]-CYP binding with an IC50 of 355 nM. Pretreatment of membranes with either chemoreactive ligand produced a time- and concentration-dependent decrease in the beta-adrenoceptor content, indicating irreversible receptor binding. DCITC at concentrations up to 10 microM did not stimulate cyclic AMP accumulation in DDT cells nor did it amplify forskolin-stimulated cyclic AMP accumulation. 3. In the rat isolated aorta, DCITC (0.1 microM) did not affect either the phenylephrine-mediated tissue contraction or the acetylcholine-mediated relaxation. DCITC attenuated the maximal (-)-isoprenaline-mediated relaxation of a phenylephrine contracted aorta in a concentration-dependent manner and shifted the dose-response curves for (-)-isoprenaline to the right. The DCITC-induced decrease in maximal response was not reversed by extensive tissue washing. By use of the operational model of agonism, the calculated dissociation constant for (-)-isoprenaline ws 286 nM and the estimated receptor reserve for this agonist was 23% at the maximal response. 4. HCITC and (-)-isoprenaline stimulated cyclic AMP accumulation in DDT cells with pD2 values (negative logarithm to base 10 of EC50) of 7.95 and 7.97, respectively, and both mediated the same maximal stimulation. In the rat isolated aorta, HCITC produced a concentration-dependent relaxation of the tissue with a pD2 value of 6.62, whereas the pD2 for (-)-isoprenaline was 7.03. However, HCITC produced a greater maximal relaxation of the tissue than (-)-isoprenaline. The HCITC-mediated stimulation of cyclic AMP accumulation and relaxation of the isolated tissue were blocked when the beta-antagonist propranolol was added concurrently. In contrast, once the HCITC-mediated responses were established, the addition of propranolol did not result in any attenuation indicating that HCITC is an irreversible beta-agonist.

Long-term hyperprolactinaemia reduces basal but not androgen-stimulated oestradiol production in small antral follicles of the rat ovary.

Hyperprolactinaemia disrupts fertility in many species, perhaps by inhibiting ovarian follicular steroidogenesis. The present studies measured oestradiol and progesterone secretion from isolated follicles from rats rendered hyperprolactinaemic in one of two ways. Sustained hyperprolactinaemia was induced by transplantation of two donor pituitary grafts under the renal capsule of adult female rats; grafts remained in place for 3 months. Transient hyperprolactinaemia was induced by pseudopregnancy initiated by cervical stimulation. Small antral follicles were isolated from both groups of rats 8-10 days after the previous vaginal oestrous smear and also from a control group of dioestrous female rats. Follicles were incubated for 3 h in the presence or absence of human chorionic gonadotrophin (hCG) or testosterone. Basal and hCG-stimulated oestradiol production were each reduced in follicles from both hyperprolactinaemic groups, relative to follicles from dioestrous control rats. In contrast, in the presence of testosterone, all groups of follicles produced comparable amounts of oestradiol. hCG stimulated comparable progesterone production by follicles from all three treatment groups. Testosterone elicited smaller increases in progesterone accumulation by follicles from all in-vivo groups. Reduced basal and gonadotrophin-stimulated, but not androgen-stimulated, oestradiol accumulation suggests that androgen production rather than aromatase activity in small antral follicles may be impaired by long-term hyperprolactinaemia.

Beta-adrenergic responsiveness and cardiac autonomic receptors after implantation of the MtTW15 pituitary adenoma in the rat.

The effects of chronic MtTW15 pituitary adenoma implantation on beta-adrenergic responsiveness, cardiac beta-adrenoreceptors, and muscarinic receptors were studied in the rat. Five weeks after s.c. administration of tissue fragments of the MtTW15 adenoma, there was a 51 and 20% increase in the heart weight and body weight, respectively, and a 49-fold increase in the serum prolactin level as compared to the controls. At this time there was also an attenuation in the adenoma-bearing group of the ability of isoproterenol to produce a dipsogenic response and to increase the heart rate. In contrast, isoproterenol stimulated cardiac ornithine decarboxylase (ODC) activity 4.2-fold in both the control and adenoma-bearing groups. There was no change between the two groups in the cardiac ventricular beta-adrenoreceptor or muscarinic receptor concentration as measured by specific (-)-[125I]iodocyanopindolol (CYP) and (-)-[3H]quinuclidinyl benzilate (QNB) respectively. In addition, the concentrations of isoproterenol and carbachol required to inhibit by 50% (IC50) [125I]CYP and [3H]QNB binding, respectively, in the absence of 5'-guanylylimidodiphosphate (Gpp(NH)p) were not different between the two groups. In the presence of Gpp(NH)p, the isoproterenol IC50 value was not different between the two groups, whereas the carbachol IC50 value was increased slightly in the adenoma-bearing group. The data indicate that chronic MtTW15 adenoma implantation attenuated beta-mediated dipsogenic and heart rate responses but had little or no effect on cardiac ODC activity or cardiac autonomic receptor concentrations and agonist binding properties.