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Biomedical subjects

M Matheny

Publications and source records attributed to M Matheny.

At least 37 records · Page 2Linked to original sources
PubMed1996

Thermoregulation with age: restoration of beta(3)-adrenergic responsiveness in brown adipose tissue by cold exposure.

The beta(3)-adrenergic-stimulated thermogenic response in brown adipose tissue (BAT) is impaired in senescent rats, whereas cold-induced thermogenesis is not. To determine if cold exposure can restore beta(3)-adrenergic receptor responsiveness in senescent rats, we examined BAT mitochondrial GDP binding in young and old rats, and UCP mRNA levels in young rats following stimulation by the beta(3)-adrenergic agonist CGP-12177 with and without prior cold exposure. F-344 male rats were maintained at thermoneutrality or exposed to 8 degrees C for 48 hr, followed by a 24-hr period of rewarming before administration of 0.75 mg/kg CGP-12177 or vehicle solution. During the rewarming period, GDP binding remained elevated but UCP mRNA levels with a half-life of 11 hr returned to levels observed in the thermoneutral controls. In young rats, both cold exposure and administration of the beta(3)-adrenergic agonist to thermoneutral controls increased GDP binding 2-fold and UCP mRNA levels 4-fold. However, in cold-exposed young rats, there was no further increase with beta(3)-agonist treatment. In senescent control rats, CGP-12177 did not increase GDP binding, but cold exposure did. However, in cold-exposed old rats, the beta(3)-agonist was now able to increase GDP binding. The induction of UCP mRNA by CGP-12177 was also investigated and found to be 25% less in senescent compared with young rats. These observations indicate that cold exposure restores the impaired beta(3)-adrenergic signal transduction in BAT from senescent rats. One possibility is that cold exposure induces the synthesis of one or more components in the beta(3)-adrenergic pathway in senescent rats.

Adipose Tissue, Brown↗
PubMed1996

Effects of age on beta adrenergic subtype activation of adenylyl cyclase in brown adipose tissue.

Thermogenesis in brown adipose tissue (BAT) is believed to be mediated mainly by beta3 adrenergic receptors. We previously demonstrated that the specific beta3 adrenergic agonist CGP-12177 increases whole body oxygen consumption and BAT GDP binding to a greater extent in young than in senescent rats. In contrast, the forskolin-induced increases were maintained with age, suggesting that early events in beta3 adrenergic signal transduction are impaired with age. To investigate whether beta1 or beta3 adrenergic function is decreased with age, we assessed beta1 and beta3 adrenergic receptor mRNA levels and the ability of beta1 and beta3 adrenergic receptors to activate adenylyl cyclase in BAT membranes from 4- and 24-month-old F-344 rats. Both beta1 and beta3 adrenergic receptor mRNA levels decreased by 50% with age. Adenylyl cyclase stimulated by the nonspecific agonist, isoproterenol, and by the specific beta3 agonist, BRL 37344, also declined by 50% with age, whereas glucagon stimulation decreased by more than 70%. The isoproterenol-stimulated adenylyl cyclase activation curves were resolved by two-site regression analysis to determine the contribution of beta1 and beta3 adrenergic receptors. The Vmax for both beta1 and beta3 adrenergic receptors decreased by 50% with age. However, stimulation of adenylyl cyclase by NaF and forskolin was also diminished by the same amount as beta adrenergic stimulation, suggesting that the activation with age may be limited by the amount of adenylyl cyclase catalytic unit rather than by receptor number. These data suggest both beta1 and beta3 adrenergic receptors and adenylyl cyclase catalytic units are deficient with age in rodent BAT.

Adenylyl Cyclases↗
PubMed1995

Capital financing is emerging as a critical success factor for integrated systems.

The bubble may burst soon, but right now capital financing is readily available to help physician-driven, integrated entities acquire practices, build infrastructure, and take on risk contracts. However, given the inflated prices some investors are paying, some of these deals will fail. HSL talks to capital financing experts to find out what the future may hold.

Capital Financing↗
PubMed1994

Thermoregulation with age: role of thermogenesis and uncoupling protein expression in brown adipose tissue.

To investigate whether attenuation of thermogenesis in interscapular brown adipose tissue (IBAT) may account for the loss of thermoregulation with age, we examined two indices of thermogenesis after two types of cold exposure: one in which the senescent rats maintained homeothermy and the other in which the senescent rats became hypothermic. To this end, we assessed body temperature, guanosine 5'-diphosphate (GDP) binding to the IBAT mitochondrial uncoupling protein (UCP) and the induction of UCP mRNA after both 1-hr and 48-hr mild cold exposures at 8 degrees C and after a more severe, 1-hr cold exposure at 4 degrees C in 3- and 24-month-old F-344 rats. Thermoneutrality was determined to occur at an ambient temperature of 26 degrees C in rats of both ages. In the 1-hr mild cold-exposed rats, there was no significant increase in GDP binding to IBAT UCP. However, after 48 hr of mild cold exposure, there was a 3-fold increase in GDP binding and a 5-fold increase in the expression of UCP mRNA despite no hypothermia in either the young or old rats. During the more severe cold exposure, the senescent rats, but not the young rats, became hypothermic. GDP binding to UCP increased 75% following cold exposure and, surprisingly was the same in young and old rats. UCP transcripts did not increase during the 1-hr cold exposure. These data, coupled with our previous findings of diminished beta 3-agonist-stimulated IBAT thermogenesis, suggest that (i) IBAT thermogenesis, at least in the senescent rats, may be mediated by other than beta 3-adrenergic receptors, and (ii) that altered heat dissipation or impaired thermogenesis at some site other than interscapular BAT is responsible for the observed hypothermia.

Adaptation, Physiological↗
PubMed1994

Understanding capitation and at-risk contracting.

New payment methods are driving the formation of integrated systems, but how do these payment plans really work? HSL researched capitation and other forms of at-risk contracting with primary care practices, specialty groups, and hospitals in both second and third generation managed care. Our story clarifies the complexities underlying capitation so leaders can identify the implications for their systems.

Capitation Fee↗
PubMed1992

Thermogenesis and mitochondrial GDP binding with age in response to the novel agonist CGP-12177A.

The ability to regulate body temperature diminishes with age in both humans and rodents. To investigate whether attenuation of sympathetically activated thermogenesis in brown adipose tissue (BAT) may account for the loss of thermoregulation with age, we assessed O2 consumption and body temperature in response to norepinephrine and the specific BAT beta-adrenergic agonist CGP-12177A in 6-, 18-, and 24-mo-old rats. In addition, the effects of this agonist on interscapular BAT mitochondrial GDP binding in young and senescent rats were determined. CGP-12177A rapidly induced an elevation in O2 consumption, which peaked at 25 min, followed by a decline over 4 h. The peak increase in O2 consumption over baseline and the cumulative 4-h response were decreased with age [P less than 0.02, analysis of variance (ANOVA)]. CGP-12177A induced an increase in body temperature that paralleled but appropriately lagged behind the increase in O2 consumption and that was decreased with age (P less than 0.02, ANOVA). The norepinephrine-induced increase in O2 consumption was also reduced with age but was not paralleled by a change in body temperature and was associated with a four- to fivefold increase in physical activity. In young rats CGP-12177A increased the number of available BAT mitochondrial GDP binding sites at 20 and 60 min post-injection, but in senescent rats GCP-12177A was unable to increase GDP binding. These data indicate that CGP-12177A is a novel agonist for BAT thermogenesis. With age there is a reduced capacity for thermogenesis that involves a failure to increase GDP binding, either due to a diminished amount of uncoupling protein with age or a failure to unmask reserve GDP binding sites.

Adipose Tissue, Brown↗
PubMed1992

Impaired febrile response with age: role of thermogenesis in brown adipose tissue.

We demonstrated previously that in Escherichia coli-infected rats, the heat necessary for the febrile response is a result of thermogenesis in brown adipose tissue (BAT). To investigate whether senescent rats have an impaired febrile response to infection and whether such an impairment is a result of attenuated sympathetically activated thermogenesis in BAT, we assessed body temperature and the increase in mitochondrial guanosine 5'-diphosphate (GDP) binding sites in interscapular BAT in response to E. coli administration in young and senescent male F-344 rats. There was a significant delay of 2 hr in the onset of fever in the older animals. In addition, in senescent rats, the peak fever (1.0 +/- 0.1 delta degrees C vs 2.2 +/- 0.1) and the cumulative fever (383 +/- 43 delta degrees C.min vs 775 +/- 69) were significantly less than in the young rats (P less than 0.005). Baseline levels of GDP binding were the same in young and old rats. In young rats, during the rising phase of the fever, E. coli infection resulted in a 50% increase in the density of GDP binding sites in BAT mitochondria. In contrast, there was no increase in GDP binding in the older rats following infection. The failure to increase GDP binding may be a result of a reduced ability to unmask reserve GDP binding sites. Alternatively, there may be fewer total GDP binding sites (masked and unmasked) in senescent rats and these sites may already be unmasked. Collectively, these data suggest that the impaired febrile response with age is due to reduced thermogenesis in BAT.

Adipose Tissue, Brown↗
PubMed1991

Adenylate cyclase agonist properties of CGP-12177A in brown fat: evidence for atypical beta-adrenergic receptors.

Thermogenesis in brown adipose tissue (BAT) is stimulated by catecholamine activation of adenylate cyclase through the beta-adrenergic receptor. Recently it was reported that the beta-adrenergic antagonist CGP-12177A stimulates oxygen consumption in BAT. To investigate the mechanism of action of CGP-12177A in BAT, we assessed the inhibitory and stimulatory affects of CGP-12177A on the adenylate cyclase system in myocardial and BAT membranes from rats. CGP-1277A inhibited isoproterenol-stimulated adenylate cyclase activity in a dose-dependent manner, with an inhibitory constant (Ki) of 1.94 +/- 0.18 microM in BAT and 0.49 +/- 0.11 microM in the heart. However, in the absence of isoproterenol, CGP-12177A stimulated adenylate cyclase in BAT with two components of activation, and half-maximal stimulation occurred at 1 microM and 1.5 mM. In contrast, CGP-12177A did not stimulate adenylate cyclase activity in heart membranes. Propranolol inhibited the isoproterenol-stimulated activity with a potency that was one log less in BAT compared with heart. Propranolol fully blocked the high-affinity component but only weakly blocked the low-affinity component of CGP-12177A-stimulated activity in BAT. Pindolol was also less potent in BAT but inhibited the CGP-12177A-stimulated activity in a manner similar to the inhibition of the isoproterenol-stimulated activity, suggesting the CGP-12177A activation was beta-receptor mediated. Binding curves of [125I]iodocyanopindolol ([125I]ICYP) in competition with CGP-12177A demonstrated a shift to lower affinity in the presence of beta,gamma-imidoguanosine 5'-triphosphate, indicating that CGP-12177A has agonist properties with respect to the [125I]ICYP binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗