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C Sumners

Publications and source records attributed to C Sumners.

At least 91 records · Page 5Linked to original sources
PubMed1991

Potentiation of angiotensin II-induced drinking by glucocorticoids is a specific glucocorticoid type II receptor (GR)-mediated event.

Earlier studies showed that pretreatment (3 and 6 h) of rats with the glucocorticoid hormone, dexamethasone, potentiated the drinking response to either central or peripheral administration of angiotensin II (AII). In the present study the specificity and mechanisms of this potentiation were examined. Intraperitoneal (i.p.) injection of rats with the pure glucocorticoid agonist, RU 28362 (0.4-1.6 mg/kg; 3-24 h), resulted in a time- and dose-dependent potentiation of the drinking responses to either peripherally (100 micrograms/kg, s.c.) or centrally (10 ng) injected AII, similar to the effects of dexamethasone. Drinking induced by central injection of carbachol (200 ng) was unaltered by pretreatment with RU 28362, suggesting that potentiation by this compound was specific for AII. The potentiation of AII-induced drinking by either dexamethasone or RU 28362 was completely abolished by pretreatment with the glucocorticoid Type II receptor (GR) antagonist, RU 38486 (2 mg/kg, i.p.), but not by the mineralocorticoid Type I receptor (MR) blocker, mespirenone (2 mg/kg, i.p.). Taken together, these results indicate that the glucocorticoid-induced potentiation of AII-induced drinking is mediated via GR. Associated with the fact that glucocorticoids potentiate AII-induced drinking is the observation that these steroids also potentiate AII-induced urine output. This enhancement of urine output may explain in part the potentiation in drinking behavior. Possible mechanisms are discussed.

Androstanols↗
PubMed1991

Angiotensin II decreases cGMP levels in neuronal cultures from rat brain.

In previous studies we have determined that both cultured neuronal and astrocyte glial cells prepared from the hypothalamus and brain stem of 1-day-old rats contain specific receptors for angiotensin II (ANG II). Astrocyte glial receptors are coupled to inositol phospholipid hydrolysis, but there is little indication of the intracellular messengers or signal transduction mechanisms coupled to the neuronal ANG II receptors. In the present study, we have determined that ANG II decreases cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels in neuronal but not in astrocyte glial cultures. This effect is both time and concentration dependent and is inhibited by the ANG II-receptor antagonist [Sar1,Ile8]ANG II, showing the involvement of specific ANG II receptors. ANG II has no effects on particulate or soluble guanylate cyclase activities or on efflux of cGMP from neuronal cultures. However, the effects of ANG II on cellular cGMP content are abolished by pretreatment with the calcium channel blockers cadmium and nifedipine, and by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. These results suggest that calcium entry and possibly activation of a phosphodiesterase enzyme are involved in this ANG II-induced effect. This represents the first demonstration of a receptor-mediated effect of ANG II on an intracellular messenger in neuronal cultures. The functional role of cGMP as an intracellular messenger coupled to ANG II receptors in cultured neurons remains to be determined.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Effect of exercise training on blood pressure in 70- to 79-yr-old men and women.

Men and women 70-79 yr of age (N = 49) were studied to assess the effect of 6 months of resistance or endurance exercise training on their blood pressure, hemodynamic parameters, and pressor hormone levels. Resistance training consisted of one set of 8-12 repetitions on ten Nautilus machines three times per week. The endurance training group progressed to training at 75-85% VO2max for 35-45 min three times per week for the last 2 months of training. No changes in body weight or estimated lean body mass occurred; however, the sum of seven skinfolds, as an index of percent body fat, decreased in both exercise groups. Upper and lower body strength increased with resistance training, while VO2max increased by 20% in the endurance training group. Blood pressure did not change with resistance training in individuals with normal or somewhat elevated blood pressures. Diastolic and mean blood pressure decreased significantly, by 5 and 4 mm Hg, with endurance training. Subjects with blood pressure greater than 140/90 reduced their systolic, diastolic, and mean blood pressure by 8, 9, and 8 mm Hg, respectively, with endurance exercise training. Cardiac output, peripheral vascular resistance, and plasma levels of angiotensin I and II and epi- and norepinephrine did not change in any of the groups. Thus, resistance exercise training does not adversely affect, or reduce, blood pressure, while endurance exercise training produces modest reductions in blood pressure in 70-79-yr-old individuals with somewhat elevated blood pressures.

Aged↗
PubMed1990

Alpha 1-adrenergic receptors in the brain: characterization in astrocytic glial cultures and comparison with neuronal cultures.

Binding of [125I]HEAT to membranes prepared from primary cultures of astrocytic glial cells was time-dependent and 70-85% specific. Various adrenergic agonists and antagonists competed for [125I]HEAT binding according to the potencies of prazosin greater than, yohimbine greater than or equal to, clonidine, norepinephrine (NE), and propranolol. Scatchard analysis showed the Bmax of 209 fmol/mg protein and a Kd of 184 pM for [125I]HEAT binding by astrocytic glial membranes. Pretreatment of astrocytes with NE resulted in a dose-dependent downregulation of [125I]HEAT binding sites with a maximal response observed after 8 h at 100 microM NE. Removal of NE from cultures after pretreatment resulted in a time- and protein synthesis-dependent recovery of binding sites to control levels within 120 h. Incubation of astrocytic glial cultures with NE stimulated phosphoinositide (PI) hydrolysis in a time- and dose-dependent manner with a maximal stimulation of 2-fold observed in 60 min by 100 microM NE. Clonidine expressed differential effects on alpha 1-adrenergic receptors of the neuronal and astrocytic glial cultures. Pretreatment with 10 microM clonidine caused a 40% decrease in the Bmax of [125I]HEAT binding without influencing the Kd value in neuronal cultures. This downregulatory effect of clonidine was associated with a reduction in the ability of NE to stimulate PI hydrolysis in clonidine pretreated cells. In contrast to neuronal cultures, clonidine neither downregulated [125I]HEAT binding sites nor stimulated PI hydrolysis in glial cultures.

Adrenergic alpha-Agonists↗
PubMed1990

Alpha-1-adrenergic receptors in the nucleus tractus solitarii region of rats with experimental and genetic hypertension.

The binding of the alpha 1-adrenergic receptors antagonist, 125I-HEAT, to membranes of nucleus tractus solitarii (NTS) regions of the brains of neurogenic hypertensive, spontaneously hypertensive (SH), and deoxycorticosterone (DOCA)/salt hypertensive rats and their respective controls was studied to quantitate the expression of alpha 1-adrenergic receptors. Scatchard analysis of the binding studies revealed a 1.8-fold increase in the Bmax of alpha 1-adrenergic receptors in NTS region membranes of SH rats when compared to their Wistar-Kyoto (WKY) control without significant difference in the Kd for 125I-HEAT. A decrease in the Kd with no difference in Bmax of receptors for 125I-HEAT was observed in the NTS region membranes of neurogenic hypertensive rats when compared with their sham-operated controls. In contrast, comparison of the Bmax and Kd values for 125I-HEAT binding in NTS region membrane of the DOCA/salt hypertensive rats and its sham-operated control showed no significant differences. We suggest that alterations in baroreceptor afferent activity may be related to alterations in central alpha 1-adrenergic receptors binding in SH rats and rats with neurogenic hypertension.

Adrenergic alpha-Antagonists↗
PubMed1990

The influence of angiotensin II on catecholamine synthesis in neuronal cultures from rat brain.

Incubation of primary neuronal cultures prepared from the hypothalamus and brainstem of neonatal rats with angiotensin II (Ang-II) resulted in a concentration-dependent effect on the incorporation of [3H]-tyrosine ([3H]-Tyr) into [3H]-catecholamines ([3H]-CA). At concentrations of 1 nM-1 microM, Ang-II (60 min. incubation) caused significant decreases (31-52%) in neuronal [3H]-CA content compared with controls. Conversely, higher concentrations of Ang-II (10-100 microM; 60 min.) caused significant increases (20-60%) in neuronal [3H]-CA content compared with controls. Both of these effects were blocked by co-incubation with the Ang-II receptor antagonist Sar1Ile8-Ang-II. These observations demonstrate that neuronal cells in primary culture have the ability to synthesize [3H]-CA from [3H]-Tyr, and that Ang-II has a receptor-mediated biphasic influence on newly synthesized [3H]-CA (norepinephrine and dopamine).

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1990

Adrenergic and calcium-mediated subcellular redistribution of protein kinase C in primary neuronal cultures.

Incubation of primary neuronal cultures prepared from the brains of neonatal rats with 50 microM epinephrine resulted in the transient redistribution of protein kinase C from the cytosol to the particulate fraction. This effect occurred after 1 and 5 min of incubation and resulted in a decrease in cytosolic protein kinase C activity with a corresponding increase in particulate protein kinase C of approximately 30% and 15%, respectively. The epinephrine-stimulated translocation of protein kinase C was blocked by 1 microM prazosin indicating the involvement of alpha 1-adrenergic receptors. Further, inclusion of 0.1 microM Ca2+ in the homogenization buffer was found to significantly enhance the binding of protein kinase C to cellular membranes prepared from neuronal cultures. These results indicate that alpha 1-adrenergic receptors in neuronal brain cell cultures are linked to the activation of protein kinase C and that the mobilization of Ca2+ may enhance this effect.

Animals↗
PubMed1990

Regulation of angiotensin II binding sites in neuronal cultures by protein kinase C.

The radioligand binding of 125I-angiotensin II (ANG II) and calcium phospholipid-dependent protein kinase C (PKC) activity were measured to study the specificity and mechanisms of PKC involvement in the regulation of ANG II-specific binding site expression in neuronal cultures prepared from the brains of 1-day-old rats. Previously, PKC-activating phorbol esters were shown to increase the specific binding of 125I-ANG II in neuronal cultures. However, phorbol esters have many biological effects, which may nonspecifically act to increase 125I-ANG II-specific binding. In the present study, mezerein and teleocidin A, two activators of PKC that are chemically unrelated to phorbol esters, increased the specific binding of 125I-ANG II in a dose- and time-dependent manner with 50% effective dose (ED50) values of 32 and 79 nM, respectively. The PKC antagonist H-7 dose dependently inhibited phorbol 12-myristate 13-acetate (TPA)-stimulated increases in 125I-ANG II binding, whereas downregulation of PKC activity by chronic phorbol ester incubations of 24 and 48 h prevented TPA-stimulated increases in 125I-ANG II-specific binding. TPA (0.8 microM), mezerein (0.76 microM), and teleocidin A (0.5 microM) all caused a rapid translocation of PKC activity from the cytosol to the particulate fraction by 15 min. Temporally, the maximal stimulation of PKC translocation by mezerein, teleocidin A, and TPA preceded their ability to stimulate maximal 125I-ANG II-specific binding. Taken together, these results suggest that PKC is directly involved in the stimulation of ANG II-specific binding site expression and that translocation of PKC is a prerequisite for the increased expression of ANG II binding sites.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Glucocorticoids potentiate the dipsogenic action of angiotensin II.

The effect of a short-term, acute treatment with a glucocorticoid, dexamethasone sodium phosphate, on the drinking induced by angiotensin II (AII) was investigated in a series of experiments. Initial studies indicated that a single injection of dexamethasone (700-750 micrograms/kg, i.p.) reduced food intake, body weight and water intake for up to 48 h, but had little effect on blood pressure when it was measured 6 h subsequent to the injection. The drinking elicited by peripherally administered AII (200 micrograms/kg, s.c.) was enhanced if the glucocorticoid (700 micrograms/kg, i.p.) was given 3 h or 6 h prior to the dipsogen. There was no effect of pretreatment with the steroid if the drinking test was delayed by 24 h. The subsequent experiment showed that the glucocorticoid effect on AII-stimulated drinking was dose dependent (100 micrograms-1600 micrograms/kg). The drinking stimulated by intracerebroventricular (i.c.v.) AII (2.5 ng) was enhanced in terms of volume and total duration by prior treatment with dexamethasone, but i.c.v. carbachol (200 ng)-induced drinking remained unaffected. The final study showed that binding of AII to its receptors in five different areas of the rat brain was not affected by prior treatment with dexamethasone.

Angiotensin II↗
PubMed1989

Effects of phorbol esters and a calcium ionophore on angiotensin II binding in rat brain synaptosomes.

In previous studies we determined that protein kinase C (PKC) and calcium are important intracellular regulators of neuronal angiotensin II (Ang II) binding sites. In the present study we investigated the effects of the protein kinase C (PKC) agonist phorbol esters (PE) and also a calcium ionophore (A23187) on the specific binding of [125I]Ang II to brain synaptosomes prepared from rats of different ages. The rationale was to determine whether the large changes in the level of brain Ang II specific binding observed in different age rats are due to changes in the regulation of these sites by PKC or by calcium. The present data indicate no qualitative differences in the effects of PE or A23187 on [125I]Ang II specific binding to hypothalamic or brain stem synaptosomes, from either 2-5 or 70-day-old rats, i.e. the active PE TPA increased while A23187 decreased Ang II binding in all situations. Thus, the dramatic differences in brain Ang II specific binding seen with age appear not to be due to changes in regulation by PKC or calcium.

Aging↗
PubMed1989

Effect of chronic dietary treatment with 1-tryptophan on spontaneous salt appetite of rats.

Chronic dietary treatment with 1-tryptophan (2.5 and 5.0% in food) reduced the exaggerated spontaneous NaCl intake induced by deoxycorticosterone acetate (DOCA) in rats. In the absence of DOCA, chronic (4-week) dietary treatment with 1-tryptophan (5.0% in food) failed to affect significantly spontaneous NaCl intake. In addition, treatment with tryptophan in the absence of DOCA failed to affect significantly systolic blood pressure, plasma renin activity, plasma aldosterone concentration, and the weights of the heart, kidneys, adrenals, and thyroid gland. It also failed to affect the specific binding of [125I]-Ang II to neuronal membranes isolated from the diencephalon of the rats. However, the contents of both serotonin and 5-hydroxyindoleacetic acid in the lower brain stem were increased significantly by chronic treatment with tryptophan. These results suggest that the effect of chronic treatment with tryptophan to reduce the salt appetite of DOCA-treated rats is a specific effect of this amino acid under these conditions and may be related to the ability of tryptophan to prevent the upregulation of specific Ang II receptors induced by DOCA.

Angiotensin II↗
PubMed1989

Alpha 2-adrenergic receptors in neuronal and glial cultures: characterization and comparison.

Membranes prepared from either neuronal or glial cultures contain alpha 2-adrenergic receptors as determined by the characteristics of [3H]yohimbine [( 3H]YOH) binding. The binding was rapid, reversible, saturable, dependent on the protein concentration used, and reached equilibrium by 5 min in membranes from both neuronal and glial cultures. Scatchard analyses of saturation isotherms revealed similar KD values of 13.7 +/- 1.35 nM (n = 10) for neuronal cultures and 18.42 +/- 2.34 nM (n = 10) for glial cultures. Glial cultures contained many more binding sites for [3H]YOH than neuronal cultures, having a Bmax of 1.6 +/- 0.33 pmol/mg protein (n = 10) compared with 0.143 +/- 0.018 pmol/mg protein (n = 10) in neurons. Drugs selective for alpha 2-adrenergic receptors were the most effective displacers of [3H]YOH binding in both neuronal and glial cultures, i.e., the alpha 2-adrenergic antagonists rauwolscine and yohimbine were better displacers than the other catecholamine antagonists prazosin, corynanthine, or propranolol. The agonists showed the same pattern with the alpha 2-selective drugs clonidine and naphazoline being the most effective competitors for the [3H]YOH site. GTP and its nonhydrolyzable analog. 5'-guanylyl-imidodiphosphate, were able to lower the affinity of the alpha 2-receptors for agonists but not antagonists in membranes from both neuronal and glial cultures, suggesting that the receptors are linked to a G protein in both cell types. The presence of alpha 2-adrenergic receptors in neuronal cultures was also substantiated by light microscopic autoradiography of [3H]YOH binding. In summary, we have demonstrated that both neuronal and glial cultures contain alpha 2-adrenoceptors.

Animals↗
PubMed1989

Effect of chronic dietary treatment with L-tryptophan on the maintenance of hypertension in spontaneously hypertensive rats.

Chronic dietary administration of L-tryptophan at 2.5 and 5.0% by weight reduced the elevated systolic blood pressure of spontaneously hypertensive (SH) rats. Blood pressure was reduced significantly by 3 weeks after initiation of treatment and continued to fall during the course of the 15 weeks of treatment. Body weights of the treated rats were not affected significantly by treatment, nor were daily food and fluid intakes and urine outputs. SH rats, treated with the higher dose of tryptophan, also significantly reduced their urinary outputs of epinephrine and norepinephrine compared with SH controls, while both doses of tryptophan increased urinary outputs of dopamine significantly above that of SH controls. Treatment with tryptophan increased significantly the specific binding of [125I]angiotensin II (Ang II) to membranes from the diencephalon in a dose-dependent manner. Measurement of catecholamine concentration of the supernatant from homogenates used for the Ang II binding assay revealed a significant correlation between the specific binding of Ang II to brain membranes of the two tryptophan-treated groups and the concentration of norepinephrine in the supernatant. There was also a significant correlation between the specific binding of Ang II and the concentration of dopamine in the supernatant of the control group and the group treated with the higher dose of tryptophan. These results show that chronic dietary administration of tryptophan can reduce the elevated blood pressure of SH rats and support the possibility that this neutral amino acid may act via its effect on the concentration of the neurohormones, norepinephrine and dopamine, in the diencephalon to regulate the binding of Ang II to its receptors.

Angiotensin II↗
PubMed1989

Modulation of angiotensin II binding sites in neuronal cultures by mineralocorticoids.

Previous studies have determined that mineralocorticoid hormones are able to increase the number of angiotensin II (ANG II)-specific binding sites in rat diencephalon and in neuronal cultures and also increase the drinking response elicited by centrally injected ANG II. In the present study, we have examined the specificity and mechanisms of this mineralocorticoid action. In neuronal cultures from the hypothalamus and brain stem (H/BS), both D-aldosterone and deoxycorticosterone acetate (DOCA) caused significant time- and dose-dependent increases in 125I-labeled ANG II-specific binding. This effect was not mimicked by the synthetic glucocorticoid dexamethasone, or by testosterone, beta-estradiol or progesterone. However, the steroid corticosterone induced a moderate increase in [125I] ANG II binding. This may have occurred as a result of its high affinity for the mineralocorticoid type I receptor. DOCA was ineffective in increasing [125I]ANG II specific binding both in neuronal cultures prepared from the cerebellum and in pure astrocytic glial cultures, indicating that this mineralocorticoid effect is specific both for neurons and for certain brain regions. The increase in [125I]ANG II-specific binding elicited by DOCA was abolished by cotreatment with the mineralocorticoid receptor blockers mespirenone or ZK97894 and by cotreatment with cycloheximide. Taken together, these observations suggest that the mineralocorticoid-induced increase in [125I]ANG II-specific binding in H/BS neuronal cultures is a specific event, which is mediated via mineralocorticoid type I receptors and which requires protein synthesis.

Aldosterone↗
PubMed1989

Release of immunoreactive angiotensin II from neuronal cultures: adrenergic influences.

The effects of adrenergic drugs on the release of immunoreactive angiotensin II (ANG II-ir) from brain cells in culture were examined. In neuronal cultures, basal release of Ang II-ir was 43.65 +/- 7.44 pg/5-min incubation period (n = 14 experiments; 52 individual determinations), and in astrocytic glial cultures, it was 21.76 +/- 5.7 pg (n = 8 experiments; 24 individual determinations) when cells were exposed to buffer alone. Incubation of neuronal cultures with the alpha 2-adrenergic antagonist yohimbine (0.1-50 microM, 5 min) caused concentration-dependent increases in ANG II-ir release above basal levels. Analysis of the released material by high-pressure liquid chromatography revealed that authentic ANG II was present. No increase in the release of ANG II-ir was seen from glial cells. Experiments using neuronal cultures revealed that the yohimbine-induced release of ANG II-ir may be secondary to increased norepinephrine (NE) release. Incubation of neuronal cultures with NE (10 nM-50 microM) caused concentration-dependent increases in the release of ANG II-ir. This effect of NE was not inhibited by the alpha 1-adrenergic blocker prazosin. However, a weaker release of ANG II-ir from neuronal cultures was stimulated by the beta-adrenergic agonist isoproterenol at 100 microM. These data show that ANG II-ir can be released from neuronal but not glial cell cultures by adrenergic receptor-mediated mechanisms.

Adrenergic alpha-Agonists↗
PubMed1989

Regulation of angiotensin II binding sites in neuronal cultures by catecholamines.

Previous studies determined that direct activation of protein kinase C (PKC) with phorbol esters increases the number of angiotensin II (ANG II)-specific binding sites in neuronal cultures prepared from the hypothalamus and brain stem of 1-day-old rats. In the physiological situation, PKC is activated by diacylglycerol, which can be produced by multiple pathways, such as stimulation of inositol phospholipid (IP) hydrolysis, phosphatidylcholine hydrolysis, or by de novo synthesis. In the present study we have examined whether stimulation of IP hydrolysis, and presumably activation of PKC, can mimic the actions of phorbol esters on ANG II-specific binding. We have incubated neuronal cultures with agents that increase IP hydrolysis and have determined the effects on ANG II-specific binding. Incubation of neuronal cultures with norepinephrine (NE) at concentrations (greater than 5 microM) and for times (15-60 min) that cause large increases in IP hydrolysis caused increases in the number of ANG II-specific binding sites, mimicking the actions of phorbol esters. The return of IP hydrolysis to control values was associated with a return of ANG II-specific binding to control levels. The upregulatory action of NE was abolished by prazosin, demonstrating the involvement of alpha 1-adrenergic receptors. In addition, this effect was blunted by the PKC antagonist H 7, suggesting PKC involvement in the response. Thus we have determined a potential physiological mechanism by which stimulation of IP hydrolysis by NE, and possible subsequent activation of PKC, leads to upregulation of ANG II-specific binding sites in neuronal cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Neonatal rat brain astroglial dipeptidyl peptidase II activity regulation by cations and anions.

Astrocytic glial cells from neonatal rat brains were grown in primary culture. Dipeptidyl peptidase II (DPP-II) enzyme activity was measured in cells disrupted by nonionic detergent. The rate of enzyme activity was measured in the presence of various ions, under isosmotic conditions adjusted using mannitol and NaCl. DPP-II activity was not affected by the candidate metal co-factors (2 mM) Co2+, Mg2+, and Mn2+, nor by the metal chelators EDTA and o-phenanthroline. However, selected cations (50 mM Cl- salts) significantly inhibited DPP-II activity compared to Na+ control; the relative inhibition ranking was Rb+ less than K+ less than Zn2+ less than Hg2+. Many test anions (50 mM Na+ salts) also inhibited DPP-II activity compared to Cl- control: SO4(2-) less than NO3- less than F- less than SO3(2-). Surprisingly, the anion S2O3(2-) was the only test agent which strongly stimulated activity. The data are consistent with the concept that specific ion species interact with the glial DPP-II enzyme to affect catalytic activity.

Animals↗