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Biomedical subjects

W Lovenberg

Publications and source records attributed to W Lovenberg.

At least 55 records · Page 3Linked to original sources
PubMed1985

CSF dopamine-beta-hydroxylase activity in Parkinson's disease.

Although the most prominent neurochemical change in parkinsonism is nigrostriatal dopamine deficiency, norepinephrine content is also diminished in the CNS. In this study, dopamine-beta-hydroxylase (DBH) activity, a marker of central noradrenergic activity, was measured in the CSF of previously unmedicated parkinsonian patients and normal controls. The parkinsonian patients showed a reduction in CSF DBH levels to 41% of control values (p less than 0.01). Possible explanations for the decrease included a decreased noradrenergic nerve pool or a diminished rate of synthesis of catecholamines.

Adult↗
PubMed1985

ATP-dependent calcium uptake in myocardial sarcoplasmic reticulum from spontaneously hypertensive rats: effect of modification of dietary protein.

Membrane fractions enriched in sarcoplasmic reticulum (SR) were isolated from the cardiac ventricles of 10-month-old, stroke-prone spontaneously hypertensive rats (SHRSP) which had been maintained for nine months on one of four experimental diets: low protein (LP) (19% protein), standard (STD) (24% protein), high protein (HP) (32% protein), or high methionine (1.9% methionine) (MET). ATPase activities, as well as ATP-dependent Ca2+ binding and Ca2+-uptake activities, of the isolated SR were determined to examine the influence of diet on myocardial Ca2+-pump activity. SR from all four groups exhibited similar Mg2+-ATPase activity. However, the (Ca2+ + Mg2+)-ATPase activity was significantly elevated in SR from rats on the MET diet while the activity in the other groups showed no significant differences. After 15 sec of incubation, Ca2+-uptake (presence of oxalate) in SR from the LP group was significantly less than Ca2+-uptake in SR from each of the three other diet groups. Ca2+ binding (absence of oxalate) in the SR from the LP group was also significantly less than that from each of the three other diet groups. Kinetic analysis of SR Ca2+-uptake over 60 sec revealed that the Bmax of the MET group was significantly higher than Bmax of the STD diet group. In addition, the Bmax of the LP group was significantly lower than Bmax of the HP and MET groups. There was no significant difference in affinity of the SR Ca2+-uptake system among the four diet groups. These results indicate that modification of dietary protein can influence myocardial SR Ca2+-pump function.

Adenosine Triphosphate↗
PubMed1985

The hypotensive action of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in spontaneously hypertensive rats.

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Amphetamines↗
PubMed1985

Mn++-stimulated 3H-inositol incorporation in cultured vascular smooth muscle cells: deficiency in cells from spontaneously hypertensive rats.

Incubation of cultured dissociated aortic smooth muscle cells from Wistar-Kyoto rats (WKY) with Mn++ resulted in a 10-fold stimulation of 3H-myo-inositol incorporation into membrane phospholipid. The stimulation was temperature and energy dependent. The Mn++ EC50 was 1 mM and maximum stimulation occurred at 10 mM Mn++. Other cations were ineffective. In cells from spontaneously hypertensive rats (SHR), the Mn++ EC50 was unchanged whereas the maximum stimulation of 3H-inositol incorporation was reduced by 50% compared to cells from parallel WKY cultures. These results suggest that in SHR cultured vascular smooth muscle cells there is a deficiency in an enzymatic process mediating exchange of free inositol with the headgroup inositol of membrane phosphatidylinositol.

Animals↗
PubMed1985

Comparison of cyclic AMP accumulation and morphological changes induced by beta-adrenergic stimulation of cultured vascular smooth muscle cells and fibroblasts.

Cyclic 3',5'-adenosine monophosphate (cAMP) accumulation and morphological changes induced by isoproterenol (ISO) on cultured vascular smooth muscle cells (SMC) and vascular fibroblasts derived from spontaneously hypertensive rats, their stroke-prone strain and normotensive Wistar Kyoto rats were investigated. At the time points studied, ISO-induced cAMP accumulation in SMC reached a peak level at 5 min. Accumulation was dose-dependent and was maximal at a concentration of 10(-5) M ISO. Maximal cAMP levels were approximately 600-fold higher than basal levels. Maximal cAMP accumulation or half maximal stimulatory ISO concentrations were similar in SMC from the three strains. ISO had no effects on cyclic 3',5'-guanosine monophosphate (cGMP) levels in SMC. Phenylephrine had no effects on cAMP or on cGMP levels. In contrast to SMC, beta-adrenergic stimulation of vascular fibroblasts resulted in only a 4-fold increase of cAMP levels. 1.5 h after administration of ISO to SMC cultures, the morphological changes were apparent in SMC but not in fibroblasts. Morphological changes induced by ISO were reversible and morphological appearances returned to normal 16 h after exposure to ISO. 10(-3) M dibutyryl cAMP had similar effects on the morphologies of both SMC and fibroblasts. These effects were antagonized by 5 X 10(-6) M colchicine, an inhibitor of microtubule assembly. These results indicate that cultured vascular SMC possess the ability to increase markedly their cellular cAMP level in response to beta-adrenergic stimulation, while fibroblasts are less responsive to the stimulation. Furthermore, cAMP accumulation results in morphological changes of SMC and fibroblasts probably through the alteration of intracellular microtubule systems. As the morphological response to intracellular cAMP (or its lipophilic derivatives) is similar in both SMC and fibroblasts, the difference in each cell line's responsiveness to ISO may be due to a difference in: (1) the density or sensitivity of beta-adrenergic receptors on the plasma membrane of each cell type, or (2) the catalytic activity of adenylate cyclase itself.

Adrenergic beta-Agonists↗
PubMed1984

Novel pharmacology of substance K-binding sites: a third type of tachykinin receptor.

The tachykinins are a family of peptides with the carboxyl terminal amino acid sequence Phe-X-Gly-Leu-Met-NH2. Three major mammalian tachykinins have been identified--substance K, neuromedin K, and substance P--but only two tachykinin receptors have been postulated. Three tachykinins were labeled with radioiodinated Bolton-Hunter reagent and their binding characteristics were determined in crude membrane suspensions from several tissues. In cerebral cortex labeled eledoisin exhibited high-affinity binding that was inhibited by tachykinins in a manner indicating a definitive SP-E receptor site. In gastrointestinal smooth muscle and bladder, high-affinity binding of labeled substance P was inhibited in a pattern indicating a definitive SP-P site. In intestinal smooth muscle and bladder, however, labeled substance K and labeled eledoisin were both bound in a pattern indicating a preference for substance K itself. The results suggest the existence of three distinct types of tachykinin receptors: SP-P, SP-E, and SP-K.

Animals↗
PubMed1984

The hypothermic effect of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in Wistar Kyoto rats.

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl], a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.

Amphetamines↗
PubMed1984

Effect of dexamethasone on biopterin levels and tyrosine hydroxylase activity in PC-12 cells.

Culture of PC-12 cells in 1 microM dexamethasone for 24, 48 or 72 hr did not alter significantly PC-12 cell total biopterin levels, although tyrosine hydroxylase activity in extracts of cell homogenates was increased 2- to 3-fold. Increasing the concentration of dexamethasone to 10 microM did not change biopterin levels or result in further increases in tyrosine hydroxylase activity measured after 72 hr. Culture of cells in dexamethasone markedly decreased the ratio of biopterin concentration to tyrosine hydroxylase activity. The molar ratio of tyrosine hydroxylase subunits to biopterin in control cells can be estimated to be approximately one. Therefore, following induction of the enzyme by dexamethasone, there appears to be an excess of enzyme molecules relative to cofactor molecules in these cells.

Adrenal Gland Neoplasms↗
PubMed1984

Photoaffinity labelling of methyltransferase enzymes with S-adenosylmethionine: effects of methyl acceptor substrates.

Radioactivity from 3H-[methyl]-S-adenosyl-L-methionine (AdoMet) was covalently bound to protein-O-carboxylmethyltransferase and phenylethanolamine N-methyltransferase following 10-15 min irradiation by short-wave ultraviolet light. This photoaffinity binding of 3H-[methyl]-AdoMet was blocked by S-adenosylhomocysteine and sinefungin, but was not affected by 5 mM dithiothreitol. The binding was also inhibited by including methyl acceptors such as calmodulin (protein-O-carboxylmethyltransferase) or phenylethanolamine (phenylethanolamine N-methyltransferase) in the photoaffinity incubation. Staphlococcus V8 protease digests of 3H-[methyl]-AdoMet/enzyme complexes revealed that the primary structure around the AdoMet binding site is different in these two enzymes. Thus, protein-O-carboxylmethyltransferase, a large molecule methyltransferase, can covalently bind 3H-[methyl]-AdoMet in a manner similar to that of phenylethanolamine-N-methyltransferase.

Affinity Labels↗
PubMed1984

Carboxylmethylation of phosphodiesterase attenuates its activation by ca2+-calmodulin.

Carboxylmethylation of several preparations of cAMP phosphodiesterase by the enzyme protein O- carboxylmethyltransferase and S-adenosylmethionine reduces the extent to which the enzyme was activated by native calmodulin. In contrast, carboxylmethylation of calmodulin produced only a slight reduction in the ability of calmodulin to activate cAMP phosphodiesterase. The effect of carboxylmethylation of calmodulin was most prominent at subsaturating calmodulin concentrations, whereas the reduction in the activation of carboxylmethylated cAMP phosphodiesterase was independent of calmodulin concentration. Kinetics and stoichiometric analysis of calmodulin carboxylmethylation indicated that less than 5% of calmodulin was methylated and that the Km of protein O- carboxylmethyltransferase for calmodulin was approximately 350 microM. The extent of calmodulin carboxylmethylation was not affected by either EGTA or Ca2+. When homogeneous bovine brain phosphodiesterase was carboxylmethylated , a rapid decrease in calmodulin-induced stimulation was noted, occurring within 30 s of incubation. Acidic sodium dodecyl sulfate-gel electrophoresis of bovine brain phosphodiesterase revealed a major band of 60,000 daltons which contained radio-activity after carboxylmethylation . Stoichiometric analysis revealed that approximately 20% of the phosphodiesterase was carboxylmethylated . Thus, although calmodulin can serve as a substrate for carboxylmethylation , it appears that carboxylmethylation has a greater effect on calmodulin-dependent phosphodiesterase activity when the target enzyme, rather than calmodulin, is carboxylmethylated .

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Coronary blood flow in genetic cardiac hypertrophy.

6he effects of cardiac hypertrophy on coronary circulation was evaluated in 4 related strains of rats: the M520/N strain (n = 7), which has genetic cardiac hypertrophy but a normal blood pressure; the LA/N strain (n = 8), which has a somewhat small heart with normal blood pressure; the SHRSP/N strain (n = 8), which is hypertensive with marked left ventricular (LV) hypertrophy; and the WKY/N strain (n = 7), from which the SHR-Sp was developed. At 11 to 12 weeks of age, systemic and coronary hemodynamics were studied by 15-mu radioactive microspheres injected through the left atrium in conscious, unrestrained rats. Coronary blood flow was determined both at rest and after maximal vasodilation by carbochrome (6 mg/kg). LV weight was significantly higher in both the SHRSP/N (3.19 +/- 0.10 mg/g [+/- standard error], p less than 0.01) and the M520/N (2.82 +/- 0.08 mg/g, p less than 0.01) strains than in the WKY/N strain (2.30 +/- 0.08 mg/g); it was significantly smaller in the LA/N strain (1.96 +/- 0.04 mg/g, p less than 0.01). Coronary flow at rest was similar among the 4 groups; however, carbochrome-induced "maximal" flow differed among the groups. It was almost equal among the SHRSP/N (1,176 +/- 151 ml/m/100 g), the LA/N (1,356 +/- 149 ml/m/100 g) and the WKY/N strains (1,263 +/- 143 ml/m/100 g), but it was markedly decreased in the M520/N strain compared with the 3 other groups (632 +/- 83 ml/m/100 g, p less than 0.05 vs WKY/N and p less than 0.01 vs SHRSP/N and LA/N).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effects of methotrexate on biopterin levels and synthesis in rat cultured pineal glands.

Culture of rat pineal glands in methotrexate (0.5, 5, or 10 microM) for 6 or 24 h did not alter pineal tetrahydrobiopterin (85-90% of total biopterin in cultured glands), except for a decrease of 30% after 24 h culture in 10 microM methotrexate. However, pineal dihydrobiopterin and/or biopterin (10-15% of total biopterin) was increased by methotrexate up to 2.5-fold. Biopterin detected in the culture medium following pineal culture was also increased to a similar extent after methotrexate treatment and appeared to represent leakage of pineal dihydrobiopterin and/or biopterin. Culture of glands in 5 microM methotrexate did not alter the conversion of [U-14C]-guanosine to [14C]biopterin, suggesting that pineal tetrahydrobiopterin synthesis was not altered by methotrexate. Complete inhibition of dihydrofolate reductase activity measured in pineal homogenates was obtained following culture of glands in all concentrations of methotrexate studied. Therefore, dihydrofolate reductase and dihydrobiopterin do not appear to be involved in a major biosynthetic pathway for pineal tetrahydrobiopterin from GTP, although they may have a minor role in tetrahydrobiopterin synthesis.

Animals↗
PubMed1984

Nutritional factors and cardiovascular disease.

Our studies with the stroke prone substrain of the spontaneously-hypertensive rat indicate that components of the diet can have an important effect on the expression of pathology associated with severe hypertension. Specifically increasing the protein intake significantly reduces the occurrence of cerebral lesions in these rats. The expression of other pathological consequences of severe hypertension are not necessarily affected by the same dietary factors. Some preliminary evidence indicates that methionine may have a role in this protective effect, but further studies are needed. Finally, a number of parallels exist between these and epidemiologic studies suggesting that the model may have some relevance to human disease.

Animals↗
PubMed1984

Modulation of rat pineal acetyl-Co A:arylamine N-acetyltransferase induction by alpha adrenergic drugs.

The modulatory effects of alpha adrenergic drugs on the induction of rat pineal acetyl-CoA:arylamine N-acetyltransferase (NAT) activity were characterized using both in vivo and organ culture techniques. Intraperitoneal administration of phenoxybenzamine (POB) to rats was followed by a 2- to 3-fold increase in activity of pineal NAT, an enzyme involved in the biosynthesis of the putative pineal hormone melatonin. The increase was greater than 60-fold when POB was administered to ganglionectomized rats. NAT induction after POB administration to ganglionectomized rats was not influenced by adrenalectomy, suggesting that the response to POB was not mediated through the release of catecholamines from adrenomedullary catecholamine stores. To determine whether the pharmacologic site of the activity of POB was located within the pineal body itself, pineals were incubated with POB in organ culture. Significant induction of pineal NAT was not observed when pineals were cultured with POB alone. However, POB shifted the dose-response curve for NAT induction by norepinephrine (NE) to the left. Modulation of NAT induction by POB in organ culture was blocked by dl-propranolol HCl, suggesting that such modulation is mediated through a beta adrenergic mechanism. POB did not modulate NE-mediated NAT induction in pineals extracted from superior cervical ganglionectomized rats. Similarly, the modulatory response to POB was eliminated by 24-hr preincubation in culture medium. These results suggest that elements that are disrupted after ganglionectomy or during a period of preincubation are vital for expression of the modulatory activity of POB.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗
PubMed1983

Inactivation of tyrosine hydroxylase by reduced pterins.

Tyrosine hydroxylase [E.C. 1.14.16.2] is inactivated by incubation with its reduced pterin cofactors L-erythro-tetrahydrobiopterin, 2-amino-4-hydroxy-6-methyl-5,6,7,8-tetrahydropterin and 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterin. Each of the two diastereoisomers of L-erythro-tetrahydrobiopterin inactivates tyrosine hydroxylase but the natural (6R) form is much more potent than the unnatural (6S) form at equimolar concentrations. The pterin analog 6-methyl-5-deazatetrahydropterin, which has no cofactor activity, also inactivates the enzyme whereas the oxidized pterins 7,8 dihydrobiopterin and biopterin do not. The inactivation process is both temperature and time dependent and results in a reduction of the Vmax for both tetrahydrobiopterin and tyrosine. Neither tyrosine nor oxygen inactivates tyrosine hydroxylase.

Adrenal Gland Neoplasms↗
PubMed1983

Phenylethanolamine N-methyltransferase: notes on its purification from bovine adrenal medulla and separation from protein carboxymethyltransferase.

Standard procedures for the purification of phenylethanolamine N-methyltransferase were modified by the addition of an affinity chromatography step utilizing immobilized S-adenosyl-L-homocysteine and by use of preparative isoelectric focusing. Enzyme derived from bovine adrenal medullae was bound to S-adenosyl-L-homocysteine agarose, and could be eluted with 0.1 M NaCl. Concentrations of S-adenosyl-L-methionine as high as 10 mM were ineffective in eluting the enzyme. Preparative isoelectric focusing of bovine phenylethanolamine N-methyltransferase showed a single peak with the pI = 4.95. The potential use of immobilized S-adenosyl-L-homocysteine in the differential separation of phenylethanolamine N-methyltransferase from other methyltransferase enzymes is discussed.

Adrenal Medulla↗