Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo binding of [3H]spiroperidol was measured in discrete areas of the brain in 7-, 9- and 16-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) controls. An increase in the [3H]spiroperidol binding in the striatum, tuberculum olfactorium and frontal cortex but not in the cerebellum was detected at all ages in SHR. The increase was more pronounced in 7- than in 9- or 16-week-old SHR. In vitro data indicated an increase in Bmax but no variation in Kd in the striatum of 7-week-old SHR. Moreover no difference was detectable in the dopaminergic cell bodies (A9, A10). This increase was specific to [3H]spiroperidol binding sites since no difference was observed in the in vivo binding of [3H]QNB and [3H]LSD in the same brain regions. No variation in dopamine level or dopamine utilization, as estimated by measuring the disappearance of the amine induced by alpha-methyl-p-tyrosine, was observed. The DOPA accumulation after injection of the DOPA decarboxylase inhibitor NSD 1015 was greater in the tuberculum olfactorium from 7-week-old SHR. An increase in [3H]spiroperidol binding sites was also observed in the striatum and tuberculum olfactorium after 7 weeks of DOCA-salt treatment. These results suggest that dopaminergic neurons might be implicated in the onset of hypertension in the rat.
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PMID:Central dopaminergic neurons during development of genetic and DOCA-salt hypertension in the rat. 722 85

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter in the central nervous system [Y. Misu et al. (1995) Adv. Pharmac. 32, 427-459]. L-DOPA as a probable neurotransmitter for the primary baroreceptor afferents tonically functions to mediate cardiodepressor control in the nucleus tractus solitarii and also tonically functions to mediate cardiopressor control in the rostral ventrolateral medulla of rats. We further attempted to clarify whether a transmitter-like L-DOPA system is altered in these areas of adult spontaneously hypertensive rats. By microdialysis in the left nucleus tractus solitarii area, the basal L-DOPA release was lower in spontaneously hypertensive rats than that in Wistar-Kyoto rats. This release was partially reduced by tetrodotoxin (1 microM) to the same absolute levels in the two strains. Tonic neuronal L-DOPA release is impaired in this nucleus of spontaneously hypertensive rats. This impairment is not secondarily due to decrease in formation or increase in decarboxylation of L-DOPA, since tyrosine hydroxylase activity was increased in spontaneously hypertensive rats, compared to Wistar-Kyoto rats, while no difference of L-aromatic amino acid decarboxylase activity was seen in the caudal dorsomedial medulla including the nucleus. L-DOPA (10-300 ng) microinjected into the nucleus produced dose-dependent hypotension and bradycardia. A maximum depressor response of spontaneously hypertensive rats to L-DOPA at higher doses was slightly greater than that of Wistar-Kyoto rats. On the other hand, in the left rostral ventrolateral medulla, the basal L-DOPA release was higher in spontaneously hypertensive rats than that in Wistar-Kyoto rats. This release was also partially reduced by tetrodotoxin to the same absolute levels in the two strains. Tonic neuronal L-DOPA release is enhanced in spontaneously hypertensive rats. This enhancement seems to include partially a decrease in decarboxylation of L-DOPA, since L-aromatic amino acid decarboxylase activity was decreased in spontaneously hypertensive rats compared to Wistar-Kyoto rats, while no difference in tyrosine hydroxylase activity was seen. L-DOPA (10-600 ng) produced dose-dependent hypertension and tachycardia. Importantly, a pressor response of spontaneously hypertensive rats to L-DOPA at lower doses was slightly greater than that of Wistar-Kyoto rats. L-DOPA seems to play a transmitter-like role in blood pressure regulation at levels of the nucleus tractus solitarii and rostral ventrolateral medulla in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Altered tonic L-3,4-dihydroxyphenylalanine systems in the nucleus tractus solitarii and the rostral ventrolateral medulla of spontaneously hypertensive rats. 747 14

Aromatic alpha-amino-alpha-methyl acids and alpha-hydrazino-alpha-methyl acids are known aromatic amino acid decarboxylase inhibitors. Specific derivatives such as 2-amino-2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Aldomet, and 2-hydrazino-2-methyl-3-(3,4- dihydroxyphenyl)propanoate, Lodosyn, have been developed as therapeutic agents to treat hypertension and Parkinson's disease, respectively. We recently reported a method for the kinetic resolution of the racemic esters of such compounds using a crude preparation of a novel enzyme catalyst from the yeast Candida lipolytica (Yee, C.; Blythe, T.A., McNabb, T.J.; Walts, A.E. J. Org. Chem. 1992, 57, 3525-3527). Here we report the purification and initial characterization of the active enzyme component, an enzyme given the name Candida lipolytica ester hydrolase (CLEH). CLEH was purified to > 95% homogeneity by chromatography on Matrex Blue B resin. The enzyme was found to be a glycoprotein with M(r) = 80,000-300,000. In addition to esterolytic activity, the enzyme was found to catalyze the hydrolysis of amides, anilides and peptides. Sequence analysis of internal peptides of CLEH revealed striking homology to a number of enzymes belonging to the group of serine carboxypeptidases (E.C. 3.4.16.1). One peptide aligned with the canonical serine carboxypeptidase active site sequence, GESYAG. Based on the structural relationship of CLEH to serine carboxypeptidases, three representative serine carboxypeptidases were evaluated for their utility in resolving racemic alpha-tertiary ester substrates and compared with the activity of CLEH. All enzymes revealed similarly high activity and enantioselectivity towards the alpha-hydrazino-alpha-methyl ester precursor of the Parkinson-drug Carbidopa. However, differences in enantioselectivity were observed with other alpha-tertiary-substituted ester substrates. Serine carboxypeptidase-catalyzed ester resolutions thus offer a new route to many sterically hindered homochiral alpha-amino, alpha-hydrazino and alpha-hydroxy carboxylic acids.
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PMID:Enzymes for the resolution of alpha-tertiary-substituted carboxylic acid esters. 785 60

By microdialysis in the rostral ventrolateral medulla (RVLM) of anesthetized rats, the spontaneous L-3,4-dihydroxyphenylalanine (DOPA) release was partially Ca(2+)-dependent and tetrodotoxin-sensitive and was markedly reduced by alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg, i.p.). K+ (50 mM) Ca(2+)-dependently evoked L-DOPA. By microinjections into unilateral RVLM, L-DOPA (30-300 ng) produced dose-dependent hypertension and tachycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine. These responses were antagonized by L-DOPA methyl ester (1.5 micrograms), a competitive L-DOPA antagonist. D-DOPA, dopamine, noradrenaline or adrenaline (300 ng) produced no effect. Furthermore, L-DOPA methyl ester alone microinjected into bilateral RVLM (2 micrograms x 2) produced prolonged hypotension and bradycardia, which were abolished by alpha-MPT. These data suggest that L-DOPA is relevant to modulation of sympathetic activity in the rat RVLM.
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PMID:Evidence for L-dopa relevant to modulation of sympathetic activity in the rostral ventrolateral medulla of rats. 790 2

By microdialysis in the unilateral caudal ventrolateral medulla (CVLM) of anesthetized rats, the spontaneous L-3,4-dihydroxyphenylalanine (L-DOPA) release was in part tetrodotoxin-sensitive or Ca(2+)-dependent and was abolished by i.p. alpha-methyl-p-tyrosine (alpha-MPT), a tyrosine hydroxylase inhibitor. High K+ (50 mM) Ca(2+)-dependently evoked L-DOPA. By unilateral microinjections into the CVLM, L-DOPA (10-100 ng) produced dose-dependent, marked hypotension and bradycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine. These responses were antagonized by L-DOPA methyl ester, a competitive L-DOPA antagonist. A depressor response to dopamine or noradrenaline (100 ng) was far smaller and slower in onset than that to L-DOPA (30 ng). D-DOPA (100 ng) produced no effect. Furthermore, L-DOPA methyl ester microinjected into bilateral CVLM produced some hypertension and tachycardia, which were markedly reduced by alpha-MPT. Transmitter-like L-DOPA tonically functions to mediate vasodepressor control in CVLM of rats.
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PMID:Transmitter-like L-3,4-dihydroxyphenylalanine tonically functions to mediate vasodepressor control in the caudal ventrolateral medulla of rats. 826 47

Experiments were designed to clarify whether a tonic L-DOPA system is altered in the caudal ventrolateral medulla (CVLM) of adult spontaneously hypertensive rats (SHR), compared to age-matched Wistar-Kyoto rats (WKY). By microdialysis in CVLM, basal L-DOPA release was constantly detectable and was lower in SHR than that in WKY. This release was reduced by tetrodotoxin perfusion (1 microM) in WKY to a basal level in SHR, whereas no modification occurred with tetrodotoxin in SHR. No difference of tyrosine hydroxylase and DOPA decarboxylase activities in the CVLM region was seen between the two strains. By microinjections into depressor sites of CVLM, L-DOPA (10-300 ng) or L-glutamate (3-300 ng) elicited dose-dependent depressor and bradycardic responses and greater depressor responses to both amino acids were seen at high doses in SHR, compared to WKY. Tonic neuronal activity to release L-DOPA is lost in the CVLM of adult SHR and this loss may contribute to maintenance of hypertension in SHR.
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PMID:Loss of tonic neuronal activity to release L-DOPA in the caudal ventrolateral medulla of spontaneously hypertensive rats. 857 91

1. L-DOPA as a probable neurotransmitter of baroreceptor afferents functions as a tonic to mediate cardiodepressor control in the nucleus tractus solitarii (NTS). We attempted to clarify further whether a transmitter-like L-DOPA system is altered in NTS of adult spontaneously hypertensive rats (SHR). 2. By microdialysis of left NTS area, the basal L-DOPA release was lower in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was lower in SHR than in WKY. 3. L-DOPA (10-300 ng) and L-glutamate (3-100 ng) microinjected into left NTS produced dose-dependent hypotension and bradycardia. No difference of responses to L-glutamate was seen in either strain. However, depressor but not bradycardic responses to L-DOPA at higher doses were slightly greater in SHR than in WKY. 4. In caudal dorsomedial medulla including NTS, tyrosine hydroxylase activity was increased in SHR compared to WKY, while there was no difference in either strain of L-aromatic amino acid decarboxylase activity. 5. Impaired tonic neuronal activity to release L-DOPA in NTS may be involved in the maintenance of hypertension in SHR. An increase in sensitivity of a recognition site for L-DOPA seems to occur as a compensatory mechanism for impairment of the neuronal activity.
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PMID:Altered basal release and depressor effect of L-DOPA in the nucleus tractus solitarii of spontaneously hypertensive rats. 907 20

1. Transmitter-like L-DOPA functions as a tonic to produce postsynaptic cardiopressor responses in the rostral ventrolateral medulla (RVLM) of rats. We attempted to clarify whether a transmitter-like L-DOPA system is altered in the RVLM of spontaneously hypertensive rats (SHR) to maintain the hypertension. 2. By microdialysis of left RVLM area, the basal L-DOPA release was higher in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was higher in SHR than in WKY. 3. L-DOPA (10-600 ng) and L-glutamate (10-300 ng) microinjected into left RVLM produced dose-dependent hypertension and tachycardia. Pressor but not tachycardiac responses to L-DOPA at lower doses were slightly greater in SHR than in WKY, whereas no difference to L-glutamate was observed in either strain. 4. In RVLM regions, there was no difference of tyrosine hydroxylase activity in SHR or WKY; however, L-aromatic amino acid decarboxylase activity was lower in SHR than in WKY. 5. Enhanced presynaptic neuronal L-DOPA release, including a decrease in decarboxylation and sensitization of postsynaptic pressor sites to L-DOPA in RVLM, may be involved in the maintenance of hypertension in SHR.
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PMID:Altered basal release and pressor effect of L-DOPA in the rostral ventrolateral medulla of spontaneously hypertensive rats. 907 38

The present report addresses the status of the renal dopaminergic system activity in patients afflicted with different renal disorders and in the remnant kidney of uninephrectomized (UNX) rats, based on the urinary excretion of L-DOPA, dopamine and amine metabolites. In renal transplant recipients with good recovery of graft function (group 1, n=11), the daily urinary excretion of DOPAC, but not that of HVA, was found to increase progressively throughout the first 12 days post-transplantation from 698+/-57 nmol in the first day to 3498+/-414 nmol on day 9, and then remained constant until day 12. This resulted in a 6-fold increase in the urinary DOPAC/dopamine ratios. In renal transplant recipients with acute tubular necrosis (group 2, n=8), the urinary levels of dopamine, DOPAC and HVA were approximately 30% of those in group 1. In a group of 28 patients with chronic renal parenchymal disorders, the daily urinary excretion of L-DOPA, free dopamine and dopamine metabolites (DOPAC and HVA) correlated positively with the degree of deterioration of renal function (P<0.01). However, the U(Dopamine/(L)-DOPA) and U(DOPAC/Dopamine) ratios in patients with chronic renal insufficiency were found to be similar to those observed in patients with normal renal function. In 14 IgA nephropathy (IgA-N) patients with near normal renal function, the changes in 24 h mean blood pressure when going from 20 to 350 mmol/day sodium intake correlated negatively with the daily urinary excretion of dopamine (r(2)=0.597, P<0.01). The urinary excretion of L-DOPA and dopamine in IgA-N patients with salt-sensitive (SS) blood pressure was lower than in salt-resistant (SR) patients (P<0.05), irrespective of their daily sodium intake. However, the rise in urinary dopamine output during salt loading (from 20 to 350 mmol/day) was greater (P<0.05) in IgA-N SS patients (21.2+/-2.5% increase) than in SR patients (6.3+/-1.4% increase). Fifteen days after the surgery, uninephrectomy (UNX) in the rat was accompanied by an enhanced (P<0.05) urinary excretion of dopamine (36+/-3 vs 26+/-2), DOPAC (124+/-11 vs 69+/-6) and HVA (611+/-42 vs 354+/-7) (nmol/g kidney/kg body weight). This was accompanied by an increase in V(max) values for renal aromatic L-amino acid decarboxylase in the remnant kidney of UNX rats (P<0.05). Sch 23390, a D1 dopamine receptor antagonist, produced a marked reduction in the urinary excretion of sodium in UNX rats, whereas in sham-operated rats the decrease in urinary sodium did not attain a significant difference. It is concluded that the study of the renal dopaminergic system in patients afflicted with renal parenchymal disorders should address parameters other than free urinary dopamine, namely the urinary excretion of L-DOPA and dopamine metabolites (DOPAC and HVA). It is also suggested that in SS hypertension of chronic renal parenchymal diseases, renal dopamine produced in the residual tubular units may be enhanced during a sodium challenge, thus behaving appropriately as a compensatory natriuretic hormone.
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PMID:Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension. 1136 22

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.
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PMID:Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. 1168 43


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