Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine decreases tubular sodium reabsorption, attributed in part to Na/K-ATPase inhibition in the proximal convoluted tubule (PCT). Because the final regulation of sodium excretion occurs in the collecting duct, where we have demonstrated specific dopamine DA1 binding sites, we examined the effects of dopamine, and of DA1 and DA2 receptor agonists on the Na/K pump in the microdissected rat cortical collecting duct (CCD) and in Madin-Darby canine kidney (MDCK) cells, a line derived from the dog distal nephron. Dopamine inhibited pump activity in CCD by approximately 40%-50%, an effect proportionally larger than in the PCT. Unlike in the latter, the effect of dopamine was reproduced by the DA1 agonist fenoldopam, which inhibited the CCD pump in dose-dependent manner (maximum, 10 microM). The DA2 agonist quinpirole was without effect, either alone or in combination with fenoldopam. These actions on Na/K-ATPase paralleled in reciprocal fashion effects on adenylate cyclase: dopamine or fenoldopam, but not quinpirole, produced a significant increase in cAMP content, and the stimulation by dopamine was blocked by SCH 23390. Inhibitors of cAMP phosphodiesterase (3-isobutyl-1-methyl-xanthine and theophylline), as well as forskolin and dibutyryl-cAMP, mimicked the effect of dopamine on the pump, underscoring the role of increased cAMP in this phenomenon. Both dopamine and fenoldopam inhibited Na/K-ATPase activity in MDCK cells. The results indicate that besides the PCT dopamine inhibits Na/K-ATPase activity in cells of the distal nephron, where its effect on the pump appears to be more pronounced and is mediated by activation of the DA1 receptor. The natriuretic effect of dopamine is probably exerted at both proximal and distal nephron sites.
 ...
PMID:Dopamine inhibits Na/K-ATPase in single tubules and cultured cells from distal nephron. 135 25

Cultured mesenteric artery vascular smooth muscle cells derived from male Wistar rats, expressing both beta 2-adrenoceptors and dopamine DA1 receptors, were prelabelled for 2 h with [3H]adenine. [3H]cAMP formation stimulated by the addition of dopamine (plus propranolol 10 microM), isoprenaline or forskolin, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (0.5 mM) was then determined. Exposure of cells to the thiol-oxidizing agent DTNB (5,5'-dithiobis-2-nitrobenzoic acid) following prelabelling, and prior to cAMP assay, resulted in a time-dependent inhibition of dopamine (0.1 mM)-induced cAMP formation, which obeyed the rules of first-order kinetics, being complete by 60 min. This inhibitory effect was observed to be dose related with 50% inhibition achieved at a concentration of 0.5 mM. Exposure to DTNB (5 mM) for 45 min abolished the cAMP response to dopamine (0.1 mM) with little effect on the response to forskolin (10 microM) or isoprenaline (10 microM). Prior addition of the dopamine DA1/D1 receptor selective partial agonist (+)-SKF 38393 (1 microM) preserved the dopamine induced cAMP formation despite DTNB exposure, while its stereo-enantiomer (-)-SKF 38393 (1 microM) protected only 25% of the response. Sequential exposure of cells to DTNB (5 mM) and then either vehicle or DTT (DL-dithiothreitol; 1 mM), each for 20 min periods, resulted in a 70% inhibition of dopamine induced cAMP formation which was almost completely reversed by the disulphide bridge cleaving compound DTT.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Thiol group identification at or near the agonist binding site of the vascular dopamine receptor. 138 85

Dopamine receptors have been identified in many tissues including the kidney. To establish an in vitro system as a model for dopamine action, we studied the effect of dopamine (DA) receptor agonists and antagonists on adenosine 3',5'-cyclic monophosphate (cAMP) formation in opossum kidney (OK) cells. The stimulation of cAMP production in these cells by dopamine was dose dependent, and markedly higher levels were observed in the presence of dopamine plus a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. Half-maximal stimulation was found with 1.15 +/- 0.22 microM dopamine. A DA1-receptor agonist, SKF 82526J, stimulated cAMP production, whereas a DA2-receptor agonist, Ly 171555, did not. The stimulatory effects of dopamine and SKF 82526J were abolished by a specific DA1-receptor antagonist, Sch 23390 with half-maximal inhibition concentrations of 1.24 +/- 0.18 and 4.0 +/- 0.5 nM, respectively. In contrast, the DA2-receptor antagonist, spiperone, had no inhibitory effect on dopamine- and SKF 82526J-stimulated cAMP production. Beta-Adrenergic antagonists failed to attenuate the stimulatory effects of dopamine and SKF 82526J on cAMP production. In addition, the beta-adrenergic receptor agonist, isoproterenol, did not stimulate cAMP production. These results suggest that the action of dopamine was not mediated through beta-adrenergic receptors. Furthermore, our results clearly demonstrated the existence of DA1-receptors linked to adenylate cyclase in OK cells.
 ...
PMID:Dopamine stimulation of cAMP production in cultured opossum kidney cells. 169 97

Dopamine relaxes precontracted rabbit isolated splenic arteries via stimulation of dopamine DA1 receptors on the smooth muscle. However, in many preparations, the effect of dopamine is small. In an attempt to increase the effectiveness of dopamine and thus increase the proportion of usable preparations, we have examined the effects, on the sensitivity of dopamine, of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the adenylate cyclase stimulant forskolin. In tissues pretreated with phenoxybenzamine, and in the presence of propranolol, IBMX (1 mumol/l) or forskolin (0.01 mumol/l) produced a small increase in the sensitivity to dopamine in otherwise insensitive preparations. The maximum relaxation of U-46619-induced tone produced by dopamine was increased to around 50%. However, after treatment with higher concentrations of IBMX (10 mumol/l) or forskolin (0.1 mumol/l), previously insensitive preparations relaxed readily to dopamine with EC50 values in the range 1-3 mumol/l. Similarly, in spontaneously dopamine-sensitive preparations IBMX (1 mumol/l) or forskolin (0.01 mumol/l) produced only a 2-3-fold parallel shift to the left in the dopamine concentration-effect curves. However, higher concentrations of IBMX (10 mumol/l) or forskolin (0.1 mumol/l) produced 10-20-fold parallel shifts to the left in dopamine concentration-effect curves. Higher concentrations of IBMX (100 mumol/l) or forskolin (1 mumol/l) abolished the ability of the spasmogen to contract the preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Potentiation of the effects of dopamine in the rabbit isolated splenic artery by 3-isobutyl-1-methylxanthine or forskolin. 248 47

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.
 ...
PMID:Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture. 790 78

The purpose of this study was to determine the mechanisms of dopamine regulation of phosphate uptake in opossum kidney (OK) cells, a model of proximal renal tubules. Dopamine stimulated cAMP generation and inhibited radiolabeled phosphate uptake into OK cell monolayers by 14.4 +/- 1.8%. The effect of dopamine was transient, as phosphate uptake returned toward control level by 3 h despite the continued presence of dopamine. Pretreatment with pertussis toxin increased dopamine inhibition of phosphate uptake to 25 +/- 3%, increased the duration of the dopamine effect to at least 3 h, and enhanced cAMP generation. In an OK cell clone that overexpressed cAMP phosphodiesterase, dopamine did not inhibit phosphate uptake, but pharmacologic inhibition of protein kinase A activation did not prevent dopamine inhibition of phosphate uptake. A DA1 receptor agonist inhibited phosphate uptake more potently than dopamine (29.5 +/- 1.1%) or a DA2 receptor agonist (7.9 +/- 2%). However, both DA1 and DA2 receptor antagonists completely blocked dopamine inhibition of phosphate uptake. DA1, but not the DA2, antagonists blocked dopamine-stimulated cAMP generation. Treatment with alpha-adrenergic receptor antagonists potentiated dopamine inhibition of phosphate uptake to the same extent as pertussis toxin and was not additive with pertussis toxin. It is concluded that dopamine inhibits phosphate uptake through DA1 and DA2 receptor stimulation by cAMP-dependent and -independent pathways and activates a pertussis toxin-sensitive counter-regulatory pathway that attenuates this response through alpha-adrenergic receptor stimulation.
 ...
PMID:Dopamine regulates phosphate uptake by opossum kidney cells through multiple counter-regulatory receptors. 962 Dec 80