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

The present study tested two hypotheses: (1) that a receptor for extracellular Ca2+ (Ca2+ receptor [CaR]) is located in the perivascular sensory nerve system and (2) that activation of this receptor by physiological concentrations of extracellular Ca2+ results in the release of vasodilator substance that mediates Ca2+-induced relaxation. Reverse transcription-polymerase chain reaction using primers derived from rat kidney CaR cDNA sequence showed that mRNA encoding a CaR is present in dorsal root ganglia but not the mesenteric resistance artery. Western blot analysis using monoclonal anti-CaR showed that a 140-kD protein that comigrates with the parathyroid CaR is present in both the dorsal root ganglia and intact mesenteric resistance artery. Immunocytochemical analysis of whole mount preparations of mesenteric resistance arteries showed that the anti-CaR-stained perivascular nerves restricted to the adventitial layer. Biophysical analysis of mesenteric resistance arteries showed that cumulatively raising Ca2+ from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED50 value of 2.47+/-0.17 mmol/L (n=12). The relaxation is endothelium independent and is unaffected by blockade of nitric oxide synthase but is completely antagonized by acute and subacute phenolic destruction of perivascular nerves. A bioassay showed further that superfusion of Ca2+ across the adventitial surface of resistance arteries releases a diffusible vasodilator substance. Pharmacological analysis indicates that the relaxing substance is not a common sensory nerve peptide transmitter but is a phospholipase A2/cytochrome P450-derived hyperpolarizing factor that we have classified as nerve-derived hyperpolarizing factor. These data demonstrate that a CaR is expressed in the perivascular nerve network, show that raising Ca2+ from 1 to 1.25 mol/L and above causes nerve-dependent relaxation of resistance arteries, and suggest that activation of the CaR induces the release of a diffusible hyperpolarizing vasodilator. We propose that this system could serve as a molecular link between whole-animal Ca2+ balance and arterial tone.
Hypertension 1997 Dec
PMID:Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated arteries. 940 64

The proinflammatory cytokine interleukin-1beta (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A2 (PLA2), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA2 and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in approximately 200-fold and 15-fold increases in PGE2 and 6-keto-PGF1alpha (the stable metabolite of PGI2), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA2 inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA2 products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.
Hypertension 1998 Jan
PMID:Phospholipase A2 metabolites regulate inducible nitric oxide synthase in myocytes. 945 6

The role of phospholipase A2 (PLA2) and related inflammatory mediators in the mechanism of hypoxic pulmonary arterial hypertension was studied. Thirty Sprague-Dawley rats were equally divided into three groups at random: group A was the normal control group; group B was given 10% oxygen ventilation; group C was given 10% oxygen ventilation too and, at the same time, dexamethasone was injected into the external jugular vein. The pulmonary arterial pressure (PAP) was measured by inserting a microcatheter into pulmonary artery. After 30 minutes of hypoxia, the activity of PLA2, platelet activating factor (PAF), prostaglandin E2 (PGE2) and tromboxane B2 (TXB2) were measured in blood and lung tissue. After hypoxia, the mean pulmonary arterial pressure (mPAP), the PLA2 activity, PGE2, TXB2 and PAF in blood and lung tissue of group B were significantly higher than in group A; in group C the same parameters were lower than in group B. In hypoxia, a positive correlations was found between the PLA2 activity and mPAP, PAF, PGE2, TXB2 respectively; positive correlations were also found between PAF, PGE2, TXB2 and mPAP. PLA2 induced release of inflammation mediators, plays an important role in the mechanism of the acute hypoxic pulmonary arterial hypertension.
 ...
PMID:The study of the relationship between the activity of phospholipase A2 and acute hypoxic pulmonary arterial pressure. 947 Feb 52

Angiotensin II in proximal tubule epithelium is known to stimulate the release of arachidonic acid after stimulation of phospholipase A2 (PLA2) independent of phospholipase C-mediated signaling. Furthermore, an angiotensin II type 2 receptor subtype has been linked to this signaling cascade. We investigated the regulation and differential stimulation of PLA2s by comparing the PLA2 activities associated with the membranes and cytosol of rabbit renal proximal tubular epithelial cells after stimulation with angiotensin II, epidermal growth factor, and bradykinin. Both fractions demonstrated PLA2 activity that was dithiothreitol insensitive, required micromolar concentrations of Ca2+ for optimal activity, and was inhibited in a dose-dependent manner by an antiserum to a cytosolic PLA2 with a molecular mass of 85 kD. However, membrane-associated PLA2 did not demonstrate significant substrate specificity, whereas 1-steroyl-2-[14C]arachidonylphosphatidyl choline was the preferred substrate for cPLA2. An antiserum generated against mastoparan, a known PLA2 activator, inhibited membrane- but not cytosol-associated PLA2 activity. Membrane fractions showed a broad pH range (7.5 to 8.5) for optimal PLA2 activity, whereas cytosol was maximum at pH 9.5. Angiotensin II stimulated membrane-associated PLA2 activity by 88%, whereas bradykinin and epidermal growth factor inhibited activity by 54% and 41%, respectively. The three agonists stimulated cPLA2. Moreover, angiotensin II-induced activation of membrane-associated PLA2 preceded the activation of cPLA2. These results demonstrate differential localization and regulation of proximal tubular epithelial PLA2 isozymes, which may determine the pattern of subsequent arachidonic acid metabolism by the cytochrome P450 system.
Hypertension 1998 Mar
PMID:Role of phospholipase A2 isozymes in agonist-mediated signaling in proximal tubular epithelium. 949 65

Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D1A, D1B, as D1-like and D2, and D3 as D2-like) have been shown within the kidney. The activation of D1-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D1-like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A2) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D1-like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D1A or D3 receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D1-like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension.
Hypertension 1998 Aug
PMID:Renal dopamine receptor function in hypertension. 971 42

The action of phospholipase A2 (PLA2) and related inflammatory mediators on the formation of hypoxic pulmonary arterial hypertension was studied. 30 Sprague-Dawley rats were equally divided into three groups at random: normal control group, hypoxic group and the group pretreated with dexamethasone plus hypoxia. The pulmonary arterial pressure (PAP) was measured by inserting a microcatheter into the pulmonary artery. After 30 min of hypoxia, the activity of PLA2, platelet activating factor (PAF), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were measured in blood and lung tissue, and it was found that the mean pulmonary arterial pressure (mPAP), the PLA2 activity, PGE2, TXB2 and PAF in blood and lung tissue were significantly increased; but pretreatment with dexamethasone relieved the changes mentioned above. In hypoxia, a positive correlations was found between the PLA2 activity and mPAP, PAF, PGE2, TXB2 respectively; positive correlations were also found between PAF, PGE2, TXB2 and mPAP. In conclusion, PLA2 induced the release of inflammation mediators, which may play roles in the formation of the acute hypoxic pulmonary arterial hypertension.
 ...
PMID:[The relationship between the activity of phospholipase A2 and acute hypoxic pulmonary arterial pressure]. 986 93

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
 ...
PMID:Vascular biology of endothelin. 988 41

We have previously shown that the regulation by interleukin-1beta (IL-1beta) of inducible nitric oxide synthase (iNOS) involves phospholipase A(2) (PLA(2)) metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS-082 is used to inhibit secretory PLA(2) and methyl arachidonyl fluorophosphonate is used to inhibit cytosolic PLA(2), our data suggest that a secretory PLA(2) metabolite was involved in the regulation by IL-1beta of iNOS. In addition, a third PLA(2) isoform, which is Ca(2+) independent (iPLA(2)), has also been detected in cardiac myocytes and shown to be regulated by cytokines. We tested whether iPLA(2) metabolites are involved in the regulation by IL-1beta of iNOS with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of iPLA(2). For this, we measured IL-1beta-stimulated nitrite (NOx) production with use of the Griess reagent, prostaglandin E(2) (PGE(2)) production with use of an enzyme immunoassay, and arachidonic acid release in the presence and absence of BEL. We also detected iNOS and iPLA(2) proteins by Western blotting. Treatment with IL-1beta (5 ng/mL) for 24 hours stimulated NOx production by 8-fold and iNOS protein levels by at least 10-fold. In addition, arachidonic acid release was increased by 1.6-fold and PGE(2) production was increased by 300-fold. When neonatal ventricular myocytes were treated with 10 micromol/L BEL, both IL-1beta-stimulated PGE(2) production and arachidonic acid release were inhibited. BEL inhibited IL-1beta-stimulated NOx production and iNOS protein by 88% and 93%, respectively. Lysophosphatidic acid, but not arachidonic acid or lysophosphatidylcholine, stimulated iNOS expression. Our results indicate that an iPLA(2) metabolite, perhaps lysophosphatidic acid, may be involved in the IL-1beta-signaling pathway, regulating the synthesis of iNOS.
Hypertension 2000 Jan
PMID:Role of Ca(2+)-independent phospholipase A(2) in the regulation of inducible nitric oxide synthase in cardiac myocytes. 1064 6

In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B(2) receptors (B(2)Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16. 0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B(2)R-green fluorescent protein (B(2)R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for [3H]BK (K(D)=1.61 nmol/L) similar to that of the wild-type rabbit B(2)R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A(2) assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [(3)H]BK binding to B(2)R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0 degrees C; at 37 degrees C, icatibant or NPC 17731 effects were not reversible. B(2)R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B(2)R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B(2)R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101- to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B(2)R expressed in an heterologous system.
Hypertension 2000 Jun
PMID:Antagonist-induced intracellular sequestration of rabbit bradykinin B(2) receptor. 1085 84

The effects of bradykinin on the regulatory mechanisms of prostacyclin synthesis in endothelial cells were investigated in association with intracellular Ca(2+) kinetics, cytosolic phospholipase A(2) (cPLA(2)) activity, and mRNA expression of cPLA(2) and prostaglandin H synthase (PGHS) isoforms. Bradykinin enhanced prostacyclin release from endothelial cells time-dependently, but pretreatment with EGTA H-7 or HOE 140 inhibited bradykinin-induced prostacyclin release. Bradykinin increased both the influx of extracellular Ca(2+) and Ca(2+) release from the intracellular Ca(2+) storage sites. These reactions occurred within 5 minutes after bradykinin stimulation. Within 15 minutes, bradykinin activated cPLA(2) to 1.3-fold the control level. The constitutive expressions of mRNA of cPLA(2), PGHS-1, and PGHS-2 was 87, 562, and 47 amol/microg RNA, respectively. With the stimulation of bradykinin, cPLA(2) mRNA increased to 746 amol/microg RNA in 15 minutes, PGHS-1 mRNA increased to 10 608 amol/microg RNA, and PGHS-2 mRNA increased to 22 400 amol/microg RNA in 180 minutes. Pretreatment with cycloheximide superinduced cPLA(2) and PGHS-2 mRNA expression but almost completely inhibited PGHS-1. Pretreatment with EGTA had effects similar to pretreatment with cycloheximide in the case of cPLA(2) and PGHS-1 but did not affect PGHS-2. These findings suggest that the elevation of cPLA(2) activity caused by the increase of intracellular Ca(2+) concentration is important in the early phase of bradykinin-induced prostacyclin synthesis and that the mechanisms regulating cPLA(2) are different from those regulating PGHS isoforms in endothelial cells.
Hypertension 2000 Aug
PMID:Effects of bradykinin on prostaglandin I(2) synthesis in human vascular endothelial cells. 1094 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>