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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II is the major effector peptide of the renin-angiotensin system. In addition to its vasoconstrictor activity, angiotensin II stimulates smooth muscle cell growth in arterial hypertension and in models of vascular injury. The angiotensin II type 1 receptor is a seven-transmembrane receptor and is responsible for virtually all the physiological actions of angiotensin II. This class of receptor signals in part through its association with heterotrimeric G proteins. A newly developed concept for guanine nucleotide protein-coupled receptors is the activation of intracellular second-messenger proteins via tyrosine phosphorylation. For instance, angiotensin II stimulates the rapid tyrosine phosphorylation and activation of phospholipase C-gamma1. Also, angiotensin II stimulates the tyrosine phosphorylation of Janus kinases. In this review, we discuss early signaling events induced by angiotensin II with an emphasis on tyrosine phosphorylation. Understanding the importance of tyrosine phosphorylation in the signaling pathways of the angiotensin II type 1 receptor may lead to new treatment modalities for cardiovascular disease.
Hypertension 1996 Mar
PMID:Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. 861 89

Deoxycorticosterone-salt (DOCA-salt) hypertension is characterized by elevated vasoconstriction to agonists that stimulate G protein-mediated activation of phospholipase C. However, the mechanisms responsible for the augmented responsiveness are unknown. This study tested the hypothesis that this augmented vascular responsiveness is due to elevated content of G(alpha)q, the G protein alpha-subunit that activates phospholipase C. Thoracic aortae from DOCA-salt hypertensive rats (systolic blood pressure 183 +/- 7 mm Hg) and normotensive controls (systolic blood pressure 115 +/- 2 mm Hg) were homogenized and G protein content determined. Western analysis revealed that G(alpha)i content was decreased in DOCA compared with control rats (1364 +/- 196 versus 2343 +/- 188 densitometry units, P < or = .05) with no differences observed for G(alpha)q or G(alpha)s. In addition, contractile responses in denuded femoral artery strips revealed a significant decrease in EC50 values in DOCA arteries to all of the agonists examined: aluminum fluoride (DOCA = 1.42, control = 2.34 mmol/L), mastoparan (DOCA = 0.51, control = 35 micromol/L), phenylephrine (DOCA = 0.08, control = 0.53 micromol/L), and serotonin (DOCA = 0.014, control = 0.04 micromol/L, EC20 values). Finally, arteries from DOCA rats contracted with aluminum fluoride had increased sensitivity to G protein antagonists but not to a phospholipase C inhibitor. The enhanced contractile responsiveness in the DOCA arteries may be mediated in part through decreased G(alpha)i levels. However, it is not caused by increased concentrations of G(alpha)q in the cell membrane or by increased phospholipase C sensitivity, and the increased constrictor response to G protein stimulators of phospholipase C appears to depend primarily on increased G protein sensitivity.
Hypertension 1996 Mar
PMID:Increased responsiveness and decreased expression of G proteins in deoxycorticosterone hypertension. 861 34

Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve C(a2+) -dependent pathways. This study assesses relationships between angiotensin II (Ang II)-stimulated phospholipase C-mediated Ca2+ transients and tyrosine kinase-dependent pathways in vascular smooth muscle cells. Intracellular free Ca2+ concentration ([Ca2+]i) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca2+]i effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 muU/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 mumol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca2+]i response (from 94 +/- 8 to 239 +/- 5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced (P < .01) Ang II-induced [Ca2+]i to 161 +/- 7, 189 +/- 3.7, and 183 +/- 5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II-stimulated [Ca2+]i remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had not significant effect on Ang II-induced [Ca2+]i. This study demonstrates that activation of tyrosine kinase pathways reduces Ang II-elicited [Ca2+]i responses, whereas tyrosine kinase inhibition prevents [Ca2+]i recovery after agonist stimulation. Interaction between tyrosine kinase- and phospholipase C-dependent signaling pathways modulates vascular smooth muscle cell [Ca2+]i responses to Ang II.
Hypertension 1996 May
PMID:Tyrosine kinase signaling pathways modulate angiotensin II-induced calcium ([Ca2+]i) transients in vascular smooth muscle cells. 862 Dec 2

The second messenger inositol-1,4,5-trisphosphate (InsP3) comes from two major pathways, one is initiated by a family of G protein-linked receptors and the other by receptors linked by tyrosine kinases. These separate receptors activate phospholipase C to hydrolyse phosphatidylinositol-4,5-bisphosphate to give both diacylglycerol and InsP3. The latter then mobilizes stored calcium and promotes an influx of external calcium. The alpha subunit of a newly discovered G protein (Gq) has recently been shown to stimulate the activity of PLC-beta 1. The alpha subunits of the Gq class of G proteins includes G alpha q, G alpha 11, G alpha 14, G alpha 15 and G alpha 16. The important pathologic changes in hypertension are arteriolar spasm and wall thickening. Many vasoactive substances can induce contractile response and proliferation of vascular smooth muscle cells and increase InsP3 level. However, the hypertension does not cause any persistent change in Gq.
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PMID:[G proteins-phosphoinositide pathways in hypertension]. 873 80

Endothelins 1, 2, and 3 did not affect basal renin secretion, but selectively inhibited to a similar extent both cAMP-stimulated renin secretion and renin gene expression in isolated renal juxtaglomerular cells. In isolated perfused rat kidneys and after cAMP-stimulated renin secretion using isoproterenol, endothelins inhibited basal renin secretion at a perfusion pressure of 80 mm Hg. Endothelin's main action is mediated via the endothelin ETB receptor. It involves activation of phospholipase C, intracellular calcium mobilization in juxtaglomerular cells that is dependent on extracellular calcium and associated with prominent calcium-activated chloride currents, and subsequent processes. In normal rats and in rats with unilateral renal artery clips, a nonselective inhibitor of endothelin receptors, Ro 47-0203, did not significantly change renin secretion and renal renin gene expression, despite complete abolition of the vasoconstrictive and renin inhibitory action of exogenous endothelins by this drug in isolated perfused rat kidneys. In spite of a marked renin inhibitory efficacy of exogenous endothelins in vitro (isolated renal juxtaglomerular cells, isolated perfused rat kidney), endogenous endothelins play no relevant regulatory role in renin secretion and renin gene expression in normal and hypoperfused rat kidneys in vivo. However, endothelins may be of physiological relevance for the development of hypertension upon renal artery stenosis.
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PMID:Role of endothelins for renin regulation. 874 30

Bradykinin is a mediator of the protection of myocardium by angiotensin I-converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 mu/L bradykinin increased IP3 production from 117 +/- 8.3 to 1011 +/- 48.6 pmol/mg protein. Treatment of the cells with 10 mu/L indomethacin or 1 mu/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 mu/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629 +/- 14.5 versus 1011 +/- 48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 mu/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 mu/L staurosporine, a protein kinase C inhibitor. Treatment with 1 microgram/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570 +/- 20.0 to 1150 +/- 51.3 and to 1016.7 +/- 21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 mu/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
Hypertension 1996 Sep
PMID:Thromboxane A2 mediates the stimulation of inositol 1,4,5-trisphosphate production and intracellular calcium mobilization by bradykinin in neonatal rat ventricular cardiomyocytes. 879 31

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

Vascular smooth muscle cells of the spontaneously hypertensive rat (SHR) are known to show increased responsiveness to angiotensin II (Ang II) compared with cells of normotensive control Wistar-Kyoto rats (WKY). We investigated the hypothesis that differential levels of cGMP lead to the different responsiveness of the cells, using vascular smooth muscle cells in culture. cGMP levels in extracts of SHR-derived cells were lower than those of WKY-derived cells. This was true for both unstimulated cells and cells treated with equal concentrations of either sodium nitroprusside or S-nitroso-N-acetylpenicillamine. Stimulation of cells with Ang II did not affect levels of cGMP but increased levels of inositol 1, 4, 5-trisphosphate (IP3) and Ca2+, which were greater in SHR- than in WKY-derived cells. When SHR and WKY cells were preincubated with different concentrations of S-nitroso-N-acetylpenicillamine to generate similar cGMP levels in each cell type, the subsequent IP3 response to Ang II was the same in the two cell types. To reduce any influence of cGMP on responses, we permeabilized the cells with alpha-toxin. Stimulation of alpha-toxin-permeabilized the cells with high Ca2+ revealed an IP3 response in SHR- but not WKY-derived cells. Similarly, permeabilized SHR cells responded to Ang II but WKY cells did not. However, GTP and GTP gamma S elevated IP3 in both cell types. Taken together, these results indicate that the low response of WKY cells can be accounted for by the inhibitory influence of cGMP. However, when this inhibition is removed by permeabilization, further differences between the cells are revealed that will contribute to the elevated SHR response.
Hypertension 1996 Nov
PMID:Angiotensin II-stimulated phospholipase C responses of two vascular smooth muscle-derived cell lines. Role of cyclic GMP. 890 22

The involvement of the early signaling messengers, inositol tris-phosphate (IP3), intracellular calcium, [Ca2+]i, and protein kinase C (PKC), in angiotensin II (AII)-induced fluid phase endocytosis was investigated in human brain capillary and microvascular endothelial cells (HCEC). ALL (0.01-10 microM) stimulated the uptake of Lucifer yellow CH, an inert dye used as a marker for fluid phase endocytosis, in HCEC by 50-230%. AII also triggered a fast accumulation of IP3 and a rapid increase in [Ca2+]i in cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. The prompt AII-induced [Ca2+]i spike was not affected by incubating HCEC in Ca(2+)-free medium containing 2 mM EGTA or by pretreating the cultures with the Ca2+ channel blockers, methoxyverapamil (D600; 50 microM), nickel (1 mM), or lanthanum (1 mM), suggesting that the activation of AII receptors on HCEC triggers the release of Ca2+ from intracellular stores. The AII-triggered increases in IP3, [Ca2+]i, and Lucifer yellow uptake were inhibited by the nonselective AII receptor antagonist, Sar1, Val5, Ala8-AII (SVA-AII), and by the phospholipase C (PLC) inhibitors, neomycin and U-73122. By contrast, the protein kinase C (PKC) inhibitors, staurosporine and calphostin C, failed to affect any of these AII-induced events. This study demonstrates that increased fluid phase endocytotosis induced by AII in human brain capillary endothelium, an event thought to be linked to the observed increases in blood-brain barrier permeability in acute hypertension, is likely dependent on PLC-mediated changes in [Ca2+]i and independent of PKC.
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PMID:Angiotensin II-induced fluid phase endocytosis in human cerebromicrovascular endothelial cells is regulated by the inositol-phosphate signaling pathway. 895 95

Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-gamma, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.
Hypertension 1997 Jan
PMID:Angiotensin II signaling in vascular smooth muscle. New concepts. 903 29


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