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

We compared the effects of angiotensin II and endothelin on mass levels of 1,2-diacylglycerol, and endogenous activator of protein kinase C, in cultured rabbit vascular smooth muscle cells with the effects of these vasoconstrictors on contractile responses of rabbit aortic strips. At a high concentration (1 microM), both angiotensin II and endothelin induced a biphasic formation of 1,2-diacylglycerol with an early transient phase and a late sustained phase. At this high concentration, angiotensin II caused a transient contraction followed by a gradual relaxation, whereas endothelin caused a slowly developing and sustained contraction. At a low concentration (EC50 for the early phase of 1,2-diacylglycerol formation), angiotensin II also induced a biphasic formation of 1,2-diacylglycerol and caused a transient contraction, but endothelin induced a monophasic formation of 1,2-diacyglycerol with only an early peak. Despite a rapid decrease of 1,2-diacylglycerol, endothelin at this low concentration still caused a sustained contraction. At both the high and low concentrations, the 1,2-diacylglycerol level was sustained higher for angiotensin II, whereas the tension during the late tonic phase of contraction was greater for endothelin. These results suggest that the unique persistent nature of endothelin-induced contraction is not attributed simply to the stimulatory effect of this peptide on the 1,2-diacylglycerol/protein kinase C pathway.
Hypertension 1990 Jan
PMID:Mass analysis of 1,2-diacylglycerol in cultured rabbit vascular smooth muscle cells. Comparison of stimulation by angiotensin II and endothelin. 240 81

Several ion fluxes are stimulated when mitogenic polypeptides are added to cells. The precise mechanism by which this activation takes place is not understood, but compelling evidence exists in the case of the activation of sodium-hydrogen exchange that it requires the tyrosine kinase activity associated with the mitogen receptor. The activation of sodium-hydrogen exchange by mitogens is associated with changes in intracellular pH that appear to be permissive but not causal in allowing cells to proceed through the cell cycle. When added to cells, mitogens also activate protein kinase C, which acts as part of a feedback loop to control the activity of the mitogen receptor. Possible mechanisms for this control are discussed.
Hypertension 1987 Nov
PMID:Control of ion fluxes by mitogenic polypeptides. 244 80

Stimulation of phosphatidylinositol metabolism by neurotransmitters produces diacylglycerol, an activator of protein kinase C, which may be involved in hormone-mediated contractions. We studied the effect of a tumor-promoting phorbol ester, 12-deoxyphorbol 13-isobutyrate 20-acetate (DPBA), on contraction of caudal artery rings of Wistar-Kyoto control (WKY) and spontaneously hypertensive rats (SHR) in order to examine whether protein kinase C-mediated mechanisms are increased in SHR. Although DPBA alone did not produce contractions of either WKY or SHR caudal artery rings, it greatly potentiated the contractions evoked by norepinephrine, norepinephrine, vasopressin, potassium, and calcium ionophore A23187. The potentiation of contractile response to these agents by DPBA was dependent on extracellular calcium. The DPBA potentiation of contractions evoked by norepinephrine, vasopressin, and potassium was significantly greater (p less than 0.05) in SHR than in WKY, while no differences were observed between strains for the contractions evoked by calcium ionophore A23187. These results indicate that the protein kinase C-mediated responses are increased in SHR caudal artery rings, and this effect appears to be due to increased calcium influx through cell membrane calcium channels.
Hypertension 1988 Feb
PMID:Contractile response of spontaneously hypertensive rat caudal artery to phorbol esters. 245 63

To investigate the role of vasoconstrictor hormones in vascular smooth muscle cell growth we have studied the effects of the potent vasoconstrictor angiotensin II on cell growth in a cultured rat aortic cell model. Angiotensin II was not mitogenic for these cells, as assessed by determining cell number, nor was it synergistic in this regard with 10% calf serum. However, 24-hour exposure to 100 nM angiotensin II caused an 80% increase in protein synthesis (compared with 0.4% increase with serum control) as measured by tritiated leucine incorporation. This was a "hypertrophic" response as indicated by a 30% increase in protein content and a 45% increase in cell volume. Angiotensin II-induced smooth muscle cell hypertrophy was maximal at 100 nM, had an ED50 of 1 nM, and was inhibited by the competitive antagonist [Sar1, Ile8]angiotensin II. The increase in protein synthesis required continuous presence of angiotensin II for 6 hours and required messenger RNA (mRNA) synthesis as suggested by complete inhibition after exposure to actinomycin D. Angiotensin II-stimulated protein synthesis was dependent on a rise in intracellular Ca2+ concentration evidenced by a 70% decrease in tritiated leucine incorporation after chelation of Ca2+ with 25 microM quin 2-AM. This treatment did not alter protein synthesis induced by 10% calf serum. Decreasing extracellular Na+ to prevent Na+/H+ exchange and intracellular alkalinization did not inhibit the angiotensin II response but decreased the 10% calf serum-stimulated protein synthesis by 35%. Downregulation of protein kinase C by 24-hour treatment with phorbol 12,13-dibutyrate did not inhibit angiotensin II-induced protein synthesis, while phorbol 12-myristate 13-acetate-stimulated protein synthesis was abolished. These findings suggest that angiotensin II-induced hypertrophy, acting via a Ca2+ mechanism, may play an important role in abnormal vascular smooth muscle cell growth in certain forms of hypertension.
Hypertension 1989 Apr
PMID:Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. 246 88

The mechanism of platelet dysfunctions in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated. Platelet aggregation was inversely correlated with blood pressure or heart weight/body weight ratios in various strains of spontaneously hypertensive rats (SHR), indicating genetic defects. Thrombin-induced 47 kDa protein phosphorylation was markedly reduced in platelets of SHRSP compared with that in Wistar-Kyoto (WKY) rat platelets, accompanying reduced aggregation and secretion, but in 20 kDa protein phosphorylation was unchanged. Ca2+ ionophore A23187-induced responses were also significantly decreased in SHRSP, and the degrees of the changes were greater than those by thrombin. However, 12-O-tetradecanoylphorbol 13-acetate-induced responses in SHRSP were similar to those in WKY rats, suggesting that protein kinase C activity and its substrate were normally present in SHRSP platelets. Phosphatidylinositol content in platelets of SHRSP was 20% less than that in WKY rat platelets, but the contents of other phospholipids, including phosphatidylinositol-4-monophosphate and phosphatidylinositol-4,5-bisphosphates, were unaltered. Thrombin-induced formation of diacylglycerols and phosphatidic acid did not differ from each other at the low concentrations. In the absence of Ca2+, thrombin-induced responses occurred to a similar degree in both platelets, whereas the enhancements by Ca2+ were much greater in WKY rats than in SHRSP. These results suggested that defective Ca2+ functions in receptor-mediated activation of protein kinase C and postkinase-mediated events appear to be an underlying mechanism for the hypofunctions in SHRSP platelets.
Hypertension 1989 Sep
PMID:Defective protein phosphorylation associated with hypofunctions in stroke-prone spontaneously hypertensive rat platelets. 250 71

The cellular mechanisms underlying the agonist-induced sustained contraction of the vascular smooth muscle are reviewed in the light of the use of Ca2+ and the change of Ca2+ sensitivity of the contractile apparatus. It is generally accepted that the main trigger for contraction of vascular smooth muscle is the elevation of intracellular Ca2+ concentration. However, the measurement of intracellular Ca2+ concentration during the sustained phase of agonist-induced contraction is reported to be lower than that of high K+ stimulation or the value obtained by the experiments with chemically skinned smooth muscle preparations. These observations indicate that a second regulatory system may exist. One possible mechanism is the effectiveness of Ca2+ use. Agonist-induced Ca2+ influx may be more effective in raising the intracellular Ca2+ in the bulk of the cytoplasm than is Ca2+ entry induced by depolarization by the inhibition of a putative sarcoplasmic reticulum buffer barrier. Another possibility is the change of Ca2+ sensitivity of the contractile apparatus. Although the survey of the recent literature concerning the phorbol ester-induced vasoconstriction tends to support a role for protein kinase C in the change of Ca2+ sensitivity of the contractile proteins, it fails to establish a clear link between receptors, protein kinase C, and myofilaments. By using new methods for permeabilizing smooth muscle fibers, which retain the function of receptors and signal transduction systems, we now provide direct evidence that the activation of G protein by norepinephrine or guanosine 5'-0-(3-triphosphate) (GTP-gamma-S), nonhydrolyzable GTP analogue, enhances myofilament sensitivity to Ca2+.
Hypertension 1989 Jun
PMID:Agonist-induced vascular tone. 254 24

This study compares vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats with respect to protein kinase C and intracellular responses to angiotensin II (Ang II). Ang II-induced degradation of polyphosphoinositides and accumulation of inositol di- and tris-phosphates was enhanced (approximately twofold) in hypertensive-derived cells, without a change (vs. normotensive-derived cells) in half-maximally effective concentrations of Ang II. Intracellular pH (approximately 6.6) was comparable between both cell isolates at quiescence, but alkalinization induced by Ang II, serum, or phorbol ester was greater (delta 0.1-0.2 pH units) for hypertensive-derived cells. For both cell types, the intracellular pH response to these agonists was prevented in the presence of Na+-H+ exchange inhibitors. S6 kinase activation induced by Ang II was enhanced (approximately twofold) in hypertensive-derived cells, whereas activation in response to serum or 12-O-tetradecanoylphorbol 13-acetate did not differ significantly between the two cell types. Quantitation of protein kinase C by immunoblotting and [3H]phorbol dibutyrate binding procedures revealed no differences between the two smooth muscle cell isolates (at quiescence or in the presence of serum) with respect to either total amounts or subcellular distribution. Sensitivity of protein kinase C to phorbol ester was apparently also not different between the two cell types, as assessed from dose-dependent (phorbol ester) S6 kinase activation profiles. Phorbol ester caused a similar subcellular redistribution of [3H]phorbol dibutyrate binding in the two cell isolates, but for both, minimal (10%) translocation occurred in response to Ang II. The data suggest that enhanced agonist responsiveness in vascular smooth muscle cells is unlikely to involve alterations in protein kinase C.
Hypertension 1989 Sep
PMID:Enhanced responsiveness to angiotensin II in vascular smooth muscle cells from spontaneously hypertensive rats is not associated with alterations in protein kinase C. 254 60

Previous studies have shown that erythrocytes from the Milan hypertensive strain of rats (MHS) differ from erythrocytes from the control normotensive strain (MNS). These differences are determined within the stem cells, are genetically associated with the development of hypertension, and are similar to those found between the tubular cells of the two strains. Moreover they seem to be dependent upon the presence of the membrane skeleton proteins. In this paper we describe our studies aimed at identifying some precise protein difference between the membrane skeletons of the two strains, which may cause the cellular differences described above. Milan hypertensive strain and MNS rats were immunized with ghost or membrane skeleton extracts prepared from the other or their own strains. Only MHS rats immunized with MNS ghost or membrane skeleton extracts produced an antibody against a 105 KD protein in about 95% of the animals. This protein has been identified with the recently described cytoskeletal protein adducin on the following bases: the protein binds calmodulin (CaM) and protein kinase C (PKc) in a Ca2+ dependent way. It also binds phosphatidylserine, is the substrate of exogenous PKc, and finally it is purified by high salt extraction of Triton-X100 insoluble erythrocyte cytoskeletons followed by affinity chromatography on CaM-sepharose. Using this antibody the isolation from a mouse spleen library, the characterization and sequencing of a partial cDNA clone coding for this protein has been carried out. In conclusion adducin may be considered a very useful tool to test the hypothesis that the cellular differences between MHS and MNS may be caused by a difference in a membrane skeleton protein.
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PMID:Erythrocyte adducin differential properties in the normotensive and hypertensive rats of the Milan strain. Characterization of spleen adducin m-RNA. 270 90

1. We have examined the effects of a range of smooth muscle relaxants on the maintained contractions produced in rat aortic rings by the protein kinase C activator, 4 beta-phorbol dibutyrate; these effects were compared with those on the contraction induced by the selective alpha 1-adrenoceptor agonist, methoxamine. The phorbol ester, at 0.3 microM, gave a sustained contraction which was, on average, of approximately the same magnitude as the maximum contraction produced by methoxamine, 10 microM. 2. The beta-adrenoceptor agonist, isoprenaline (0.01-1 microM) caused a dose-related relaxation of the methoxamine-induced contraction but had no effect on the contraction induced by the phorbol ester. 3. An activator of adenylate cyclase, forskolin (0.01-1 microM) produced a dose-related relaxation of the methoxamine-induced contraction and at 0.01-10 microM caused relaxation of the contraction induced by the phorbol ester. Similar results were obtained with the potassium channel activator, cromakalim (0.001-10 microM). 4. An activator of guanylate cyclase, sodium nitroprusside (0.001-100 microM) caused a dose-related relaxation of both the methoxamine-induced and the phorbol ester-induced contraction, being more effective on the former than on the latter. Similar results were obtained with enprofylline (1-1000 microM). 5. Methoxamine (10 nM-100 microM), given cumulatively, caused a dose-related contractile response. Pretreatment with isoprenaline (1 microM), enprofylline (10 microM) and nicorandil (1 microM) resulted in partial decrease of the subsequent response to methoxamine, while nicorandil (10 microM), forskolin (1 microM), sodium nitroprusside (10 microM) and cromakalim (1 microM) totally abolished it. 6. The phorbol ester, given cumulatively, caused increasing contraction in the concentration range 30 nM-10 microM. Pretreatment with forskolin (1 microM), sodium nitroprusside (10 microM), isoprenaline (1 microM), enprofylline (10 microM), nicorandil (1 microM or 10 microM), or cromakalin (1 microM or 10 microM), resulted in partial decrease of the subsequent response to 4 beta-phorbol dibutyrate. 7. These results are discussed in the light of the suggestion that protein kinase C may have a role in the 'latch-bridge' phase of smooth muscle contraction, and that inappropriate activation of protein kinase C may contribute to the pathogenesis of hypertension and other conditions involving vasospasm.
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PMID:The effect of relaxants working through different transduction mechanisms on the tonic contraction produced in rat aorta by 4 beta-phorbol dibutyrate. 275 36

The most common haemodynamic abnormality in human essential hypertension is an increase in systemic vascular resistance. Morphologic substrate for increased flow resistance is a narrowing of the lumen of arteriolar resistance vessels. During the course of essential hypertension, this is associated with an increase in wall (mainly media) thickness due to hypertrophy and hyperplasia of vascular smooth muscle cells. In contrast to concepts interpreting media thickening strictly as structural adaptation to increased perfusion pressure, various lines of evidence also point to pressure independent factors. In this context, extracellular factors such as "growth factors" as well as alterations in the activity of intracellular messenger systems must be considered. Recent studies suggest that substances generally known to act as vasoconstrictors such as angiotensin II, noradrenaline and arginine-vasopressin may also stimulate vascular smooth muscle cell growth and proliferation. Intracellular messenger systems with possible significance in the response to trophins and/or mitogens of vascular smooth muscle cells are phospholipase C, protein kinase C and the Na+/H+-antiport. These systems have been demonstrated to be altered in hypertension supporting the concept that one endogenous factor in human essential hypertension with pathophysiological significance, at least in a subgroup of patients, may be an enhanced reactivity of vascular smooth muscle cells to trophic and mitogenic stimuli. In this context, intracellular messenger systems such as phospholipase C, protein kinase C and/or the Na+/H+-antiport may play an important pathophysiological role.
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PMID:[Mechanism and significance of arteriolar media hypertrophy/ hyperplasia in arterial hypertension. Role of the Na+/H+ antiport]. 285 Apr 7


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