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)

Inhibition of the Na(+)-K+ pump by digitalis compounds has been reported to increase intracellular Na+ and Ca2+ concentrations and to stimulate Na(+)-H+ exchange. The activity of endogenous digitalis-like compounds, proposed to promote natriuresis and to raise blood pressure, has been found to be increased in volume expansion and hypertension. The enhanced cytosolic [Ca2+] present in platelets from hypertensive patients may thus originate from inhibition of the Na(+)-K+ pump by endogenous inhibitors, enhanced mobilization of internal Ca2+ stores due to phospholipase C activation and/or structural membrane defects. In unstimulated platelets from essential hypertensives, the increase in [Ca2+]i depends on external Ca2+, thereby underlining the importance of Ca2+ influx. The observation that [Ca2+]i was also enhanced in erythrocytes (p = 0.03) demonstrates that intracellular stores are not required for this rise. Plasma digitalis-like activity was positively correlated with platelet [Ca2+]i (inhibition of renal Na+,K(+)-ATPase, competition with ouabain binding, p less than 0.01). Platelet [Ca2+]i also rose during chronic digoxin administration (p less than 0.02) but not after acute in vitro ouabain treatment. The alkalinisation of platelet cytosol (p = 0.005) also agrees with the stimulation of the Na(+)-H(+)-exchange. In conclusion, these results are compatible with a participation of endogenous Na(+)-K+ pump inhibitors in the control of cytoplasmic [Ca2+] and cell excitability.
 ...
PMID:Endogenous inhibitors of the Na+, K(+)-pump and platelet Ca2+ handling in hypertension. 216 68

In order to determine whether phosphoinositide metabolism is altered in hypertensive cardiac hypertrophy, phospholipase C (PLC) and protein kinase C activities were measured in hearts from 4- and 20-week-old spontaneously hypertensive rats (SHR) and age-matched, normotensive Wistar-Kyoto rats (WKY). PLC activities were assayed using phosphatidylinositol (PI) and phosphatidylinositol-4,5-bisphosphate (PIP2) as substrates to assess the substrate specificity. PI-hydrolyzing PLC activity (PI-PLC) was predominantly located in the cytosol, and its activity was similar in both strains. Membrane-bound PIP2-hydrolyzing PLC activity (PIP2-PLC) was significantly lower in 20-week-old SHR than in WKY, but there was no significant difference in soluble PIP2-PLC. Protein kinase C activity was significantly elevated in 20-week-old SHR and Ca2(+)-phospholipid-dependent phosphorylation was observed in the proteins of molecular weight 26, 32, 43, and 95 KDa. In 4-week-old prehypertensive SHR, there were no significant differences in PI-PLC, PIP2-PLC, or protein kinase C activities as compared with age-matched WKY. These data demonstrated that protein kinase C and membrane-bound PIP2-PLC are altered during the period of hypertension development. These alterations may have important roles in the development or maintenance of hypertensive cardiac hypertrophy in SHR.
 ...
PMID:Alterations of phosphoinositide-specific phospholipase C and protein kinase C in the myocardium of spontaneously hypertensive rats. 217 34

In spontaneously hypertensive rats (SHR), enhanced responsiveness of phospholipase C has been reported in various cells and tissues. In SHR and in some patients with essential hypertension particularly, the increased phospholipase C responsiveness of platelets has been described as involved in the hyperreactivity to thrombin. To determine the relation between such an enzymic abnormality and hypertension, the platelet phospholipase C activity was investigated in various models of experimental hypertension (i.e., in the Dahl salt-resistant and salt-sensitive strains inbred by John Rapp at Toledo, Ohio, SR/Jr and SS/Jr, respectively) fed either on a low or a high NaCl-containing diet, and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In phosphorus-32-prelabeled platelets, phospholipase C was determined by measurement of the thrombin-induced [32P]phosphatidic acid formation; the labeling of the P47 protein with 32P was also measured. In parallel experiments, the platelet reactivity was assessed by measurement of the thrombin-induced serotonin release. Under thrombin (0.05-0.5 units/ml) stimulation, phospholipase C activity, [32P]P47 labeling, and serotonin release were significantly increased in SS/Jr rats fed a high NaCl diet compared with SS/Jr rats fed a low NaCl diet. NaCl-rich diet did not modify phospholipase C in SR/Jr rats. Platelet reactivity and phospholipase C responsiveness were also normal in DOCA-salt hypertensive rats compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1990 Apr
PMID:Platelet phospholipase C activity in salt-dependent hypertension. 231 20

The present study was designed to study the functional properties of Angiotensin II (Ang II) binding sites in vascular smooth muscle cells in the Milan hypertensive rat (MHS), a model of low renin hypertension. Smooth muscle cells from MHS rats exhibited increased growth in culture in comparison with the Milan normotensive strain (MNS) as determined by population doubling times (24.5 +/- 2 and 34.8 +/- 2 hours, n = 4, respectively). Hormone receptor number, evaluated by binding assays using [125I]Ang II, showed no difference in either receptor number or affinity for both cell types. The functional responsiveness of Ang II receptors was evaluated by measuring the activation of phospholipase C, Na(+)-H+ exchange, and cytosolic Ca2+ levels. Phospholipase C activity was determined as tritium-labeled inositol trisphosphate and bisphosphate release before and after 15-second exposure to 10(-7) M Ang II. Ang II-stimulated phospholipase C activity in MNS (p less than 0.02) but not in MHS cells. Na(+)-H+ exchange was measured as the dimethylamiloride-sensitive 22Na+ influx into acid-loaded vascular smooth muscle cells with and without 10(-7) M Ang II. In MNS cells, Ang II significantly stimulated (p less than 0.001) antiporter activity but not in MHS cells, which showed a uniformly blunted response. MHS cells exhibited higher basal cytosolic Ca2+ levels than MNS cells, but Ca2+ rapidly increased in the presence of Ang II in MNS but not in MHS cells. Direct activation of phospholipase C by GTP-gamma-S in permeabilized cells indicated that both strains exhibited similar coupling levels by guanine-nucleotide binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1990 Jun
PMID:Vascular smooth muscle cells from the Milan hypertensive rat exhibit decreased functional angiotensin II receptors. 234 21

alpha-Toxin, the major, pore-forming exotoxin of Staphylococcus aureus, caused acute hypertension when perfused through blood-free rabbit lungs (21). This reaction is mediated by pulmonary thromboxane generation, for which toxin-induced calcium flux into target cells with subsequent stimulation of arachidonic acid metabolism is predominantly responsible. In the present study, we investigated the effects of alpha-toxin on the integrity of the lung microvasculature. Thromboxane generation was inhibited in all experiments to suppress the development of pulmonary hypertension. Application of low alpha-toxin concentrations (5 to 40 ng/ml) induced protracted, severe vascular leakage in a dose-dependent manner. After a lag period of 40 to 120 minutes, gravimetrically determined capillary filtration coefficients progressively increased to greater than 10-fold values, and this was followed by pronounced weight gain of the isolated organs. These physiologic alterations were paralleled by dose- and time-dependent structural changes documented by electron microscopic examination of perfusion-fixed lungs. Increasing electron density of microvascular endothelial cell nuclei and subsequently of their cytoplasma was noted, followed by detachment of these cells from the mutual endoepithelial basal lamina. Edema was localized in the blood-gas exchange area, in contrast to hydrostatically induced lung fluid accumulation. These results identify pulmonary microvascular endothelium cells as highly susceptible targets for attack by alpha-toxin. Given a similar sensitivity of human endothelial cells, alpha-toxin might directly contribute to the pathogenesis of acute respiratory failure under conditions of severe infection with Staphylococcus aureus.
 ...
PMID:Staphylococcal alpha-toxin-induced vascular leakage in isolated perfused rabbit lungs. 239 29

In spontaneously hypertensive rats (SHR), enhanced activity of phospholipase C (PLase C) has been reported in various cells and tissues. In particular, the increased PLase C activity of platelets has been described as being involved in the hyperactivity to thrombin exhibited by these cells in SHR and in some patients with essential hypertension. In order to determine the relationship between such an enzymic abnormality and hypertension, the PLase C activity of platelets was investigated in various models of experimental hypertension, i.e. Dahl rats and DOCA-salt hypertensive rats. PLase C activity was determined by measuring the thrombin-induced 32P-phosphatidic acid (32P-PA) formation from 32P-prelabeled platelets. In parallel, experiments on the platelet reactivity was assessed by measuring the thrombin-induced serotonin secretion from 3H-serotonin prelabeled platelets. In Dahl salt-resistant rats (DR), the blood pressures were 123 +/- 6 and 118 +/- 7 mmHg for animals fed a low (0.3 p. 100) and high (4 p. 100) salt diet, respectively; the blood pressures of Dahl salt-sensitive rats (DS) were 159 +/- 6 and 202 +/- 11 mmHg, respectively. Hypertensive rats of the DOCA/salt--treated group exhibited a blood pressure of 210 +/- 8 mmHg compared with 137 +/- 4 mmHg for those of the control group. At rest (ie before stimulation) the platelets of all groups of animals behave similarly with respect to the incorporation of 32P and its metabolism into phospholipids as well as the uptake of serotonin. These data indicate therefore that platelets were in a similar quiescent status.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Phospholipase C hypersensitivity in hypertensive rats results from innate and acquired factors]. 251 Jun 65

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K, 1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar-Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K,1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension. 255 50

Previous studies from our laboratory have shown that platelets from both spontaneously hypertensive rats and essential hypertensive patients exhibited an increased thrombin-triggered phospholipase C activity compared with normotensive subjects. In order to determine the relationship between phospholipase C and hypertension we investigated this enzymatic activity in Dahl salt-resistant (Dahl R/Jr) and salt-sensitive (Dahl S/Jr) rats fed either a low- or a high-NaCl diet, and in DOCA-NaCl hypertensive rats. Phospholipase C activity was increased in the Dahl S/Jr rats fed a high-NaCl diet compared to a low-NaCl diet. This difference was not observed in the Dahl R/Jr rats, irrespective of diet. Likewise, phospholipase C activity was similar in the DOCA-NaCl hypertensive rats compared with their controls. Our results indicate that the increased platelet phospholipase C activity was not a consequence of either the blood pressure elevation or the high NaCl intake and was probably of genetic origin. While the increased phospholipase C activity was not correlated with blood pressure, the enhanced enzymatic activity in Dahl S/Jr hypertensive rats may be involved in the elevation of blood pressure and may be NaCl-regulated.
 ...
PMID:Salt-induced and spontaneous hyperactivity of phospholipase C in primary hypertension. 263 92

We have reviewed studies of the role played by abnormalities of vascular smooth muscle in hypertension. The basic contractile apparatus of this muscle appears to be qualitatively normal, but the synthetic function of the cell is exaggerated so that more contractile protein is produced. Activation pathways of the smooth muscle cell, initiated by phospholipase C, are enhanced. A reduced ability of the endothelium to produce vascular smooth muscle relaxation may contribute to an enhanced contraction of this muscle in hypertension. Furthermore, the intrinsic cellular mechanisms that produce relaxation of this muscle may also be impaired in hypertension. However, the many abnormalities observed in membrane transport systems in this muscle in hypertension suggest that the primary defect in the cell may be a lack of stability in the membrane caused by an impairment in its ability to bind calcium.
 ...
PMID:Vascular smooth muscle in hypertension. 268 88

The cytosolic free Ca2+ concentration [( Ca2+]i) was measured in cultured human umbilical vein smooth muscle cells using fura-2 as a Ca2+ indicator and microscopic digital image analysis system. Activation of cells with histamine and vasopressin resulted in a prompt though transient rise in [Ca2+]i 10- to 12-fold higher than the resting [Ca2+]i. The [Ca2+]i then declined rapidly during the first 30-40 seconds after hormonal stimulation and then gradually decreased to near resting levels in 2-3 minutes in the continued presence of hormones. The magnitude of the increase in peak [Ca2+]i was similar in buffered salt solution containing 1.8 mM Ca2+, zero Ca2+, and zero Ca2+ buffered salt solution containing 10 mM La3+, suggesting that receptor-mediated increase in [Ca2+]i is primarily due to the release of Ca2+ from the intracellular stores. Addition of La3+ produced oscillations in [Ca2+]i in approximately half the cells in response to both hormones. Addition of 10 microM forskolin did not significantly affect the resting [Ca2+]i, the hormone-stimulated peak [Ca2+]i, or the time course of hormone-stimulated [Ca2+]i transients. These data suggest that mechanisms involved in A-kinase-mediated smooth muscle relaxation may be subsequent to the changes in [Ca2+]i. Activation of C-kinase by 1 microM 12 deoxyphorbol 13-isobutyrate-20 acetate (DPBA) did not affect the resting [Ca2+]i, though it attenuated the histamine and vasopressin-mediated peak elevation in [Ca2+]i. Since DPBA inhibited the peak [Ca2+]i response to both the hormones to the same extent, it would appear that C-kinase activation may uncouple the receptor-mediated activation of phospholipase C.
Hypertension 1989 Jun
PMID:Regulation of cytosolic free Ca2+ concentration in vascular smooth muscle cells by A- and C-kinases. 273 23


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