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

Hypertension is often accompanied by abnormalities of calcium homeostasis, including hyperparathyroidism with reduced target organ responses to PTH in kidney and bone. Due to this association between PTH and hypertension and since PTH and the paracrine factor PTH-related protein (PTHrp) have both been shown to exert marked changes in cardiovascular activity, these actions of PTH and PTHrp were examined in spontaneously hypertensive rats (SHR) and in control normotensive Wistar-Kyoto rats (WKY). Fourteen-week-old SHR [systolic blood pressure (SBP), 201 +/- 4.4 mm Hg] and WKY (SBP, 141 +/- 2.5 mm Hg) were studied. Renal cortical membranes were prepared and assayed for radioligand binding with [125I]PTH-(1-34) and [125I]PTHrp-(1-34). There was no apparent alteration in the affinity of the binding sites to either peptide in the SHR, but specific binding in SHR renal tissue was only 60% of that observed in WKY tissue for both peptides. Serum immunoreactive PTH levels were 4-fold higher in SHR than WKY, while serum total calcium and 1,25-dihydroxyvitamin D3 levels were not different. The iv administration of both PTH and PTHrp produced dose-dependent reductions in SBP and increases in heart rate in conscious unrestrained SHR and WKY. Both peptides caused greater absolute reductions in blood pressure in SHR than in WKY. However, when the hypotensive response was normalized for the higher baseline pressure in the SHR, the blood pressure reductions caused by PTH and PTHrp were not different in SHR and WKY. Conversely, the chronotropic responses to PTH and PTHrp were lower in SHR compared to WKY. These findings indicate that the SHR exhibits elevated PTH levels, with a reduced number of renal PTH/PTHrp receptors and a depressed chronotropic response to either PTH or PTHrp. In contrast, the hypotensive response to PTH or PTHrp was not altered, indicating possible tissue-specific receptor subclasses or tissue-specific regulation of PTH and PTHrp receptors.
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PMID:Cardiovascular responsiveness to parathyroid hormone (PTH) and PTH-related protein in genetic hypertension. 131 38

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolonged exposure to elevated levels of PTH is often associated with hypertension. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segments within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskolin, isoproterenol, isobutylmethyl-xanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP attenuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similarly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization. Nle8, 18Tyr34 bovine PTH(3-34) amide did not desensitize vascular tissue to PTH or PTHrP. Our results suggest that homologous desensitization to PTH or PTHrP in vascular tissue requires receptor stimulation, occurs proximal to G stimulatory protein, and impairs attenuation of calcium mobilization by PTH or PTHrP. This may be a mechanism by which vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.
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PMID:Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein. 775 Apr 71

Approximately 50% of the annual mortality in patients with end-stage renal disease (ESRD) is attributed to cardiovascular-related events. Multiple factors, including volume overload, hypertension, electrolyte abnormalities, and the presence of comorbid diseases, such as diabetes mellitus, may have an adverse effect on left ventricular function in ESRD. The purpose of this brief review is to advance the hypothesis that parathyroid hormone (PTH) is a cardiotoxin and a potential mediator of cardiac dysfunction in uremia. Recent studies have provided evidence that cardiocytes possess a distinct class of binding sites for PTH, and the PTH receptor has recently been cloned. Furthermore, the PTH receptor may be coupled to more than one effector pathway. Finally, the possibility that a PTH-related protein autocrine system may be present in cardiocytes and the implications of this signaling pathway on cardiocyte function are discussed.
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PMID:The cardiocyte as a target for parathyroid hormone in end-stage renal disease. 803 77

Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.
Hypertension 1994 Mar
PMID:Parathyroid hormone analogues inhibit calcium mobilization in cultured vascular cells. 812 68

The effect of human parathyroid hormone-related protein, a powerful vasodilator, on endothelin-1 production in cultured bovine pulmonary arterial endothelial cells was studied. Treatment with parathyroid hormone-related protein(1-34) at concentrations of 10(-9) to 10(-6) mol/L for 24 hours caused dose-dependent suppression of the secretion of endothelin-1, with maximal suppression at 10(-7) mol/L to 74% of the control value. This inhibitory effect was completely abolished by coincubation with 100 ng/mL pertussis toxin, an inhibitor of GTP binding protein. Furthermore, addition of Ng-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, at 10(-3) mol/L significantly blocked the suppressive effect of parathyroid hormone-related protein (1-34) on endothelin-1 secretion, and further addition of 5x10(-3) mol/L L-arginine significantly attenuated the blocking effect of N(G)-monomethyl-L-arginine. Parathyroid hormone-related protein (1-34) at 10(-7) mol/L resulted in an approximately fivefold increase in intracellular cGMP level. Northern blot analysis revealed that parathyroid hormone-related protein (1-34) inhibited both basal and thrombin-induced endothelin-1 gene expression. These findings suggest that the vasodilating property of parathyroid hormone-related protein may be mediated in part through its inhibitory effect on endothelin-1 production, which is probably mediated through nitric oxide and cGMP in endothelial cells. Thus, a feedback regulatory mechanism may exist between parathyroid hormone-related protein and endothelin-1 in the vascular wall.
Hypertension 1996 Mar
PMID:Parathyroid hormone-related protein inhibits indothelin-1 production. 869 38

The effect of parathyroid hormone-related protein on interleukin-1beta-induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1beta time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone-related protein(1-34) alone up to 10(-7) mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid hormone-related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1beta or interleukin-1beta with parathyroid hormone-related protein(1-34) was completely inhibited by coincubation with 3x10(-3) mol/L N(G)-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthase, or with 10(-3) mol/L 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin-1 potentiated interleukin-1beta induction of nitric oxide, which might be mediated by endogenous parathyroid hormone-related protein. Neutralization of exogenous or endogenous parathyroid hormone-related protein with antibody attenuated the synergistic effect of parathyroid hormone-related protein, but did not affect interleukin-1beta induction of nitric oxide. These results suggest that locally produced parathyroid hormone-related protein acts as a synergistic regulator upregulating interleukin-1beta-induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.
Hypertension 1997 Oct
PMID:Parathyroid hormone-related protein upregulates interleukin-1beta-induced nitric oxide synthesis. 933 94

Parathyroid hormone-related protein (PTHrP) appears to play crucial roles in the cardiovascular system. Over the past few years it has become apparent that there is more than one receptor recognizing parathyroid hormone or PTHrP, or both, and that PTHrP is not only a potent vasodilator of vascular smooth muscle cell tone, but is also a regulator of vascular smooth muscle cell proliferation and a secretagogue of renin and vasopressin. Investigators in several laboratories have started to query whether PTHrP intervenes in vascular diseases such as hypertension, (re)stenosis-atherosclerosis and endotoxaemia.
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PMID:Parathyroid hormone-related peptide--a smooth muscle tone and proliferation regulatory protein. 944 59

Parathyroid hormone-related protein (PTHrP) is expressed throughout the renovascular system, and it dilates renal vessels, increases renal blood flow and glomerular filtration rate, and stimulates renin release. Mechanical forces and experimental hypertension have been shown to stimulate PTHrP expression in smooth muscles, suggesting a negative feedback control of vascular tone by PTHrP in hypertension. In this study, we compared the impact of a PTHrP receptor antagonist, PTHrP (7-34), and a PTHrP receptor agonist, PTHrP (1-36), on the vascular resistance of perfused kidneys isolated from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Endogenous PTHrP appears not to act as a renal vasodilator in either WKY or SHR. However, the vasodilation following infused PTHrP (1-36) is blunted markedly in SHR, possibly due to desensitization or down-regulation of PTH/PTHrP receptors. Negative feedback control of vascular tone by PTHrP in SHR thus appears unlikely. The results raise the question of whether endogenous renovascular PTHrP behaves rather as a growth factor than as a vasodilator.
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PMID:Renovascular parathyroid hormone-related protein in spontaneously hypertensive rats: dilator or trophic factor? 973 92

Maternal hypertension, vasoconstriction and placental insufficiency are features of pre-eclampsia. Alterations in calcium homeostasis and in the production of calciotropic hormones and vasoactive agents have also been described in association with pre-eclampsia. Parathyroid hormone-related protein (PTHrP) is abundantly expressed in intrauterine tissues during normal pregnancy and has roles in fetal growth and calcium homeostasis, placental calcium transport and vascular tone regulation. Intrauterine PTHrP mRNA expression and tissue PTHrP content were determined by Northern blot analysis and radio-immunoassay, respectively, in preterm and term pre-eclamptic women. PTHrP mRNA expression and PTHrP content in placenta, amnion over placenta, reflected amnion and choriodecidua from preterm pre-eclamptic women (n=8-10) were not different from preterm controls (n= 10-12). PTHrP mRNA expression and content in amnion over placenta and reflected amnion were significantly greater in term compared to preterm pre-eclamptics (P<0.05). PTHrP mRNA expression was significantly lower in choriodecidua from term pre-eclamptic women (n=8) compared to term controls (n=28, P<0.05), but was not different in placenta or amnion. PTHrP content was not altered in term pre-eclamptic women (n=8) compared to controls (n=25) for any tissue. In summary, PTHrP expression in placenta and amnion was not increased in pre-eclamptic women in association with maternal hypertension, placental insufficiency and vasoconstriction. PTHrP mRNA expression was decreased in choriodecidua in association with term but not preterm pre-eclampsia, however, levels of the protein were not decreased. The data suggest that PTHrP is not involved in the placental pathophysiology of pre-eclampsia in late gestation.
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PMID:Intrauterine expression of parathyroid hormone-related protein in normal and pre-eclamptic pregnancies. 985 63

The ability of the dopamine-1 (D1)-like receptor to stimulate adenylyl cyclase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D1-like receptors on RPT sodium transport is also reduced in some patients with essential hypertension, we measured D1-like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (n=6) and HT (n=4). However, the D1-like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum response=67+/-1%) than in HT (maximum response=17+/-5%), with a potency ratio of 105. Dopamine also increased cAMP production to a greater extent in NT (32+/-3%) than in HT (14+/-3%). The fenoldopam-mediated increase in cAMP production was blocked by SCH23390 (a D1-like receptor antagonist) and by antisense D1 oligonucleotides in both HT and NT, indicating action at the D1 receptor. The stimulatory effects of forskolin and parathyroid hormone-related protein of cAMP accumulation were not statistically different in NT and HT, indicating receptor specificity and an intact G-protein/AC pathway. The fenoldopam-stimulated PLC activity was not impaired in HT, and the primary sequence and expression of the D1 receptor were the same in NT and HT. However, D1 receptor serine phosphorylation in the basal state was greater in HT than in NT and was not responsive to fenoldopam stimulation in HT. These studies demonstrate the expression of D1 receptors in human RPT cells in culture. The uncoupling of the D1 receptor in both rats (previously described) and humans (described here) suggests that this mechanism may be involved in the pathogenesis of hypertension; the uncoupling may be due to ligand-independent phosphorylation of the D1 receptor in hypertension.
Hypertension 1999 Apr
PMID:Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension. 1020 44


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