[Case of primary aldosteronism associated with heart and kidney failure].
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Aldosterone↗
Biomedical subjects
K Yasunari
Publications and source records attributed to K Yasunari.
Heparin inhibits human coronary artery smooth muscle cell migration.
Heparin, an anticoagulant, has been shown to reduce neointimal proliferation and restenosis following vascular injury in experimental studies, but the clinical trials of heparin in coronary balloon angioplasty have been negative. The current study, therefore, examined the effect of heparin on basal or stimulated migration by serum and platelet-derived growth factor (PDGF)-BB in cultured human coronary artery smooth muscle cells (SMCs) by Boyden's chamber method. In addition, the reversibility of the heparin effect on human coronary artery SMC migration was examined. Fetal calf serum (FCS) and PDGF-BB stimulated SMC migration in a concentration-dependent manner. Heparin in moderate to high concentration (10 to 100 U/mL) exhibited concentration-related inhibition of FCS- and PDGF-BB-stimulated SMC migration; however, a low concentration (1 U/mL) of heparin had no inhibitory effects. Heparin also had weak inhibitory effects on nonstimulated SMC migration. The SMCs that were exposed to a high concentration (100 U/mL) of heparin for 6 hours were capable of migrating after a short lag period of removal of heparin from the culture medium. These SMCs also showed recovery of responses to FCS and PDGF-BB by migrating significantly greater than the nonstimulated level. Furthermore, heparin-containing medium did not contain detached cells. These results indicate that heparin inhibits human coronary artery SMC migration, especially when stimulated by FCS or PDGF-BB, and that this inhibitory effect of heparin is reversible and not simply a function of killing cells.
Anticoagulants↗
Effect of the endothelin family of peptides on human coronary artery smooth-muscle cell migration.
The migration of coronary artery medial smooth-muscle cells (SMCs) is one of the key events in the process of intimal thickening in coronary atherosclerotic lesions. The objectives of the present study were to determine whether any of the three isoforms of endothelin (ET), ET-1, ET-2, and ET-3, or an intermediate form of ET, big ET-1, induces migration of human coronary artery SMCs, and to investigate the possible interaction of ET peptides and well-known migration-stimulatory factors, platelet-derived growth factor (PDGF)-BB and angiotensin II (Ang II), on SMC migration by the Boyden's chamber method. None of the ET peptides alone induced SMC migration between 10(-9) and 10(-7) mol/L. In contrast, ET-1 and ET-2 significantly induced SMC migration in the presence of low concentrations of PDGF-BB (0.5 ng/mL) or Ang II (10(-9) mol/L), although ET-3 was less active (ET-1 = ET-2 > ET-3). In contrast, big ET-1 was without significant activity on PDGF-BB-or Ang II-induced SMC migration. The potentiation of SMC migration by ET peptides was clearly inhibited by the ETA receptor antagonist BG-123 in a concentration-dependent manner. These results suggest that the ET family of peptides, especially ET-1 and ET-2, can induce human coronary artery SMC migration in combination with PDGF-BB or Ang II, probably via ETA receptors. Taken together with the finding that the concentrations of ET, PDGF-BB and Ang II are locally increased at sites of endothelial injury, this indicates that ET may be an initial stimulus for human coronary artery medial SMC recruitment during coronary atherosclerosis, possibly in combination with PDGF-BB or Ang II.
Angiotensin II↗
Heparin suppresses cyclosporine-induced endothelin-1 synthesis in rat endothelial cells.
Cyclosporine stimulates vasoconstrictor endothelin-1 (ET-1) synthesis. This study examined the effect of heparin on cyclosporine-induced ET-1 synthesis in Wistar rat aortic endothelial cells in culture. Cyclosporine (0.01-5 mumol/L) stimulated ET-1 mRNA expression in a dose-dependent manner. A nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA) (10(-5) mol/L), did not affect cyclosporine-induced ET-1 mRNA expression. Heparin (1-20 U/ml) suppressed cyclosporine-induced ET-1 mRNA expression in a dose-dependent manner. The inhibitory effect of heparin was blunted in the presence of either L-NMMA (10(-5) mol/L) or calmodulin inhibitors such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (5 x 10(-5) mol/L) or calmidazolium (5 x 10(-5) mol/L) in the presence of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (0.1 mmol/L). These results suggest that heparin suppresses cyclosporine-induced ET-1 mRNA expression via both NO- and calmodulin-dependent pathways.
Animals↗
Suppression of endothelin-3-induced nitric oxide synthesis by triglyceride in human endothelial cells.
Reduced endothelium-derived nitric oxide (NO) production characterizes several vascular diseases. This study examined the effect of triglyceride on NO production induced by endothelin-3 (ET-3) in cultured human umbilical vein endothelial cells. Triglyceride-rich human plasma obtained after a high-carbohydrate diet with white wine was used in an ex vivo study. The plasma triglyceride fraction was found to consist of large amounts of palmitic and oleic acids detected by gas-liquid chromatography. Therefore, the effect of synthetic tripalmitin and triolein emulsion on NO production was also examined. ET-3 stimulated NO and guanosine 3',5'-cyclic monophosphate production and increased cytosolic Ca2+ levels in the endothelial cells (ECs). After incubation of the ECs with the triglyceride-rich plasma for 2 h, these responses to ET-3 were ameliorated in a triglyceride concentration-dependent manner (50-200 mg/dl). A synthesized emulsion of tripalmitin (100 mg/dl) and triolein (100 mg/dl) also blunted the responses to ET-3. Neither endothelial constitutive NO synthase mRNA expression nor its protein level was affected by treatment with triglycerides. These results suggest that triglyceride suppresses ET-3-induced NO synthesis in human ECs by inhibiting cytosolic Ca2+ elevation.
Blotting, Northern↗
Improvement of erythrocyte deformability by cholesterol-lowering therapy with pravastatin in hypercholesterolemic patients.
Erythrocyte deformation is an important regulatory factor of the microcirculation. The present study was designed to examine whether erythrocyte deformability is altered in hypercholesterolemic patients and, if so, whether cholesterol-lowering therapy affects this parameter in these patients. The erythrocyte deformability of 37 hypercholesterolemic patients was evaluated before and after 1 year of therapy with pravastatin, an inhibitor of hepatic hydroxymethyl glutaryl coenzyme A reductase, under various shear stresses (4.7, 9.5, 23.6, 47.3, 118.1, and 236.2 dyne/cm2) using laser diffractometry. At study entry, erythrocyte deformability under 4.7 and 9.5 dyne/cm2 shear stress, which is actually observed in human vessels, was reduced compared with that in 20 age-matched normocholesterolemic subjects and was inversely correlated with serum cholesterol and low-density lipoprotein (LDL) cholesterol. Pravastatin therapy for 1 year, which reduced serum cholesterol from 288 +/- 28 to 223 +/- 20 mg/dL, significantly improved erythrocyte deformability by approximately 20%. There was a significant relation between the improvement of erythrocyte deformability and the reduction of serum cholesterol or LDL cholesterol. The results suggest that erythrocyte deformability is reduced in hypercholesterolemic patients, and that long-term cholesterol-lowering therapy can improve reduced erythrocyte deformability, which may contribute to the improvement of organ perfusion.
Adult↗
Renoprotective effects of a combined endothelin type A/type B receptor antagonist in experimental malignant hypertension.
We previously showed that plasma endothelin-1 (ET-1) concentration was increased in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension in spontaneously hypertensive rats (SHR). In contrast, in normal SHR, this value is similar to that seen in Wistar-Kyoto (WKY) rats. The purpose of this study was to examine the effects of the new combined ET type A/type B (ETA/B) receptor antagonist, TAK-044, on the development of hypertension in this model of malignant hypertension. TAK-044 10 mg/kg, which effectively blocks both ETA and ETB receptors, was administered intraperitoneally once per day for 4 weeks in DOCA-salt SHR, and the effects on ET-1 and other parameters were compared with the same values in untreated WKY rats, untreated DOCA-salt SHR, and hydralazine-treated DOCA-salt SHR. DOCA-salt caused marked increases in blood pressure, blood urea nitrogen (BUN), serum creatinine, and plasma ET-1 concentrations in SHR. Both TAK-044 and hydralazine significantly suppressed the increase in blood pressure in DOCA-salt SHR to the same extent. Both treatments also suppressed the increase in BUN and serum creatinine, but this attenuation was less marked with hydralazine than with TAK-044. Neither TAK-044 nor hydralazine affected plasma ET-1 concentration in this model. TAK-044 significantly reduced kidney weight in DOCA-salt SHR, whereas the decrease seen with hydralazine was less marked. Prevention of DOCA-salt-induced renal structural injury (mesangial hypercellularity, glomerular sclerotic changes, and tubulointerstitial damage) in this model was clearly greater with TAK-044 treatment than with hydralazine treatment. These results suggest that endogenous ET-1 may, at least in part, contribute to renal functional and structural damage in malignant DOCA-salt SHR. Our results raise the possibility of renoprotective effects of ETA/B receptor blockers in certain forms of malignant hypertension.
Animals↗
Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors.
Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine and specific D1-like agonists SKF 38,393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration and proliferation were studied. We observed that cells stimulated by PDGF-BB (5 ng/mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 (1 to 10 mumol/L), and this prevention was reversed by Sch 23,390 (1 to 10 mumol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mumol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89), but not blocked by its negative control, N-[2-(N-formyl)-p-chlorociannamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/mL)-mediated activation of phospholipase D, protein kinase C, and mitogen activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration and proliferation of VSMC, possibly through protein kinase A activation and suppression of activated phospholipase D, protein kinase C, and mitogen-activated protein kinase activity.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells.
Vascular smooth muscle cell (SMC) migration is proposed to be an important process in the initiation and/or progression of atherosclerosis. The present study examined the effects of the natriuretic peptide family (atrial, brain, and C-type natriuretic peptides; ANP, BNP, and CNP) on the migration of cultured rat SMCs, using Boyden's chamber methods. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB potently stimulated SMC migration. Rat ANP(1-28), rat BNP-45, and rat CNP-22 clearly inhibited SMC migration stimulated with FCS or PDGF-BB in a concentration-dependent manner. CNP-22 had the most potent inhibitory effect compared with other natriuretic peptides. When PDGF-BB-induced migration was separated into chemotactic and chemokinetic activities, the chemotactic component was strongly inhibited by these natriuretic peptides. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cyclic GMP. The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, and an activator of the cytosolic guanylate cyclase, sodium nitroprusside, significantly inhibited FCS- and PDGF-BB-stimulated migration in a concentration-dependent manner. These results suggest that natriuretic peptides, especially CNP-22, inhibit FCS- or PDGF-BB-stimulated SMC migration at least in part through a cyclic GMP-dependent process. Thus, the natriuretic peptide family may play a role as an antimigration factor of SMCs under certain circumstances.
Animals↗
Dopamine D1-like receptor stimulation inhibits hypertrophy induced by platelet-derived growth factor in cultured rat renal vascular smooth muscle cells.
Vascular smooth muscle cell (VSMC) hypertrophy is believed to play some roles in atherosclerosis. To elucidate the role of vascular D1-like receptors in VSMC hypertrophy, the effects of dopamine and specific D1-like receptor agonists SKF 38393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC hypertrophy was studied. We observed that cells stimulated by PDGF-BB 5 ng/mL showed increased VSMC hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, and YM 435 1-10 mumol/L, and this prevention was reversed by Sch 23390 1 to 10 mumol/L, a specific D1-like receptor antagonist. These actions are mimicked by forskolin 1 to 10 mumol/L, a direct activator of adenylate cyclase and 8-bromo-cAMP 0.1 to 1 mmol/L, and are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(P-bromcoinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89) but not blocked by its negative control. PDGF-BB (5 ng/mL)-mediated mitogen-activated protein kinase (MAPK) activity was significantly suppressed by coincubation with D1-like receptor agonists, which were reversed by PKA inhibitor H 89. These results suggest that vascular D1-like receptor agonists inhibit hypertrophy of VSMC, possibly through PKA activation and suppression of activated MAPK activity.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells.
The migration of coronary artery medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerotic lesions. In the current study, we examined the possible interaction of adrenomedullin, a novel vasorelaxant peptide, and angiotensin II (Ang II) on human coronary artery SMC migration using Boyden's chamber method. Ang II stimulated SMC migration in a concentration-dependent manner between 10(6) and 10(8) mol/L. This stimulation was clearly blocked by the Ang II type 1 receptor antagonist losartan but not by the type 2 receptor antagonist PD 123319. The migration stimulatory effect of Ang II was chemotactic in nature for cultured human coronary artery SMCs but was not chemokinetic. Human adrenomedullin clearly inhibited Ang II-induced migration in a concentration-dependent manner. Human adrenomedullin stimulated cAMP formation in these cells. Inhibition by adrenomedullin of Ang II-induced SMC migration was paralleled by an increase in the cellular level of cAMP. 8-Bromo-cAMP, a cAMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the Ang II-induced SMC migration. These results suggest that Ang II stimulates SMC migration via type 1 receptors in human coronary artery and adrenomedullin inhibits Ang II-induced migration at least partly through a cAMP-dependent mechanism. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, this peptide may play a role as a local antimigration factor in certain pathological conditions.
8-Bromo Cyclic Adenosine Monophosphate↗
Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells.
The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.
Cell Movement↗
Mechanisms of action of troglitazone in the prevention of high glucose-induced migration and proliferation of cultured coronary smooth muscle cells.
Recent findings suggest that high glucose levels may promote atherosclerosis in coronary vascular smooth muscle cells (VSMCs). To explore the intracellular mechanisms of action by which troglitazone affects this process, we examined the effect of troglitazone on the migration and growth characteristics of cultured rabbit coronary VSMCs. Treatment with chronic high glucose medium (22.2 mmol/L) for 5 days increased VSMC migration by 92%, [3H]thymidine incorporation by 135%, and cell number by 32% compared with VSMCs treated with normal glucose (5.5 mmol/L glucose + 16.6 mmol/L mannose) medium. Trolitazone at 100 nmol/L and 1 mumol/L significantly suppressed high glucose-induced VSMC migration by 34% and 42%, respectively, the proliferative effect (as measured by cell number) by 17% and 27%, and [3H]thymidine incorporation by 45% and 60% (n = 6, P < .05). The high glucose-induced impairment of insulin-mediated [3H]deoxyglucose uptake was blocked by a protein kinase C (PKC) inhibitor (calphostin C, 1 mumol/L) and was also improved by troglitazone without any change in insulin receptor number and affinity. The high glucose-induced insulin-mediated increase in cell number and in [3H]thymidine incorporation was suppressed by troglitazone. Troglitazone (1 mumol/L) also suppressed high glucose-induced phospholipase D activation, elevation of the cytosolic NADH/NAD+ ratio (as measured by the cytosolic ratio of lactate/pyruvate), and membrane-bound PKC activation. Flow cytometric DNA histogram analysis of cell cycle stage showed that high glucose-induced increase in the percentage of cells in the S phase was suppressed by 1 mumol/L troglitazone. These findings suggest that PKC may be a link between impairment of insulin-mediated glucose uptake and the increase in migration and proliferation induced by high glucose levels and that troglitazone may be clinically useful for the treatment of high glucose-induced coronary atherosclerosis.
Animals↗
Vascular dopamine-I receptors and atherosclerosis.
Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.
Animals↗
Changes in plasma cardiac natriuretic peptides concentrations during 1 year treatment with angiotensin-converting enzyme inhibitor in elderly hypertensive patients with left ventricular hypertrophy.
Plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) are high in patients with hypertension and congestive heart failure. The present study examined changes in plasma ANP and BNP concentrations during 1 year of monotherapy with enalapril in elderly hypertensive patients with left ventricular (LV) hypertrophy. Eight elderly hypertensive patients with LV hypertrophy were treated with enalapril for 1 year, during which time serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of ANP and BNP. Enalapril maintained systolic and diastolic blood pressure in the normal range for over 1 year. Treatment significantly reduced posterior wall thickness at 6 months, and more so at 1 year, and tended to reduce septal wall thickness and LV mass index at 1 year. LV ejection fraction was slightly but significantly increased at 1 year. Plasma ANP and BNP, which were markedly elevated at study entry, both decreased after 1 year of enalapril. These results suggest that 1 year of treatment with enalapril caused both a modest regression of LV hypertrophy and a modest improvement in LV systolic function in our selected group of elderly hypertensive patients. The drug reduced elevated plasma ANP and BNP levels but did not alter BUN and serum creatinine levels. Enalapril appears to be useful for the treatment of elderly hypertensive patients with LV hypertrophy.
Aged↗
Plasma brain natriuretic peptide during ergometric exercise in hypertensive patients with left ventricular hypertrophy.
Cardiac ventricle is shown to be an important source of circulating brain natriuretic peptide (BNP) in hypertensive rats with left ventricular hypertrophy (LVH). This study examined the effect of short-term exercise with a bicycle ergometer on plasma BNP concentrations in 21 essential hypertension patients with LVH established by echocardiography. The results were compared with those from 24 age-matched hypertensives without LVH. Blood pressure, heart rate, plasma renin activity (PRA), and plasma norepinephrine level increased during exercise, but the mean increases of these parameters were not different in the two groups. Resting BNP levels were slightly but significantly higher in the LVH group than in the non-LVH group. This peptide increased during exercise in the two groups, but the exercise-induced increase (percent increase) in plasma BNP was significantly greater in the LVH group than in the non-LVH group (207% +/- 50% v 141% +/- 36%, P < .05). The exercise-induced increase in BNP was significantly correlated with the left ventricular (LV) mass index (N = 45, r = .60, P < .01). By contrast, the exercise-induced increase in BNP was not correlated with the exercise-induced increase in heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, PRA, or noradrenaline level. These results suggest that short-term exercise induces an accelerated increase of plasma BNP in hypertensive subjects with LVH. The LV mass appeared to be related to the observed increase of plasma BNP concentration, at least in our hypertensive patients with LVH.
Adult↗
Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells.
OBJECTIVE: The present study was designed to examine whether adrenomedullin affects fetal calf serum (FCS)-stimulated proliferation in cultured rat vascular smooth muscle cells (VSMCs). METHODS: Rat VSMCs were grown from explants of Sprague-Dawley rat aorta and were grown using the standard cell culture method. After incubation for 24 h with various concentrations of adrenomedullin in the presence of 5% FCS, trichloroacetic acid-insoluble tritiated thymidine was measured in a liquid scintillation counter. After incubation for 48 h, cell counts were performed. Cyclic adenosine 3',5'-monophosphate (AMP) levels were determined by radioimmunoassay. RESULTS: Rat adrenomedullin exhibited concentration-dependent inhibition of the FCS-stimulated increase in thymidine incorporation between 10(-7) and 10(-9) mol/l and of cell number at 10(-7) mol/l. However, the calcitonin generelated peptide (CGRP) receptor antagonist human CGRP(8-37) abolished these antiproliferative effects of rat adrenomedullin. Inhibition by adrenomedullin of FCS-stimulated cellular proliferation was paralleled by an increase in the cellular level of cyclic AMP. 8-Bromocyclic AMP, a cyclic AMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the FCS-stimulated increase in thymidine incorporation and cell number. CONCLUSIONS: These results suggest that adrenomedullin inhibits FCS-stimulated proliferation in cultured rat VSMCs, probably through a cyclic AMP-dependent process. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, adrenomedullin may play a role as an antiproliferative factor for VSMCs in a paracrine fashion.
8-Bromo Cyclic Adenosine Monophosphate↗
Plasma adrenomedullin concentrations in essential hypertension.
We designed the present study to assess any changes in plasma concentrations of the novel vasorelaxant peptide adrenomedullin in patients with essential hypertension. Plasma adrenomedullin concentrations were measured in 45 patients with untreated essential hypertension, 15 patients with borderline hypertension, and 30 normotensive control subjects. After 4 weeks of effective calcium channel blocker-based antihypertensive therapy, adrenomedullin concentrations were measured again. The concentrations were higher in hypertensive patients with increased serum creatinine levels or decreased glomerular filtration rates compared with borderline hypertensive patients and normotensive subjects, although values in normotensive and hypertensive individuals overlapped. Plasma adrenomedullin concentrations were positively correlated with serum creatinine levels and inversely correlated with glomerular filtration rates in the hypertensive patients, whereas adrenomedullin values were not correlated with blood pressure level, left ventricular mass index, or left ventricular ejection fraction. Despite blood pressure control with antihypertensive therapy, plasma adrenomedullin concentrations were not changed. Reversed-phase high-performance liquid chromatographic analysis showed that a major component of immunoreactive adrenomedullin in the plasma of normotensive subjects and hypertensive patients is human adrenomedullin-(1-52). These results indicate that plasma adrenomedullin concentrations are elevated in many hypertensive patients with renal dysfunction and its major component is human adrenomedullin-(1-52).
Adrenomedullin↗