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ABSTRACT: Bioactive substances secreted from various cells of heart and vessels play a very important role in functional homeostasis of cardiovascular system. Discoveries of new bioactive peptides not only boost the cognition of the diseases, but also have extensive clinically prospectives in preventing and treating cardiovascular diseases. Bioactive peptides secreted from cardiovascular system have both multiple forms and diverse functions. The functional complexities of peptides correlated with receptor, distribution and expression of receptor subtype, and splicing of gene. In additon, the multifunctions of peptides are concerned with other fragments of the same peptide precursor, and with the choices of the same ligend for multiple receptors.
Sheng li ke xue jin zhan [Progress in physiology] 02/2007; 38(1):19-24.
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ABSTRACT: To investigate the effects of intermedin 1-53 on oleic acid induced acute lung injury (ALI) in rats and its possible mechanisms.
Twenty-four male Wistar rats, weighting 280-300 g, were randomly divided into three groups (n = 8). In the oleic acid group, ALI was induced by injecting oleic acid (0.2 ml/kg) intravenously. In the intervention group, the rats received oleic acid as above, but intraperitoneal injection of intermedin 1-53 (2 nmol/kg in l ml saline) was given 1 h before and 2 h after oleic acid infusion, respectively. The control group was given normal saline (0.2 ml/kg). The animals were observed for 6 h after intravenous infusion. The histopathological changes of lung tissue were studied. The arterial blood gases, lung wet/dry weight ratio (W/D), leukocyte count and neutrophil differentials in bronchoalveolar lavage fluid (BALF) were measured. Contents of intermedin 1-53 in the plasma were detected with radioimmunoassay, myeloperoxidase activity, and malondialdehyde (MDA) and conjugated diene (C-diene) level of lung tissue were also measured.
The PaO(2) was higher and lung wet/dry weight ratio, leukocyte count and neutrophil counts in BALF were significantly lower in the intermedin group [(81.7 +/- 4.6) mm Hg (1 mm Hg = 0.133 kPa), 5.49 +/- 0.63, (57.9 +/- 7.4) x 10(4)/ml, 0.718 +/- 0.085, respectively] as compared to the oleic acid group [(60.8 +/- 3.2) mm Hg, 6.18 +/- 0.34, (122.0 +/- 16.6) x 10(4)/ml, 0.878 +/- 0.026], q value was 16.74, 3.43, 17.23, 6.32, respectively, all P < 0.05 or 0.01).
Intermedin 1 - 53 treatment significantly attenuated oleic acid-induced lung injury in rats. Intermedin 1-53 exerts pulmo-protective effects by inhibiting formation of lipid oxide products.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 12/2006; 29(12):808-11.
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ABSTRACT: 1. In recent studies, the vascular adventitia has been established as an important source of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) production, even more powerful than the media in response to certain inflammatory factors, such as lipopolysaccharide (LPS). The adventitia has an independent L-arginine (L-Arg)/NOS/NO pathway and is involved in the regulation of vascular function. In the present study, we explored the changes in and the pathophysiological significance of the L-Arg/NOS/NO pathway in the adventitia of rats with sepsis. 2. Sepsis was induced by caecal ligation and puncture in order to observe changes in L-Arg transport, NOS gene expression and activity and NO generation in the vascular adventitia to determine the mechanism of activation of the L-Arg/NOS/NO pathway. 3. Severe sepsis resulted in severe disturbance of haemodynamic features, with decreased mean arterial blood pressure, brachycardia and inhibited cardiac function (decreased left ventricular +/-dP/dt(max)). Left ventricular end-diastolic pressure was elevated threefold (P < 0.01) under anaesthesia. Rats with sepsis showed severe glucopenia and lacticaemia. Plasma levels of the inflammatory factors macrophage chemoattractant protein-1 and interleukin-8 were increased five- and 29-fold, respectively (P < 0.01). 4. In the adventitia of the thoracic and abdominal aortas, the L-Arg/NO pathway was similarly characterized: the uptake of [(3)H]-L-Arg was Na(+) independent, with the peak occurring at approximately 40 min incubation. Total NOS activity was largely calcium independent (> 90%). The V(max) of L-Arg transport in the sepsis group was increased by 83.5% (P < 0.01), but the K(m) value was not significantly different compared with controls. 5. The mRNA levels of cationic amino acid transporter (CAT)-1 and CAT-2B in the sepsis group were increased by 86 and 62%, respectively (both P < 0.01). Inducible NOS activity was increased 2.8-fold compared with controls (P < 0.01) and iNOS mRNA levels were elevated approximately sixfold (P < 0.01). The NO levels in the plasma and incubation media (incubation for 40 min) in the sepsis group were increased by 144 and 273%, respectively (both P < 0.01). 6. The Arg/NOS/NO pathway was activated in the vascular adventitia of rats with sepsis shock. The L-Arg/NOS/NO pathway in the aortic adventitia may play an important role in the pathogenesis of sepsis and septic shock.
Clinical and Experimental Pharmacology and Physiology 12/2006; 33(12):1202-8. · 1.85 Impact Factor
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ABSTRACT: Stress gastric ulcer is a serious complication, but the mechanism involved is not fully clarified. It is well known that mucosal cell apoptosis plays a crucial role in the pathogenesis of gastric ulceration. Recent studies have shown that endoplasmic reticulum (ER) stress is an important pathway leading to cellular apoptosis. To investigate the role of ER stress in the pathogenesis of stress gastric ulcer, we studied the alteration in the expression of ER stress markers GRP78 (glucose-regulated protein 78) and caspase-12 (an ER stress-specific proapoptotic molecule) and their relations with gastric mucosal apoptosis during development of stress gastric lesions in the water-immersion and restraint stress (WRS) model in rats. Rats developed severe gastric lesions after 6 h of WRS. Typical apoptosis was observed at the edge cells of WRS induced gastric lesions. Western blot analysis showed that GRP78 and activated caspase-12 were over-expressed in the gastric tissues of WRS rats. Immunohistochemical analysis demonstrated that increased GRP78 and caspase-12 were distributed only under the lesions. In addition, dithiothreitol and tunicamycin (ER stress inducers), which increased the expression of GRP78 and activated caspase-12, caused gastric mucosal injury and mucosal cell apoptosis in vitro. These findings suggest that ER stress might be involved in the development of stress gastric ulcer through an apoptotic mechanism.
Life Sciences 11/2006; 79(19):1856-64. · 2.53 Impact Factor
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Yue-Xia Jia,
Jing-Hui Yang,
Chun-Shui Pan,
Bin Geng,
Jing Zhang,
Yang Xiao,
Jing Zhao,
Helen Gerns,
Jun Yang,
Jaw-Kang Chang,
Jin Kun Wen,
Chao-Shu Tang, Yong-Fen Qi
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ABSTRACT: Intermedin is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family peptide, which has vasodilatory and hypotensive actions identical to those of adrenomedullin and CGRP. Cleavage sites located between 2 basic amino acids at Arg93-Arg94 result in the production of prepro-intermedin95-147, namely intermedin1-53. The bioactive action of intermedin1-53 and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin1-53 on acute myocardial injury induced by isoproterenol. Myocardial ischemia injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of intermedin1-53 was observed. Plasma lactate dehydrogenase activity, myocardial and plasma malondialdehyde content were higher in the isoproterenol group than that in controls. Isoproterenol-treated rats showed lower maximal rate of increase and decrease of left-ventricle pressure development (+/-left-ventricle dp/dtmax) and higher left-ventricle end-diastolic pressure (all P<0.01), which suggested severe heart failure and myocardial injury. Semi-quantitative RT-PCR analysis showed that the gene expression of calcitonin receptor-like receptor and receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 in ventricular myocardia were up-regulated by 79% (P<0.01), 48% (P<0.01), 31% (P<0.05) and 130% (P<0.01), respectively, compared with controls. In myocardial sarcolemmal membranes, the maximum binding capacity for [125I]-intermedin1-53 was increased by 118% (P<0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin1-53 (5 nmol/kg/day, 2 days) showed 21% (P<0.05) higher myocardial cAMP content, 18% and 31% higher+left-ventricle dp/dtmax and -left-ventricle dp/dtmax respectively, 288% lower left-ventricle end-diastolic pressure (all P<0.01), and attenuated myocardial lactate dehydrogenase leakage and malondialdehyde formation (all P<0.01). Treatment with high dosage intermedin1-53 (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin1-53. These results suggest that the intermedin receptor system was up-regulated in isoproterenol-induced myocardial ischemic injury and intermedin1-53 might play a pivotal cardioprotective role in such injury.
European Journal of Pharmacology 11/2006; 549(1-3):117-23. · 2.52 Impact Factor
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ABSTRACT: To investigate the changes of pulmonary IMD and its receptor system-calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs) mRNA in acute lung injury(ALI) induced by oleic acid of rats.
Contents of IMD in plasma and lung homogenates were measured by radioimmunoassay(RIA). The lung mRNA of IMD, CL and RAMPs was determined by semi-quantitative RT-PCR.
Compared with control group, in ALI group, the contents of IMD1-53 in plasma and lung homogenates were decreased by 20.8% and 74.5% (all P < 0.05) , respectively. Furthermore , it was found that the levels of IMD, CL, RAMP1 and RAMP2 mRNA in lung were decreased by 30%, 38%, 26% and 37.9% (all P < 0. 05) , respectively. The levels of CL , RAMP1 or RAMP2 mRNA were positively correlated with down-regulations of IMD mRNA in ALI. However, compared with control group, the maximum binding capacity of IMD1-53 to plasma membranes was significantly increased in ALI group, and the affinity of IMD1-53 for its receptor almost had no change.
The amount of IMD 1-53 is down-regulated and IMD receptor system also down-regulated in Oliec acid induced ALI of rats. These changes suggest that IMD and its receptor system probably are involved in the development of ALI.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 10/2006; 38(5):496-500.
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ABSTRACT: Because apelin may play an important regulatory role in human cardiac dysfunction, we investigated alterations in cardiovascular content of apelin and its receptor, APJ, during hypertension and the effect of exercise training on the cardiovascular apelin/APJ system in hypertensive animals. Spontaneously hypertensive rats (SHRs) underwent swimming training consisting of 54 swimming sessions of 60 min each (6 days/week for 9 weeks). Systolic blood pressure (SBP) was verified weekly by tail-cuff plethysmography. Apelin levels in plasma and cardiovascular tissues were determined by radioimmunoassay. The level of apelin/APJ mRNA was determined by RT-PCR. SHRs showed severe hypertension and pathological cardiomegaly. The level of apelin immunoreactivity (apelin-ir) in plasma and ventricular and aortic tissues was lower, by 40%, 40% and 42% (all P<0.01), respectively, in SHRs than in control Wistar-Kyoto rats, and the mRNA level of apelin and APJ in myocardium and aorta was markedly decreased. Compared with sedentary SHRs, swimming-trained SHRs showed decreased SBP and elevated mRNA expression of apelin and APJ in cardiovascular tissues and elevated apelin-ir level in plasma, myocardium and aorta (all P<0.01). SBP and level of apelin-ir in plasma and cardiovascular tissues were negatively correlated. Long-term swimming training relieved the pathogenesis of hypertension and reversed the downregulation of the cardiovascular apelin/APJ system induced by hypertension, which suggests that the improving effect of exercise training on hypertension could be mediated by upregulating the cardiovascular apelin/APJ system.
Life Sciences 08/2006; 79(12):1153-9. · 2.53 Impact Factor
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ABSTRACT: To determine the cardioprotective action of ghrelin and des-octanoyl ghrelin in rats with isoproterenol-induced myocardial injury.
Rats were subcutaneously injected with isoproterenol (ISO; 20, 10, and 5 mg/kg) on d 1, 2 and 3, respectively, and then 3 mg/kg for the next 7 d with or without ghrelin or des-octanoyl-ghrelin (100 microg/kg, twice daily). Plasma ghrelin and growth hormone levels were assayed using radioimmunoassay methods. Growth hormone secretagogue receptor (GHSR) and ghrelin mRNA were determined using RT-PCR. The maximal binding capacity and the affinity for [3H]ghrelin were determined by receptor binding assays.
Compared with controls, ISO-treated rats showed severe myocardial injury, cardiomegaly, infarction-like necrosis and massive fibrosis with increases in irradiated-ghrelin (ir-ghrelin) content in plasma by 67% and myocardia by 66% and in the mRNA level in the myocardia by 93% (P<0.01). ISO-treated rats had 95% (P<0.01) higher GHSR mRNA levels in the myocardia. The maximal binding capacity of [3H]ghrelin for myocardial sarcolemma was higher in ISO-treated rats than in controls. Ghrelin administration improved cardiac function and ameliorated cardiomegaly and attenuated myocardial lipid peroxidation injury and relieved cardiac fibrosis as compared with ISO treatment alone. Administration of des-octanoyl ghrelin effectively antagonized ISO-induced myocardial injury and improved all parameters measured. However, the therapeutic effect of des-octanoyl ghrelin was significantly weaker than that of ghrelin. The plasma growth hormone level increased markedly, by 1.5-fold (P<0.01), with ghrelin administration as compared with that in controls, but was unaltered in des-octanoyl ghrelin group.
Myocardial ghrelin and GHSR were up-regulated during ISO-induced myocardial injury. The protective effect of ghrelin against ISO-induced cardiac function injury and fibrosis was more potent than that of des-octanoyl ghrelin, which suggests that ghrelin could be an endogenous cardioprotective factor in ischemic heart disease, and that its effects include growth hormone-dependent and -independent pathways.
Acta Pharmacologica Sinica 06/2006; 27(5):527-35. · 1.95 Impact Factor
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ABSTRACT: To explore the change of endogenous hydrogen sulfide and the effect of exogenously applied H(2)S on Bleomycin-induced pulmonary fibrosis in rats.
(1) Forty-eight male Wistar rats were randomly divided into control group, fibrosis group, fibrosis+NaHS-low group (1.4 micromol/kg, bid intraperitoneally) and fibrosis+NaHS-high group (7.0 micromol/kg, bid intraperitoneally). Pulmonary fibrosis was induced by intratracheal instillation of bleomycin. The control group and pulmonary fibrosis group were injected with the same volume of normal saline. Pulmonary pathology changes were observed, the plasma H(2)S concentration,the activity of CSE in lung tissue and the contents of MDA, hydroxyproline were detected on the 7th and 28th days respectively after bleomycin administration. CSE mRNA was also measured using quantitative RT-PCR. (2) Isolated lung tissues were exposed to Fe(2+)/H(2)O(2) without or with different concentrations of NaHS (10(-5), 5 x 10(-5), 10(-4), 10(-3) mmol/L) at 37 degree Celsius for 10 minutes, and the MDA content was assayed by biochemical method.
(1) Compared with rats in control group, the concentration of plasma H(2)S and the activity of CSE in lung tissues in fibrosis group decreased on day 7 (all P<0.01); On the 28th day, the level of plasma H(2)S increased clearly (P<0.01) and the activity of CSE was ascendant without significant difference compared with that of control group. Relative CSE mRNA amounts in lung tissues increased 34%, 144%, respectively (all P<0.01) in rats of fibrosis group compared with those of control group. The contents of MDA and hydroxyproline increased significantly in fibrosis group compared with those of control group on days 7, 28 (all P<0.01). In NaHS-low group and NaHS-high group, the contents of MDA and hydroxyproline decreased markedly (all P<0.01). (2) The contents of MDA in incubation of lung tissues at different concentrations of NaHS were all decreased as compared with those in incubation with Fe(2+)/H(2)O(2) alone (all P<0.01). When NaHS was at 10(-4) mol/L, the MDA content reversed to the lowest value, which had the highest value at 10(-3) mol/L of NaHS.
Endogenous CSE/H(2)S pathway was involved in the pathogenesis of rat pulmonary fibrosis. Exogenously applied H(2)S could attenuate the process of pulmonary fibrosis possibly because of reducing oxidative stress.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 05/2006; 38(2):140-5.
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ABSTRACT: Intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family, has similar or more potent vasodilatory and hypotensive actions than adrenomedullin (ADM) and CGRP. The present study was designed to observe the effects of synthetic rat IMD1-53 on L-arginine (L-Arg) cellular transport, nitric oxide synthase (NOS) activity, and nitric oxide (NO) production in the isolated rat aortic ring to illustrate its direct effect on the L-Arg/NOS/NO pathway in vasculature. IMD1-53 significantly increased NO production and cNOS activity in rat aortas and was more potent than equivalent ADM. But the peptides of both IMD and ADM had no effect on inducible NOS expression and activity. Otherwise, IMD1-53 induced a concentration-dependent increase in [3H]L-Arg transport and its effect was more potent than that of an equivalent concentration of ADM. Semiquantitative RT-PCR revealed that IMD1-53 significantly increased cationic amino acid transport (CAT)-1 and CAT-2B mRNA expression, and its effect was similar to that of ADM. All these results suggest that IMD1-53 might regulate vessel function homeostasis via upregulating the L-Arg/NOS/NO pathway.
Biochemical and Biophysical Research Communications 04/2006; 341(2):567-72. · 2.48 Impact Factor
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ABSTRACT: To investigate the role of the endogenous cystathionine gamma-synthase (CSE)/hydrogen sulfide (H2S) pathway in vascular calcification in vivo.
A rat vascular calcification model was established by administration of vitamin D3 plus nicotine (VDN). The amount of CSE and osteopontin (OPN) mRNA was determined by using semi-quantitative reverse-transcription polymerase chain reaction. The calcium content, 45Ca2+ accumulation and alkaline phosphatase (ALP) activity were measured. H2S production and CSE activity were measured.
von Kossa staining produced strong positive black/brown staining in areas among the elastic fibers of the medial layer in the calcified aorta. The calcium content, 45Ca2+ accumulation and ALP activity in calcified arteries increased by 6.77-, 1.42-, and 1.87-fold, respectively, compared with controls. The expression of the OPN gene was upregulated (P<0.01). Expression of the CSE gene was downregulated. However, calcium content, 45Ca2+ uptake and ALP activity in the VDN plus NaHS group was lower than that in the VDN group. The content of calcium and 45Ca2+ accumulation and activity of ALP in the aorta were 34.8%, 40.75% and 63.5% lower in the low-dosage NaHS group than in the VDN group, respectively (P<0.01), and the calcium content and deposition of 45Ca2+ and activity of ALP was 83.9%, 37.8 % and 46.2% lower in the aorta in the high-dosage NaHS group than in the VDN group, respectively (P<0.01). The expression of the OPN gene was downregulated.
The production of H2S, and CSE activity were decreased and CSE gene expression was downregulated in rats with vascular calcification. H2S can ameliorate vascular calcification, suggesting that the H2S/CSE pathway plays a regulatory role in the pathogenesis of vascular calcification.
Acta Pharmacologica Sinica 03/2006; 27(3):299-306. · 1.95 Impact Factor
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ABSTRACT: Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family identified from human and other vertebrate tissues. Preprointermedin can generate various mature peptides by proteolytic cleavage. Amino acid sequence analysis showed cleavage sites located between two basic amino acids at Arg93-Arg94 resulting in the production of prepro-IMD(95-147), namely IMD(1-53). The present study was designed to determine the effects of the IMD(1-53) fragment in the central nervous system (CNS) on mean arterial blood pressure and heart rate in normal rats and its possible mechanism. Rats were given doses of adrenomedullin (ADM) or IMD(1-53), intracerebroventricularly or intravenously, respectively, with continuous blood pressure and heart rate monitoring for 45min. Analysis with CGRP receptor antagonist CGRP(8-37), ADM receptor antagonist ADM(22-52), and anti-prepro-IMD antibody showed that 0.1, 0.5, and 1.0 nmol/kg IMD(1-53), caused a dose-dependent elevation in blood pressure, which was more prominent than the increase with equivalent IMD(1-47) or ADM. As well, IMD(1-53) caused a persistent increase in heart rate. The CNS action of IMD(1-53) could be blocked by ADM(22-52), CGRP(8-37), or prepro-IMD antibody. In contrast to the CNS action, intravenous administration of IMD(1-53) induced a depressor effect. These results suggest that IMD(1-53) is an important regulatory factor in mean arterial blood pressure and heart rate through its central and peripheral bioaction.
Peptides 02/2006; 27(1):74-9. · 2.43 Impact Factor
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ABSTRACT: We aimed to explore the change in level of apelin and its receptor APJ during myocardial injury and the therapeutic effects of apelin in myocardial injury. Rat myocardial injury was induced by subcutaneous injection of a high dose of isoproterenol (ISO); apelin and APJ mRNA levels were determined by RT-PCR; APJ protein was determined by Western blot; EIA and RIA were used to measure the apelin content and receptor binding, respectively. Plasma lactate dehydrogenase (LDH) activity and myocardial and plasma malondialdehyde (MDA) contents were higher in ISO-treated hearts than that in controls. ISO-treated rats showed lower +/-LV dp/dt(max) values and higher LVEDP value (all P<0.01), which suggested severe heart failure. As well, the apelin content in plasma, atrial and ventricular myocardium was decreased by 27%, 30% and 25% (P<0.01), respectively. The mRNA levels of apelin and APJ in myocardia were also markedly reduced; but the APJ protein level in myocardia was increased. However, administration of apelin significantly ameliorated myocardial injury and ISO-induced heart failure. Compared with the ISO-alone group, the group given low-dosage apelin (5 nmol/kg/day) had 39% and 66% higher +LV dp/dt(max) and -LV dp/dt(max) values, and 40.7% lower LVEDP value (P<0.01), and the leakage of myocardial LDH and increased MDA content were attenuated (all P<0.01). Interestingly, bolus injections of apelin (10 nmol/kg/day) resulted in potent inotropic effects in ISO-treated rats. ISO-induced myocardial injury resulted in hypoexpression of apelin and its receptor APJ, and the administration of exogenous apelin ameliorated heart failure and myocardial injury. Apelin could have a cardioprotective effect, and the apelin-APJ system may be a new therapeutic target in myocardial injury and heart failure.
Regulatory Peptides 02/2006; 133(1-3):147-54. · 2.11 Impact Factor
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ABSTRACT: To investigate simple, economical, stable and efficient methods of in vivo and in vitro cardiovascular calcification models in rats.
Rats received Vitamin D(3) (300 000 U/kg, i.m.) and nicotine (25 mg/kg, 5 mL/kg in peanut oil, p.o.) at 8 a.m. on day 1. The nicotine administration was repeated at 6 p.m. Rats in control group received an injection of normal saline (i.m.) and two gavages of medium oil. All of the rats were then allowed to recover for 4 weeks and given standard rodent chow. After the measurement of cardiac function the rats were sacrificed and the calcium content in myocardium and aorta were measured. Von Kossa staining was used to detect the deposit of calcium in myocardium and aorta. Cultured smooth muscle cell(SMC) derived from rat thoracic aorta was treated with beta-glycerophosphate for 14 days, then the calcium content and deposit were measured.
Compared with control group, the rats with cardiovascular calcification showed a lower body weight, The ratio of left heart to body weight, myocardial and aortic calcium content were increased respectively. Alkaline phosphatases activity in calcified myocardium and aorta were increased respectively, compared with the control. The values of animal mean blood pressure (MBP), heart rate (HR) and left ventricle end-distolic pressure (LVEDP) showed no significant alteration (P>0.05) in vitamin D3 plus nicotine (VDN) group. The values of +LV dp/dt(max) and -LV dp/dtmax were significantly lower in VDN group (P<0.05 and P<0.01, respectively). In calcified vascular smooth muscle cells(VSMCs), von Kossa staining for calcification, showed positive staining as black/brown areas within the main, large, nodular structures as shown in extracellular matrix and cytoplasma. The content of calcium, (45)Ca(2+) uptake and alkaline phosphatase (ALP) activity in calcified VSMCs were increased (all P<0.01), respectively, compared with that of the control.
These methods can be used to produce calcification models in vivo and in vitro, which save money and time and are easy to manipulate.
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 01/2006; 37(6):656-8.
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ABSTRACT: In this work, we aimed to observe the changes in adrenomedullin (ADM) and its receptor-calcitonin receptor-like receptor (CL), receptor activity-modifying protein (RAMP) 1, RAMP2 and RAMP3-in cardiac ventricles and aortas of hypertensive rats, and the responsiveness of injured cardiovascular tissue to ADM, then to illustrate the protective mechanism of ADM on the cardiovascular system. Male SD rats were subjected to treatment with chronic N(G)-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. The ADM contents and cAMP production in myocardia and aortas were measured by RIA. The mRNA levels of ADM, CL, and RAMP1-3 were determined by RT-PCR. L-NNA induced severe hypertension and cardiomegaly. The ir-ADM content in plasma, ventricles and aortas in L-NNA-treated animals increased by 80%, 72% and 57% (all p<0.01), respectively. Furthermore, mRNA levels of ADM, CL, RAMP2 and RAMP3 were elevated by 91%, 33%, 50% and 72.5% (all p<0.01), respectively, in ventricles and by 95%, 177%, 74.7% and 85% (all p<0.01), respectively, in aortas. mRNA level of RAMP1 was elevated by 129% (p<0.01) in aortas but no significant difference in ventricles. The elevated mRNA levels of RAMP2 and RAMP3 were positively correlated with that of ADM in hypertrophic ventricles (r=0.633 and 0.828, p<0.01, respectively) and the elevated mRNA levels of CL, RAMP2 and RAMP3 were positively correlated with that of ADM in aortas (r=0.941, 0.943 and 0.736, all p<0.01, respectively). The response of ventricular myocardia and aortas to ADM administration potentiated, and the production of cAMP was increased by 41% and 68% (both p<0.01), respectively. ADM-stimulated cAMP generation in ventricular myocardia and aortas was blocked by administration of both ADM22-52, the specific antagonist of ADM receptor, and CGRP8-37, the antagonist of the CGRP1 receptor. The results showed an increased in cardiovascular ADM generation and an up-regulation of the gene expression of ADM and its receptor-CL, RAMP1-3 during hypertension, augmented responsiveness of ventricular myocardia and aortas of hypertensive rats to ADM, suggesting that these receptors may play a role in the cardiovascular adaptation in response to sub-chronic NO-inhibition.
Life Sciences 12/2005; 78(4):398-405. · 2.53 Impact Factor
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ABSTRACT: The omnipresent 6-kDa polypeptide relaxin (RLX) is emerging as a multifunctional endocrine and paracrine factor in a broad range of target tissues including cardiovascular tissues. To explore the pathophysiological roles of RLX in ischemic cardiovascular diseases, we studied the changes in RLX mRNA level in the myocardium and the effect of RLX supplements in rats with isoproterenol (ISO)-induced myocardial injury. In ISO-treated rats, RLX levels in myocardia and plasma increased 3.7- and 6.9-fold, respectively (P<0.01), the mRNA level increased significantly in myocardia compared with controls. Co-administration of RLX (0.2 and 2.0 microg/kg/d) and ISO increased left-ventricular pressure development and decreased left ventricular end-diastolic pressure (LVDEP) (all P<0.01). Malondialdehyde content in myocardia and lactate dehydrogenase and creatine phosphokinase activities in plasma in RLX-treated rats decreased markedly compared with that in ISO-treated alone rats (P<0.01 or P<0.05). In the high-dose RLX group, fibroblastic hyperplasia was relieved in myocardia, hydroxyproline level was lower, by 33% (P<0.05), and endothelin content in plasma was lower, by 31% (P<0.01) than in the ISO-alone group. Compared with control group, any indexes in sham rats treated with high-dose RLX were unaltered (all P>0.05). These results showed an up-regulation of myocardial RLX during ISO-induced myocardial ischemia injury and the protective effect of RLX on ISO-induced cardiac inhibition and fibrosis, which suggests that RLX could be an endogenous cardioprotective factor in ischemic heart diseases.
Peptides 09/2005; 26(9):1632-9. · 2.43 Impact Factor
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ABSTRACT: Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP). The present study aimed to investigate the cardiovascular effects of IMDs (IMD1-47 and IMD8-47) in rats. Intravenous administration of 150 nmol IMDs continuously decreased mean arterial pressure and inhibited cardiac function. Administration with IMDs decreased left ventricular end-systolic pressure (LVESP) and maximal rate of left-ventricle pressure development (+/-LVdp/dt(max)), and elevated left ventricular end-diastolic pressure (LVEDP). Changes with IMD1-47 treatment were close to that with IMD8-47 (P>0.05). Perfusion of isolated rat hearts in vitro with IMD8-47 (10(-8) and 10(-7)mol/L) resulted in lower LVSP, by 40 and 56% (P<0.01); lower +LVdp/dt (max), by 33 and 47% (P<0.01); lower -LVdp/dt(max), by 25 and 39% (P<0.01); but higher coronary perfusion flow (CPF), by 25% (P<0.05) and 33% (P<0.01), respectively, than controls. However, both IMD8-47 and IMD1-47 (from 10(-13) to 10(-7)mol/L) relaxed preconstricted aortic rings in a dose-dependent manner. Intravenous administration of IMD1-47 and IMD8-47 (10(-7)mol/L) in vivo increased the cyclic adenosine monophosphate (cAMP) content by 68 and 150% (both P<0.01), respectively, in myocardia and 320 and 281% (both P<0.01), respectively, in aortas, compared with controls. Perfusion of isolated hearts with IMD1-47 and IMD8-47 (10(-7)mol/L) enhanced cAMP content by 24% (P<0.05) and 73% (P<0.01), respectively, compared with controls. IMDs inhibited 3H-Leucine incorporation in cardiomyocytes in a concentration-dependent manner. IMD1-47 and IMD8-47 (10(-7) and 10(-8)mol/L) decreased 3H-Leucine incorporation by 12-25% (P<0.01) and 14-18% (P<0.01), respectively. IMD mRNA was detected in cultured neonatal cardiomyocytes and isoproterenol-induced hypertrophic myocardia but not normal myocardia of adult rats. These results suggest that IMD might be a regulatory factor for cardiovascular function and myocardial hypertrophy as a cardiovascular active peptide.
Peptides 09/2005; 26(9):1640-6. · 2.43 Impact Factor
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Sheng li ke xue jin zhan [Progress in physiology] 08/2005; 36(3):223-6.
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ABSTRACT: Adrenomedullin (ADM) is a potent vasodilatory peptide. It regulates blood pressure by increasing cyclic adenosine monophosphate (cAMP) and guanosine-3',5'-monophosphate (cGMP). We sought to investigate the effect of ADM on heme oxygenase-1 (HO-1) gene expression and cGMP formation in cultured rat vascular smooth muscle cells (VSMCs). ADM treatment, 10(-9) and 10(-8) mol/L, increased cGMP production, and it increased the intracellular cGMP content of platelets coincubated with VSMCs. It increased cGMP content by 158.8% and 273.5%, respectively; increased HO-1 activity by 49.5% and 87%, respectively; augmented HO-1 protein levels by 66% and 126%, respectively; upregulated the steady-state level of HO-1 mRNA by 73% and 159%, respectively, and increased HO-1 mRNA transcription synthesis by four- and seven-fold, respectively. These results suggest that ADM induces HO-1 gene expression and cGMP formation in rat VSMCs.
Peptides 08/2005; 26(7):1257-63. · 2.43 Impact Factor
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ABSTRACT: To illustrate the pathophysiological role of metallothionein (MT) in gastric ulcer induced by stress.
Wistar rats underwent water-immersion-restraint (WIR) stress, ZnSO(4) (an MT inducer) treatment, WIR+ZnSO(4) or WIR+MT, and the ulcer index (UI) was estimated in excised stomach and liver tissues. The mRNA level of gastric MT was determined by semi-quantitative RT-PCR. The MT content in gastric and hepatic tissues was determined by Cd/hemoglobin affinity assay. The lipid peroxidation products malondialdehyde (MDA) and conjugated dienes (CD) were estimated by use of thiobarbituric acid reactive species and ultraviolet spectrophotometry.
WIR stress induced severe gastric mucosal lesions in rats. Compared with control rats, stressed rats had increased lipid peroxide content in serum and stomach and liver tissues. MDA content was increased by 34%, 21% and 29% and CD level by 270%, 83% and 28%, respectively. MT content in the stomach and liver was increased by 0.74- and 1.8-fold, and the MT-mRNA level in the stomach was increased by 26%. Pretreatment with ZnSO(4) prevented gastric lesion development (the UI was 87% lower than that without pretreatment), and the MDA and CD content in serum and tissues was lower. The MT content in the liver was double in rats that were not pretreated, and the MT mRNA level in the stomach was 35% higher. MT administration 1 h before the WIR stress prevented gastric lesion development (the UI decreased by 47% compared with that in rats not pretreated), and the MDA and CD content in serum and tissues was significantly lower.
In WIR-stressed rats, the MT level was increased in serum and in stomach and liver tissues. Pre-administration of exogenous MT or pre-induction of endogenous MT can protect the gastric mucosa against stress-induced ulcers and inhibits the formation of stress-induced lipid peroxide. MT could have a gastroprotective effect and might be a new interventive and therapeutic target in stress-induced gastric ulcers.
World Journal of Gastroenterology 06/2005; 11(18):2739-43. · 2.47 Impact Factor
