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Research has identified the vasoconstrictors endothelin-1 (ET-1) and urotensin-II (U-II) as having a role in the development of atherosclerotic cardiovascular disease. We aimed to observe alterations in plasma levels of both ET-1 and U-II in patients with coronary heart disease (CHD) undergoing percutaneous transluminal coronary angioplasty (PTCA) and stent therapy from November 2006 through May 2007. We examined plasma levels of ET-1 and U-II in 40 patients with CHD and 40 age-matched healthy subjects by radioimmunoassay (RIA). Chi-square test, Student’s t-test, and one-way analysis of variance were used for statistical analyses. Correlations between variables were tested by simple linear regression analysis. Coronary heart disease patients had significantly higher ET-1 and UII levels than healthy controls (20.05 ± 4.65 vs 8.16 ± 3.38 and 71.90 ± 11.61 vs 20.89 ± 7.00 pg/ml, respectively, all P < 0.01). Importantly, plasma levels of U-II and ET-1 were correlated in patients with CHD ( r = 0.64, P = 0.01). On day 1 after PTCA and stent therapy, plasma levels of ET-1 and U-II were significantly higher, by 99% and 25%, respectively, than those before therapy (all P < 0.01). On day 3 after therapy, ET-1 levels were higher by 25% ( P < 0.01) than before therapy, and U-II levels decreased rapidly and were close to baseline levels ( P > 0.05). On day 7 after therapy, CHD patients had significantly lower ET-1 and U-II levels than before therapy (all P < 0.01). Since ET-1 and U-II levels may be increased in plasma of patients with CHD, their activation might have clinical significance in terms of early intervention in patients with CHD, especially after PTCA and stent therapy. [ABSTRACT FROM AUTHOR]

Aim: To study whether urotensin II (UII), a potent vasoconstrictive peptide, is involved in the development of cardiac hypertrophy and fibrogenesis of rats induced by isoproterenol (ISO). Methods: Thirty male Wistar rats were randomly divided into 3 groups. Group 1 was the healthy control group, group 2 was the ISO group, and group 3 was the ISO+UII group. In groups 2 and 3, ISO (5 mg·kg−1·d−1) was given (sc) once daily for 7 d. Group 3 was also given UII in the first day [3 nmol/kg (5 ug/kg), iv], followed by sc (1.5 ug/kg) twice daily. Group 1 received 0.9% saline. UII receptor (UT) mRNA expression was determined by RT-PCR. The contents of UII and angiotensin II (Ang II) were determined by radioimmunoassay. In vitro, the effects of UII on DNA/collagen synthesis of cardiac fibroblasts were determined by [3H]thymidine/[3H]proline incorporation. Results: The ratio of heart weight/body weight, plasma lactate dehydrogenase activity, myocardial malondialdehyde and hydroxyproline concentration increased significantly in the ISO group, as well as UT mRNA expression, plasma and cardiac UII and ventricular Ang II, compared with the control group (P<0.01). ISO induced significant myocardial fibrogenesis. Moreover, UII+ISO co-treatment significantly increased the changes of biochemical markers of injury and the degree of cardiac hypertrophy and fibrosis. In vitro, 5×10−9-5×10−7mol/L UII stimulated [3H]thymidine/[3H] proline incorporation into cardiac fibroblasts in a dose-dependent manner (P<0.01). Conclusion: These results suggest that UII was involved in the development of cardiac fibrosis and hypertrophy by synergistic effects with ISO. [ABSTRACT FROM AUTHOR]

Adrenomedullin (AM) is a multifunctional regulatory peptide, and endogenous AM is an important factor in regulating cardiovascular and renal homeostasis as a potent cardio–reno–protective factor. To illustrate the protective mechanism of adrenomedullin (AM) on the cardiovascular system by observing (1) the changes in mRNA and protein levels of AM and its receptor—calcitonin receptor–like receptor (CL) and receptor activity–modifying proteins (RAMPs)—in myocardia and aortas of spontaneously hypertensive rats (SHRs) and (2) the response of cardiovascular tissue to AM. The AM content and cyclic adenosine monophosphate (cAMP) production in myocardia and aortas were measured in SHRs and Wistar Kyoto (WKY) rats (11–week-old) by radioimmunoassay (RIA). The mRNA levels of brain natriuretic peptide (BNP), AM, CL, RAMP1, –2, –3 were determined by semi–quantitative RTPCR. Protein levels of CL, RAMP1, –2, –3 were assayed by Western blotting. SHRs had severe hypertension, and the tail–blood pressure was 76.7% higher, the ratio of heart weight to body weight (heart coefficient) 45.5% higher, and the BNP gene expression 4.5–fold higher than that of WKY rats (all p < 0.01). The AM–ir content in plasma, myocardia and aortas of SHRs increased by 42.5%, 68.3% and 80.4%, respectively (all p < 0.01) compared with WKY rats. Furthermore, the mRNA levels of AM, CL, RAMP1, RAMP2 and RAMP3 were elevated by 46% ( p < 0.01), 62% ( p < 0.05), 51.2% ( p < 0.01), 41% ( p < 0.01) and 54% ( p < 0.01), respectively, in myocardia and by 72%, 87%, 155%, 53% and 74% (all p < 0.01), respectively, in aortas. The elevated mRNA level of CL, RAMP1 RAMP2 and RAMP3 correlated positively with that of AM mRNA in hypertrophic myocardia (r= 0.943, 0.621, 0.688 and 0.633, respectively, all p < 0.01) and aortas (r = 0.762, 0.892, 0.828 and 0.736, respectively, all p < 0.01). The protein levels of CL, RAMP1, RAMP2 and RAMP3 in myocardia and aortas of SHRs were increased compared with that of WKY rats. The response to AM was potentiated in myocardia and aortas in SHRs, and the production of cAMP was increased by 47% and 65% (both p < 0.01), respectively. AM–stimulated cAMP generation in myocardia and aortas was blocked by both AM22–52, the specific antagonist of AM, and calcitonin gene–related peptide (CGRP)8–37, the antagonist of the CGRP1 receptor. In myocardia and aortas of SHRs, the gene expressions and protein levels of AM, CL, RAMP1, RAMP2 and RAMP3 were increased, and the response to AM was potentiated. AM–stimulated cAMP generation in myocardia and aortas was blocked by both AM22–52 and CGRP8–37. The results suggest that the changes of AM and its receptors in cardiovascular tissue, and the increased response of cardiovascular tissue to AM might importantly impact the pathogenesis of hypertension. [ABSTRACT FROM AUTHOR]

Aim: To determine the cardioprotective action of ghrelin and des-octanoyl ghrelin in rats with isoproterenol-induced myocardial injury. Methods: 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 μg/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. Results: 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 the des-octanoyl ghrelin group. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of the endogenous cystathionine γ-synthase (CSE)/ hydrogen sulfide (H2S) pathway in vascular calcification in vivo. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

To investigate effects of taurine on ischemia/reperfusion (I/R)-induced compartment syndrome in rabbit hind limbs. Rabbits underwent femoral artery occlusion after ligation of branches from terminal aorta to femoral artery. After a 7-h ischemia, reperfusion was established with the use of heparinized polyethylene shunts. Rabbits received taurine (1 g/kg) or normal saline (control) by iv infusion 10 min before shunt placement. During reperfusion, anterior compartment pressure (ACP) was monitored continuously in the left lower extremity. Gastrocnemius muscle triphenyltetrazolium chloride (TTC) level, taurine content and myeloperoxidase activity were assayed. Oxidative stress was induced in the in vitro gastrocnemius muscle slices by free radical generating systems (FRGS), and the malondialdehyde content was measured in presence or absence of taurine. After 7 h of ischemia, none of the parameters that we measured were different from those before ischemia, except that TTC reduction decreased by 80%. In the control group, after 2 h of reperfusion, ACP increased 4.5-fold, and gastrocnemius muscle taurine content was reduced by 33%. In taurine-treated animals, at 2 h reperfusion, the mean arterial blood pressure and heart rate were increased, by 6% and 10%. ACP decreased by 39%, muscle edema decreased by 16%, TTC reduction increased by 150%, and lactate dehydrogenase decreased by 36% compared to control group. Plasma and muscle taurine content increased by 70% and 88%, respectively. In the taurine-treated group, at 2 h reperfusion, plasma malondialdehyde and conjugated diene content were decreased by 38% and 23%, respectively, and muscle malondialdehyde and conjugated diene content decreased by 22% and 30%, respectively compared to the control group. At 2 h reperfusion, myeloperoxidase activity was increased 3.5-fold in control animals. In the in vitro study, taurine decreased malondialdehyde content in muscle slices incubated with hypochlorous acid in a dose-dependent manner, but there was no change when incubated with hydrogen peroxide and xanthine oxidase. Treatment with taurine inhibited I/R-induced compartment syndrome by at least in part attenuating oxidative stress injury induced by I/R, suggesting clinical application of taurine might be a new strategy for the prevention and treatment of compartment syndrome. [ABSTRACT FROM AUTHOR]