OBJECTIVETo observe the effects of phlegm-dispelling and blood stasis-resolving traditional Chinese drugs on the cell cycle of cardiac myocytes and left ventricular reconstruction in hypertensive rats.

METHODSBilateral renal artery stenosis was conducted to induce hypertension in rats, which were randomly divided into hypertensive model group (n = 10), sham-operated group (n = 8), high-dose drug group (n = 11) and low-dose drug group (n = 11), with 8 normal untreated rats as the normal control group. The systolic blood pressure (SBP) was measured in the tail artery of the rats. Two months after the operation, the left ventricular mass (LVM) and LVM index (LVI) were calculated in all the rats. The cell cycle changes in the left ventricular cardiac myocytes were evaluated using flow cytometry.

RESULTSThe mean blood pressure and LVI of the hypertensive model group were significantly higher than those of the normal control (P < 0.05) and sham-operated group (P < 0.01). After treatment with preparation of the traditional Chinese drugs at either high or low dose, the mean blood pressure and LVM of the rats showed obvious reduction, and LVI was decreased significantly compared with that of the model group (P < 0.05). Compared with the hypertensive model group which showed obviously decreased cell percentage in G0/G1 phase and increased S phase cells, the treatment at both doses significantly increased the cells in G0/G1 phase (P < 0.05) and decreased the S-phase cells (P < 0.05) to levels comparable to those in the normal control and sham-operated groups (P > 0.05). The percentage of G2/M-phase cells showed no significant difference between the groups (P > 0.05).

CONCLUSIONThe traditional Chinese drugs can significantly decrease blood pressure and LVI in hypertensive rats, and induce cell cycle arrest in G0/G1 phase to reverse left ventricular hypertrophy by regulating the cell cycle and inhibiting the division and proliferation of the cardiac myocytes.

Animals ; Cell Cycle ; drug effects ; Cells, Cultured ; Drugs, Chinese Herbal ; therapeutic use ; Hypertension ; complications ; drug therapy ; Hypertrophy, Left Ventricular ; drug therapy ; etiology ; pathology ; Male ; Myocytes, Cardiac ; pathology ; Phytotherapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Ventricular Remodeling ; drug effects

OBJECTIVETo investigate the different effects of an angiotensin II type 1 (AT(1)) receptor antagonist, losartan, and an angiotensin converting enzyme (ACE) inhibitor, fosinopril, on cardiomyocyte apoptosis, myocardial fibrosis, and angiotensin II (Ang II) in the left ventricle of spontaneously hypertensive rats (SHRs).

METHODSSHRs of 16-week-old were randomly divided into 3 groups: SHR-L (treated with losartan, 30 mg.kg(-1) x d(-1)), SHR-F (treated with fosinopril, 10 mg x kg(-1) x d(-1)), and SHR-C (treated with placebo). Each group consisted of 10 rats. Five rats, randomly selected from each group, were killed at the 8th and 16th week after treatment. Cardiomyocyte apoptosis, collagen volume fraction (CVF), perivascular collagen area (PVCA) and Ang II concentrations of plasma and myocardium were examined.

RESULTSCompared with the controls at the 8th and 16th week, systolic blood pressures were similarly decreased in both treatment groups. Left ventricular weight and left ventricular mass indexes were significantly lower in both treatment groups. However, the latter parameter at the 16th week was reduced to a less extent in the fosinopril group than that in the losartan group. Compared with the controls, cardiomycyte apoptotic index was significantly reduced at the 8th week only in the fosinopril group, and at the 16th week in both treatment groups. The index of the fosinopril group was lower than that of the losartan group at the latter endpoint examined. Compared with the controls, the left ventricular collagen volume fraction and perivascular collagen area at the 8th and 16th weeks were significantly reduced in the SHRs treated with either fosinopril or losartan. However, the collagen volume fraction at the latter endpoint in the fosinopril group was lower than that in the losartan group. Compared with the controls at endpoints, plasma and myocardium Ang II levels were significantly increased in the losartan group. However, plasma Ang II concentrations were not altered, and myocardium Ang II concentrations at the 8th and 16th weeks were significantly reduced in the fosinopril group.

CONCLUSIONSBoth losartan and fosinopril could effectively inhibit cardiomyocyte apoptosis and myocardial fibrosis and reverse heart hypertrophy. Fosinopril may be more effective in these cardioprotective effects, suggesting that the effects of both drugs are related to the inhibition of myocardium renin-angiotension-aldsterone system.

Angiotensin II ; analysis ; Animals ; Antihypertensive Agents ; therapeutic use ; Apoptosis ; drug effects ; Blood Pressure ; drug effects ; Fibrosis ; Fosinopril ; therapeutic use ; Hypertension ; complications ; drug therapy ; Hypertrophy, Left Ventricular ; drug therapy ; Losartan ; therapeutic use ; Myocardium ; chemistry ; pathology ; Rats ; Rats, Inbred SHR

The transmural heterogeneous changes of transient outward potassium currents (Ito) in rabbit hypertrophic cardiaomyocytes and the effects of long-term prophylactic treatment with volsartan were investigated. Rabbits were divided into hypertrophy group (left ventricular hypertrophy induced by partial ligation of abdominal aorta), vol-treated group (volsartan was administrated after the ligation), and control group (sham operated). Myocytes were isolated by a two-step enzymatical method. The sub-endocardial (Endo) and sub-epicardium (Epi) tissues were separated from midmyocardium (Mid) with a razor. Whole-cell patch-clamp technique was used to record potassium currents. The results showed that membrane capacitance was larger in hypertrophic cells than those in control and vol-treated cells (P<0.01 vs control cells, n=30). The densities of Ito in hypertrophic cells were reduced by sub-epicardium (Epi) (27.8 +/- 2.9) %, midmyocardium (Mid) (41.0+/-4.7) %, and sub-endocardium (Endo) (20.3 +/- 3.4) % compared with those in control cells. The decrease of Ito density was more pronounced in Mid than in Epi and Endo (P<0.01 vs Epi or Endo). There were no significant differences in Ito densities between vol-treated group and control group in three layers separately. In conclusion, volsartan can inhibit the transmural heterogeneous changes of Ito in left ventricular hypertrophic cardiomyocytes in rabbit.
Animals ; Antihypertensive Agents ; pharmacology ; Biological Transport, Active ; drug effects ; Female ; Hypertrophy, Left Ventricular ; drug therapy ; pathology ; Male ; Myocytes, Cardiac ; pathology ; Patch-Clamp Techniques ; Potassium Channels ; drug effects ; Rabbits ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

BACKGROUND: Increased aortic stiffness measured by pulse wave velocity (PWV) and left ventricular hypertrophy (LVH) are independent risk factors of cardiovascular events in hypertensive patients. We have conducted a prospective study to examine the effects of the angiotensin II receptor antagonist (irbesartan) on PWV and LVH in hypertensive patients. METHODS: A total of 52 untreated hypertensive patients (age:53.3+/-8.0 yrs) were enrolled; they had no evidence of associated cardiovascular complications. Blood pressure, heart rate, aortic PWV and left ventricular mass index (LVMI) by 2-D echocardiography were measured at baseline and after irbesartan treatment (150 mg or 300 mg/day) at 12 weeks and 24 weeks. RESULTS: Blood pressure was significantly decreased after 12 weeks and 24 weeks of treatment compared to baseline (SBP: 134.6+/-13.3 mmHg, 134.0+/-11.0 mmHg vs 163.7+/-13.8 mmHg p<0.001, DBP: 86.0+/-10 mmHg, 83.07 mmHg vs 102.4+/-9.6 mmHg p<0.001, respectively) without significant change in heart rate. LVMI decreased at 12 weeks and at 24 weeks after treatment compared to baseline (from 145.5+/-35.1 g/m2 at baseline to 137.5+/-35.4 g/m2 at 12 weeks, p=0.017 and 135.3+/-35.4 g/m2 at 24 weeks, p=0.008). Aortic PWV was decreased after irbesartan treatment at 12 weeks (from 9.6+/-2.8 m/sec to 8.7+/-3.1 m/sec at 12 weeks, p=0.064) and at 24 weeks (from 9.6+/-2.9 m/sec to 7.7+/-2.1 m/sec at 24 weeks, p=0.007). CONCLUSIONS: Long-term treatment with irbesartan may reduce arterial stiffness and regression of LVH in hypertensive patients. The pleiotropic effects of irbesartan, further decreasing PWV without change of BP between 12 and 24 weeks of treatment, may have favorable vascular effects on arterial stiffness and LVH.
Tetrazoles/*therapeutic use ; Prospective Studies ; Middle Aged ; Male ; Hypertrophy, Left Ventricular/*prevention & control ; Hypertension/*drug therapy/pathology/physiopathology ; Humans ; Female ; Biphenyl Compounds/*therapeutic use ; Aorta/*drug effects/physiopathology ; Angiotensin II Type 1 Receptor Blockers/*therapeutic use ; Aged ; Adult

Parathyroid hormone (PTH) treatment was previously shown to improve cardiac function after myocardial infarction by enhancing neovascularization and cell survival. In this study, pressure overload-induced left ventricular hypertrophy (LVH) was induced in mice by transverse aortic banding (TAB) for 2 weeks. We subsequently evaluated the effects of a 2-week treatment with PTH or saline on compensated LVH. After another 4 weeks, the hearts of the mice were analyzed by echocardiography, histology, and molecular biology. Echocardiography showed that hearts of the PTH-treated mice have more severe failing phenotypes than the saline-treated mice following TAB with a greater reduction in fractional shortening and left ventricular posterior wall thickness and with a greater increase in left ventricular internal dimension. Increases in the heart weight to body weight ratio and lung weight to body weight ratio following TAB were significantly exacerbated in PTH-treated mice compared to saline-treated mice. Molecular markers for heart failure, fibrosis, and angiogenesis were also altered in accordance with more severe heart failure in the PTH-treated mice compared to the saline-treated mice following TAB. In addition, the PTH-treated hearts were manifested with increased fibrosis accompanied by an enhanced SMAD2 phosphorylation. These data suggest that the PTH treatment may accelerate the process of decompensation of LV, leading to heart failure.
Animals ; Blotting, Western ; Echocardiography ; Hypertrophy, Left Ventricular/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Parathyroid Hormone/pharmacology/*therapeutic use ; Phosphorylation/drug effects ; Random Allocation ; Reverse Transcriptase Polymerase Chain Reaction ; Smad2 Protein/metabolism

BACKGROUNDConnexin43 (Cx43) is the predominant gap junction protein in heart and is involved in the control of cell-to-cell communication to modulate the contractility and the electrical coupling of cardiac myocytes. Left ventricular (LV) hypertrophy is accompanied by changes of Cx43 expression. Recent studies have demonstrated that statins reduced cardiac hypertrophy. However, it is unknown whether statins can affect Cx43 expression in hypertrophied left ventricular myocardium. This study was designed to assess the effects of atorvastatin on LV hypertrophy and Cx43 expression in spontaneously hypertensive rats (SHR).

METHODSNine-week old SHRs were randomly divided into two groups. Some received atorvastatin at 30 mg/kg by oral gavage once daily for 8 weeks (SHR-A); others received vehicle. Age-matched Wistar-Kyoto rats (WKY) received atorvastatin or vehicle for 8 weeks were used as controls. At the end of the experiment, we investigated LV hypertrophy and the expression of Cx43 in LV myocardium in four groups. Cx43 expression was investigated by the methods of Western blotting, immunohistochemistry, and transmission electron microscope. LV hypertrophy was accessed by pathological analysis and plasma brain natriuretic peptide (BNP) level.

RESULTSLV hypertrophy was prominent in untreated SHR. In SHR, LV myocardium Cx43 level was upregulated, and the distribution of Cx43 was displaced from their usual locations to other sites at various distances away from the intercalated disks. After atorvastatin treatment, myocardium Cx43 level was reduced in SHR-A, and the distribution of Cx43 gap junction became much regular and confined to intercalated disk. Statins also prevented LV hypertrophy in SHR.

CONCLUSIONSThese results provide novel in vivo evidence for the key role of Cx43 gap junctions in LV hypertrophy and the possible mechanism in anti-hypertrophic effect of statins. Atorvastatin treatment may have beneficial effects on LV hypertrophy in spontaneously hypertensive rats.

Animals ; Anticholesteremic Agents ; pharmacology ; Atorvastatin Calcium ; Blood Pressure ; drug effects ; Blotting, Western ; Connexin 43 ; metabolism ; Heart ; drug effects ; physiopathology ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Hypertrophy, Left Ventricular ; blood ; drug therapy ; metabolism ; pathology ; Immunohistochemistry ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Male ; Microscopy, Electron, Transmission ; Myocardium ; metabolism ; pathology ; ultrastructure ; Natriuretic Peptide, Brain ; blood ; Pyrroles ; pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P<0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P<0.01). Compared with U, UH has lower HW/BW and LV/BW (P <0.05) and UE has normal HW/BW but lower LV/BW than U (P<0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal alpha-actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure- overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.
Actins/genetics/metabolism ; Anemia/*complications/drug therapy/metabolism ; Animals ; Atrial Natriuretic Factor/genetics/metabolism ; Erythropoietin/pharmacology/therapeutic use ; *Gene Expression ; Heart Ventricles/chemistry/drug effects/pathology ; Hydralazine/pharmacology/therapeutic use ; Hypertension/*complications/drug therapy/metabolism ; Hypertrophy, Left Ventricular/etiology/*genetics/metabolism ; Male ; Peptidyl-Dipeptidase A/genetics/metabolism ; RNA, Messenger/analysis/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta/genetics/metabolism ; Uremia/etiology/*genetics/metabolism

OBJECTIVETo assess the effect of angiotensin II type 1 (AT(1)) receptor antagonist losartan on myocardium connexin43 (Cx43) gap junction (GJ) expression in spontaneously hypertensive rats (SHRs) and investigate possible mechanisms.

METHODSSixteen 9-week-old male SHRs and 8 age-matched male Wistar-Kyoto (WKY) rats were included in this study. SHRs were randomly divided into two groups to receive losartan at 30 mg/(kg x d) by oral gavage once daily for 8 weeks (SHR-L) or vehicle (0.9% saline) to act as controls (SHR-V); WKY rats receiving vehicle for 8 weeks served as normotensive controls. At the end of the experiment, rats were sacrificed and the hearts were removed. Expressions of Cx43 and nuclear factor-kappaB p65 (NF-kappaB p65) proteins in all three groups were observed and further investigations on the effect of angiotensin II type 1 receptor antagonist losartan (30 mg/(kg x d), 8 weeks) on Cx43 expression were conducted with Western blot and immunohistochemistry. NF-kappaB p65 protein in nuclear extracts was determined by Western blot.

RESULTSLeft ventricular (LV) hypertrophy was prominent in SHRs, Cx43 and NF-kappaB p65 protein expressions were obviously upregulated and Cx43 distribution was dispersed over the cell surface. Treatment with losarton reduced the over-expressions of Cx43 and NF-kappaB p65 in LV myocardium. The distribution of Cx43 gap junction also became much regular and confined to intercalated disk after losartan treatment.

CONCLUSIONCx43 level was upregulated in LV myocardium of SHR during early stage of hypertrophy. Angiotensin II type 1 receptor antagonist losartan prevented Cx43 gap junction remodeling in hypertrophied left ventricles, possibly through the NF-kappaB pathway.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Animals ; Blood Pressure ; drug effects ; Blotting, Western ; Connexin 43 ; metabolism ; Hypertension ; drug therapy ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; drug therapy ; metabolism ; pathology ; Losartan ; pharmacology ; Male ; Myocardium ; metabolism ; Natriuretic Peptide, Brain ; blood ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Transcription Factor RelA ; metabolism

OBJECTIVETo investigate the effects and mechanisms of Shexiang Baoxin Pill (SBP) on myocardial fibrosis in spontaneous hypertensive rats (SHR).

METHODSSHR of 12 weeks old were divided into the SBP group, the control group (treated with benazepril) and the model control group. The effects on such indexes as systolic blood pressure (SBP), left ventricular mass (LVM), left ventricular mass index (LVMI), content of myocardial collagen (MC) in left ventricle, extracellular matrix fibronectin (FN), laminin (LN), cardiac fibroblast (cFb) and transforming growth factor-beta1 (TGF-beta1) were determined after 12 weeks of treatment.

RESULTSSBP had no marked pressure depressive effect, but had the effect similar to that of benazepril in reducing the level of LVM, LVMI and content of MC (P < 0.05), as well as the content of LN, FN in myocardium, cFb count and TGF-beta1 expression (P < 0.05).

CONCLUSIONSBP can prevent and treat myocardial fibrosis, whose action is independent of its hypotensive effect. The mechanism may be associated with such factors as the decrease of MC synthesis in left ventricle and the deposition of extracellular matrix.

Animals ; Collagen ; biosynthesis ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Fibrosis ; prevention & control ; Hypertension ; drug therapy ; pathology ; Hypertrophy, Left Ventricular ; prevention & control ; Male ; Myocardium ; pathology ; Phytotherapy ; Random Allocation ; Rats ; Rats, Inbred SHR ; Transforming Growth Factor beta ; biosynthesis ; genetics ; Transforming Growth Factor beta1