Animals ; Chronic Disease ; Heart Failure ; drug therapy ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; adverse effects ; therapeutic use

Adult ; Altitude ; Female ; Heart ; physiology ; Humans ; Male ; Occupational Health ; Railroads ; Tibet

AIMIn order to look for new active compounds, the structure of (+)-praeruptorin A is modified.

METHODS(+)-Praeruptorin A was isolated from the root of Peucedanum praeruptorum, basic hydrolysis of (+)-praeruptorin A and acyled reactions of hydrolysis product of (+)-praeruptorin A were carried out.

RESULTSEighteen compounds were semi-synthesized from (+)-praeruptorin A.

CONCLUSIONFourteen compounds (5-18) among them are new compounds. Preliminary bioactivity assay indicated that the new compounds show calcium antagonist activity, but they are not as strong as (+)-praeruptorin A.

Animals ; Aorta, Thoracic ; drug effects ; Apiaceae ; chemistry ; Calcium Channel Blockers ; chemical synthesis ; isolation & purification ; pharmacology ; Coumarins ; chemical synthesis ; isolation & purification ; pharmacology ; Drugs, Chinese Herbal ; chemical synthesis ; isolation & purification ; pharmacology ; Molecular Structure ; Muscle Contraction ; drug effects ; Muscle, Smooth, Vascular ; drug effects ; Plants, Medicinal ; chemistry ; Rats

AIMTo evaluate the effects of beta3-adrenergic receptors (ARs) agonist (BRL-37344) on beating rate and cAMP levels and investigate the influence on the chronotropic action of beta3-ARs in cultured cardiomyocyte of rats.

METHODSCultured neonatal rat cardiomyocytes were divided randomly into eight groups, control group, ISO group, Nadolol + ISO group, BRL group, PIX + BRL group, L-NAME + BRL group, Nadolol + BRL group and Bupranolol + BRL group. Beating rate of culture neonatal rat cardiomyocytes was observed and cAMP measured by enzyme immunoassay kit. Expression levels of beta3-ARs mRNA in cardiomyocytes was evaluated by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTSISO, nonspecific beta-ARs agonist increased beating rate and intracellular cAMP production, antagonized by Nadolol, beta1, beta2-ARs antagonist. BRL37344 decreased beating rate and intracellular cAMP levels. FPTX, Gi protein inhibitor and Bupranolol, nonspecific beta-ARs antagonist totally blocked the effect and L-NAME, nitric oxide synthase (NOS) inhibitor partly blocked the effect, but Nadolol did not. There was the expression of beta3-AR mRNA in cardiomyocytes by RT-PCR.

CONCLUSIONSBeta3-ARs showed in cardiomyocytes and produced negative chronotropic effects. beta1, beta2-ARs antagonist did not affect it. It suggested beta3-ARs signal transduction was related with G1 protein. The negative inotropic effect of beta3-ARs stimulation was mediated by activation of the NOS pathway.

Adrenergic beta-Agonists ; pharmacology ; Animals ; Animals, Newborn ; Cells, Cultured ; Cyclic AMP ; metabolism ; Ethanolamines ; pharmacology ; Myocytes, Cardiac ; drug effects ; metabolism ; RNA, Messenger ; genetics ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta-3 ; metabolism

OBJECTIVETo evaluate the effects of different doses of N(G)-nitro-L-arginine methyl ester (L-NAME) on hemodynamics, cyclic guanosine monophosphate (cGMP) production and the level of beta-adrenergic receptors (beta-ARs) mRNA in a heart failure rat model after BRL-37344 (beta(3)-ARs agonist) injection. Meanwhile, to investigate the influence of beta(3)-ARs and L-NAME on signal transduction in failing heart.

METHODSThe rats were randomly divided into six groups, control group (group I), Iso (isoproterenol) group (group II), Iso + BRL group (group III), Iso + BRL + low dose of L-NAME group (5 mg/kg, group IV), Iso + BRL + moderate dose of L-NAME group (50 mg/kg, group V), Iso + BRL + high dose of L-NAME group (100 mg/kg, group VI). The hemodynamics [left ventricular end systolic pressure (LVESP), +/- dp/dt, left ventricular end diastolic pressure (LVEDP)], cardiac cGMP and the levels of beta(1)-, beta(2)-, and beta(3)-ARs mRNA were measured.

RESULTS(1) LVESP, +/- dp/dt values in group II were significantly lower, and LVEDP was significantly higher than that in group I (except -dp/dt P < 0.05, the rest were P < 0.01). Comparing with group II, group III had lower -dp/dt value and LVESP, higher LVEDP (P < 0.05). The level of +dp/dt had a trend to be lower but lacked statistical significance between two groups. The value of +/- dp/dt got higher and LVEDP got lower along with higher dose of L-NAME, but a large dose of L-NAME had more deteriorated cardiac functions. (2) The cardiac cGMP in group I, II and III had a higher tendency (P < 0.01). The tendency of cardiac cGMP in group IV, V and VI was inversed with the dose of L-NAME. After a large dose of L-NAME was applied, cGMP returned to the same level as Group I. (3) Among groups I, II and III, the level of beta(1)-AR mRNA was the highest in group I and the lowest in group III (P < 0.01). The levels of beta(2)-AR mRNA were also tended to be lower among three groups but with no significance. While the level of beta(3)-AR mRNA was the highest in group III. The levels of beta-AR mRNA were all the same in group VI, V and VI.

CONCLUSIONSThe negative inotropic effect of beta(3)-ARs stimulation was mediated by activation of the NOS pathway. L-NAME blocked beta(3)-ARs agonist negative chronotropic effect on failing heart partly and improved hemodynamics, but a large dose of L-NAME had more deteriorated cardiac functions.

Adrenergic Agonists ; therapeutic use ; Animals ; Cyclic GMP ; metabolism ; Heart Failure ; drug therapy ; metabolism ; physiopathology ; Male ; NG-Nitroarginine Methyl Ester ; administration & dosage ; pharmacology ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta-3 ; metabolism

OBJECTIVE: Bilateral oophorectomy leads to reduced bone mineral density (BMD), and reduced BMD is associated with increased marrow fat and reduced marrow perfusion. Purpose of this study was to investigate how soon these changes occur following surgical oophorectomy. MATERIALS AND METHODS: Six patients who underwent hysterectomy and bilateral salpingo-oophorectomy were studied. At baseline, mean patient age was 49.5 years (range: 45-54 years). Third lumbar vertebral body BMD measurement using quantitative CT, marrow fat fraction (FF) using MR spectroscopy and marrow perfusion using dynamic contrast enhanced MRI were conducted immediately prior to surgery and at 3, 9, and 21 months after surgery. RESULTS: Reduced BMD, increased marrow FF, and reduced marrow perfusion occurred synchronously post-oophorectomy. There was a sharp decrease of 12.5 +/- 7.2% in BMD (n = 6), a sharp increase of 92.2 +/- 46.3% (n = 6) in FF, a sharp decrease of 23.6 +/- 3.9% in maximum contrast enhancement (n = 5), and of 45.4 +/- 7.7% for enhancement slope (n = 5) during the initial 3 months post surgery. BMD and marrow perfusion continued to decrease, and marrow FF continued to increase at a slower rate during the following 18 months. Friedman test showed a significant trend for these changes (p < 0.05). CONCLUSION: Bilateral oophorectomy leads to a rapid decrease in lumbar BMD, an increase in marrow fat content, and a decrease in marrow blood perfusion.
Body Mass Index ; Bone Density ; Bone Marrow/*metabolism ; Contrast Media/diagnostic use ; Female ; Humans ; Hysterectomy ; Lipids/analysis ; Longitudinal Studies ; Lumbar Vertebrae/*radiography ; *Magnetic Resonance Imaging ; Middle Aged ; Ovariectomy ; Prospective Studies

OBJECTIVE: It was reported lately that to obtain consistent liver T1rho measurement, at 3T MRI using six spin-lock times (SLTs), is feasible. In this study, the feasibility of using three or two SLT points to measure liver T1rho relaxation time was explored. MATERIALS AND METHODS: Seventeen healthy volunteers underwent 36 examinations. Three representative axial slices were selected to cut through the upper, middle, and lower liver. A rotary echo spin-lock pulse was implemented in a 2D fast field echo sequence. Spin-lock frequency was 500 Hz and the spin-lock times of 1, 10, 20, 30, 40, and 50 milliseconds (ms) were used for T1rho mapping. T1rho maps were constructed by using all 6 SLT points, three SLT points of 1, 20, and 50 ms, or two SLTs of 1 and 50 ms, respectively. Intra-class correlation coefficient (ICC) and Bland and Altman plot were used to assess the measurement agreement. RESULTS: Two examinations were excluded, due to motion artifact at the SLT of 50 ms. With the remaining 34 examinations, the ICC for 6-SLT vs. 3-SLT T1rho measurements was 0.922, while the ICC for 6-SLT vs. 2-SLT T1rho measurement was 0.756. The Bland and Altman analysis showed a mean difference of 0.19 (95% limits of agreement: -1.34, 1.73) for 6-SLT vs. 3-SLT T1rho measurement, and the mean difference of 0.89 (95% limits of agreement: -1.67, 3.45) for 6-SLT vs. 2-SLT T1rho measurement. The scan re-scan reproducibility ICC (n = 11 subjects) was 0.755, 0.727, and 0.528 for 6-SLT measurement, 3-SLT measurement, and 2-SLT measurement, respectively. CONCLUSION: Adopting 3 SLTs of 1, 20, and 50 ms can be an acceptable alternative for the liver T1rho measurement, while 2 SLTs of 1 and 50 ms do not provide reliable measurement.
Adult ; Eating ; Echo-Planar Imaging/*methods ; Fasting ; Female ; Humans ; Liver/*anatomy & histology ; Magnetic Resonance Imaging/*methods ; Male ; Young Adult

OBJECTIVETo investigate sex hormone deficiency related osteoporosis and efficacy of different therapies.

METHODSOrchiectomized and ovariectomized rat models are used to investigate sex hormone deficiency related osteoporosis and efficacy of different therapies. A rat vertebral body can be longitudinally divided into central portion, which contain more trabecular bone, and para-endplate portions which contain more compact bone. In matured male and female Wistar and Sprague-Dawley rat lumbar spines, we investigated baseline bone mineral density (BMD) characteristics and the differential segmental responses in bone loss within the lumbar vertebral body post gonadal surgery with clinical multidetector computed tomography.

RESULTSPara-endplate sections had a higher BMD than central sections. The cephalad para-endplate sections had a higher BMD than the caudad para-endplate sections. Eight weeks after gonadal removal, there was more bone loss in central sections than para-endplate sections. The relative difference of bone loss between para-endplate and central sections was more apparent in male rats than in female rats. There was more bone loss in caudad sections than cephalad sections; this lead to a further increase of BMD difference between caudad para-endplate sections and cephalad para-endplate sections post gonadal surgery.

CONCLUSIONThe approach described in this study provided a consistent way to study BMD change within predominantly compact bone portion and trabecular bone portion of the vertebral body.

Animals ; Bone Density ; drug effects ; Female ; Gonadal Steroid Hormones ; deficiency ; metabolism ; Lumbar Vertebrae ; physiology ; Male ; Orchiectomy ; Ovariectomy ; Rats ; Sex Factors

There are sex differences in some brain areas in mammalians. Parkinson's disease (PD), caused by the mesencephalic substantia nigra (SN) dopaminergic neuronal loss, displays sexual difference, i.e., the incidence is higher and the symptoms are more intense in males than that in females. However, it has not been known whether sexual dimorphisms exist in the SN. Sixty adult Sprague-Dawley rats were randomly divided into 5 groups: (1) Female intact group (F-INT group); (2) Male intact group (M-INT group); (3) Ovariectomized group (OVX group); (4) Castration group (CAST group); (5) Ovariectomized + estrogen-replaced group (OVX-E(2) group): The rats received sequentially physiological dose of estrogen for 3 d from the 7th day after ovariectomization. P50 auditory evoked potential (P50) was recorded for 14 d from electrodes inserted in the rat right SN in quiet and awake state. After recording, the brain tissues were dissected and the tyrosine hydroxylase (TH)-expressing neurons in the compact zone of the SN were counted using immunohistochemical method. The results showed that the number of TH-positive (TH(+)) cells in the SN of normal male animals was less than that in normal female rats (P<0.05), and the T/C ratio of P50 in normal males was significantly less than that in normal females (P<0.01), indicating that there exists sexual difference in function and structure in the SN. No differences in the T/C ratio of P50 or the number of TH(+) cells were found between M-INT and CAST groups. The T/C ratio of P50 and the number of TH(+) cells in the SN in OVX group were reduced significantly compared with those in F-INT group (P<0.01). There was no significant difference in the T/C ratio of P50 and the number of TH(+) cells in the SN between OVX- E(2) and F-INT groups 15-20 d after estrogen replacement, suggesting that estrogen can promote the survival and functional recovery of dopaminergic neurons in the SN. The results suggest that there exist sex-specific differences in the dopaminergic neurons in the SN structurally and functionally. The difference of estrogen level in cerebra between male and female animals may account for the sexual differences. Endogenous estrogen plays an important role in maintaining the integrity and modulating the functional activity of dopamine system in the SN.
Animals ; Dopaminergic Neurons ; cytology ; Estrogens ; pharmacology ; Evoked Potentials, Auditory ; Female ; Male ; Orchiectomy ; Ovariectomy ; Rats ; Rats, Sprague-Dawley ; Sex Characteristics ; Substantia Nigra ; cytology

AIMIn order to compare the calcium antagonist activity between the derivatives of (+)-praeruptorin A with C-3' and C-4' cis-configuration and trans-configuration, and to look for new active compounds, some derivatives with C-3', C-4' trans-configuration of (+)-praeruptorin A were semi-synthsized.

METHODS(+)-Praeruptorin A was isolated from the root of Peucedanum praeruptorum. Basic hydrolysis of (+)-praeruptorin A was carried out. From the alkaline hydrolysis product (2), eight new products (5-12) with C-3', C-4' trans-configuration were semi-synthsized whose C-3' was linked to angeloyloxy and C-4' was linked to various acyloxy, using respective acids as acylating agents, DCC as a dehydrant, DMAP as catalyst. From the alkaline hydrolysis product (4), five new products (13-17) with C-3', C-4' trans-configuration were obtained whose C-3', C-4' is linked to various same acyloxys, using respective acids as acylating agents, DCC as dehydrant, DMAP as catalyst. Also from the alkaline hydrolysis product (4), using respective acyl chlorides as acylating agents, anhydrous dichloromethane containing minor pyridine as a solvent, the improved Schotten-Baumann reactions were carried out, two new products (18, 20) with C-3', C-4' trans-configuration were obtained whose only C-3' linked to acyloxy and two other new products (19, 21) with C-3', C-4' trans-configuration were obtained whose C-3' and C-4' linked two acyloxys. The structures of all the products were elucidated by spectral analyses including IR, 1HNMR and EIMS. The calcium antagonist activity of all of the products were tested by inhibition of the systole of rat artery ring.

RESULTSSeventeen compounds with C-3', C-4' trans-configuration were semi-synthesized from (+)-praeruptorin A for the first time and their calcium antagonist activity were evaluated.

CONCLUSIONAll of the derivatives were new compounds. Bioactivity assay indicated that some new compounds with C-3', C-4' trans-configuration showed obvious calcium antagonist activity, but they are not as strong as (+)-praeruptorin A. The activity of some products was shown to be similar to that of the derivatives with C-3', C-4' cis-configuration for the first time.

Animals ; Aorta, Thoracic ; drug effects ; Calcium Channel Blockers ; chemical synthesis ; pharmacology ; Coumarins ; chemical synthesis ; chemistry ; pharmacology ; Drugs, Chinese Herbal ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Muscle Contraction ; drug effects ; Muscle, Smooth, Vascular ; drug effects ; Rats ; Stereoisomerism