cyclic-gmp and tetramethylpyrazine

Topics: Animals; Calcium Channel Blockers; Cell Division; Cyclic GMP; Endothelins; Fibrinolytic Agents; Humans; Microcirculation; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation Inhibitors; Pyrazines; Vasoconstriction; Vasodilator Agents

ADTM, a previously reported novel Danshensu (DSS)/tetramethylpyrazine (TMP) derivative with cardioprotective and antiplatelet aggregative effects, is a promising therapeutic candidate for ischemic heart diseases. In the present study, ADTM increased coronary blood flow and protected myocardium against ischemic injury in dogs. In addition, the relaxing effect of ADTM on rat thoracic aorta and its underlying mechanisms were examined. ADTM relaxed KCl- and phenylephrine-precontracted arotic rings in a concentration-dependent manner. The relaxation by ADTM was greater than that by DSS, TMP and the mixture of DSS and TMP. ADTM induced endothelium-independent relaxation, which couldn't be abolished by removal of endothelium and the preincubation with inhibitors of nitric oxide synthase (L-NAME) and guanylate cyclase (ODQ). Potassium channel blockers including tetraethylammonium, BaCl

Topics: Animals; Arterial Pressure; Calcium; Cardiotonic Agents; Coronary Circulation; Cyclic GMP; Dogs; Extracellular Matrix; Intracellular Space; Lactates; Male; Myocardial Infarction; Nitric Oxide; Potassium Channels; Pyrazines; Rats; Receptors, Adrenergic, beta; Vasodilation; Vasodilator Agents

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) leads to intimal thickening of the aorta and is, therefore, important in the development of arteriosclerosis. As a result, the use of antiproliferative and antimigratory agents for VSMCs offers promise for the treatment of vascular disorders. Although several studies have demonstrated that ligustrazine may be used to treat heart and blood vessel diseases, the detailed mechanism underlying its actions remain to be elucidated. In the present study, the inhibitory effect of ligustrazine on platelet-derived growth factor (PDGF)-BB-stimulated VSMC proliferation and migration, and the underlying mechanisms were investigated. The findings demonstrated that ligustrazine significantly inhibited PDGF-BB-stimulated VSMC proliferation. VSMCs dedifferentiated into a proliferative phenotype under PDGF-BB stimulation, which was effectively reversed by the administration of ligustrazine. In addition, ligustrazine also downregulated the production of nitric oxide and cyclic guanine monophosphate, induced by PDGF-BB. Additionally, ligustrazine significantly inhibited PDGF-BB-stimulated VSMC migration. Mechanistic investigation indicated that the upregulation of cell cycle-associated proteins and the activation of the extracellular signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (MAPK) signaling induced by PDGF-BB was suppressed by the administration of ligustrazine. In conclusion, the present study, demonstrated for the first time, to the best of our knowledge, that ligustrazine downregulated PDGF-BB-induced VSMC proliferation and migration partly, at least, through inhibiting the activation of the ERK and P38 MAPK signaling.

Topics: Arteriosclerosis; Becaplermin; Cell Movement; Cell Proliferation; Cyclic GMP; Gene Expression Regulation; Humans; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-sis; Pyrazines; Signal Transduction

Tetramethylpyrazine (TMP), an ingredient of Chinese herbal Szechwan lovage rhizome, shows vasorelaxant effect. Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) is associated with high mortality and morbidity. Here, we evaluated the effect of TMP in a model of CVS and sought to identify the underlying mechanisms of action. A rabbit SAH model was established by injection of the autoblood via cisterna magna. Cerebral blood flow and arterial diameter were measured by Transcranial Doppler (TCD) and Computed Tomography Angiography (CTA). Expression of eNOS and PDE-V in basilar artery (BA) was assessed by western blots. Levels of nitric oxide (NO) in plasma and cerebral spinal fluid, and of intra-endothelium Ca(2+) were measured. Significantly reduced diameter and accelerated blood flow velocity were detected in BAs of SAH animals (P<0.05 vs. sham group). Expression of eNOS and NO was increased, and PDE-V expression was reduced by TMP.TMP ameliorated cerebral vasospasm (P<0.05 vs. SAH group), and L-NAME (a NOS inhibitor) partly abrogated the effects of TMP. TMP induced a dose-dependent increase of intra-endothelium Ca(2+). The current results demonstrated that the vasorelaxant effect of TMP was at least in part via regulation of NO/cGMP signaling.

Topics: Animals; Basilar Artery; Blotting, Western; Calcium Signaling; Cerebral Angiography; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelial Cells; Male; Microscopy, Confocal; Nitric Oxide; Nitric Oxide Synthase Type III; Pyrazines; Rabbits; Signal Transduction; Subarachnoid Hemorrhage; Tomography, X-Ray Computed; Ultrasonography, Doppler, Transcranial; Vasodilator Agents; Vasospasm, Intracranial

In the present study, role of guanosine-3',5'-cyclic monophosphate (cGMP) in the vasodilatation of tetramethylpyrazine (TMP), one of the active ingredients of the Chinese herb Chuang-xion, was investigated. We found that the TMP could decrease the vascular tone of isolated rat aorta precontracted with phenylephrine (10(-8) M) in a concentration-dependent manner from 10(-5) M to 10(-3) M. Also, the TMP-induced relaxation was reduced by 1H-(1,2,4)-oxadiazol-(4,3-a)-quinoxalin-1-one (ODQ) or methylene blue, the inhibitor of soluble guanylyl cyclase. Moreover, the vasodilative response to TMP was enhanced significantly in the presence of sildenafil, a well-known inhibitor of phosphodiestrase type 5 that is sensitive to cGMP. In addition, TMP could increase the cGMP level in the isolated aortic rings and TMP-induced vasodilatation was deleted by cGMP-dependent protein kinases (PKG) blockade. These results suggest that relaxation of rat aortic strip by TMP is induced in the cGMP-dependent manner.

Topics: Animals; Aorta; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Guanylate Cyclase; In Vitro Techniques; Male; Pyrazines; Rats; Rats, Wistar; Vasodilation

To investigate the effects of chuanxiongzine on the relaxation of isolated rabbit corpus cavernosum tissues.. Observations were made on the relaxing effect of chuanxiongzine on phenylephrine (PE)-precontracted corpus cavernosum and cavernosal strips preincubated with L-NAME, and ODQ, using endothelium removal and experimental method of smooth muscle strips. The effect of chuanxiongzine on cAMP and cGMP levels in corpus cavernosum was measured by 125I radioimmunoassay.. Chuanxiongzine had concentration-dependent relaxing effect on the cavernosal muscle contraction induced by PE (EC50 1.58 x 10(-4) mol/L). This relaxing effect was partially antagonized by ODQ and not blocked by L-NAME or endothelium removal. In PE-precontracted cavernosal strips, chuanxiongzine induced relaxation accompanied with an increase in cAMP and cGMP levels.. Chuanxiongzine was effective in relaxing cavernosal muscle precontracted by PE in vitro. And its relaxing effect may be enhanced by increasing cGMP and cAMP levels in the corpus cavernosum.

Topics: Animals; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth; Penis; Pyrazines; Rabbits

Tetramethylpyrazine (TMPZ) is an active ingredient of a Chinese herbal medicine (Ligusticum wallichii Franchat). In this study, TMPZ (50-200 microM) significantly increased production of nitrate and cyclic GMP in human platelets within a 15-min incubation period. TMPZ concentration-dependently inhibited intracellular Ca2+ mobilization in human platelets stimulated by collagen (5 microg/ml). Furthermore, TMPZ concentration (50 and 200 microM)- and time (15 and 30 min)-dependently triggered endothelial-type constitutive nitric oxide synthase (ecNOS) protein expression in human platelets. These results indicated that TMPZ at micromolar concentrations stimulated nitric oxide production in human platelets via a novel mechanism that activated ecNOS protein expression.

Topics: Blood Platelets; Calcium; Cyclic GMP; Enzyme Activation; Humans; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Platelet Aggregation Inhibitors; Pyrazines

Effects of tetramethylpyrazine (TMP) on endothelial cells damaged by low-density lipoproteins (LDL) were investigated. When endothelial cells were incubated with LDL (1.5 mg protein.ml-1) the level of malondialdehyde (MDA) was increased and the activity of superoxide dismutase (SOD) was inhibited, and levels of cGMP and epoprostenol were decreased. TMP at concentrations of both 20 and 150 mg.L-1 nullified the inhibition of SOD activity and the reduction of cGMP and epoprostenol content elicited by LDL. However, the elevation of MDA content induced by LDL was negated by TMP only at 150 mg.L-1. TMP also caused a reduction in MDA content and an increase of epoprostenol level in normal endothelial cells. This study suggests that TMP protects endothelial cells against damages elicited by LDL and that the protection of TMP might be due to reduction in lipid peroxidation through stimulation of production and/or release of epoprostenol.

Topics: Animals; Aorta; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Lipoproteins, LDL; Malondialdehyde; Pyrazines; Superoxide Dismutase

The vasodilatation of isolated rat aorta by tetramethylpyrazine (TMP) was studied by examining its effect on phenylephrine-induced contraction. We found no difference between the effects on intact and on endothelium-denuded preparations. The effect of TMP was similar to that of theophylline because propranolol did not block the vasodilatation. Also, there was a summation effect when the pyrazine was combined with theophylline. Furthermore, like that due to theophylline, the vasodilatation was accompanied by an increase in cyclic AMP. The pyrazine, as do other dilators, affected differently the two separate phases of the contractile response elicited with either phenylephrine or high potassium. The drug predominantly suppressed the phasic responses but both the phasic and tonic phases could be inhibited significantly if the concentration of the pyrazine was high enough. The present results suggest that intracellular accumulation of cyclic AMP and blockade of the release of calcium from internal stores may be important elements of the mechanism by which TMP reduces the development of tension in rat aortic smooth muscle.

Topics: Animals; Aorta, Thoracic; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Female; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Phenethylamines; Potassium; Pyrazines; Rats; Rats, Inbred Strains; Theophylline; Vasodilation