[The vasodilation and its mechanism of C-type natriuretic peptide].

AIM AND METHODS: With routine blood vessel perfusion in vitro, the vasodilation and its mechanism of C-type natriuretic peptide, a new member of natriuretic peptide family were observed in rabbits. RESULTS: CNP had the dose-dependent vasodilation effects on abdominal artery and celiac vein at the range of 10(-10)-10(-6) mol/L, its action on vein was just like nitroglycerin, its action on artery was weaker than that of ANP. Atropine (10(-7) mol/L), Regitine (20 microg), and indomethacin (20 microg) had nothing effect on the vasodilation of CNP on abdominal artery. But glibenclamide (10(-6) mol/L) and propranolol (10(-6) mol/L) could decrease the vasodilation of CNP obviously, in addition, CNP couldn't inhibit the vasoconstriction of NE. CONCLUSION: (1) CNP might be kind of venous systemic vasodilator, and it was also a arterial selective peptide controlling the vessel tone. (2) CNP dilated the vessel at least through two ways: (a) ATP-sensitive K+ channel, (b) beta-receptor.

[Blocking effects of extracellular Ba(2+) on the inward rectifier potassium channel].

Two-microelectrode voltage clamp (TEV) method was used to study the blocking effects of extracellular Ba(2+) on the inward rectifier potassium channel (IRK1) expressed in Xenopus oocytes. Blockage of Ba(2+) on IRK1 (1 ms after voltage applied) is Ba(2+) concentration (0,1,3,10 or 100 micromol/L) dependent with 10 or 90 mmol/L potassium and also voltage-dependent. Ba(2+) almost has no effect on the open/close of IRK1. IRK1 is not permeable to Ba(2+). Three exponential fitting analysis indicates that Ba(2+) and K(+) compete the same binding site in IRK1 when external Ba(2+) concentration is lower (1 or 3 micromol/L). The time constant of IRK1 does not increase, but the concentration dependency of the weights of the fittings increases with the increase of external Ba(2+) concentration. As a result, the inactivation becomes faster and faster as the external Ba(2+) concentration increases. Moreover, since the time constant of the channel decreases and the weights of the fittings concentration dependently increase with the increase of external Ba(2+) concentration (10 or 100 micromol/L), the inactivation becomes faster and faster. It is demonstrated that Ba(2+) can contact with deeper binding sites in IRK1 as external Ba(2+) concentration increases. It is suggested that two different mechanisms may underlie the external Ba(2+) blocking effect. External Mn(2+) or Mg(2+) can compete with external Ba(2+) at the IRK1 binding site at an external Ba(2+) concentration of 30 mol/L and K(+) concentration of 90 mmol/L. Inactivation becomes slower and slower and Ba(2+) is repelled from the IRK1 binding site when Mg(2+) or Mn(2+) con-centration is further increased. Mg(2+), but not Mn(2+), can contact with deeper binding sites of IRK1 to block the channel, suggesting that multiple-ion blockage may exist in IRK1.

[Effect of halothane on the muscarinic potassium current of the heart].

Acetylcholine (ACh) released from parasympathetic nerves binds to muscarinic (M2) ACh receptor (mAChR) in the heart, which leads to activation of muscarinic K(+) channel via the betagamma subunit of a G protein. The effect of a general anaesthetic (halothane) on the muscarinic K(+) channel (i(K,Ach)) in guinea-pig atrial cells was investigated using the whole-cell patch clamp technique. Halothane suppressed i(K,Ach), slowed down activation of i(K,Ach) and decreased peak i(K,Ach). When i(K,Ach) was activated by ACh acting via the muscarinic ACh receptors in the normal way, the decrease of i(K,Ach) was greater than the decrease when the muscarinic ACh receptor was bypassed and i(K,Ach) was activated by GTPgammaS. The above finding suggests that the suppression of i(K,Ach) by halothane is, in part, a result of the direct effect on the muscarinic K(+) channel or associated G protein. The decrease of i(K,Ach) by halothane may interfere with parasympathetic control of the heart.

[The blocking effects of extracellular Mn2+ on the inward rectifier potassium channel (IRK1)].

AIM AND METHODS: Two-microelectrode voltage clamp (TEV) method was used to study the blocking effects of extracellular Mn2+ on the inward rectifier potassium channel (IRK1) expressed in the Xenopus oocytes. RESULTS: Mn2+ can concentration-, time- and vol-tage dependently block IRK1 instantaneous currents (2 ms after voltage applied). Mn2+ has almost no effect on the gating property of IRK1. IRK1 can not permeate Mn2+ because reverse potential did not changed. External Mn2+ can inhibit IRK1 macroscopic currents more powerfully when external Mn2+ concentration is lower and external Mn2+ can increases standard chord conductance of IRK1. CONCLUSION: External Mn2+ works through surface potential mechanism. Ba2+ is considered as one fast open channel blocker of IRK1 and three exponential fitting results indicates that external Mn2+ can compete with Ba2+ in the same binding site in IRK1 when external Ba2+ concentration is 30 mumol/L. These mean two different mechanisms about external Mn2+ blocking exist.

[Comparison of vasorelaxing actions of vasonatrin peptide, C-type natriuretic peptide and atrial natriuretic peptide].

The vasorelaxing effects of vasonatrin peptide (VNP), C-type natriuretic peptide (CNP) and atrial natriuretic peptide (ANP) on isolated rat pulmonary artery, abdominal aorta and celiac vein were measured by in vitro perfusion. The results showed that VNP, CNP and ANP caused concentration-dependent relaxation in isolated rat pulmonary artery, abdominal aorta and celiac vein with endothelium or without endothelium. The maximal responses (Rmax) of VNP were (76 +/- 17)%, (51 +/- 14)% and (62 +/- 14)% in pulmonary artery, abdominal aorta and celiac vein with endothelium respectively, whereas those of CNP were (31 +/- 8)%, (22 +/- 7)% and (41 +/- 8)%, and ANP (38 +/- 10)%, (41 +/- 10)% and (11 +/- 4)%. The median effective concentration (EC50) of VNP were 16 +/- 11, 35 +/- 18 and 12 +/- 8 nmol/L in pulmonary artery, abdominal aorta and celiac vein with endothelium respectively, while those of CNP were 148 +/- 112, 299 +/- 84 and 14 +/- 12 nmol/L, and ANP 66 +/- 47, 16 +/- 15 and 909 +/- 445 nmol/L. VNP were more effective than CNP and ANP, and the differences were statistically significant (P < 0.05-0.01). The potency of these peptides for relaxing the blood vessels can be summarized as: VNP > ANP > or = CNP for pulmonary artery; VNP > ANP > CNP for abdominal aorta; VNP > CNP > ANP for celiac vein. There was no significant difference between vessels with intact endothelium and those denuded of endothelium (P > 0.05).

[Effects of monocarboxylic acid derivatives on cardiac ventricular CFTR Cl- channels in guinea pig].

Using the whole-cell recording technique, the effects of monocarboxylic acid derivatives on cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-)-channel were examined in guinea pig ventricular myocytes. Anthracene-9-carboxylic acid (9-AC) added to the bath solution further enhanced the outward component of isoproterenol-induced currents in a reversible manner, whereas 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) or diphenylamine-2-carboxylic acid (DPC) induced a biphasic effect on the currents. Either NPPB or DPC first produced a transient increase in the outward component of current before ensuing inhibition. Intracellular NPPB was found to potentiate isoproterenol-activated currents. It is concluded that these monocarboxylic acid derivatives have different binding sites in cardiac ventricular myocytes, which might partially account for the varied effects in blocking anion channels.

[Study on pharmacokinetic characteristics of tetramethylpyrazine and hemodynamics of heart blood stasis in dogs].

"Blood stasis syndrome pharmacokinetics" means the pathophysiological state of blood stasis syndrome affectes significantly the pharmacokinetic parameters. In order to provide scientific evidence for the new hypothesis, the authors studied the hemodynamic changes induced by quantitative coronary artery stenosis and pharmacokinetics of tetramethylpyrazine (TMP) in dog model with heart blood stasis (HBS) and in normal dog (for control) simultaneously. Compared with healthy dog, serum TMP concentration, drug concentration time, area under curve (AUC) and t1/2 beta in HBS dog were increased significantly (P < 0.01). The mechanism might be related with the abnormal changes in hemodynamics (indude decrease in cardiac output, left ventricular systolic pressure and coronary blood flow, etc.) caused by coronary artery stenosis.

[The effect of batroxobin on coronary segmental resistance and coronary blood flow in acute myocardial ischemic dogs].

To study the effects of batroxobin on coronary circulation and cardiac performance in acute myocardial ischemia, Batroxobin was given intravenously to dogs with experimental coronary stenosis. A dose-dependent increase of coronary blood flow (CBF) was observed. Forty minutes after batroxobin (2 BU.kg-1 at infusion rate 0.1 BU.kg-1.min-1) administration, CBF increased by 12% (P < 0.05), small coronary resistance(RS) decreased from 4.1 +/- 0.5 to 3.2 +/- 0.5 mmHg.min.ml-1 (P < 0.01), while large coronary resistance(RL) changed insignificantly from 3.9 +/- 0.8 to 3.8 +/- 0.7 mmHg.min.ml-1 (P > 0.05). Two hours following drug administration, the changes in CBF, RS and RL still remained and RT decreased by 13% (P < 0.05). The + LV(dp/dt)max and -LV(dp/dt)max increased by 14% and 16% (P < 0.05) respectively compared with those in control group. It is concluded that batroxobin improves the ischemic canine coronary circulation and cardiac performance by way of lowering the small coronary resistance and thus increasing CBF. The data also suggest the benificial effect of batroxobin in acute myocardial ischemia.

Synthesis and biological activity of atriopeptin III and its small molecular analog.

Atriopeptin III (AP III) and its small molecular analog were synthesized manually by stepwise solid-phase method. The peptides were oxidized with iodine in 30% acetic acid at very high dilution to form intramolecular disulfide bridge and purified to homogeneity by conventional means, including Sephadex G15, dialysis and reversed-phase HPLC. Bioassay study demonstrated that the synthetic AP III possesses potent bioactivities identical to those of the same product of Peninsula Lab both in vitro and in vivo; whereas the linear peptide, having the same primary structure as AP III, showed very limited bioactivity. The small analog, with Ser-Ser-residue deleted from the N-terminal of AP III, was equipotent as AP III while exhibiting a longer half-life in vivo resulting from the peptide modification.

[Effects of tetraethylammonium chloride and verapamil on the effective refractory period of ischemic myocardium in rabbits].

The effects of potassium ion channel blocker TEA and calcium ion channel blocker verapamil on effective refractory period (ERP) of ischemic ventricular muscle were studied in rabbits. The results showed that ERP of the ventricular muscle in central ischemic zone (CIZ) and border ischemic zone (BIZ) were shortened, respectively, at 10 min and 30 min after coronary occlusion (P < 0.01). The changes of ERP in TEA-treated and verapamil-treated rabbits after coronary occlusion were found to be significantly less than those in untreated rabbits. The results suggest that TEA and verapamil alleviated the degree of ERP shortening after coronary occlusion and may exhibit protective effects on the ischemic myocardium.

[Effect of nicorandil on coronary circulation in ischemic region].

To clarify the role of nicorandil (Nic) in relieving myocardial ischemia, the effects of Nic in canine models of coronary arterial stenosis were studied. During stenosis of the anterior descending coronary artery by an external micrometer constrictor, intracoronary infusion of Nic 1, 5 micrograms/(kg.min) increased coronary blood flow and decreased distal coronary pressure, total coronary arterial resistance and small coronary arterial resistance; but did not affect mean aortic pressure, heart rate and large coronary arterial resistance. Whole blood viscosity, plasma viscosity and hematocrit in coronary vein after intracoronary infusion of Nic were reduced. The results intravenous infusion of Nic were similar to those of intracoronary infusion. These results indicate that Nic is capable of increasing coronary blood flow, alleviating myocardial ischemia due to direct dilatation of coronary artery and reduction of blood viscosity in ischemic region.

[Effect of nitroglycerin on coronary circulation of the ischemic region in dogs].

The purpose of this study was to define the effects of nitroglycerin on coronary circulation in ischemic region. In 18 open chest dogs, a critical stenosis of the left anterior descending coronary artery was produced by an external micrometer constrictor. Intracoronary infusion of nitroglycerin 0.5 micrograms/kg. min-1 increased coronary blood flow (CBF) and decreased distal coronary pressure (DCP), total coronary artery resistance (RT), small coronary artery resistance (RS); but did not affect mean aortic pressure, heart rate and large coronary artery resistance (RL). The whole blood viscosity in coronary vein was reduced. Intracoronary infusion of nitroglycerin 1 microgram/kg.min-1, CBF increased and RT, RL, RS, DCP decreased during the first 5min. Then the CBF decreased, RT and RL increased. These were associated with a decrease in DCP and an increase in whole blood viscosity. A passive narrowing of the stenotic area was observed. These results indicate that nitroglycerin has two effects on coronary circulation, it can increase CBF and decrease coronary artery resistance in relieving myocardial ischemia; it can also decrease CBF and cause passive narrowing of coronary artery in worsing myocardial ischemia. The beneficial or harmful effect of nitroglycerin may depend on its doses and DCP.

[The consumption of fibronectin content in coronary artery stenosis in dogs].

Changes in plasma fibronectin (Fn) content of the coronary sinus were observed in coronary artery stenosis of dogs. The results showed that coronary artery stenosis produced an acute inflammatory response and decreased Fn when coronary artery stenosis was more than 75%, which was associated with an increase in platelet aggregation and activation. Histopathologic examination confirmed the presence of damaged endothelial cell and capillary and showed the adhesion of leukocyte and platelet also. The results suggest that injured coronary artery may impair protective function in coronary circulation.