Xiao-Chun Yu

Cardiac effects of the extract and active components of radix stephaniae tetrandrae. II. Myocardial infarct, arrhythmias, coronary arterial flow and heart rate in the isolated perfused rat heart.

The primary purpose of the present study was to compare the cardioprotective effects of the extract from radix stephaniae tetrandrae (RST) and its individual compounds, tetrandrine (Tet) and fanchinoline (Fan). Secondly, we also compared the cardiac effects of the individual compounds and the RST extract with those of verapamil, a classical Ca2+ channel blocker. The Langendorff isolated perfused rat heart preparation was used. Regional ischaemia and reperfusion was employed to induce myocardial infarct and arrhythmia. Infarct, arrhythmia, heart rate and coronary artery flow were determined in hearts treated with vehicle, RST extract, Tet, Fan, or verapamil. It was found that RST extract, of which only 9% was Tet, and Tet alone produced equally potent ameliorating effects on arrhythmia and infarct induced by ischaemia and reperfusion without further inhibiting ischaemia-reduced heart rate and coronary artery flow. Fan had no effects on arrhythmia and infarct induced by ischaemia and reperfusion; but it induced S-T segment elevation and further reduced heart rate and coronary artery flow during ischaemia. Verapamil also ameliorated the effects of ischaemia and reperfusion on arrhythmia and infarct. It should be noted that 1 microM verapamil, that produced comparable effects on infarct and arrhythmia to the RST extract and Tet, further inhibited heart rate during ischaemia. The results indicate that the RST extract produces equally potent cardioprotective and anti-arrhythmic effects as Tet alone. Both RST extract and Tet may be better choices for the treatment of arrhythmia and infarct induced by myocardial ischaemia and reperfusion than the classical Ca2+ channel blocker, verapamil as they do not further reduce heart rate during ischaemia.

Antihypertensive and anti-arrhythmic effects of an extract of Radix Stephaniae Tetrandrae in the rat

In this study, we determined the effects of an extract of Radix Stephaniae Tetrandrae (RST) on arterial blood pressure and heart weight in deoxycorticosterone acetate‐salt (DOCA‐salt) hypertensive rats. We also determined the effects of the extract on arrhythmia and infarct induced by myocardial ischaemia and reperfusion in anaesthetized rats. We further compared the effects of the extract with those of tetrandrine, which makes up 7% of the extract and is known to act as a calcium‐channel antagonist, and verapamil, a prototype calcium‐channel antagonist. Treatment with RST extract returned the arterial blood pressure, cardiac compliance and coronary flow towards normal, and reduced right ventricular hypertrophy in the DOCA‐salt hypertensive rat. In the anaesthetized rat, the RST extract reduced arrhythmia and infarct size induced by myocardial ischaemia and reperfusion; the effects were similar to those of tetrandrine and verapamil. The findings indicate that the RST extract acts like a calcium‐channel antagonist. It may be used in the treatment of cardiovascular diseases, as are the calcium‐channel antagonist and tetrandrine. More interestingly, the effects of the RST extract were of the same potency as tetrandrine. Since only 7% of the extract was tetrandrine, the observation indicates that tetrandrine was not the only component that was responsible for the actions of the extract.

Cardiac effects of the extract and active components of radix stephaniae tetrandrae: I. Electrically-induced intracellular calcium transient and protein release during the calcium paradox

The present study was designed to compare the cardiac actions of the extract and individual components, tetrandrine (Tet) and fangchinoline (Fan), of Radix stephaniae tetrandrae (RST). We measured the electrically induced [Ca2+]i transient in single rat ventricular myocytes and protein release following perfusion with a Ca2+ free solution (the Ca2+ paradox) from the isolated perfused rat heart, both of which are known to relate to Ca2+ influx. We found that Tet inhibited both electrically induced [Ca2+]i transient and protein release during the Ca2+ paradox, while Fan had no significant effects. The RST extract containing 9% Tet and 6% Fan by weight also affected the [Ca2+]i transient, and was only slightly, though significantly, less effective/potent than Tet alone. On the other hand, RST extract had a significantly greater inhibitory effect on protein release during the Ca2+ paradox than Tet alone. The observations suggest that the RST extract, which contains a mixture of components, may have more potent effects in the heart than its main active component.

k-opioid receptor agonist inhibits the cholera toxin sensitive G-protein in the heart

Summary: To explore the signaling mechanisms of the negative modulation of &bgr;‐adrenoceptors by &kgr;‐opioid receptors (&kgr;‐OR) in the heart, the possibility of the interaction at the level of G protein and receptor was determined. Cholera toxin, an activator of the stimulatory G protein (Gs), elevated electrically induced intracellular Ca2+ ([Ca2+]i) transients and induced ribosylation of the &agr;‐subunit of Gs (Gs&agr;) in rat ventricular myocytes. The effects were significantly attenuated by U50,488H, a specific agonist of &kgr;‐OR, and were abolished by nor‐binaltorphimine, a selective &kgr;‐OR antagonist. The content of Gs&agr;, however, was not affected by U50,488H. Receptor binding experiments showed that neither Bmax nor Kd of the binding of [3H]CGP‐12177, a &bgr;‐adrenoceptor antagonist, was affected by U50,488H. The current study provides the first evidence that &kgr;‐OR stimulation inhibits the ribosylation of the &agr;‐subunit of the Gs protein, thus inhibiting the action of cholera toxin on the protein.

PRO- AND ANTI-ARRHYTHMIC EFFECTS OF A KAPPA OPIOID RECEPTOR AGONIST : A MODEL FOR THE BIPHASIC ACTION OF A LOCAL HORMONE IN THE HEART

1. The effects of κ opioid receptor stimulation on cardiac rhythm and the underlying signal pathways were investigated in the rat.

Reduced inhibitory actions of adenosine A1 and kappa 1-opioid receptor agonists on beta-adrenoceptors in spontaneously hypertensive rat heart.

1. The modulatory actions of both adenosine A1 and K1‐opioid receptor agonists on β‐adrenoceptor stimulation in the heart of both spontaneously hypertensive rats (SHR) and nor‐motensive Wistar‐Kyoto (WKY) rats were compared.

Acidosis antagonizes intracellular calcium response to κ-opioid receptor stimulation in the rat heart

To study the effects of κ-opioid receptor stimulation on intracellular Ca2+ concentration ([Ca2+]i) homeostasis during extracellular acidosis, we determined the effects of κ-opioid receptor stimulation on [Ca2+]iresponses during extracellular acidosis in isolated single rat ventricular myocytes, by a spectrofluorometric method. U-50488H (10-30 μM), a selective κ-opioid receptor agonist, dose dependently decreased the electrically induced [Ca2+]itransient, which results from the influx of Ca2+ and the subsequent mobilization of Ca2+ from the sarcoplasmic reticulum (SR). U-50488H (30 μM) also increased the resting [Ca2+]iand inhibited the [Ca2+]itransient induced by caffeine, which mobilizes Ca2+ from the SR, indicating that the effects of the κ-opioid receptor agonist involved mobilization of Ca2+ from its intracellular pool into the cytoplasm. The Ca2+responses to 30 μM U-50488H were abolished by 5 μM nor-binaltorphimine, a selective κ-opioid receptor antagonist, indicating that the event was mediated by the κ-opioid receptor. The effects of the agonist on [Ca2+]iand the electrically induced [Ca2+]itransient were significantly attenuated when the extracellular pH (pHe) was lowered to 6.8, which itself reduced intracellular pH (pHi) and increased [Ca2+]i. The inhibitory effects of U-50488H were restored during extracellular acidosis in the presence of 10 μM ethylisopropyl amiloride, a potent Na+/H+exchange blocker, or 0.2 mM Ni2+, a putative Na+/Ca2+exchange blocker. The observations indicate that acidosis may antagonize the effects of κ-opioid receptor stimulation via Na+/H+and Na+/Ca2+exchanges. When glucose at 50 mM, known to activate the Na+/H+exchange, was added, both the resting [Ca2+]iand pHi increased. Interestingly, the effects of U-50488H on [Ca2+]iand the electrically induced [Ca2+]itransient during superfusion with glucose were significantly attenuated; this mimicked the responses during extracellular acidosis. When a high-Ca2+ (3 mM) solution was superfused, the resting [Ca2+]iincreased; the increase was abolished by 0.2 mM Ni2+, but the pHi remained unchanged. Like the responses to superfusion with high-concentration glucose and extracellular acidosis, the responses of the [Ca2+]iand electrically induced [Ca2+]itransients to 30 μM U-50488H were also significantly attenuated. Results from the present study demonstrated for the first time that extracellular acidosis antagonizes the effects of κ-opioid receptor stimulation on the mobilization of Ca2+ from SR. Activation of both Na+/H+and Na+/Ca2+exchanges, leading to an elevation of [Ca2+]i, may be responsible for the antagonistic action of extracellular acidosis against κ-opioid receptor stimulation.