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Aim To explore the arrhythmic risk of Chan Su intravenous injection(CS)and its underlying mechanismin in the absent or presence of IL-6.Methods The recording techniques of guinea pig in vivo ECG, the action potential, L-type Ca2+ and Na+ currents from left ventricular myocytes were used to analyze heart rate(HR), P-R, QRS and QTc intervals and the underlying mechanism.Results① CS at one time CRD(clinically relevant dose)insignificantly changed the guinea pig in vivo ECG.However, the IL-6(18.4 μg·kg-1)only and the combinational use of IL-6(18.4 μg·kg-1)plus CS(one time CRD)remarkably prolonged the P-R and QTc intervals.② The CS at one time CRC(clinically relevant concentration)had no significant change in the action potential duration at 90% repolarization level(APD90).The IL-6(20 μg·L-1)only and the combination of CS at one time CRC plus IL-6(20 μg·L-1)significantly prolonged APD90.③ Moreover, the IL-6(20 μg·L-1)combined with CS at one time CRC significantly inhibited the L-type Ca2+ current. CS at one, five, ten time CRC, IL-6(20 μg·L-1)alone and IL-6(20 μg·L-1)combined with CS had no significant effects on Na+current.Conclusions CS intravenous injection has low risk of arrhythmia in the clinical settings.However, in presence of high titer of IL-6 characterized by inflammation, CS may induce the atrioventricular conduction block due to the blockade effect on Ca2+ current by both of CS and IL-6.
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This study aimed to explore the positive inotropic effect of phosphodiesterase type 9 (PDE9) inhibitor PF-04449613 in ratsand its cellular and molecular mechanisms. The heart pressure-volume loop (P-V loop) analysis was used to detect the effects of PF-04449613 on rat left ventricular pressure-volume relationship, aortic pressures and peripheral vessel resistance in healthy rats. The Langendorff perfusion of isolated rat heart was used to explore the effects of PF-04449613 on heart contractility. The cardiomyocyte sarcoplasmic reticulum (SR) Ca
Subject(s)
Animals , Rats , Calcium/metabolism , Myocardial Contraction , Myocytes, Cardiac/metabolism , Phosphodiesterase Inhibitors , Phosphoric Diester Hydrolases , Ryanodine Receptor Calcium Release Channel , Sarcoplasmic ReticulumABSTRACT
Aim To investigate the inotropic effect of PF-04957325, a phosphodiesterase type 8 inhibitor, in normal rats and its underlying molecular mechanism. Methods The techniques of in vivo rat left ventricular pressure-volume loop (P-V loop) and isolated perfusion rat heart were used to analyze the hemodynamics and positive inotropic effect of rat hearts. The Ca transient induced by field stimulation was used to analyze the hemodynamics of sarcoplasmic reticulum (SR) Ca + uptaking. Western blot was used to analyze the phosphorylation levels of SR phospolamban (PLB) and ryanodine receptor type 2 (RyR2). Results The P-V loop experiment indicated that PF-04957325 (0.5 mg · kg
ABSTRACT
ObjectiveIvabradine reduces heart rate by inhibiting If current of cardiomyocyte and is used clinically to treat stable angina pectoris and myocardial ischemia. However, the mechanism of positive inotropic effect by Ivabradine is still not well understood. This study aims to investigate the Ivabradine's positive inotropic effect both in vivo and in vitro and the underlying mechanism involved.Methods①A Millar catheter with double-pressure was inserted into the right carotid artery of general anesthesia rats. The pressure-volume of left ventricle, HR (heart rate) and aortic pressure were recorded as a blank group (n=7). The effect of Ivabradine (1 mg/kg) administrated via left external jugular vein was recorded as a drug treated group (n=7). The cardiac output, left ventricular and aortic pressure of the rats in the blank group A and the administration group A were compared, and the results were used to analyze the Ivabradine's inotropic effectin vivo.②Langendorff setup was used to analyze the left ventricular pressure of the isolated heart. The normal perfusion solution was used as the blank group (n=6), while the Ivabradine (10 μmol/L) perfusion was used as the treated group (n=6). In addition, the treatment of H89 (200 nmol/L) (a PKA inhibitor) was recorded as the blank group (n=6) and the combined use of H89 (200 nmol/L) and Ivabradine (10 μmol/L) was recorded as drug treated group (n=6). Following the above protocol, KN-93 (500 nmol/L) (a CaMKII inhibitor) or CA (10 nmol/L) (a protein phosphatase 1 and 2A inhibitor) was used to analyze the inhibitory effect on inotropic effect of Ivabradine (n=6 for each group). ③The field stimulation induced Ca2+ transient from cardiomyocyte was used to investigate the mechanism underlying the positive inotropic effect of Ivabradine (10 μmol/L).The perfusion orders and concentrations of Ivabradine or/and H89, KN-93 and CA were the same as that in isolated rat heart experiment (n= 6 for each group).Results① Ivabradine (1 mg/kg) significantly increased the left ventricular develop pressure (from 102.43±11.06 in blank group to 109.86±11.65 mmHg in ivabradine treated group, P<0.01, n=7) and cardiac output (from 33.72±1.96 in blank group to 36.27±2.22 mL/min in ivabradine treated group, P<0.01, n=7). It reduced the heart rate (from 348.56±10.02 in blank group to 324.17±11.33 beats/min in ivabradine treated group, P<0.01, n=7) and increased the systolic blood pressure (from 99.74±8.67 in blank group to 108.57±9.24 mmHg in Ivabradine treated group, P<0.01, n=7) without significant change in diastolic blood pressure. ② Ivabradine (1, 10 μmol/L) significantly increased the left ventricular developed pressure (LVDP) (P<0.05, n=6). The positive inotropic effect of Ivabradine was blocked by CaMKⅡ inhibitor of KN-93. ③ Ivabradine (10 μmol/L) significantly increased the amplitude of SR Ca2+ transient (P<0.01,n=6). The enhanced amplitude of Ca2+ transient was blocked by CaMKⅡ inhibitor of KN-93.ConclusionIvabradine shows a positive inotropic effect in rat hearts both in vivo and in vitro and its underlying mechanism involved the action which was mediated by CaMKⅡ.