Adrenergic-cholinergic interactions in left atria: a study using K+ channel agonists, antagonist and pertussis toxin.

1. The role of activation of potassium conductance in the antagonism by the muscarinic agonist carbachol of positive inotropic responses to alpha- and beta-adrenoceptor stimulation was studied in electrically driven left atrial strips of the rabbit. 2. The potassium channel antagonist, 4-aminopyridine, attenuated the direct negative inotropic response to carbachol and the reversal by carbachol of positive inotropic responses to the alpha-adrenoceptor agonist phenylephrine (in the presence of timolol). The inhibitory effect of carbachol on positive inotropic responses to the beta-adrenoceptor agonist isoprenaline was much less affected by 4-aminopyridine. 3. Pretreatment of rabbits with pertussis toxin also attenuated the direct negative inotropic response to carbachol and the inhibitory effect of carbachol on positive inotropic responses to phenylephrine. 4. Neither carbachol nor phenylephrine, alone or in combination, had any effect on left atrial adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 5. The potassium channel agonist, pinacidil, exerted a dose-dependent negative inotropic response in rabbit left atria and reversed positive inotropic responses to phenylephrine and isoprenaline. In the dose-range tested, pinacidil had a greater inhibitory effect on positive inotropic responses to phenylephrine than on positive inotropic responses to isoprenaline. 6. Pretreatment of left atria with pinacidil or cromakalim, another potassium channel agonist, antagonized positive inotropic responses to phenylephrine but not to isoprenaline. 7. These results suggest that activation of potassium conductance plays an important role in the inhibition by carbachol of positive inotropic responses of rabbit left atria to phenylephrine but not to isoprenaline.     

苦楝化学成份的研究

从苦楝(Melia azedarach L.)果中分得苦楝新醇(Ⅰ),苦楝醇(Ⅱ)、苦楝酮(Ⅲ)、苦楝二醇(Ⅳ)、香草醛(Ⅴ)和香草酸(Ⅵ)。根据波谱(IR,MS,~1HNMR,~(13)CNMR)分析和理化常数测定,确定了它们的结构。其中苦楝新醇(Ⅰ)为新化合物,对菜青小虫有一定的拒食活性。     

SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β-adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca²⁺ into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca²⁺ load and induction of SR Ca²⁺ leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.