No abstract

The effects of sympathomimetic amines on Ca 2+ transients and isometric contractions were assessed in isolated rabbit papillary muscles in which multiple superficial cells had been microinjected with the calcium-sensitive bioluminescent protein aequorin. In the presence of /3-adrenoceptor blockade, the a-receptor agonist phenylephrine increased both the amplitude of the aequorin signals and the force of contraction in a concentration-dependent manner. However, the maximum increase i n the aequorin signals was less than 10% of that produced by the /3-receptor agonist isoproterenol, while the maximum increase in force of contraction produced by a-stimulation was about 50% of that elicited via /3-adrenoceptors. For a given increase in the force of contraction, stimulation of a-adrenoceptors produced much less change in the amplitude of the aequorin signals than did elevation of the extracellular Ca 2+ concentration; we interpret this to mean that the positive inotropic effect of a-adrenoceptor stimulation is in large part the result of an increase 1 in myofibrillar sensitivity to Ca 2+ . Stimulation of a-adrenoceptors produced little change or a slight decrease i n the duration of the aequorin signal and an increase in the duration of contraction, while stimulation of /3-adrenoceptors significantly decreased the time to peak and duration of both the aequorin signals and the contractions. For a given level of inotropic effect, high concentrations of isoproterenol often increased the aequorin signals more than did elevations of Ca 2+ , which is consistent with other evidence that the cyclic AMP-dependent phosphorylation of troponin I leads to a decrease in myofibrillar Ca 1+ sensitivity. However, concentrations of isoproterenol that did not produce evidence of this sort of desensitization also abbreviated the contractions much more than they did the aequorin signals. This suggests that the traditionally accepted mechanisms -a decrease in the Ca 2+ affinity of troponin C and an acceleration of Ca uptake by the sarcoplasmic reticulum -may not be sufficient to account for the actions of/3-receptor stimulation on the time course of contraction. In the absence of blocking agents, the naturally occurring catecholamines norepinephrine, epinephrine, and dopamine appear to influence the function of the rabbit papillary muscle through both a-and /3-adrenoceptors. Dopamine has a relatively greater effect on a-adrenoceptors than the other catecholamines. (Circulation Research

Thoracoscopic pulmonary segmentectomy under 3-dimensional multidetector computed tomography simulation is a safe technique.

Background-Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gq␣ protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. Methods and Results-To test this hypothesis, we generated transgenic (DGK-TG) mice with cardiac-specific overexpression of DGK. There were no differences in heart size and heart weight between DGK-TG and wild-type littermate mice. The left ventricular function was normal in DGK-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGK-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGK-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGK-TG mouse hearts, suggesting that DGK regulated PKC activity by controlling cellular diacylglycerol levels. Conclusions-These results demonstrated the first evidence that DGK negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts. (Circulation. 2006;113:60-66.)