Tender Endothelium Syndrome: Combination of Hypotension, Bradycardia, Contrast Induced Chest Pain, and Microvascular Angina.

Hypotension, bradycardia, and contrast induced chest pain are potential complications of cardiac catheterization and coronary angiography. Catheter-induced coronary spasm has been occasionally demonstrated, but its relationship to spontaneous coronary spasm is unclear. We describe a 64-year-old female who underwent coronary artery bypass surgery in 1998 on the basis of an angiographic diagnosis of severe left main disease, who recently presented with increasingly frequent typical angina. Repeat coronary angiography was immediately complicated by severe chest pain, hypotension, and bradycardia but demonstrated only mild disease of the left main artery and entire coronary tree with complete occlusion of her prior grafts. This reaction was almost identical to that observed during her original coronary angiogram. We now believe her original angiogram was complicated by severe catheter-induced left main spasm, with the accompanying contrast reaction attributed to left main disease, and the occlusion of coronary grafts explained by the absence of significant left main disease. The combination of these symptoms has not been documented in the literature. In this instance, these manifestations erroneously led to coronary bypass surgery. It is unknown whether routine, systematic injection of intracoronary nitroglycerin prior to angiography might blunt the severity of such reactions.

Feasibility of sonographer-administered echocontrast in a large-volume tertiary-care echocardiography laboratory.

BACKGROUND: Contrast echocardiography has been shown to improve diagnostic quality, especially in technically difficult patients. However, the learning curve and increased time for preparation and image acquisition have led to low use. METHODS: We sought to determine whether the contrast echocardiography procedure performed independently by a specialized, trained sonographer could improve efficiency. In our centre, routine echocardiograms were scheduled for 1 hour, and any study exceeding 1 hour would result in patient booking cancellations. We compared the standard of care, in which a physician or nurse administers echocontrast, with a sonographer-administered program (SAP). RESULTS: The time to complete contrast echocardiograms was significantly reduced by the SAP strategy (43 min 17 s ± 23 min 42 s vs 1 h 1 min 6 s ± 31 min 0 s, P < 0.001). Subgroup analysis of the inpatients and outpatients demonstrated similar results. Only 10% of studies (6 of 61) in the SAP exceeded 60 minutes, compared with 45% (34 of 76) in the standard-of-care group (P < 0.001). Based on study volumes in our centre, the net improvement in productivity with the SAP could be up to 5.3% annually. CONCLUSION: Sonographer-administered echocontrast is feasible and potentially removes a barrier to implementation of contrast echocardiography.

Ca2+-dependent activator protein for secretion 1 is critical for constitutive and regulated exocytosis but not for loading of transmitters into dense core vesicles.

Although CAPS1 was originally identified as a soluble factor that reconstitutes Ca(2+)-dependent secretion from permeabilized neuroendocrine cells, its exact function in intact mammalian cells remains controversial. Here we investigate the role for CAPS1 by generating stable cell lines in which CAPS1 is strongly down-regulated. In these cells, Ca(2+)-dependent secretion was strongly reduced not only of catecholamine but also of a transfected neuropeptide. These secretion defects were rescued by infusion of CAPS1-containing brain cytosol or by transfection-mediated expression of CAPS1. Whole cell patch clamp recording revealed significant reductions in slow burst and sustained release components of exocytosis in the knockdown cells. Unexpectedly, they also accumulated higher amounts of endogenous and exogenous transmitters, which were attributable to reductions in constitutive secretion. Electron microscopy did not reveal abnormalities in the number or docking of dense core vesicles. Our results indicate that CAPS1 plays critical roles not only in Ca(2+)-dependent, regulated exocytosis but also in constitutive exocytosis downstream of vesicle docking. However, they do not support the role for CAPS1 in loading transmitters into dense core vesicles.

RalA and RalB function as the critical GTP sensors for GTP-dependent exocytosis.

Although it has been established that the activation of GTPases by non-hydrolyzable GTP stimulates neurotransmitter release from many different secretory cell types, the underlying mechanisms remain unclear. In the present study we aimed to elucidate the functional role(s) for endogenous Ras-like protein A (RalA) and RalB GTPases in GTP-dependent exocytosis. For this purpose stable neuroendocrine pheochromocytoma 12 (PC12) cell lines were generated in which the expressions of both RalA and RalB were strongly downregulated. In these double knock-down cells GTP-dependent exocytosis was reduced severely and was restored after the expression of RalA or RalB was reintroduced by transfection. In contrast, Ca2+-dependent exocytosis and the docking of dense core vesicles analyzed by electron microscopy remained unchanged in the double knock-down cells. Furthermore, the transfected RalA and RalB appeared to be localized primarily on the dense core vesicles in undifferentiated and nerve growth factor-differentiated PC12 cells. Our results indicate that endogenous RalA and RalB function specifically as GTP sensors for the GTP-dependent exocytosis of dense core vesicles, but they are not required for the general secretory pathways, including tethering of vesicles to the plasma membrane and Ca2+-dependent exocytosis.

N-terminal insertion and C-terminal ankyrin-like repeats of alpha-latrotoxin are critical for Ca2+-dependent exocytosis.

Alpha-latrotoxin, a potent stimulator of exocytosis from neurons and neuroendocrine cells, has been studied intensively, but the mechanisms of its actions are poorly understood. Here, we developed a new method to generate active recombinant alpha-latrotoxin and conducted a structure/function analysis of the toxin in stimulating Ca2+-dependent exocytosis. alpha-Latrotoxin consists of a conserved N-terminal domain and C-terminal ankyrin-like repeats. After cleavage of an N-terminally fused purification tag of glutathione S-transferase (GST), the recombinant toxin strongly stimulated exocytosis, whereas the GST-fused toxin was much less potent. The GST-fused toxin bound to the receptors [neurexin 1alpha; CL1 (CIRL/latrophilin 1)] as efficiently as did the GST-cleaved toxin but was much less effective in inserting into the plasma membrane and inducing cation conductance. The toxin with deletion of the last two ankyrin-like repeats still bound the receptors but could neither stimulate exocytosis nor induce cation conductance efficiently. The abilities of the mutated toxins to stimulate exocytosis correlated well with their abilities to induce cation conductance, but not their binding to the receptors. Our results indicate that (1) C-terminal ankyrin-like repeats and a free (unfused) N terminus are both required for the toxin to form pores, which is essential for Ca2+-dependent exocytosis, and (2) receptor binding alone is not sufficient to stimulate Ca2+-dependent exocytosis.