In human septic shock, continuously infused MB counteracts myocardial depression, maintains oxygen transport, and reduces concurrent adrenergic support. Infusion of MB appears to have no significant adverse effects on the selected organ function variables.

Corticotropin-releasing factor (CRF) receptor type 2beta (CRFR2beta) is expressed in the heart. Urocortin (Ucn)-I activation of CRFR2beta is cardioprotective against ischemic reperfusion (I/R) injury by stimulation of the ERKs1/2 p42, 44. However, by binding CRF receptor type 1, Ucn-I can also activate the hypothalamic stress axis. Ucn-II/stresscopin related peptide and Ucn-III/stresscopin are two new members of the CRF/Ucn-I gene family and are selective for CRFR2beta. We propose that CRFR2beta selective Ucn-II or Ucn-III will protect cardiomyocytes and the ex vivo Langendorff perfused rat heart from I/R injury by activation of ERK1/2-p42, 44. Ucn-II is expressed in mouse cardiomyocytes, and Ucn-II or Ucn-III can bind to CRFR2beta, resulting in ERK1/2-p42, p-44 phosphorylation and cAMP stimulation. Phosphorylation of ERK1/2-p42, p-44 is regulated by the Ras/Raf-1 kinase pathway, independent of adenylate cyclase and, therefore, cAMP activation. Ucn-II and Ucn-III protect cardiomyocytes from I/R injury and reduce the percentage of infarct size:risk ratio in Langendorff perfused rat hearts exposed to regional I/R (P<0.001). The CRFR2 selective antagonist astressin2-B and an ERK1/2-p42, 44 inhibitor abolish the cardioprotective actions of Ucn-II and Ucn-III in reperfusion. Cardiomyocytes isolated from CRFR2-null mice are less resistant to I/R injury, compared with wild-type cardiomyocytes. We propose the use of CRFR2 selective agonists, Ucn-II and Ucn-III, to treat ischemic heart disease because of their potent cardioprotective effects in the murine heart and their minimal impact on the hypothalamic stress axis. We emphasize an important endogenous cardioprotective role for CRFR2beta in the murine heart.

Objective-The high and low responder phenomenon describes individual differences in lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) activity. We characterized patterns of intracellular accumulation, externalization, and shedding of TF in response to LPS in mononuclear cells (MNCs) from high responders (HRs) and low responders (LRs). T ightly controlled exposure of tissue factor (TF) to components of the plasma coagulation cascade is important for maintenance of normal rheological properties of blood. Failure to manipulate TF levels available for the initiation of blood clotting leads to thrombotic or bleeding disorders in humans. Circulating monocytes are presumably the major cell type that respond to variable stimuli by developing coagulant activity 1 through the expression of TF. 2 Originally, intersubject variability in developing of monocyte TF activity was described by Østerud et al. 3 By comparing lipopolysaccharide (LPS)-induced monocyte TF activity and tumor necrosis factor-␣ (TNF-␣) production in a whole blood system, an up to a 50-fold difference between individuals was observed. 4 This finding was defined as the "highlow responder phenomenon." 4 Also noteworthy, the individual usually remains a high responder (HR) or low responder (LR) for several years. 5,6 Later, high intersubject variability in cytokine production by LPS-stimulated monocytes was demonstrated. 7 It was also shown that patients with high levels of TNF-␣ production were more susceptible to heart transplant rejection. 8 Monocytes isolated from septic shock patient survivors revealed higher TNF-␣ production than monocytes from nonsurvivors. 9 Many studies have been undertaken to describe the significance of this phenomenon, but so far, no general explanation has been found. Diverse plasma factors and direct cell interactions play an important role in the development of monocyte TF activity. 10 -15 High expression of monocyte TF activity is associated with higher risk of acute coronary syndrome. 16 Platelets have been suggested to be responsible for inducing monocyte TF activity. 17 Platelet-rich plasma induced significantly higher TF activity in LPS-stimulated monocytes than platelet-poor plasma. 18 Moreover, when blood cells without platelets from HRs were mixed with platelet-rich plasma of an LR, LPS-induced TF activity was reduced up to 76% compared with an autologous system. 18 It was shown that granulocytes enhance LPSinduced monocyte TF activity in a platelet-dependent reaction involving P-selectin, platelet factor 4, plateletactivating factor, hydroxyl-eicosatetraenoic acid, and platelet-derived growth factor. 18 -21 Here we report several observations concerning the relationships between intracellular-and membrane-located TF antigen in resting and LPS-stimulated monocytes in groups of HRs and LRs, using fluorescence-activated cell sorter (FACS) analysis, fluorescence confocal microscopy, in-cell Methods and Results-After Materials and Methods Blood Sampling and Experimental DesignBlood samples from 16 healthy ...