The e ects of the recently identi®ed human peptide urotensin-II (hU-II) were investigated on human cardiac muscle contractility and coronary artery tone. In right atrial trabeculae from non-failing hearts, hU-II caused a concentration-dependent increase in contractile force (pEC 50 =9.5+0.1; E max =31.3+4.8% compared to 9.25 mM Ca 2+ ; n=9) with no change in contraction duration. In right ventricular trabeculae from explanted hearts, 20 nM hU-II caused a small increase in contractile force (7.8+1.4% compared to 9.25 mM Ca 2+ ; n=3/6 tissues from 2 out of 4 patients). The peptide caused arrhythmic contractions in 3/26 right atrial trabeculae from 3/9 patients in an experimental model of arrhythmia and therefore has less potential to cause arrhythmias than ET-1. hU-II (20 nM) increased tone (17.9% of the response to 90 mM KCI) in 7/7 tissues from 1 patient, with no response detected in 8/8 tissues from 2 patients. hU-II is a potent cardiac stimulant with low e cacy.

Coronary artery bypass grafting (CABG) triggers a systemic inflammatory response that may contribute to adverse outcomes. Dendritic cells (DC) and monocytes are immunoregulatory cells potentially affected by CABG, contributing to an altered immune state. This study investigated changes in DC and monocyte responses in CABG patients at 5 time-points: admission, peri-operative, ICU, day 3 and day 5. Whole blood from 49 CABG patients was used in an ex vivo whole blood culture model to prospectively assess DC and monocyte responses. Lipopolysaccharide (LPS) was added in parallel to model responses to an infectious complication. Co-stimulatory and adhesion molecule expression and intracellular mediator production was measured by flow cytometry. CABG modulated monocyte and DC responses. In addition, DC and monocytes were immunoparalysed, evidenced by failure of co-stimulatory and adhesion molecules (eg HLA-DR), and intracellular mediators (eg IL-6) to respond to LPS stimulation. DC and monocyte modulation was associated with prolonged ICU length of stay and post-operative atrial fibrillation. DC and monocyte cytokine production did not recover by day 5 post-surgery. This study provides evidence that CABG modulates DC and monocyte responses. Using an ex vivo model to assess immune competency of CABG patients may help identify biomarkers to predict adverse outcomes. K E Y W O R D Scardiac surgery, coronary artery bypass, Dendritic cells, immune modulation, immunoparalysis, monocytes

Chronic increases in myocardial blood flow have been shown to stimulate capillary proliferation in normal growing hearts. It is unknown, however, if elevated myocardial blood flow stimulates precapillary and/or capillary growth in hearts undergoing hypertrophy. Accordingly, renal hypertension was produced in rabbits (Page, 1-kidney, 1-wrap model) in which one group of Page (n = 9) and one group of normotensive sham (n = 10) rabbits were given dipyridamole (4.0 mg/kg sc) twice daily for 2 mo. Another group of Page (n = 7) and sham (n = 12) rabbits received vehicle injections. In separate acute studies performed on conscious rabbits, this does of dipyridamole increased myocardial blood flow 35-60% over time without altering transmural distribution of flow or systemic blood pressure. Two months later, minimal coronary vascular resistance (MCVR/100 g) was calculated from perfusion during maximal coronary vasodilation in conscious animals. Histomorphometric methods were then utilized to evaluate various indexes of capillarity in perfuse-fixed hearts. Systolic pressure and left ventricle weight-to-body weight ratios were significantly higher in Page vs. sham rabbits; dipyridamole treatment did not alter these parameters within either group. Similarly, dipyridamole treatment did not significantly alter MCVR/100 g values in either normotensive or hypertensive rabbits. In contrast, dipyridamole treatment increased endomyocardial capillary length density by 33% in the hypertensive group (P less than 0.05) and 11% in the sham group (P not significant) compared with the respective vehicle-treated rabbits. In addition, intercapillary distance was significantly reduced in the endomyocardial region of both groups receiving dipyridamole injections.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARYMercuric chloride (HgCl 2 ) induces a T cell-dependent autoimmune syndrome in Brown-Norway (BN) rats characterized by a humoral response, tissue injury with an accumulation of CD8 and CD4 T cells, and an increase in tissue IL-4 mRNA and serum IgE suggesting Th2 cell activation. In other models of autoimmune disease, CD8 cells act in both anti-and pro-inflammatory capacities, suggesting that functionally distinct CD8 populations exist in vivo. The effect of treatment with OX8, a depleting anti-CD8 MoAb, on the initiation of HgCl 2 -induced autoimmunity was assessed in two experiments in a total of 20 BN rats, and compared with 20 animals treated with a control MoAb or PBS. OX8 significantly depleted peripheral blood CD8 lymphocytes, had no effect on HgCl 2 -induced anti-collagen or myeloperoxidase antibodies, nor on the incidence or severity of caecal vasculitis. The severity of HgCl 2 -induced arthritis was significantly reduced in OX8-treated animals; median peak score reduced from 7 . 5 to 3 . 0 (experiment 1) and from 7 . 0 to 4 (experiment 2) (P 0 . 009, Mann-Whitney U-test). OX8 treatment also exacerbated the early rise in HgCl 2 -induced IgE and induced a significant rise in plasma interferon-gamma (IFN-°), suggesting that CD8 cells may have a regulatory influence on Th cell populations. These data provide direct evidence that CD8 cells may act in a proinflammatory capacity in both this model of autoimmunity and the pathogenesis of inflammatory arthritis.