BACKGROUND AND PURPOSEWe hypothesized that proteinase-activated receptor-2 (PAR2)-mediated vasorelaxation in murine aorta tissue can be due in part to the release of adipocyte-derived relaxing factors (ADRFs). EXPERIMENTAL APPROACHAortic rings from obese TallyHo and C57Bl6 intact or PAR2-null mice either without or with perivascular adipose tissue (PVAT) were contracted with phenylephrine and relaxation responses to PAR2-selective activating peptides (PAR2-APs: SLIGRL-NH2 and 2-furoyl-LIGRLO-NH2), trypsin and to PAR2-inactive peptides (LRGILS-NH2, 2-furoyl-OLRGIL-NH2 and LSIGRL-NH2) were measured. Relaxation was monitored in the absence or presence of inhibitors that either alone or in combination were previously shown to inhibit ADRF-mediated responses: L-NAME (NOS), indomethacin (COX), ODQ (guanylate cyclase), catalase (H2O2) and the K + channel-targeted reagents, apamin, charybdotoxin, 4-aminopyridine and glibenclamide. KEY RESULTSEndothelium-intact PVAT-free preparations did not respond to PAR2-inactive peptides (LRGILS-NH2, LSIGRL-NH2, 2-furoyl-OLRGIL-NH2), whereas active PAR2-APs (SLIGRL-NH2; 2-furoyl-LIGRLO-NH2) caused an L-NAME-inhibited relaxation. However, in PVAT-containing preparations treated with L-NAME/ODQ/indomethacin together, both PAR2-APs and trypsin caused relaxant responses in PAR2-intact, but not PAR2-null-derived tissues. The PAR2-induced PVAT-dependent relaxation (SLIGRL-NH2) persisted in the presence of apamin plus charybdotoxin, 4-aminopyridine and glibenclamide, but was blocked by catalase, implicating a role for H2O2. Surprisingly, the PAR2-inactive peptides, LRGILS-NH2 and 2-furoyl-OLRGIL-NH2 (but not LSIGRL-NH2), caused relaxation in PVAT-containing preparations from both PAR2-null and PAR2-intact (C57Bl, TallyHo) mice. The LRGILS-NH2-induced relaxation was distinct from the PAR2 response, being blocked by 4-aminopyridine, but not catalase. CONCLUSIONSDistinct ADRFs that may modulate vascular tone in pathophysiological settings can be released from murine PVAT by both PAR2-dependent and PAR2-independent mechanisms.

Background: Mechanisms underlying abnormalities of circulation and renal function in cirrhosis are not completely understood. Our previous study revealed that primary afferent denervation by neonatal capsaicin treatment prevented the development of hyperdynamic circulation in portal hypertensive and cirrhotic rats. Aims: The present study aimed to clarify the role of capsaicin sensitive nerves in the development of renal dysfunction and ascites formation in cirrhosis. Methods: Rat pups were injected with capsaicin (50 mg/kg) or vehicle and allowed to grow. When they reached adulthood, cirrhosis was induced by bile duct ligation while controls received sham operation. Cardiac output and regional blood flows were measured by radioactive microspheres, glomerular filtration rate by

Lung cancer patients report the highest distress levels of all cancer groups. In addition to poor prognosis, the self-blame and stigma associated with smoking might partially account for that distress and prevent patients from requesting help and communicating with their partners. The present study used innovative methods to investigate potential links of shame and guilt in lung cancer recovery with distress and marital adjustment. A specific emphasis was an examination of the impact of shame on partner communication. Lung cancer patients (n = 8) and their partners (n = 8) completed questionnaires and interviews that were videotaped. We report descriptive statistics and Spearman correlations between shame and guilt, relationship talk, marital satisfaction, distress, and smoking status. We coded the interviews for nonverbal expressions of shame. Greater self-reported shame was associated with decreased relationship-talk frequency and marital satisfaction, and with increased depression and smoking behaviour. Nonverbal shame behaviour also correlated with higher depression and increased smoking behaviour. Guilt results were more mixed. More recent smoking behaviour also correlated with higher depression. At a time when lung cancer patients often do not request help for distress, possibly because of shame, our preliminary study suggests that shame can also disrupt important partner relationships and might prevent patients from disclosing to physicians their need for psychosocial intervention and might increase their social isolation. Even if patients cannot verbally disclose their distress, nonverbal cues could potentially give clinicians an opportunity to intervene.

1 Cirrhosis is associated with cardiovascular and renal dysfunction including sodium retention. Many vasoactive peptides such as atrial natriuretic peptide (ANP) and endothelin-1 (ET-1) are degraded by neutral endopeptidase 24.11 (NEP). We investigated the hemodynamic and renal effects of thiorphan, a NEP inhibitor, in a rat cirrhosis model. 2 Cirrhosis was induced by chronic bile duct ligation, and controls had sham operation. Systemic and renal hemodynamics in conscious, restrained animals were determined using radiolabeled microspheres, and glomerular filtration rate (GFR) was measured by 3 H-inulin clearance. Plasma ANP and ET-1, and renal cGMP and Na + -K + ATPase activity were assayed. These variables were measured at baseline and after intravenous infusion of thiorphan (0.5 mg kg À1 loading dose followed by 0.1 mg kg À1 min À1 Â 30 min). 3 Thiorphan significantly decreased cardiac output, and increased systemic vascular resistance in controls, whereas in cirrhotic rats these variables were unchanged. 4 Compared to the controls, cirrhotic rats showed a decreased baseline GFR and urine sodium excretion, and the latter was significantly increased by thiorphan. 5 Thiorphan increased plasma ET-1 levels in controls, but not cirrhotic rats. ANP levels were not significantly increased in either group by thiorphan. 6 Thiorphan significantly increased cGMP concentrations and decreased Na + -K + ATPase activity of renal medulla but not cortex in cirrhotic rats; no effect was observed in the control rats. 7 We conclude that thiorphan induces natriuresis in cirrhotic rats by a direct renal medullary mechanism via cGMP and Na + -K + ATPase, without affecting systemic hemodynamics. This may potentially be useful in patients with ascites.