Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Cirrhotic patients are endotoxemic, and activation of vascular cannabinoid CB1 receptors has been implicated in endotoxin-induced hypotension. Here we show that rats with biliary cirrhosis have low blood pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipient rats and showed significantly elevated levels of anandamide. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These results implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management.

Diabetes affects multiple systems in complex manners. Diabetic foot ulcers (DFUs) are a result of diabetes-induced microarterial vessel disease and peripheral neuropathy. The presence of arteriosclerosis-induced macroarterial disease can further complicate DFU pathophysiology. Recent studies suggest that mesenchymal stromal cell therapies can enhance tissue regeneration. This phase I study was designed to determine the safety and explore the efficacy of local injections of autologous adiposederived stromal vascular fraction (SVF) cells to treat nonhealing DFUs greater than 3 cm in diameter. Sixty-three patients with type 2 diabetes with chronic DFU-all amputation candidates-were treated with 30 × 10 6 SVF cells injected in the ulcer bed and periphery and along the pedal arteries. Patients were seen at 6 and 12 months to evaluate ulcer closure. Doppler ultrasounds were performed in a subset of subjects to determine vascular structural parameters. No intervention-related serious adverse events were reported. At 6 months, 51 subjects had 100% DFU closure, and 8 subjects had ≥75% closure. Three subjects had early amputations, and one subject died. At 12 months, 50 subjects had 100% DFU healing and 4 subjects had ≥85%

The endogenous cannabinoid anandamide causes hypotension and mesenteric arteriolar dilation. A detailed analysis of its effects on systemic and portal venous hemodynamics had not yet been performed. We assessed the effects of anandamide (0.4-10 mg/kg) on systemic and portal hemodynamics with and without prior treatment with various antagonists. The specific antagonists used included SR-141716A, N(omega)-nitro-L-arginine methyl ester, indomethacin, and nordihydroguaiaretic acid. Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output. Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB(1) antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide. Antagonism of nitric oxide synthetase, cyclooxygenase, or 5-lipoxygenase did not prevent the systemic nor the portal hemodynamic effects of anandamide. Furthermore, the use of R-methanandamide, a stable analog of anandamide, produced similar hemodynamic effects on the mesenteric vasculature, thereby implying that the effects of anandamide are not related to its breakdown products. Anandamide produced profound, dose-dependent alterations in both the systemic and portal circulations that could be at least partially blocked by pretreatment with SR-141716A.

Hepatic hydrothorax occurs in approximately 5 to 12% of patients with cirrhosis and portal hypertension. Various therapeutic modalities ranging from dietary and pharmacologic interventions to surgical approaches are available for the management of this condition. Treatment must be individualized based on the patient's response to conservative management as well as the severity of the underlying liver disease. Hepatic hydrothorax may be complicated by spontaneous bacterial empyema, which portends a poor prognosis with a mortality rate of up to 20%. All patients with hepatic hydrothorax should be evaluated for possible liver transplantation.