Electrophysiological characteristics of the rat azygos vein under electrical pacing and adrenergic stimulation.

Rodent thoracic veins are characterized by an extended myocardial coating. In the present study, the electrical activity in the cardiac tissue of the rat azygos vein (AZV) was investigated for the first time. The atrial-like action potentials (AP) and atrial-like conduction of the excitation were observed in the rat AZV under continuous electrical pacing. Termination of electrical pacing resulted in spontaneous positive shift of resting membrane potential (RMP) in AZV. Boradrenaline induced biphasic effects on RMP in all quiescent AZV preparations but only in 25% preparations-bursts of spontaneous AP, which were suppressed by both α- and ß-adrenoreceptor antagonists. Phenylephrine induced additional depolarization of RMP in quiescent AZV preparations, while isoproterenol caused hyperpolarization. In conclusion, bioelectrical properties of the rat AZV resemble those of atrial myocardium under continuous electrical pacing; however, depolarized RMP and NA-induced spontaneous AP characterize AZV as a tissue prone to rare automaticity.

Physiological contractility of cardiomyocytes in the wall of mouse and rat azygos vein.

We recently demonstrated the abundant presence of cardiomyocytes in the wall of thoracic veins of adult mouse and rat. The highly differentiated morphology and myofilament protein contents of the venous cardiomyocytes suggested contractile functions. Here we further investigated the contractility of mouse and rat azygos venous rings compared with that of atrial strips and ventricular papillary muscle. 5-Bromo-4-chloro-indolyl-galactopyranoside (X-gal) staining of transgenic mouse vessels expressing lacZ under a cloned cardiac troponin T promoter demonstrated that the venous cardiomyocytes are discontinuous from atrial myocardium and aligned in the wall of thoracic veins perpendicular to the vessel axis. Histological sections displayed sarcomeric striations in the venous cardiomyocytes, which indicate an encirclement orientation of myofibrils in the vessel wall. Mechanical studies found that the rings of mouse and rat azygos vein produce strong cardiac type twitch contractions when stimulated with electrical pacing in contrast to the weak and slow smooth muscle contractions induced using 90 mM KCl. The twitch contraction and relaxation of mouse azygos veins further exhibited a cardiac type of ß-adrenergic responses. Quantitative comparison showed that the contractions of venous cardiomyocytes are slightly slower than those of atrium muscle but significantly faster than those of ventricular papillary muscle. These novel findings indicate that the cardiomyocytes abundant in the wall of rodent thoracic veins possess fully differentiated cardiac muscle phenotype despite their anatomical and functional segregations from the heart.

Octreotide bolus injection and azygos blood flow in patients with cirrhosis: is the effect really predictable?

BACKGROUND: Octreotide (OCT) improves the management of variceal bleeding, but the pattern of administration is not clearly defined. Available data show a transient decrease in portal pressure and azygos blood flow (AzBF) after OCT bolus injection with desensitization at readministration. AIM: To explore the sustained hemodynamic effects of OCT and changes associated with readministration at 60 minutes on AzBF in patients with portal hypertension. PATIENTS AND METHODS: AzBF was measured invasively (thermodilution technique) in 12 patients at baseline and at 10 minutes intervals after OCT 50-µg IV bolus for a total of 60 minutes. Readministration of OCT was followed by AzBF measurement for another 15 minutes. Patients [age 51.4 y (30 to 69)] had cirrhosis (alcoholic in 9 patients; Pugh's score 8.8±0.3), portal hypertension (HVPG 19±1 mm Hg), and elevated AzBF (658±138 mL/min). RESULTS: The bolus of OCT was followed at 10 minutes by a 34% decline in AzBF as compared with baseline value. This AzBF reduction was sustained over the 60-minute study period (-36%±1.4%) with the values that remained decreased as compared with baseline (P<0.01). Mean arterial pressure remained stable. At 60 minutes, the repeat OCT bolus induced a further significant (P<0.01) decline in AzBF, although the response was blunted (-18%±1.2%). CONCLUSION: The AzBF showed a sustained decrease of value after a bolus injection of 50-µg OCT. A further hemodynamic response is detectable at OCT readministration after 60 minutes. The pattern of hemodynamic response to OCT may not be uniform among cirrhotics.

Validation of color Doppler EUS for azygos blood flow measurement in patients with cirrhosis: application to the acute hemodynamic effects of somatostatin, octreotide, or placebo.

BACKGROUND: Color Doppler EUS (CD-EUS) allows minimally invasive measurement of azygos blood flow (AzBF) in portal hypertension, but further validation of the method is needed. Because a limited number of patients has been studied, the acute hemodynamic effects of somatostatin and octreotide on AzBF and gastric mucosal perfusion are poorly defined in portal hypertension. METHODS: A double-blind hemodynamic study was designed to assess rapid changes in AzBF over a 60-minute period after intravenous administration of somatostatin, octreotide, and placebo in 30 stable patients with biopsy-proven cirrhosis. AzBF was measured by using both CD-EUS and the invasive thermal dilution technique in the first 10 patients (phase 1). Then, with CD-EUS alone, the hemodynamic study was extended to a further 20 patients (phase 2). In addition, gastric mucosal perfusion changes were assessed by using laser Doppler flowmetry at endoscopy. RESULTS: In phase 1, the 2 methods for AzBF measurement showed significant correlations both for baseline values (r = 0.685) and for AzBF changes over 60 minutes after drug administration (r = 0.733). In phase 2, a reduction was observed in AzBF 10 minutes after octreotide or somatostatin administration (-47% and -23%, p < 0.0001 vs. placebo, p = 0.058 vs. placebo, respectively). After 60 minutes of somatostatin infusion, AzBF increased 27% over placebo values (p < 0.04). Gastric mucosal perfusion was transiently reduced 5 minutes after octreotide or somatostatin (-21% and -32%, respectively, p < 0.02 vs. placebo). CONCLUSIONS: This is the first study to validate CD-EUS AzBF measurement with reference to the invasive thermodilution technique in cirrhosis. It confirmed the transient effects of somatostatin and octreotide on both AzBF and gastric mucosal perfusion. In addition, a significant rebound phenomenon after 60 minutes of continuous intravenous somatostatin infusion was observed.

Daily variation of azygos and portal blood flow and the effect of propranolol administration once an evening in cirrhotics.

BACKGROUND/AIMS: Esophageal variceal bleeding occur more often at night, however, the mechanism for this remains unclear. This study investigated the daily variation of azygos blood flow (AzBF) and portal blood flow (PBF) and the effects of propranolol administration given once in evening in cirrhotics. METHODS: Blood flow were measured using magnetic resonance imaging. Hemodynamic parameters were determined at 08:00, 16:00 24:00 and again 08:00 h, and were measured at baseline and after 14 days oral administration of propranolol (30 mg, n = 7) or placebo (n = 7) at 19:00 h in 14 patients. RESULTS: A daily fluctuation of AzBF and PBF was observed, peaking at 24:00 h in nine patients. In three other patients, peak AzBF and PBF were observed both at 16:00 and 24:00 h. Two patients were constant throughout the day. When the daily variation was compared, ANOVA showed a significant difference (P < 0.001). Propranolol administration at 19:00 h reduced AzBF (-40.7 +/- 17.9% vs. baseline, P < 0.001) and PBF (-26.5 +/- 10.7% vs. baseline, P < 0.01) at 24:00 h. CONCLUSIONS: We found that in most cirrhotics, AzBF and PBF peaks at midnight. Dosing of propranolol in the evening may be important for its role in preventing variceal bleeding.

Use of color Doppler EUS in assessing azygos blood flow for patients with portal hypertension.

BACKGROUND: Azygos blood flow is an index of blood flow through gastroesophageal collateral vessels and varices in portal hypertension. Conventional measurement of azygos blood flow involves catheterization of the azygos vein. We studied the feasibility of assessing azygos blood flow with color Doppler endosonography and of monitoring the effects of vasoactive agents on azygos blood flow. METHODS: Patients with portal hypertension were examined by means of linear array color Doppler endoscopic ultrasonography (EUS). Patients who had taken propranolol or nitrates in the 4 weeks before the day of measurement of azygos blood flow were excluded. After identification of the azygos vein and recording of baseline readings of mean arterial blood pressure, pulse rate, and azygos blood flow, patients were selected in a random manner to receive a bolus injection of 2 mg terlipressin, 250 microg somatostatin, or saline solution (control). Azygos blood flow was measured 1, 5, and 10 minutes after injection (AzBF-1, AzBF-5, AzBF-10). RESULTS: Six patients were recruited in each treatment group. Basal azygos blood flow showed a positive association with the Child-Pugh grade of cirrhosis (p < 0.005). After bolus injection of terlipressin and somatostatin, there was a marked decrease in AzBF-1 (24% and 37%), AzBF-5 (42% and 19%), and AzBF-10 (40% both) compared with baseline. The control group showed no significant change in azygos blood flow. CONCLUSIONS: Color Doppler EUS is useful in assessing azygos blood flow in portal hypertension and in monitoring the effects of vasoactive agents.

Hemodynamic effects of glucagon in portal hypertension.

It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 +/- 167 vs. 186 +/- 25 pg/ml, p less than 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half-life of exogenously administered glucagon (4.9 +/- 0.4 vs. 2.7 +/- 0.1 min, p less than 0.1). Control subjects had marked increases in heart rate (+ 19% +/- 4%, p less than 0.01), cardiac index (+ 16% +/- 4%, p = 0.01) and arterial pressure (+ 10% +/- 3%, p less than 0.05), but corresponding changes in patients with cirrhosis (+ 7% +/- 1%, + 6% +/- 1%, and + 6% +/- 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = -0.804, p less than 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be caused by a down-regulation of vascular glucagon receptors. In addition, glucagon administration caused a significant increase in portal pressure (from 18.1 +/- 1.1 to 19.0 +/- 1.2 mm Hg, p less than 0.01), as well as in azygos blood flow (from 0.54 +/- 0.03 to 0.64 +/- 0.04 L/min, + 19% +/- 4%, p less than 0.02), reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.

The effects of ethanol administration on portal pressure and gastroesophageal collateral blood flow in patients with alcoholic cirrhosis.

The pathogenesis of variceal hemorrhage is not well understood. Portal pressure and gastroesophageal collateral (azygous) blood flow are similar in patients with cirrhosis with or without a history of variceal bleeding. However, acute increases in these parameters in individual patients might predispose them to variceal rupture. Fifteen patients with alcoholic cirrhosis and portal hypertension were evaluated to test the hypothesis that ethanol intake acutely increases portal pressure or gastroesophageal blood flow and is a possible risk factor in variceal hemorrhage. A 10% solution of ethanol in 5% dextrose in water was infused intravenously at a rate sufficient to raise the blood-alcohol level to 100 mg/dl over 30 min. Eight patients received ethanol 5% dextrose in water; seven patients received a placebo (5% dextrose in water alone). Ethanol did not produce a significant change in wedged hepatic-vein pressure, free hepatic-vein pressure, azygous blood flow, mean arterial pressure or heart rate compared with the effects of 5% dextrose in water alone. Acute administration of ethanol does not increase portal pressure or gastroesophageal blood flow. It is unlikely that acute ethanol ingestion is a risk factor for variceal hemorrhage.

Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension.

The effects of pharmacological manipulation of the lower esophageal sphincter pressure on the esophageal circulation in patients with cirrhosis and portal hypertension were investigated in 33 patients by measuring the azygos venous blood flow, which is an index of blood flow through esophageal varices and periesophageal collaterals draining into the azygos venous system. Measurements were performed in baseline conditions and after the blind administration of metoclopramide (20 mg i.v.) (12 patients), domperidone (10 mg i.v.) (12 patients) and placebo (9 patients). Both metoclopramide and domperidone caused a significant reduction of azygos blood flow, that decreased by 11.5% (p less than 0.01) and 15.6% (p less than 0.02) respectively, while no change was observed in patients receiving placebo (+1.4%, not statistically significant). Reduction of azygos blood flow represents a selective effect of metoclopramide and domperidone on the esophageal circulation, since portal pressure, hepatic blood flow, cardiac output, heart rate and arterial blood pressure were unchanged by the administration of metoclopramide, domperidone or placebo. These results indicate that the administration of drugs that increase the lower esophageal sphincter pressure may reduce the inflow of blood into the esophageal varices in cirrhotic patients with portal hypertension.

Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis.

The effects of propranolol on blood flow through gastroesophageal collaterals and on systemic and hepatic hemodynamics were investigated in 23 cirrhotic patients with portal hypertension. Gastroesophageal collateral blood flow was evaluated by the measurement of azygos venous blood flow by continuous thermal dilution. Azygos venous blood flow was markedly increased in these patients (544 +/- 48 ml per min, as compared with 132 +/- 18 ml per min in subjects without portal hypertension (p less than 0.001). Propranolol at doses achieving effective beta-blockage (83 +/- 5 mg) (mean +/- S.E.M.) markedly reduced azygos venous blood flow (to 354 +/- 34 ml per min, p less than 0.001). Reduction of azygos venous blood flow (-34.2 +/- 3.6%) was significantly greater (p less than 0.01) than reductions in cardiac output (-22.6 +/- 1.9%), hepatic venous pressure gradient (-11.5 +/- 2.4%) and hepatic blood flow (-13.4 +/- 7.4%). The hemodynamic effects of propranolol were not related to plasma norepinephrine levels. Reduction of gastroesophageal collateral blood flow may be the mechanism by which oral propranolol therapy reduces the risk of repeated episodes of variceal bleeding in cirrhotic patients with portal hypertension.