May C.M. Yang

Plasma endothelin levels in patients with cirrhosis and their relationships to the severity of cirrhosis and renal function

BACKGROUND/AIMS Increased plasma endothelin levels have been reported in patients with cirrhosis. However, the relationship between plasma endothelin concentrations and hyperdynamic circulation or renal functions has not been documented. METHODS We measured the plasma endothelin-1 and endothelin-3 concentrations using radioimmunoassay in 96 patients with cirrhosis (Pughs A in 26, Pughs B in 45 and Pughs C in 25) and compared these values to 56 age- and sex-matched healthy subjects. Systemic and portal hemodynamic measurements, effective renal plasma flow, creatinine clearance, plasma aldosterone concentration and plasma renin activity were recorded for each patient. RESULTS Plasma endothelin-1 and endothelin-3 levels were significantly increased in patients with cirrhosis compared to healthy subjects. Additionally, plasma endothelin-1 and endothelin-3 values were higher in patients with cirrhosis and ascites than in those without ascites. Moreover, plasma endothelin-1 levels increased in relation to the severity of cirrhosis. On the other hand, modest negative correlations were found between endothelin-1 and creatinine clearance or effective renal plasma flow. CONCLUSIONS Plasma endothelin-1 and endothelin-3 levels are increased in patients with cirrhosis compared to healthy subjects. The increase in plasma endothelin-1 levels is related at least in part to the severity of cirrhosis. Increased endothelin-1 levels may possibly contribute to renal dysfunction in patients with cirrhosis.

FRUCTUS AURANTII REDUCED PORTAL PRESSURE IN PORTAL HYPERTENSIVE RATS

The purpose of this study was to investigate the effects of Fructus Aurantii (the unripe fruits of Citrus aurantium L.) on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Sham-operated (Sham) rats served as controls. Hemodynamic and in vitro contractile studies were performed at 14 days after surgery. Both the aqueous extract of Fructus Aurantii and synephrine, one of its purified principles with pressor activity, were infused into the conscious PVL and Sham rats via a syringe pump. Fructus Aurantii (1.25, 2.5, & 5.0 mg/kg/min) dose-dependently reduced portal pressure in PVL and Sham rats, with the percentage change in portal pressure more pronounced in PVL rats. Mean arterial pressure was dose-dependently elevated by Fructus Aurantii. Synephrine (0.095, 0.19, & 0.38 mg/kg/min) also dose-dependently reduced portal pressure and elevated mean arterial pressure in PVL and Sham rats. Fructus Aurantii (2.8-280 micrograms/ml) induced dose-dependent contractile responses mainly in aorta and mesenteric artery, but little response in portal vein. The results showed that Fructus Aurantii infusion reduced portal pressure, possibly by way of arterial vasoconstriction.

The hypotensive and negative chronotropic effects of dehydroevodiamine

The cardiovascular effects of dehydroevodiamine, an alkaloid isolated from Evodia rutaecarpa Jussieu, were studied in both in vivo and in vitro experiments. The in vivo experiments revealed that i.v. administration of dehydroevodiamine elicited a slight but significant reduction in blood pressure and a marked decrease in heart rate which was confirmed by an increased cycle length of the electrocardiogram. However, a hemodynamic experiment with microspheres showed that the total peripheral resistance was not altered by dehydroevodiamine. The blood flows of various organs were not significantly changed except those of kidney and skin, in which blood flow was decreased. In vitro, the spontaneously beating atria were significantly suppressed by dehydroevodiamine in a dose-dependent manner. These findings suggested an important effect of dehydroevodiamine in suppressing the heart, which may largely contribute to the hypotensive effect of this alkaloid. However, its vasodilator effect on hindquarter muscles cannot be neglected.

CHANGES IN INTRA‐ AND EXTRACRANIAL TISSUE BLOOD FLOW UPON STIMULATION OF A RETICULAR AREA DORSAL TO THE FACIAL NUCLEUS IN CATS

1. A small area in the dorsal part of the lateral tegmental field specifically responsible for the increase of blood flow in the common carotid artery (CCA) without accompanying change in the resting blood pressure was first identified in our laboratory. Since the area is located just dorsal to the facial nucleus, we named it the dorsal facial area (DFA; Kuo et al. 1987).

Change in Vascular cAMP and cGMP Contents in Portal Hypertensive Rats

The purpose of this study was to investigate the possible changes of cyclic nucleotide contents in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Sham-operated rats served as controls. Hemodynamic and cyclic nucleotide measurements were performed at 14 days after surgery. The portal venous pressure was significantly higher, while systemic arterial pressure and heart rate were lower in PVL rats than those in controls. Basal cAMP (PVL, 10.91 +/- 0.98, vs. sham, 8.08 +/- 0.81 pmol/mg protein) and cGMP (PVL, 0.91 +/- 0.12, vs. sham, 0.59 +/- 0.05 pmol/mg protein) contents in the tail artery were significantly higher in PVL rats. Isobutyryl methylxanthine (10(-5) M), a nonspecific phosphodiesterase inhibitor, exerted similarly stimulating effects on the tissue cGMP (PVL, 158 +/- 10, vs. sham, 178 +/- 20%) and cGMP (295 +/- 28 vs. 316 +/- 71%) levels in both PVL and control rats; so did forskolin (10(-6) M) on the cAMP (184 +/- 20 vs. 197 +/- 66%) content in both groups. Our results showed that the arterial cAMP and cGMP contents were higher in PVL rats, which may contribute to the reduction of peripheral resistance in portal hypertension.

Castration May Not Affect the Penile Erection Ability In Terms of Peripheral Neurocavernous Mechanism in Dogs

The penile erection ability (PEA) was assessed in 27 dogs with intact orchids (Group I), seven dogs with bilateral orchidectomy for one month (Group II) and four dogs with bilateral orchidectomy for three months (Group III). PEA was indicated by the increase of the intracorporeal pressure (ICP) upon electrical stimulation of the cavernous nerves. PEA was significantly decreased in both orchidectomized groups. However, when reduction in the blood pressure was considered, the difference in PEA between Group I and the orchidectomized group was no longer significant. Before the orchidectomy, plasma testosterone level of 22 adult male dogs varied widely from 105 to 6302 pg./ml. At one or three months after the orchidectomy in 11 dogs, it decreased to a level below 100 pg./ml. There was no significant change in the body weight in the post orchidectomy period. These findings indicate that the castration and/or the resulting low plasma testosterone level does not directly affect PEA through the peripheral neural and cavernosal mechanism.

Effect of octreotide on total effective vascular compliance in patients with posthepatitic cirrhosis

BACKGROUND/AIMS This study aimed to evaluate the effect of octreotide on total effective vascular compliance, measured during rapid volume expansion, in patients with posthepatitic cirrhosis. METHODS Twenty-nine patients with posthepatitic cirrhosis were randomly assigned to receive a 100-micrograms/h infusion of octreotide after a 100-micrograms bolus (n = 15), or a placebo (n = 14). Hemodynamic measurements were recorded before and 30 min after drug administration. Thereafter, rapid volume expansion was performed in each patient and hemodynamic measurements were repeated immediately after volume expansion. RESULTS Before volume expansion, placebo administration did not affect any of the hemodynamic values, while the hepatic blood flow was significantly decreased following octreotide administration. After volume expansion, the hemodynamic changes were similar between patients receiving octreotide and the placebo. However, the increase in right atrial pressure from the beginning to the end of volume expansion was higher and the total effective vascular compliance was lower in patients receiving octreotide (+3.5 +/- 0.3 mmHg, p = 0.05 and 1.69 +/- 0.16 ml.mmHg-1.kg-1, p < 0.05) compared to patients receiving placebo (+2.5 +/- 0.3 mmHg, 2.60 +/- 0.34 ml.mmHg-1.kg-1). CONCLUSIONS The present study suggests that octreotide decreased total effective vascular compliance in patients with posthepatitic cirrhosis. It is possible that, in patients with posthepatitic cirrhosis, venoconstriction was induced following octreotide administration.

Effects of endothelin and vasopressin on portal pressure of rats.

Endothelin is a vasoconstrictor peptide which has recently been isolated and sequenced from the vascular endothelial cells. It was reported to increase blood pressure in vivo and produce a prolonged contraction with a slow onset in vitro. The purpose of this study was to investigate whether endothelin can lower the portal pressure as another endogenous vasoconstriction peptidevasopressin (AVP) can. Heart rate, systemic blood pressure, portal pressure, and portal vein blood flow were measured. Effects of endothelin on these parameters were compared with those of AVP. Endothelin 10(-10) mol/Kg significantly decreased all of the parameters mentioned. At the higher dose (5 x 10(-10) mol/Kg), however, the portal pressure and blood pressure were increased and portal vein blood flow was unchanged. On the other hand, AVP decreased the portal pressure and portal vein blood flow but elevated the systemic blood pressure. In vitro experiments revealed that endothelin contracted both tail artery and portal vein of rat and vasopressin contracted only tail artery. We concluded that although both are endogenous vasoconstricting peptides, endothelin and AVP affect differently on arterial and venous vascular beds as well as on portal pressure.

The Hemodynamic Effects of AT-112, an Analog of Ketanserin, in Portal Hypertensive Rats

A serotonin mechanism has been reported to contribute to the hyperdynamic circulation of portal hypertension. Different studies have demonstrated that serotonin antagonists decrease portal pressure in portal hypertensive patients and animals. The present study was undertaken to investigate the effect of AT-112, an analog of ketanserin, on portal hypertension induced by partial portal vein ligation in rats. Since ketanserin is known to possess alpha 1-adrenergic antagonistic activity, the effect of AT-112 was compared to that of prazosin. A single dose (prazosin 4.2 micrograms/kg, AT-112 1 mg/kg) was chosen to produce a similar hypotensive effect (-20 +/- 4% for prazosin and -24 +/- 4% for AT-112). At this dose, prazosin significantly decreased total peripheral resistance whereas AT-112 significantly decreased cardiac index and heart rate. Both agents significantly decreased the portal tributary blood flow and portal pressure. In rats receiving AT-112, a significant correlation was found between the magnitudes of decrease in cardiac index and the decrease in portal tributary blood flow. We also found that the magnitude of reduction in portal pressure was greater following AT-112 administration. This study suggested that AT-112 may have more beneficial hemodynamic effects than prazosin in portal hypertensive rats. Our results provide further support for the serotonergic mechanism in the pathogenesis of hyperdynamic circulation in portal hypertension.

Decreased vascular reactivity of portal vein in rats with portal hypertension

BACKGROUND/AIMS Vascular hyporesponsiveness in portal hypertension is well documented in the arterial tissue. The present study aimed to investigate the possible changes in the portal vein from portal hypertensive rats. METHODS Portal hypertension was induced by partial portal vein ligation. Fourteen days after surgery, portal veins were removed for contractile study and measurement of cAMP, cGMP and [Ca2+]i. RESULTS In vitro tension preparation showed a decreased maximum response to norepinephrine in portal vein of portal vein ligated rats (38.3 +/- 4.1 vs. 23.4 +/- 1.5 mN/mm2). The pA2 values of WB4101 and yohimbine (alpha1- and alpha2-adrenoceptor antagonist, respectively) were not different between the two groups. Tissue cAMP (14.4 +/- 0.9 vs. 12.2 +/- 0.7 pmol/mg protein), but not cGMP, content was increased and intracellular calcium [Ca2+]i levels (247 +/- 9 vs. 281 +/- 13 nM) were decreased in portal vein ligated rats. CONCLUSIONS These results showed that in portal vein from portal vein ligated rats, vascular hyporesponsiveness and an increase in basal cAMP content and a decrease in basal [Ca2+]i were observed.