Effects of exercise-induced sympathoadrenergic activation on portal blood flow.

We examined the relationship between portal venous blood flow and sympathoadrenergic activation after muscle exercise. For this purpose, we used echo Doppler and measured plasma noradrenaline concentration before and after mild (7 metabolic units, N = 8) and maximal exercise (14 metabolic units, N = 8) in 16 patients without significant disease. Portal venous flow did not change after mild exercise. In contrast, a significant reduction in portal venous flow was observed after maximal exercise (P < 0.01). This was due to reductions in both cross-sectional area of the portal vein (P < 0.01) and portal venous velocity (P < 0.01). Overall, there were significant inverse relationships between the change in plasma noradrenaline concentration and that in cross-sectional area of the portal vein [r = -0.44, P < 0.01 (absolute change); r = -0.47, P < 0.01 (relative change)], that in portal venous velocity (r = -0.63, P < 0.01; r = -0.61, P < 0.01), and that in portal venous flow (r = -0.54, P < 0.01; r = -0.59, P < 0.01). These results suggest that the reduction in portal venous flow after exercise is related to the degree of sympathoadrenergic activation. This reduction may be due mainly to splanchnic vasoconstriction.

Cardiovascular responsiveness after isotonic exercise in cirrhotic patients: study on sympathoadrenergic and renin-angiotensin systems.

OBJECTIVES: The aim of this study was to evaluate cardiovascular responsiveness after isotonic exercise in cirrhotic patients. METHODS: Included were 11 cirrhotic patients and 10 age-matched normal subjects, who served as controls. Hemodynamic data were obtained on each subject before and after muscle exercise on a treadmill (7 metabolic units). Plasma noradrenaline concentration and plasma renin activity also were determined. RESULTS: In both groups, isotonic exercise increased heart rate and systolic arterial pressure, whereas diastolic arterial pressure was not modified. The increase in heart rate and systolic arterial pressure did not differ significantly between the two groups. Plasma noradrenaline concentration and plasma renin activity also were increased. The changes in plasma noradrenaline concentration and plasma renin activity was higher in cirrhotic patients than in controls (p < 0.05, p < 0.05), although the differences were not significant when calculated as a percentage. CONCLUSIONS: Cardiovascular responsiveness to isotonic exercise is almost intact in cirrhotic patients. However, supernormal activation of the sympathoadrenergic and renin-angiotensin systems is required to maintain cardiovascular homeostasis in these patients.

Portal vein hemodynamics in cirrhotic patients with portal hypertensive gastropathy: an echo-Doppler study.

Portal hypertensive gastropathy is a major complication of cirrhosis. The aims of this study were to characterize portal vein hemodynamics and sympathetic nervous activity in cirrhotic patients with gastropathy. Forty-seven cirrhotics (mild gastropathy in 7) and 25 controls were included in this study. Portal vein hemodynamics was assessed by echo-Doppler, and sympathetic nervous activity by plasma adrenaline and noradrenaline concentrations. Portal blood flow was similar in cirrhotics and controls. However, the congestion index of the portal vein (calculated as the ratio of cross-sectional area and blood velocity) was significantly higher in the former than in the latter. Furthermore, the congestion index of the portal vein paralleled the severity of the gastropathy (ANOVA, p < 0.05). Plasma adrenaline and noradrenaline concentrations were higher in cirrhotics than in controls. However, there was no linear relationship between plasma adrenaline (ANOVA, NS) and noradrenaline (ANOVA, NS) concentrations and the severity of gastropathy. These results suggest a relative contribution of "passive congestion" in the pathogenesis of gastropathy.

Reduced portosystemic hemodynamic responsiveness after orthostasis in patients with cirrhosis.

We studied portosystemic hemodynamic responsiveness after 1 min orthostasis in nine patients with cirrhosis and nine age-matched normal subjects. Orthostasis increased diastolic arterial pressure, which is a close indicator of arterial tone, in normal subjects (+17%, P < 0.01). In contrast, no significant change in diastolic arterial pressure was observed in patients with cirrhosis (-3%, NS). The increase in heart rate was less in patients with cirrhosis than in normal subjects (+15% vs +28%, P < 0.05). Orthostasis also decreased portal blood flow, which was assessed by an echo-Doppler flowmetry, in normal subjects (-27%, P < 0.01), but in patients with cirrhosis it was not modified (-3%, NS). Plasma noradrenaline concentration showed similar increase in both groups (normal vs cirrhosis; +61% vs +55%, NS). Although the change in plasma noradrenaline concentration was related with that in diastolic arterial pressure (r = 0.71, P < 0.05) and inversely with that in portal blood flow (r = -0.69, P < 0.05) in normal subjects, no such significant correlation was found in patients with cirrhosis. We conclude that (1) a reduced hemodynamic responsiveness to sympathetic stimulation exists on both systemic and portohepatic vascular beds and (2) such a blunted baroreflex function is probably located at the receptor or effector level in patients with cirrhosis.

Correlation between mitochondrial enlargement in renal proximal tubules and microalbuminuria in rats with early streptozotocin-induced diabetes.

To clarify the ultrastructural changes in renal proximal tubules causing microalbuminuria in the early stage of diabetic nephropathy, three different groups of rats were prepared: rats with streptozotocin (STZ)-induced diabetes given no treatment (DMut; n = 7), rats with STZ-induced diabetes treated with insulin (DMt; n = 7), and non-diabetic rats injected with citrate buffer (control; n = 7). In each group, the laboratory findings, ATP content of the renal cortex, and the size of proximal tubule cells and their nuclei and mitochondria (MT) were determined. In two weeks after the start of the study, MT in renal proximal tubules showed diffuse enlargement in the DMut group as compared with those in the control group. Renal cortical ATP content, fractional sodium excretion (FENa), urinary excretion of beta 2-microglobulin and albumin were also increased significantly in the DMut group relative to the controls. In the DMt group, most of the examined parameters returned almost to normal. There were positive correlations between each of the following parameters: hyperglycemia and MT enlargement, MT enlargement and increased cortical ATP content, increased cortical ATP content and increased FENa, increased FENa and increased urinary excretion of beta 2-microglobulin and albumin. On the basis of these results, we conclude that mitochondrial enlargement, resulting from disturbed metabolism of ATP, may reduce active transport in renal proximal tubules, which, in turn, may impair reabsorption in the tubules. This would cause urinary excretion of low-molecular-weight proteins and microalbumin in the early stage of diabetic nephropathy.

Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines.

As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.

Synthesis and calcium antagonistic activity of (+)-(R)- and (-)-(S)-3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5- trimethoxyphenethyl)amino]butoxy]phenyl]benzothiazoline hydrochloride.

SA2572 ((+)-1), 3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl) amino] butoxy]phenyl]-benzothiazoline hydrochloride is a newly synthesized Ca2+ antagonist having a inhibitory effect on the fast Na+ inward channel. In order to clarify the absolute configurations and the pharmacological properties of both enantiomers, compounds ((+)-1 and (-)-1) were synthesized. The configurations of these compounds were assigned on the basis of an X-ray crystallographic analysis of synthetic precursor (5). The in vitro Ca2+ channel blocking activities of (+)-1 and (-)-1 were evaluated in terms of the inhibitory activities on depolarization-induced contraction of guinea pig taenia cecum and rabbit aorta. The in vivo efficacy of the enantiomers was evaluated with their hypotensive effects in spontaneously hypertensive rats. Compound (-)-1 showed more potent Ca2+ antagonistic activities on guinea pig taenia cecum and rabbit aorta and the hypotensive effect than those activities of (+)-1. In the electrophysiological study of Langendorff perfused rabbit hearts, compound (+)-1 showed more potent inhibitory effect on the fast Na+ inward channel than that of compound (-)-1, and an approximately equal potent inhibitory effect on the slow Ca2+ inward channel as compared with compound (-)-1. Stereoselectivity of the pharmacological activity was found.

Novel calcium antagonists. Synthesis and structure-activity relationship studies of benzothiazoline derivatives.

A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic activity than the corresponding thiazolidine derivatives (2). Effects of substituents R1-R4, the substitution position of the aminoalkoxy group and R2, and the length of the methylene chain on biological activities were examined. Compound 4 [3-acetyl-2-[5-methoxy-2-[4-[N-methyl-N-(3,4,5-trimethoxyphenethyl ) amino]butoxy]phenyl]benzothiazoline hydrochloride] showed a potent Ca2+ antagonistic activity in vitro and dual inhibition on the fast Na+ inward channel and the slow Ca2+ inward channel in Langendorff perfused rabbit hearts. Compound 4 also showed a long-acting hypotensive effect in spontaneously hypertensive rats and prevented acute pulmonary thrombotic death in mice.

A new potent inhibitor of converting enzyme: (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid(SA446).

(2R, 4R)-2-(2-Hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) is a novel potent converting enzyme inhibitor having a sulfhydryl group in the molecule. SA446 inhibited the activity of semi-purified rabbit lung converting enzyme (IC50 = 6 nM). The contractile response of isolated guinea pig ileum to angiotensin I (AI) was markedly inhibited by SA446 (IC50 = 28 nM). On the other hand, SA446 augmented the contraction to bradykinin (BK) (AC50 = 0.7 nM), but did not affect the contraction caused by angiotensin II (AII), acetylcholine and histamine. These in vitro potencies of SA446 were 4 to 5 times larger than those of captopril. SA446 inhibited the pressor response to AI in rats (ID50 = 0.06 mg/kg, i.v., 0.48 mg/kg, p.o.) and dogs (ID50 = 0.01 mg/kg, i.v.). SA446 augmented the depressor response to BK (AD50 = 0.009 mg/kg, i.v.), but did not affect the pressor responses to AII and norepinephrine in rats. These in vivo activities of SA446 in dogs were more potent than those of captopril, but the reverse was seen in rats. Oral administration of SA446 had a hypotensive effect on two-kidney, one-clip renal hypertensive rats and spontaneously hypertensive rats, at doses over 3 and 10 mg/kg, respectively. However, the blood pressure of normotensive and DOCA-salt hypertensive rats was not affected by SA446, in doses up to 100 mg/kg. These results indicate that oral SA446 is a potent active inhibitor of converting enzyme and may be classed as an antihypertensive agent.

The role of prostaglandins in experimental ocular inflammations.

Intraocular inflammations (uveitis) were produced in rabbits by intravitreal injection of killed and dried Mycobacterium butyricum or E. coli endotoxin, or paracentesis of the anterior chamber. The increase in permeability of the blood-aqueous barrier and the leucocyte migration into the aqueous humor were observed after these stimuli, although the leucocyte did not migrate after paracentesis. Topically applied indomethacin reduced these inflammatory parameters in the latter two models. However, ththacin, though the leucocyte was not affected by indomethacin, though the leucocyte migration was reduced. On the other hand, prostaglandin-like substances in thces of these substances were detected in the former model. These results indicated that, unlike the increase in the permeability of the blood-aqueous barrier after endotoxin injection andparacentesis, the response after M. butyricum injection is not mediated by prostaglandins. The role of prostaglandins in the leucocyte migration in these ocular inflammations was also discussed.

Potentiating mechanism of bradykinin action on smooth muscle by sulfhydryl compounds.

(4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS-980), a potent angiotensin I (AI) converting enzyme inhibitor, inhibited the contractile response of isolated guinea-pig ileum to AI but not to AII, while it potentiated the response to bradykinin. Other sulfhydryl compuonds also produced inhibition of AI action, and the effects were closely correlated with their potentiating activities against bradykinin action. These results suggest that it is mainly inhibition of the enzyme in the tissue which participates in the mechanism of potentiation of kinin action by YS-980.

Potentiative effects of sulfhydryl compounds on carrageenin-induced oedema in rats and relationship to their potencies as inhibitors of angiostin-coverting enzyme in vivo.

Carrageenin-induced oedema in rats was potentiated by oral administration of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (SA291) and related sulfhydryl compounds, and the effect was closely correlated with their potencies as inhibitors of angiotensin-converting enzyme in vivo.