The role of cadherin-catenin-cytoskeleton complex in angiogenesis: antisense oligonucleotide of plakoglobin promotes angiogenesis in vitro, and protein kinase C (PKC) enhances angiogenesis through the plakoglobin signaling pathway.

Angiogenesis plays an important role in various diseases and conditions such as malignant tumor, wound healing, and atherosclerosis. Since cell-to-cell adhesion may play a key role in angiogenesis, we investigated the effect of the cadherin-catenin-cytoskeleton complex on angiogenesis in human umbilical vein endothelial cells (HUVECs). Immunofluorescence staining revealed that alpha-catenin, beta-catenin, and plakoglobin were concentrated at cell-cell contacts in HUVECs. Antisense oligonucleotide (AS-oligo), complementary to the region of human plakoglobin was dissolved in saline and applied to the media at 1 mM every 12 h for 4 days, and sense oligonucleotide (S-oligo) was used as control. HUVEC migration from an injury line was enhanced by AS-oligo. Interestingly, HUVECs migrated in line with S-oligo, and in a scattered fashion with AS-oligo. Tube formation on Matrigel occurred earlier with AS-oligo than with S-oligo. These findings indicate that plakoglobin inhibited HUVEC migration and tube formation (angiogenesis) by regulating cell-cell adhesion.

Effect of pectin on formyl methionyl-leucyl-phenylalanine (FMLP)-injured intestinal mucosa of rat.

(1) We investigated the trophic effect of pectin on the intestinal mucosa injured by formyl methionyl-leucyl-phenylalanine (FMLP), a chemoattractant produced by the intestinal bacterial flora. (2) We first demonstrated that oral administration of FMLP for 7 days reduced the disaccharidase activities and increased the permeability, measured by fluorescein-isothiocyanate-conjugated dextran, of rat small intestine. (3) After 7 days of FMLP administration, rats were divided into fiber-free group which was given liquid elemental diet (Elental) and the pectin group which was given Elental supplemented with 2.5% pectin. (4) After 3 days of feeding (Day 3), the maltase activities of the pectin group was significantly greater than that of the fiber-free group and than that of the initial level just after the 1 week administration of FMLP. At Day 7, there was no difference of maltase activity between the two groups. The sucrase activity of the pectin group was also significantly greater than that of fiber-free group at Day 3. (5) Plasma enteroglucagon was significantly increased in the pectin group. We conclude that pectin-supplemented diet promoted the recovery of disaccharidase activities in the FMLP-injured intestinal mucosa which may be mediated by enteroglucagon.

Hyponatremia and hyperreninemic hypoaldosteronism in a critically ill patient: combination of insensitivity to angiotensin II and tubular unresponsiveness to mineralocorticoid.

A 62-year-old man with pneumonia and left flank pain had a clinical syndrome of hyponatremia, hypotension, dehydration, and high urinary sodium excretion in the presence of a normal glomerular filtration rate. The plasma level of antidiuretic hormone was relatively high despite decreased serum osmolality. Thyroid function and excretion of glucocorticoid and sex steroids were normal. The serum aldosterone level was very low despite elevated plasma renin activity. Angiotensin II failed to stimulate any secretion of aldosterone, despite the occurrence of a progressive rise in blood pressure. On the other hand, rapid ACTH administration increased both serum aldosterone and cortisol. The patient showed no effective response to increased salt intake, but large doses of mineralocorticoid resulted in a normal serum sodium level without dehydration. Subsequently, he suffered cardiac arrest secondary to ventricular tachycardia. Postmortem examination showed well differentiated adenocarcinoma in the left pleura and an intact, histologically normal adrenal zona glomerulosa and kidney. This is the first reported case of a critically ill patient with hyponatremia caused by hyperreninemic hypoaldosteronism possibly due to angiotensin II insensitivity and tubular unresponsiveness to mineralocorticoid.

Effects of pectin on fatty acid and glucose absorption and on thickness of unstirred water layer in rat and human intestine.

Effects of pectin, a soluble dietary fiber, on fatty acid and glucose absorption were studied in vivo in rats and humans by perfusing the intestine with linoleic acid and glucose solutions with and without pectin. Linoleic acid and glucose absorption decreased with increasing concentrations of pectin. The reduction in linoleic acid absorption was not caused by binding of linoleic acids by pectin or impaired micelle formation due to binding of bile acid by pectin. The unstirred water layer expanded with increasing concentrations of pectin. These results suggest that enlargement of the unstirred water layer is closely associated with the reduction of absorption of fatty acid and glucose ingested with pectin.

The role of endogenous dopamine in congestive heart failure.

Although the effects of epinephrine and norepinephrine in congestive heart failure have been extensively studied, and exogenous dopamine, another of the catecholamines, has been widely used for the treatment of congestive heart failure, little attention has been paid to the physiological significance of endogenous dopamine in this condition. The present study was therefore designed to assess the physiological significance of endogenous dopamine in congestive heart failure. Nineteen patients with congestive heart failure caused by such conditions as acute myocardial infarction, valvular disease and dilated cardiomyopathy were examined before and after treatment with diuretics, digitalis and vasodilators. Electrolyte, creatinine and catecholamine concentrations in plasma and urine were analyzed. Urinary dopamine levels were increased in 13 out of 19 cases before treatment and returned to the normal range after treatment, falling from 2448 +/- 950.7 to 528.8 +/- 56.3 micrograms/day (normal level, less than 700 micrograms/day). Urinary dopamine excretion was markedly elevated within 24 hours after the onset of symptoms of heart failure, such as chest pain, palpitations and dyspnea. The relationship between urinary dopamine excretion and time after the onset of symptoms showed a strong statistical correlation (r = 0.55, p less than 0.001). Urinary dopamine excretion was also well correlated with plasma dopamine concentration, urinary norepinephrine excretion and venous pressure. From these results, it is concluded that endogenous dopamine seems to play an important role during the acute phase of congestive heart failure.

Effect of pectin, a soluble dietary fiber, on functional and morphological parameters of the small intestine in rats.

We investigated the effects of pectin, a soluble dietary fiber, on functional and morphological parameters of the small intestine in rats. A control group and a pectin-fed group were given a fiber-free elemental liquid diet and an elemental liquid diet containing 2.5% (w/w) pectin, respectively, for 2 weeks. The ileal mucosal specific activities of maltase, sucrase and alkaline phosphatase increased significantly in the pectin-fed group. Maltose absorption of the ileum, studied in vitro by the method of everted sacs and disaccharide-dependent potential difference, increased significantly in the pectin-fed group. The length of the small intestine as well as the villus height and crypt depth of both the jejunum and the ileum were significantly greater in the pectin-fed group. The crypt cell production rate of the jejunum and the ileum was also significantly greater in the pectin-fed group. Plasma enteroglucagon, but not gastrin, increased significantly in the pectin-fed group. These data suggest that pectin feeding results in hyperplasia of the small-intestinal mucosa and a significant increase in the enzyme activities of the brush border membrane of the ileum.

Cardiac arrhythmias in hemodialysis patients. A study of incidence and contributory factors.

Cardiac arrhythmias were evaluated in 100 patients undergoing regular maintenance hemodialysis for chronic renal failure by Holter ECG monitoring a 72-hour period beginning on the day of hemodialysis. Clinically significant ventricular arrhythmias (more than 700 beats/24 h) were found in 18 patients (the frequent group) in whom premature ventricular contractions (PVCs) were recorded frequently during and for 4 h after hemodialysis. In the frequent group, the values of the serum calcium concentration times those of phosphorus were significantly higher than those of patients without PVCs (the no arrhythmia group) or those with fewer PVCs (less than 700 beats/day; sporadic group) (54.9 +/- 3.5 vs. 43.8 +/- 3.2, 43.0 +/- 1.8, respectively; p less than 0.005). Also, in the frequent group, the percent fractional shortening of the left ventricle, as measured by two-dimensional echocardiography, was significantly lower than those in the no arrhythmia and sporadic groups (30.7 +/- 1.8% vs. 40.7 +/- 1.9%, 37.7 +/- 1.1%, respectively; p less than 0.01). On the other hand, in those with frequent premature atrial contractions, the left atrial end-diastolic dimension was significantly enlarged (42.1 +/- 1.2 mm vs. 36.5 +/- 1.1 mm, 38.1 +/- 0.9 mm, respectively; p less than 0.01). From these results, we conclude that impaired cardiac performance and a high calcium phosphate product predialysis may be correlated with an increased incidence of ventricular arrhythmias in uremic patients.

Combination therapy with diltiazem and nifedipine in patients with effort angina pectoris.

The antianginal effects of diltiazem and nifedipine alone and in combination were evaluated in a double-blind, randomized, placebo-controlled trial in 11 patients (nine men and two women, 57 +/- 8 years old) with stable effort angina. Each patient received placebo, 30 mg of diltiazem, 10 mg of nifedipine, and 30 mg of diltiazem plus 10 mg of nifedipine four times daily for 1 week each. Antianginal efficacy was assessed by means of a treadmill exercise test. The exercise tolerance time was significantly prolonged from 235.1 +/- 52 (placebo period) to 342.2 +/- 101 sec by diltiazem (p less than .01) and to 325.6 +/- 73 sec by nifedipine (p less than .01). The drug combination further prolonged exercise time to 451.1 +/- 103 sec, which was significantly longer than the interval attained with either diltiazem (p less than .01) or nifedipine (p less than .01) alone. The plasma concentration of diltiazem was unaffected by the addition of nifedipine, whereas the plasma nifedipine concentration was significantly increased from 34.8 +/- 11 to 106.4 +/- 37 ng/ml (p less than .001) by the concomitant administration of diltiazem. These data suggest that exercise tolerance in patients with effort angina is increased by the concomitant administration of diltiazem and nifedipine associated with an increase in the nifedipine plasma concentration.

Acute and chronic hypotensive effects of nifedipine and niludipine in hypertensive patients with chronic renal failure.

The present study was aimed to evaluate the acute and chronic hypotensive effects of nifedipine (Bay a 1040, Adalat) and niludipine (Bay a 7168) in hypertensive patients with chronic renal failure. 1. The decrease of blood pressure lasted for at least 3 h and maximum decrement was achieved in 60 min (26% decrement, p less than 0.05) after oral administration of nifedipine (10 mg). On the other hand, niludipine (20 mg) caused decrease of blood pressure for at least 4 h and attained maximum decrement in 90 min (13% decrement, p less than 0.05) after oral administration. 2. In chronic studies of both drugs, the maximum decrease of blood pressure (p less than 0.05) was attained after one week and lasted at least 4 weeks. There were no significant changes of pulse rate, body weight and urine volume in both nifedipine and niludipine groups. 3. Nifedipine caused great diurnal or day-to-day fluctuations of blood pressures after chronic administrations. On the other hand niludipine did not cause any significant fluctuations. Any serious complications could not be seen during these studies. In conclusion, these results provide clinical evidence that niludipine could be usefused great diurnal or day-to-day fluctuations of blood pressures after chronic administrations. On the other hand niludipine did not cause any significant fluctuations. Any serious complications could not be seen during these studies. In conclusion, these results provide clinical evidence that niludipine could be useful for treatment of hypertension associated with chronic renal failure. Results also suggest that the optimal efficacy of nifedipine and niludipine in part depends on the specific clinical situation at hand. For example, nifedipine seems to be the drug of choice in hypertensive emergencies when there is a need for rapid lowering of blood pressure.

Hypotensive effect of nifedipine in hypertensive patients with chronic renal failure.

The hypotensive effect of 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxydimethylester (nifedipine, Adalat) was studied in 15 hypertensive patients with chronic renal failure. The decrease of blood pressure lasted for approximately 3 h and maximum decrement was achieved in 1 h after oral administration of nifedipine (10 mg). Hypotensive action of the drug was associated with a constant decrease in total peripheral resistance and an increase in cardiac output, plasma renin activity (PRA), and plasma norepinephrine (noradrenaline). Initial PRA was apparently the major determinant of the rise in PRA since a close correlation was present between the initial value and the increase induced by nifedipine (r = 0.93, p less than 0.05). Marked reduction of blood pressure without noticeable side effects was observed in two cases who had not responded to previous antihypertensive treatment. These data suggest that nifedipine exerts its hypotensive action through peripheral vasodilation and may be an effective drug for treatment of hypertension during chronic renal failure.