Venodilator effects of pranidipine, a 1,4-dihydropyridine Ca2+ channel antagonist, in rats: comparison with nifedipine and amlodipine.

The effects of pranidipine, a dihydropyridine Ca2+ channel antagonist, on mean circulatory filling pressure, an index of body venous tone, were compared with those of other dihydropyridines (nifedipine and amlodipine) and nitroglycerin in anaesthetized hexamethonium- and norepinephrine-treated rats. In this study, the compounds were used at doses having a equi-hypotensive effect. Intravenous bolus injection of pranidipine (10 and 30 microg/kg) significantly decreased mean circulatory filling pressure in a dose-dependent manner, as did nitroglycerin (30 and 100 microg/kg). Nifedipine (30 and 100 microg/kg), however, did not affect mean circulatory filling pressure. Amlodipine (1000 and 3000 microg/kg) decreased mean circulatory filling pressure only at the higher dose. These results suggest that pranidipine has a greater venodilator effect than nifedipine and amlodipine.

Differential properties of the optical-isomers of pranidipine, a 1,4-dihydropyridine calcium channel modulator.

Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.

Venodilatory effect of pranidipine, a calcium channel blocker, monitored with perfluorocarbon in vivo (19)F-NMR spectroscopy.

We previously reported that the (19)F-NMR signal intensity of perfluorocarbon was increased by a venodilator, nitroglycerine, and decreased by an arteriodilator, hydralazine. In the present study, we demonstrated that pranidipine, a calcium channel blocker, increased the intensity of the FC-43 signal, while nifedipine, a prototype of calcium channel blockers, did not. These results suggest that pranidipine dilates the venous system in contrast to nifedipine.

Three cases of primary pulmonary amyloidosis.

In three cases of primary pulmonary amyloidosis the chief complaint was hemosputum. The diagnosis of amyloidosis was made using histochemical analysis of bronchial wall biopsy in all cases; multiple nodular lesions were observed in trachea and bronchi on flexible fiberoptic bronchoscopy. The surface of the tracheobronchial mucosa was smooth but bled easily. In one patient, chest X-ray film showed a solitary nodular shadow in the left lower lung field. These three cases were tracheobronchial amyloidosis, and one case was combined with nodular parenchymal type amyloidosis.

Spontaneous bacterial peritonitis in an adult patient with nephrotic syndrome.

Most cases of spontaneous bacterial peritonitis (SBP) in association with nephrotic syndrome are children. The complication of SBP in adults with nephrotic syndrome is extremely rare. Herein, we report a 25-year-old man with nephrotic syndrome and chronic renal failure who suffered from SBP. Citrobacter freundii was isolated from ascites. Irreversible deterioration of renal function followed the development of SBP, though the peritonitis was cured with antibiotic treatment. This case suggests that SBP is a rare, but serious complication of adult nephrotic syndrome with ascites.

Nephrogenic diabetes insipidus associated with bilateral ureteral obstruction.

Nephrogenic diabetes insipidus associated with ureteral obstruction is rare. We report a case of nephrogenic diabetes insipidus associated with ureteral obstruction caused by ileal leiomyosarcoma in a 32-year-old man. The treatment with trichlorothiazide and diclofenac sodium reduced urine output from 8 L/day to 4 L/day. Six months after nephrostomy, urine output decreased to 2.5 L/day without any drug administration. This case suggests that ureteral obstruction may cause an increase in urine output to 8 L/day and that surgical treatment for ureteral obstruction is effective in reducing urine output in nephrogenic diabetes insipidus patients with ureteral obstruction.

Effects of the new long-acting dihydropyridine calcium antagonist pranidipine on the endothelium-dependent relaxation in isolated rat aorta in vitro.

The action of methyl 3-phenyl-2 (E)-propenyl 1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (pranidipine, OPC-13340, CAS 99522-79-9) on the endothelium-dependent relaxation in the isolated aorta in vitro was examined in comparison with other calcium antagonists (nifedipine, nitrendipine, nicardipine, diltiazem and verapamil). In the isolated aortic preparation of Wistar rats, acetylcholine (10(-5) mol/l), ATP (10(-5) mol/l or histamine (10(-5)-10(-4) mol/l) caused endothelium-dependent relaxation when the strips were previously contracted with prostaglandin F2 alpha. This endothelium-dependent relaxation recovered within a few minutes, although the mechanisms of this contraction after relaxation were not clear. The pretreatment with pranidipine for 20 min extended the duration of the endothelium-dependent relaxation, however, there was no potentiation in magnitude of the relaxation. This effect on the duration of endothelium-dependent relaxation was prominent in pranidipine, namely, other calcium antagonists tested had not this action at clinical concentrations. This phenomenon was also observed when the strips were pre-contracted with norepinephrine. This action of pranidipine might be some beneficial feature for therapeutic use of the compound.

Natriuretic response to acute sodium chloride or sodium bicarbonate infusions in humans.

We compared the natriuretic responses to acute sodium chloride or sodium bicarbonate loading. 2.25 mEq/kg of sodium as sodium chloride, or sodium bicarbonate was infused intravenously in 1 h. Sodium chloride infusion resulted in a gradual increase in urinary sodium excretion (UNaV) for 4 h after starting the infusion, while sodium bicarbonate infusion caused a transient increase in UNaV for the first 2 h followed by a decrease. The amount of sodium excreted over 4 h in the sodium chloride and sodium bicarbonate groups were 20.7 +/- 4.7 and 34.8 +/- 2.3% of the sodium loaded, respectively (p < 0.05). This difference could not be ascribed to divergent responses in glomerular filtration rate, aldosterone, atrial natriuretic peptide, or serum albumin concentration. The difference in UNaV might be caused by the differences in renal tubular handling of chloride and bicarbonate.

Effects of bile salts on plasma concentration of beta-endorphin-like immunoreactivity in men.

The effects of bile salts on the release of beta-endorphin-like immunoreactivity (beta-END-LI) were investigated in men using a specific radioimmunoassay developed by the authors. Plasma beta-END-LI was determined after extraction by the acid-acetone method (recovery: 73 +/- 5%). Oral administration of 400 mg of sodium taurocholate caused a rise in plasma beta-END-LI from 9.9 +/- 0.5 pmol/liter to 21.3 +/- 1.2 pmol/liter after 30 min and 18.1 +/- 0.5 pmol/liter after 60 min, with return to the initial value after 90 min. Oral administration of chenodeoxycholic acid (CDCA) also increased plasma beta-END-LI from a basal level of 8.4 +/- 0.7 pmol/liter to 18.7 +/- 0.8 pmol/liter after 30 min. Oral administration of ursodeoxycholic acid (UDCA) increased plasma beta-END-LI from 7.3 +/- 0.3 pmol/liter to 30.6 +/- 0.2 pmol/liter after 30 min. In gel chromatography, the beta-END-LI released after UDCA administration separated into two components, which eluted in the same positions as human beta-lipotropin and human beta-endorphin, respectively. These results suggested that bile salts may participate the release of beta-END-LI.

Dobutamine prevents both myocardial stunning and phosphocreatine overshoot without affecting ATP level.

Catecholamines can overcome myocardial stunning. However, a previous report on energy metabolism in stunned myocardium during catecholamine infusion was based on the conventional biochemical methods which might affect contractile function. Twenty farm pigs were anesthetized and underwent 15 min coronary artery occlusion and 2 h reperfusion. Ten pigs were given 10 micrograms/kg/min dobutamine from immediately after and throughout the reperfusion (dobutamine group). The other ten pigs were given saline (control group). Phosphorus-31 magnetic resonance spectroscopy and sonomicrometry were done alternately. Dobutamine improved percent segment shortening after reperfusion (control/dobutamine = 3.8%-5.7%/11.7%-13.4%; P < 0.01). At 15 min ischemia, adenosine triphosphate (ATP) decreased (control/dobutamine = 72 +/- 8%/73 +/- 10%, n.s.), and remained depressed after reperfusion in both groups. After reperfusion, phosphocreatine (PCr) returned to and maintained the preischemic value in the dobutamine group, while in the control group, PCr overshoot (112 +/- 5%) was observed. Except for the presence and absence of PCr overshoot, there was no significant difference of ATP and PCr between the two groups, although rate pressure product was significantly higher in the dobutamine group than in the control group. Regional myocardial blood flow after reperfusion was significantly higher in the dobutamine group. Dobutamine may improve "stunning" through effective improvement of energy utilization and production, indicated by the disappearance of PCr overshoot and maintained ATP level.

An elevated type of gastric ulcer scar in patients treated with cimetidine.

An elevated type of gastric ulcer scar (EUS) (A) was noted in 8 out of 227 ulcer patients treated with cimetidine. These were compared with 15 patients with EUS (B), not treated with cimetidine and the etiology of the lesion was discussed. The incidence of EUS (3.5%) and the average age of the patients were higher (61 years) in the A group than in the B group. The scar was seen all over the stomach in the A group. The period from detection of gastric ulcer to confirmation of EUS averaged 4 weeks, and there was no difference between the two groups. No difference was seen in the histological findings of elevated lesions either. In the A group, it appears that EUS was induced by rapid tissue regeneration due to the strong anti-ulcer effect of cimetidine in ulcer lesions, since it was noted in the regions where it had previously been considered unlikely to occur.

Ischemic preconditioning preserves creatine phosphate and intracellular pH.

BACKGROUND: Ischemic preconditioning slows ATP depletion and ultrastructural damage during the final episode of ischemia. To define the influence of creatine phosphate (CP) and intracellular pH (pHi) on this effect, CP and pHi were serially measured in porcine hearts without collateral circulation by using 31P-NMR spectroscopy and ultrastructural examination. METHODS AND RESULTS: Farm pigs weighing 12-15 kg were anesthetized with Fluothane. The control group underwent a single occlusion (20 minutes or 60 minutes); the preconditioned group underwent four episodes of 5-minute occlusion and 5-minute reperfusion followed by a sustained occlusion (20 minutes or 60 minutes). After ischemic preconditioning, CP increased to 115 +/- 11% (p less than 0.05) of preischemic value and ATP decreased to 84 +/- 8% (p less than 0.05) of preischemic value, but pHi returned to preischemic value. At 5 and 10 minutes of sustained ischemia, CP was significantly preserved in the preconditioned group (control group, 19 +/- 3% versus preconditioned group, 29 +/- 4% at 5 minutes; control group, 5 +/- 3% versus preconditioned group, 11 +/- 3% at 10 minutes; p less than 0.05). At 15 and 20 minutes of sustained ischemia, ATP was significantly preserved in the preconditioned group (control group, 64 +/- 3% versus preconditioned group, 73 +/- 3% at 15 minutes; control group, 51 +/- 7% versus preconditioned group, 62 +/- 2% at 20 minutes; p less than 0.05). At 10, 15, 20, and 25 minutes of sustained ischemia, pHi was significantly higher in the preconditioned group (control group, 6.5 +/- 0.05 versus preconditioned group, 6.7 +/- 0.1 at 10 minutes; control group, 6.3 +/- 0.05 versus preconditioned group, 6.6 +/- 0.06 at 15 minutes; control group, 6.1 +/- 0.1 versus preconditioned group, 6.4 +/- 0.1 at 20 minutes; control group, 6.0 +/- 0.2 versus preconditioned group, 6.3 +/- 0.1 at 25 minutes; p less than 0.05). Ultrastructural changes were milder in the preconditioned group at 20 minutes of sustained ischemia. CONCLUSIONS: In addition to ATP and ultrastructure, preconditioning preserved CP and pHi during sustained ischemia. These protective effects might be due to overshoot phenomenon of CP and/or reduced ATP consumption. The relatively longer period of preservation of pHi, which probably is the result of reduced ATP consumption, indicates its greater contribution to reducing infarct size than that of CP and ATP.

[Video-assisted bedside pleuroscopy under local anesthesia: use of a rigid cystoureteroscope in patients with undiagnosed pleural effusion].

Up to 20% of pleural effusions remain undiagnosed despite history-taking, physical examination, thoracentesis, and percutaneous closed pleural biopsy. The next diagnostic procedure used is often thoracoscopy under general anesthesia in an operating room. We report a technique for beside pleuroscopy and pleural biopsy that can be done without assistance of surgeons. We performed video-assisted pleuroscopy with a rigid cysto-ureteroscope in seven patients with pleural effusion that remained undiagnosed despite extensive clinical evaluation. A sterile 19.8 Fr. rigid cysto-ureteroscope was placed into the pleural space under local anesthesia. Pneumothorax was induced to enhance visualization of the surfaces. Forceps-biopsy specimens were taken of suspicious lesions on the parietal pleural. In three patients the pleural surface appeared smooth and in two the parietal pleural surface was studded. A localized coin-like lesion was seen in one patient, and extensive fibrinogenic adhesions and diffuse opacity of the parietal pleura was seen in another. Using this bedside procedure, we diagnosed pleural tuberculosis in three patients and pleural metastases of adenocarcinoma in one. When done under local anesthesia with a rigid cyst-ureteroscopy, video-assisted pleuroscopy can be a safe and useful diagnostic aid in patients with undiagnosed pleural effusion.

[Effects of pranidipine (OPC-13340), a novel 1,4-dihydropyridine derivative Ca-antagonist, on isolated porcine coronary contraction and acute myocardial ischemia in the pig].

Pranidipine (OPC-13340) is a novel, potent and long-acting 1,4-dihydropyridine derivative Ca-antagonist being developed for clinical use as an antihypertensive and antianginal drug. Pranidipine at concentrations of 10(-9) - 10(-6) M suppressed the contraction induced by serotonin (10(-8) - 10(-5) M) or histamine (10(-8) - 10(-4) M) in isolated porcine coronary arteries in a non-competitive and concentration-dependent manner. The potency of this effect of pranidipine was almost similar to that of nifedipine. In anesthetized open-chest pigs with coronary artery occlusion, pranidipine at a dose of 10 micrograms/kg, i.v. lowered blood pressure and increased heart rate, peak dP/dt and % segment shortening of the non-ischemic zone before occlusion. Pranidipine inhibited the ST elevation of the electrocardiogram and the increase in left ventricular end-diastolic pressure during ischemia. These results suggest that pranidipine might relieve symptoms via inhibition of coronary spasm and reduce myocardial ischemia due to reduction of both preload (left ventricular end-diastolic pressure) and afterload (blood pressure).

In vivo and in vitro effects of bradykinin on the release of beta-endorphin-like immunoreactivity.

The effect of bradykinin (BK) on the release of beta-endorphin-like immunoreactivity (beta-EpLI) in rats was studied in vivo and in vitro. Intraperitoneal injection of BK at 5 micrograms/100 g body weight resulted in significant increase in the plasma beta-EpLI level after 15 min. BK at concentrations of 10(-12)-10(-7) M also caused dose-dependent stimulation of beta-EpLI release from dispersed cells of rat anterior pituitary. On gel chromatography, the beta-EpLI released by incubation of the cells with 10(-7) M BK separated into two components, eluted in the same positions as human beta-lipotropin and human beta-endorphin, respectively. BK did not stimulate beta-EpLI release in Ca++-free medium. Addition of 10(-3) M verapamil or 10(-6) M dexamethasone to the incubation medium inhibited BK-induced beta-EpLI release from the cells. Quabain (10(-5) M) also stimulated beta-EpLI release, but its effect was not additive with that of BK. These results indicate that BK stimulates beta-EpLI release and that calcium ion is involved in the mechanism of this effect.

Postprandial release of neurotensin-like immunoreactivity and its mechanism.

The effects of various ingested materials on plasma neurotensin-like immunoreactivity (NTLI) in humans were investigated using a newly developed, specific radioimmunoassay. Plasma NTLI was determined after its extraction with acid/acetone (recovery 77 +/- 4%). The intraassay and interassay coefficients of variation were 3.6% and 8.9%, respectively. The plasma concentration of human NTLI in normal subjects was 5.6 +/- 2.9 pmol/l and showed no significant sex difference. Ingestion of a test meal (150 g of Campbell's condensed meat soup) caused a biphasic rise in plasma NTLI from a basal level of 5.7 +/- 1.0 pmol/l to 10.8 +/- 1.2 pmol/l after 30 min and 9.6 +/- 1.1 pmol/l after 120 min. Ingestion of 5.5 g fat resulted in a biphasic rise in plasma NTLI from a basal level of 4.8 +/- 0.3 pmol/l to 8.9 +/- 0.3 pmol/l after 15 min and 11.9 +/- 0.4 pmol/l after 90 min. When 100-150 mg of ileal mucosa was perfused with a solution of 2 mEq/l fatty acids, 1 mM or 5 mM sodium taurocholate or 154 mM sodium bicarbonate (NaHCO3), the release of NTLI from the mucosa into the perfusate was 2.3-fold, 4.3-fold and 7.5-fold, respectively, over the base level. These results indicate that NTLI release is stimulated by ingestions of meat soup and fat and that NTLI present in the human ileum is released by the direct actions of solutions of fatty acid, sodium taurocholate, and NaHCO3 on the ileal mucosa. These findings strongly suggest that neurotensin (NT) has a physiological role in gut physiology.

Protective effect of verapamil in ischemic porcine hearts: analysis of ultrastructural and metabolic changes using in vivo 31P-NMR spectroscopy.

To assess the protective effect of verapamil on ischemic myocardium, the changes in high energy phosphates, inorganic phosphate, and intracellular pH were serially and quantitatively measured in ischemic porcine hearts without collateral circulation using 31P-NMR spectroscopy, together with ultrastructural examination. Twenty-six farm pigs weighing 11 to 14 kg were anesthetized with fluothane and were divided into control (C) group and verapamil pretreatment (V) group. In V group 0.2 mg/kg of verapamil was administered for 20 mins before occlusion of the anterior descending coronary artery. 31P-NMR spectra were serially obtained throughout the experiment, and ultrastructural examination was done at 20-min occlusion and at 120-minute occlusion in each group. At 10-min ischemia, creatine phosphate was significantly preserved in V group (C/V = 11 +/- 4%/16 +/- 5% P less than 0.05). At 20 min ischemia, ATP was significantly preserved (C/V = 60 +/- 9%/73 +/- 8% P less than 0.05), and intracellular pH was significantly higher in V group (C/V = 6.4 +/- 0.2/6.6 +/- 0.1 P less than 0.05). Morphologically, clumping of the nuclear chromatin, mitochondrial swelling and decrease in glycogen were milder in V group at 20 min ischemia. However, these beneficial effects disappeared at 120 min ischemia. Thus pretreatment with verapamil attenuated depletion of high energy phosphates, progression of acidosis, and ultrastructural changes. There was no significant difference of rate pressure product and regional blood flow between hearts with and without pretreatment of verapamil. Therefore, this protective effect may be due to the energy sparing effect or other direct subcellular effect of verapamil on ischemic myocyte.

Cardiovascular effects of OPC-13340, a potent, long-acting 1,4-dihydropyridine calcium channel blocker, in dogs.

The cardiovascular effects of OPC-13340, a newly developed 1,4-dihydropyridine calcium channel blocker, were examined in several canine preparations. In conscious normotensive and DOCA-salt hypertensive dogs, OPC-13340, at doses of 10 to 30 micrograms/kg, i.v., and 0.3 to 3 mg/kg, p.o., exerted an hypotensive action in a dose-dependent manner. The hypotensive action of OPC-13340 was longer lasting and more potent than that of nicardipine and nifedipine. In conscious, normotensive instrumented dogs, OPC-13340, at doses of 1 and 3 mg/kg, p.o., dose-dependently decreased total peripheral resistance and mean blood pressure and increased heart rate, cardiac output and left ventricular contractility. In anesthetized open-chest dogs, OPC-13340, at doses of 1 to 30 micrograms/kg, i.v., increased coronary blood flow and decreased mean blood pressure, heart rate, coronary vascular resistance, arteriovenous oxygen difference and myocardial oxygen consumption. In contrast to OPC-13340, nicardipine did not change the myocardial oxygen consumption. From these results it was concluded that OPC-13340 lowered blood pressure and improved coronary circulation in dogs and that the duration of these actions was longer lasting than that of nifedipine and nicardipine. These actions of OPC-13340 may be useful in the treatment of hypertension and angina pectoris.