Numerical modelling of the petroleum oil penetration into sandy beach sediments.

A numerical model describing the penetration of petroleum oil into sandy beach sediments was developed to assess the behavior of stranded oil at tidal zone as a result of tanker accidents, and so on. To understand the penetration behavior, penetration rate of three species of petroleum oil (two species of fuel oil C and one species of crude oil) was observed experimentally with artificial tidal zone equipment. As a consequence, two types of oil were distinguished from the viewpoint of penetration rate. One (fuel oil C-1) kept its homogeneity in composition and showed relatively rapid penetration, the other (fuel oil C-2 and crude oil) became heterogeneous and slow in penetration. Considering this aspect as the adsorption of polar compounds (i.e. asphaltenes) on the sediment surface, a numerical model that described oil penetration into sandy beach was developed. As a result, the difference in penetration rate between these two types of oil could not be replicated sufficiently only by consideration of the adsorption. However, the change of a parameter value which represents the apparent viscosity of oil led to good agreement with observations. Simulation results indicated that when fuel oil C or crude oil used in this study was stranded at a sandy beach located in Hiroshima Bay, Japan, 2 to 39% of total stranded oil might penetrate into the deeper zone (> 3 cm in depth) over 50 days.

Effect of non-aqueous phase liquid on biodegradation of PAHs in spilled oil on tidal flat.

Biodegradation rates of polycyclic aromatic hydrocarbons (PAHs) in spilled oil stranded on tidal flats were studied using model reactors to clarify the effects of NAPL on the biodegradation of PAHs in stranded oil on tidal flat with special emphasis on the relationship between dissolution rates of PAHs into water and viscosity of NAPL. Biodegradation of PAHs in NAPL was limited by the dissolution rates of PAHs into water. Biodegradation rate of chrysene was smaller than that for acenaphthene and phenanthrene due to the smaller dissolution rates. Dissolution rates of PAHs in fuel oil C were smaller those in crude oil due to high viscosity of fuel oil C. Therefore, biodegradation rates of PAHs in fuel oil C were smaller than those in crude oil. Biodegradation rates of PAHs in NAPL with slow decrease rate like fuel oil C were slower than those in NAPL with rapid decrease like crude oil. The smaller decrease rate of fuel oil C than crude oil was due to higher viscosity of fuel oil C. Therefore, not only the dissolution rate of PAHs but also the decrease rates of NAPL were important factors for the biodegradation of PAHs.

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors.

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.

Cardioprotection of SM-15681, an Na+/H+ exchange inhibitor in ischemic and hypoxic isolated perfused rat hearts.

We investigated the effects of SM-15681 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide monohydrochloride) on Na+/H+ exchange activity in the myocardium and in ischemic and hypoxic injury in isolated perfused rat hearts. These effects were compared with those of ethylisopropyl amiloride (EIPA). Na+/H+ exchange activity was studied with a NH4Cl prepulse technique under HCO3(-)-free conditions. SM-15681 (10(-8)-10(-7) M) inhibited pH recovery of acidosis in the rat myocardium in a concentration-dependent manner and the IC50 value of SM-15681 (80 nM) was similar to that of EIPA. In perfused rat hearts, SM-15681 (10(-6) M) and EIPA (10(-6) M) significantly improved cardiac functions and prevented enzyme release and abnormal elevation of tissue Ca2+ content during 20 min of reperfusion after 40 min of ischemia and 20 min of reoxygenation after 30 min of hypoxia. We conclude that an Na+/H+ exchange inhibitor, SM-15681, shows cardioprotective effects on ischemia/reperfusion and hypoxia/reoxygenation injury. Our results also support the hypothesis that Na+/H+ exchange contributes to the pathophysiology of cardiac ischemic reperfusion injury.

Salt-sensitive hypertension in transgenic mice overexpressing Na(+)-proton exchanger.

Essential hypertension is one of the most common diseases that exacerbate the risk of cardiovascular or cerebrovascular attacks. Although the etiology of essential hypertension remains unclear, recent investigations have revealed that an enhancement of Na(+)-proton (Na(+)-H+) exchange activity is a frequently observed ion transport abnormality in hypertensive patients and animal models. To test the hypothesis that increased Na(+)-H+ exchange causes hypertension, we produced transgenic mice overexpressing Na(+)-H+ exchanger and analyzed their Na+ metabolism and blood pressure. Urinary excretion of water and Na+ was significantly decreased in transgenic mice, and systolic blood pressure was elevated after salt loading. The impaired urinary excretion of Na+ suggested that the Na(+)-H+ exchanger overexpressed in the renal tubules increased reabsorption of Na+, which caused a blood pressure elevation by Na+ retention after excessive salt intake. Our results demonstrate that overexpression of Na(+)-H+ exchanger can be a genetic factor that interacts with excessive salt intake and causes salt-sensitive blood pressure elevation.

Activation of Na(+)-H+ antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system.

The Na(+)-H+ antiporter is a unique transmembrane protein with multiple roles in cellular functions through intracellular alkalization. It participates in the regulation of intracellular pH, cell volume and intracellular signalling in response to various mitogenic stimuli. To clarify its role as a subcellular signal in cardiovascular remodeling like vascular hyperplasia or cardiac hypertrophy, we determined mRNA levels of the Na(+)-H+ antiporter isoform, NHE-1, in vascular smooth muscles and pressure-overloaded hearts in rabbits. The NHE-1 mRNA levels in rabbit aortas and hearts were developmentally regulated with high levels at embryonic and neonatal stages than in adults. In primary-cultured smooth muscle cells (SMC), the mRNA levels were increased during exponential growth, but decreased to initial levels at confluency. Growth of a mutant SMC line, C5, which is deficient in Na(+)-H+ antiporter activity, was markedly reduced in bicarbonate-free medium. However, when the activity was restored by transfecting cells with a full-length NHE-1 cDNA in an expression vector, the growth rate of C5 was accelerated again. After balloon injury to the vascular wall, the NHE-1 mRNA levels of the injured arteries were also increased, suggesting that Na(+)-H+ antiporter contributes to the network of the growth promoting systems in smooth muscle cells in vivo. Pressure-overload on the ventricle increased the NHE-1 mRNA levels in hearts approximately two-fold of sham-operated rabbits after 3 days and remained for at least two weeks (P < 0.05). We further demonstrated that 3-methylsulfonyl-4-piperidino-benzoyl guanidine mesylate (Hoe 694), a potent antagonist of Na(+)-H+ antiporter, partially inhibited stretch-induced activation of mitogen-activated kinase (MAP kinase) in the cultured cardiomyocytes. From these results, we conclude that activation of the Na(+)-H+ antiporter and its gene expression is involved in molecular mechanisms of both cardiac hypertrophy and vascular smooth muscle cell proliferation, indicating a potential target in developing new therapeutics for cardiovascular diseases.

Calcium channel blocking properties of SM-6586 in rat heart and brain as assessed by radioligand binding assay.

The interaction of SM-6586 (methyl 1,4-dihydro-2,6-dimethyl-3-[3-(N-benzyl-N-methyl-aminomethyl)-1,2,4- oxadiazolyl-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate) with the specific binding of 3H-PN200-110 to rat heart and brain membranes was characterized and compared with those of other Ca2+ antagonists. The blockade of 3H-PN200-110 binding sites induced by nifedipine, nitrendipine and nimodipine was reversed by washing, whereas the blockade by SM-6586 was not readily reversed under these conditions. No significant difference was found in irreversibility between SM-6586 enantiomers. When rat aortic strips were pretreated with SM-6586, the contractions induced by 50 mM KCl were inhibits even though SM-6586 was not present in the extracellular medium. This residual inhibitory effect was much stronger than that of nicardipine. The inhibition of KCl-induced contractions by nifedipine and nitrendipine was easily reversed by washing. Thus, we suggest that (+)SM-6586 is a novel 1,4-dihydropyridine derivative having a very slow rate of dissociation from the binding site. This property may explain its long-lasting antihypertensive effect.

Assessment of Ca(2+)-antagonistic effect of SM-6586 and its isomers, novel 1,4-dihydropyridine derivatives, by radioligand binding assay.

The Ca(2+)-antagonistic effects of the 1,4-dihydropyridine derivative (+/-)SM-6586 and its optical isomers were compared with those of its two derivatives ((+/-)SM-7297 and (+/-)SM-7548) and other Ca(2+)-antagonists using a radioligand binding assay. The Ca(2+)-antagonistic effects of the optical isomers of SM-6586 were in the order of (+) greater than (+/-) greater than (-)SM-6586 in both rat brain and heart. The pKi value of (+)SM-6586 was comparable to those of nimodipine, nicardipine, nifedipine and nitrendipine. The pA2 value for (+)SM-6586 was the highest among the SM-6586 isomers, thus suggesting that (+)SM-6586 has a potent Ca(2+)-antagonistic effect.

Prevention of cerebral stroke by arotinolol in salt-loaded SHRSP.

The preventive effects of long-term treatment with arotinolol on the development of cerebral stroke were examined in SHRSP fed a high salt diet. Arotinolol (4.87 mg/kg per day for 20 weeks) prevented cerebral lesions, reduced signs of stroke and delayed early mortality but did not alter blood pressure from control SHRSP, when the administration of the drug was started before the onset of hypertension. At dosage levels similar to arotinolol, both pindolol and labetalol were less effective in preventing cerebral lesions despite lower blood pressure. Propranolol produced no detectable effect on blood pressure or frequency of cerebral lesions. Furthermore, arotinolol (4.27 mg/kg per day) markedly inhibited the development of stroke without blood pressure reduction, when the administration was started after the onset of severe hypertension. These results suggest that arotinolol is more effective in preventing cerebral stroke than pindolol, labetalol and propranolol, and that factors other than blood pressure reduction may be involved in this preventive effect.

Adrenoceptor blocking effects of arotinolol, a new combined alpha- and beta-adrenoceptor blocking agent.

In isolated tissues and anesthetized animals, beta- and alpha-adrenoceptor blocking properties of arotinolol were studied in comparison with those of other typical adrenoceptor antagonists. The following order of beta-adrenoceptor blocking activities were obtained in isolated tissues: arotinolol = pindolol greater than propranolol = oxprenolol = alprenolol greater than or equal to labetalol for beta 1-adrenoceptors (guinea-pig right atrium) and pindolol = oxprenolol = arotinolol greater than propranolol greater than labetalol for beta 2-adrenoceptors (guinea-pig trachea). In anesthetized cats, arotinolol was about 9 and 25 times more potent than propranolol, about 30 and 100 times more potent than labetalol in blocking beta 1- and beta 2-adrenoceptors, respectively. Furthermore arotinolol showed a competitive antagonistic effect on phenylephrine-induced contraction of isolated rat aortic strips. The relative order of alpha 1-adrenoceptor blocking potencies was as follows: prazosin greater than phentolamine greater than labetalol greater than arotinolol = yohimbine. Presynaptic alpha 2-adrenoceptor blocking action of arotinolol was also assessed in isolated rat vas deferens and arotinolol was revealed to be a much weaker presynaptic alpha 2-adrenoceptor antagonist. In anesthetized rats arotinolol was 4-5 times less potent than labetalol and about 26 times less potent than phentolamine in blocking alpha 1-adrenoceptors. Thus, as for the selectivity for 2 subtypes of alpha-adrenoceptors, arotinolol showed a selectivity for alpha 1-adrenoceptors over presynaptic alpha 2-adrenoceptors.

[Antihypertensive effect of arotinolol (S-596), a new adrenergic beta blocking agent, on experimental hypertension].

Effects of a new adrenergic beta-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other beta-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the beta- or alpha-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day) propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the beta-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596, (10-50 mg/kg/day) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic alpha-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the 1st administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.

Effects of the new beta-adrenoceptor blocking agent, S-596 on the peripheral autonomic nervous system and smooth muscles.

The effects of the new beta-adrenoceptor blocking agent, S-596, on the peripheral autonomic nervous system and smooth muscles were studied in comparison with propranolol. In urethane or alpha-chloralose anesthetized cats S-596 (10 micrograms/kg, i.v.) antagonized the cardiovascular responses induced by isoproterenol. S-596, in doses ranging from 100 to 300 micrograms/kg (i.v.) reduced the contractions of the nictitating membrane induced by electrical stimulation of preganglionic and postganglionic fibers to the superior cervical ganglion. Higher doses of S-596 were required to depress the effects of noradrenaline and tyramine. In spinal cats the tyramine and noradrenaline dose-response curve was shifted to the right by S-596. In isolated rat aortic strips S-596 displaced the noradrenaline dose-response curve to the right in a parallel fashion indicating a competitive antagonism. Its potency was about one tenth of that of phentolamine. These results suggest that S-596 possesses both alpha-and beta-adrenoceptor blocking activities.

[Pharmacological properties of dl-2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl) thiazole hydrochloride (S-596), a new beta-adrenergic blocking agent (author's transl)].

We developed a new beta-adrenergic blocking, antiarrhythmic compound S-596 and compared the findings with those of propranolol or practolol. S-596 antagonized the positive chronotropic and inotropic actions of adrenaline in isolated guinea-pig atria, and blocked the relaxant response to adrenaline of isolated guinea pig tracheal strips. In anesthetized mongrel dogs, S-596 given intravenously inhibited increases in heart rate and myocardial contractile force and decreases in systemic blood pressure induced by isoproterenol. In conscious dogs, the oral administration of S-596 reduced the isoproterenol induced tachycardia and the maximal effect was attained one hour after administration. In this regard S-596 was about 5 times more potent than propranolol, and S-596 was significantly longer-acting than propranolol. Thus, S-596 has greater beta-blocking activity than propranolol. S-596 has a lesser degree of myocardial depressant action than propranolol in spontaneously contracting rat or guinea pig atria and no intrinsic sympathomimetic activity in reserpinized rats. S-596 also has a weaker local anesthetic and antiarrhythmic activity than propranolol, as determined in guinea pigs and rabbits.

Synthesis and beta-adrenergic blocking action of a new thiazolylthiopropanolamine derivative.

The synthesis of (+/-)-2-(3'-tert-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole hydrochloride is described. The new compound antagonized the cardiovascular effects, such as positive chronotropic, positive inotropic, or depressor arterial blood pressure responses, elicited by intravenous isoproterenol; it was 9--14 times as potent as propranolol in anesthetized open chest dogs. The oral administration of the compound reduced isoproterenol tachycardia in conscious dogs. It was about five times as potent as propranolol in this test, with maximal action after 1 hr, and its duration was significantly longer than that of propranolol.