Effects of protamine and lanthanum on contractile responses of isolated guinea pig ileum segment or ileum longitudinal muscle strip plus relaxtion responses of the isolated guinea pig taenia coli have been demonstrated herein. Protamine and lanthanum inhibited nonspecifically contractile responses of the ileum to various agonists such as acetylcholine, serotonin, bradykinin, potassium chloride and barium chloride and caused a depression of the maximum response in the acetylcholine dose-response curve. Nonspecific inhibitory actions were similar to papaverine action since the inhibitory actions were overcome easily with addition of calcium ion to the organ bath fluids. Protamine and lanthanum, however, inhibited to a greater degree contractile responses by such agonists as serotonin and bradykinin that act through receptors rather than through membrane. Both protamine and lanthanum blocked the relaxation response by isoproterenol in taenia coli without reducing the resting tone of the muscle. From these findings, it is presumed that protamine and lanthanum have the same mechanism or site of action, that is, they replace the surface site calcium ion on the cell membrane, thus blocking the utilization of calcium which is essential for a receptor-agonist interaction.
Using a thermoelectrical method, relationships between the elevation in brain activities caused by CNS stimulants and convulsants and those in regional blood flow were observed. Brain temp. and regional blood flow increased, closely in accordance with the degree of changes in the brain activities, especially just before seizure discharges. There were a few exceptions however, when sympathetic innervation was greatly affected.
Calcium or sodium polystylene sulphonate resin was orally administered to nephrectomized rats, and the survival rate and duration, serum electrolytes and enzyme activities, and other serum chemistry were examined. Both resins clearly increased the survival rate and duration. Ca-resin lowered K+ without effects on Na+, Mg++, and Ca++. Na-resin lowered K+ with increase in Na+ and decrease in Mg++ and Ca++. Neither resin influenced serum enzyme activities, and was practically ineffective regarding serum urea nitrogen, cholesterol, protein and sugar.
I. Action of spasmogens. Evidence has been obtained suggesting that (1) for all of the spasmogens (K, ACh, Ba) tested, phasic contraction is produced by Ca release while tonic contraction is maintained by the energy-dependent influx of Ca. (2) Only in case of Ba, is a direct stimulation to the contractile protein of muscle partly concerned with contraction. This is implied by a residual contraction by Ba in the Ca-free bath solution. (3) Ba releases Ca from the store of easily releasable Ca, as K and ACh, and in addition from the store of less easily releasable Ca. II. Action of antispasmodics. As the result of various experiments, it was concluded that (1) antispasmodic action of isoproterenol is attributed to the depression of muscle cell membrane, that is, due to the pseudo-competitive (or functional) inhibition of release and then influx of Ca with increased concentrations used. (2) Antispasmodic actions of papaverine and chlorpromazine are attributed to the depression of membrane (competitive inhibition of influx and then release of Ca) followed by a non-competitive inhibition against the contracting action of Ca on the muscle contractile system with increase of concentrations.
In a previous paper, it was reported that F-1, a new non-steroidal compound, had a potent inhibitory effect similar to that of fiufenamic acid (FA) and phenylbutazone (PB) on experimental acute inflammation. General pharmacological actions of F-1 are described herein. Analgesic action of F-1 was similar to that of mefenamic acid (MA) and more potent than that of FA and PB. F-1 did not show significant activities in such tests as locomotion, rotarod, anticonvulsion, hypnotic potentiation to barbiturates, hypothermic and anti-pyretic action. It appeared, therefore, not to have side effects on the central nervous system. It was also free of any effect on the cardiovascular and respiratory systems, renal function, blood coagulation and blood sugar level in doses causing anti-inflammatory effect. F-1 inhibited isolated intestinal movement and relaxed smooth muscle in a high concentration and did not show specific antagonistic action on such spasmogens as histamine, acetylcholine and BaCl2. F-1 inhibited contraction of the intestine by 5-HT and diarrhea by 5-HTP. Therefore, F-1 was found to have weak anti-serotonic action. F-1 was found to have potent anti-inflammatory action and few side effects. It may be considered that F-1 can be classified as a non-steroidal analgesic and anti-inflammatory agent.
Since the report of Mizushima in which it was stated that a number of acidic anti-inflammatory drugs inhibited heat denaturation of protein, the interaction between anti-inflammatory agents and protein has been studied in various materials. F-1, a non-steroidal acidic analgesic and anti-inflammatory agent, was also investigated concerning the interaction with protein. F-i inhibited heat denaturation of bovin serum albumin (BSA) at pH 5.3 and the activity was more potent than that of phenylbutazone and similar to fenamates. F-i had a more potent inhibitory effect than phenylbutazone and fenamates on binding of pyridoxal-5-phosphoric acid and trinitrobenzaldehyde to BSA. Interaction of F-1 with the above BSA correlated with the inhibitory effect on hypotonic-hyperthermic hemolysis and enzyme activity of trypsin and α-chymotrypsin. F-1 showed a similar affinity to fenamates on erythrocytes in rats. Serum protein in adjuvant arthritis rats differed from control serum (decrease of albumin contents and A/G ratio, increase of haptoprotein and heat denaturation). F-1 improved qualitatively and quantitatively those serum changes. From the above results, F-1 was found to bind with protein and to have the same properties as known acidic antiinflammatory agents. Mode of interaction of F-1 differed to some extent from fenamates.
In order to examine the effect of sodium hydrodextran sulfate (HDS) on experimental atherosclerosis spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NR) were fed a high-fat diet with and without the drug. Blood samples were collected for 5 months to measure serum levels of cholesterol, triglyceride and clearing factor lipase activity. Effect of HDS on certain blood factors were as follows: 1) HDS inhibited the increase of serum cholesterol levels in rats. 2) HDS did not change the triglyceride concentration. 3) HDS elevated the clearing factor lipase activity. 4) A high-fat diet increased the intimal thickening of arteries in SHR. 5) Intimal thickening of arteries decreased slightly in the HDS treated group.
In adjuvant arthritic rats, the relationship between hind paw swelling and mucopolysac-charase (β-glucuronidase, N-acetyl-β-glucosaminidase and lysozyme), protease (pH 3.1 and7.0) and collagenolytic activities in serum and hind paws was investigated. Furthermore, the effects of various anti-inflammatory drugs (phenylbutazone, bucolome, indomethacin, prednisolone, azathioprine, chloroquine diphosphate and a anti-plasmin agent, DV-1006) administered orally once a day were examined 3 and 21 days after adjuvant injection. The swelling of right (injected) hind paw increased remarkably after adjuvant injection and reached a first peak on day 3, after which it decreased gradually. About 10 days later, however, it began to increase again and the swelling of left (non-injected) hind paw also occurred simultaneously. The swelling reached maximum intensity by day 21 in the right hind paw and by day 28 in the left. The activities of three mucopolysaccharases and protease at pH 3.1 in both hind paws changed as did swelling of each hind paw after adjuvant injection. Changes of these enzyme activities in serum ran parallel with those of right paw swelling. On the other hand, the collagenolytic activity in both hind paws increased rapidly and remarkably after 14 days. On day 3, swelling of the right paw was strongly inhibited by the drugs except for azathioprine, chloroquine diphosphate and DV-1006. On day 21, the swelling of both hind paws was remarkably inhibited by all drugs except chloroquine diphosphate. On day 21, a parallel relationship was proved between anti-swelling activity and anti-mucopolysaccharase or anti-protease (pH 3.1) activity in left hind paw and serum by drugs, although not necessarily on day 3. On day 21, collagenolytic activity was inhibited by all drugs. These results suggest that these lysosomal enzymes are main mediators in the development of a secondary lesion in adjuvant arthritic rats.
The effects on Monoamine Oxidase (MAO) in rat brain and liver and production of methemoglobin (Met-Hb) in blood by the administration of NaNO2 and NH2OH have been studied and the following results were obtained : Administration of NaNO2 and NH2OH caused a marked increase in the blood level of Met-Hb. Met-Hb in blood was 6.4 and 4.5 g/dl after i. p. administration of 100mg/kg NaNO2 and NH2OH, respectively. The blood level of Met-Hb reached a maximum at 15 and 30min following i. p. administration of 50mg/kg NaNO2 and NH2OH, respectively and then disappered gradually. Rats were administered NaNO2 i. p. in a dose of 50mg/kg/day for 30 days. The blood level of Met-Hb was increased slightly on the 3rd-4th day. The increasing MAO activity in rat liver was observed immediately and on the 2nd day following i. p. administration of 50mg/kg NaNO2 when tyramine was used as substrate. When benzylamine was used as substrate, MAO activity increased at 2-3 hours and on the 4th day. MAO activity in rat brain markedly increased on the 3 rd-4th day following i. p. administration of NaNO2 with tyramine as substrate. Similar results were obtained when serotonin (5-HT) was used as substrate. Rats were administered NH2OH i. p. in a dose of 50mg/kg/day for 30 days. The blood level of Met-Hb was increased slightly on the 3rd-4 th day. When tyramine was used as substrate, increasing MAO activity was observed on the 5th day of administration. Significant change of MAO activity was not observed when benzylamine was used as substrate. In case of brain, MAO activity increased on the 4th-6th day and decreased 1st-2nd day and 14th-20th day of administration when tyramine was used as substrate. Almost similar results were obtained when 5-HT was used as substrate.