The concept of clinical application of the vasodilator therapy for the treatment of cardiac failure is based on the experimental findings that defined the inverse relationship between force and velocity or extent of muscle shortening at constant muscle lengths. In the intact heart, a new construct has recently been proposed in hopes of better understanding the behavior of the normal or depressed human ventricle in which the shortening during ejection is considered to reflect the appropriateness of the matching between the existing afterload and the level of inotropic state, as modulated by the preload (or Frank-Starling) reserve. In the normal left ventricle, if the preload is not allowed to compensate for an acute increase in afterload, or if the limit of preload reserve is reached, shortening of the ventricular wall will diminish; that is, afterload mismatch will ensue. The view that an afterload mismatch can exist in the basal state provides an explanation for the fact that cardiac output and ventricular function can be improved when afterload is reduced in patients with severe left ventricular failure complicated with acute myocardial infarction or with mitral or aortic regurgitation. However, in the ischemic myocardium, the effect of interventions which alter the afterload on the left ventricular ejection is also determined by the pre-existing ischemic status. Thus, depending on the magnitude of coronary flow reduction, a potentially beneficial drug can be detrimental to an ischemic myocardium.

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Effects of tofisopam on the gastric ulceration induced by immobilization stress in olfactory-bulbectomized rats, propulsion of the small intestine caused by water immersion-stress in rats and autonomic responses to electrical stimulation of the hypothalamus in rabbits were investigated. Immobilization stress loading of 16.5 hours each for 10 days caused the augmentation of incidence and average index of gastric ulceration in olfactory-bulbectomized rats, compared with non-treated rats. Tofisopam 100 mg/kg, p.o. significantly inhibited the gastric ulceration in olfactory-bulbectomized rats. Water immersion-stress loading for 2 hours caused a significant increase in propulsion of the small intestine in rats. This increase was reversed to control levels after the oral administration of tofisopam in a dose of 100 mg/kg. Tofisopam at dose of 1 mg/kg i.v. inhibited the contraction of ear microvessels, the decrease in earlobe temperature and the mydriasis induced by electrical stimulation of the medial hypothalamic area in rabbits. Moreover, these inhibitions were also shown by the intra-cerebrospinal injection of tofisopam at a dose of 0.1 mg/kg. From these results, it is concluded that tofisopam could restore the autonomic abnormality induced by stress-loading and exerts such effects by acting on the hypothalamus, an area of the brain, which regulates autonomic nervous functions.

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D-Penicillamine (D-PA), 80-100 mg/kg/day enhanced the early phase of adjuvant arthritis (AA) in rats when it was administered orally for about 4 weeks after the adjuvant injection day, whereas dexamethasone (1 mg/ kg/day, p.o.) and chloroquine diphosphate (25 mg/kg/day, p.o.) inhibited AA in the same dosing regimen. On the other hand, subcutaneous injection of sodium aurothiomalate (12.5 mg/kg/day) enhanced AA initially, but inhibited it later. The enhancing effect of D-PA on the early phase of AA was observed also at doses of 50 mg/kg/day and 200 mg/kg/day, but, in the case of 200 mg/kg/day, inhibited the later phase of AA. When the administration of D-PA was started before the adjuvant injection, it showed a tendency to suppress AA on proportion to the dosing period. The effect of D-PA, however, was not observed in the model when the drug administration was started after the establishment of arthritis. The co-administration of pyridoxine HCl did not influence the effect of D-PA on AA. A good correlation was not obtained between the inflammatory score and the PPD induced skin reaction, serum metals level and histopathological changes of lymph node in the AA rats treated with D-PA. Thus the effect of D-PA on AA was related to dose, timing and duration of the administration. It was suggested that the enhancing and inhibitory effects of D-PA on AA were not based on vitamin B₆ depletion, but rather were caused by inhibition of T₁ and T₂ lymphocytes which may be regulating this arthritis process.

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Ventricular arrhythmias due to myocardial infarct were produced in 14 dogs, and the antiarrhythmic effects of quinidine (Qd), lidocaine (Lid), aprindine (Apr), and dl-propranolol (dl-Prop) were investigated. While recording the blood pressure and lead II ECG, a coroaary cannula was inserted into a coronary orfice via the left carotid artery and a glass bead (diameter, 1.5 mm) was flushed into the left coronary artery. Beads were found at the descending branches in 12 and circumflex branches in 2 out of 14 dogs, at autopsy. Using a telemetry system to record the lead II ECG of conscious, non-restricted dogs, the antiarrhythimic effects of Qd, Lid, Apr, and dl-Prop on ventricular arrhythmias 24 hours after coronary occlusion were compared. Apr and dl-Prop were about three times more potent than Qd and Lid. Although the durations of the antiarrhythmic effects of Apr, Lid, and dl-Prop were 20 to 30 min, that of Qd lasted longer. Since stable ventricular arrhythmias can be obtained by surgical intervention and the antiarrhythmic effects of standard compounds can be clearly recognized in conscious, non-restricted dogs, ventricular arrhythmias due to coronary occlusion with glass beads can be used to study antiarrhythmic effects.

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Using Hornstra's “filter loop” technique, effects of prostaglandins and vasodilators on ADP-induced platelet aggregation were studied in anaesthetized dogs. ADP-induced platelet aggregation was observed as a transient, reversible elevation of pressure before filter. This pressure change was reproducible and dose-related. PGI₂ and PGE₁ suppressed the elevation of pressure induced by ADP and decreased the spontaneous elevation of pressure. Thus, it was reconfirmed that PGI₂ and PGE₁ not only suppressed ADP-induced platelet aggregation but also produced a disaggregation of aggregated platelets. After indomethacin, ADP-induced platelet aggregation was potentiated and sometimes became exceedingly protracted, indicating that anti-aggregatory prostaglandin was always present in the circulating blood. Close-injection of bradykinin did not suppress ADP-induced platelet aggregation, while intravenous injection did produce a suppression. After indomethacin, this inhibitory effect was greatly attenuated, indicating a release of anti-aggregatory prostaglandin (PGI₂?) by bradykinin. Coronary vasodilators, such as dipyridamole and nifedipine did not inhibit ADP-induced platelet aggregation, nor did sulfinpyrazone. It is concluded that the “filter loop” technique is a useful method that allows aggregation and disaggregation reactions to be followed continuously and quantitatively in the flowing blood. The effects of drugs on platelet aggregation can be assessed in connection with hemodynamic changes such as blood pressure and heart rate induced by systemic administration of the drugs.

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The inhibitory effects of anti-inflammatory drugs on the erythema induced by arachidonic acid in guinea pigs were studied. Values of ED50 (mg/kg, p.o.) were; diclofenac sodium (19.9), indomethacin (28.1), naproxen (52.4), phenylbutazone (67.1), ibuprofen (81.3), aspirin (92.6). These drugs, however, were ineffective on the erythema induced by prostaglandin E₂. Basic nonsteroidal and steroidal anti-inflammatory drugs and anti-oxidants were negative in the inhibition of arachidonic acid-induced erythema. Cyproheptadine as an anti-histamine and -serotonin agent and morphine as a CNS acting agent were also negative. Erythema did not occur following treatment with linoleic acid, linolenic acid and γ-linolenic acid. Bishomo-γ-linolenic acid-induced erythema was inhibited by diclofenac sodium. The inhibition of acidic nonsteroidal anti-inflammatory drugs in this system seemed to be the result of a block of the enzymatic conversion of arachidonic acid to prostaglandin. The arachidonic acid-induced erythema in guinea pigs can serve as a new animal model for evaluating prostaglandins biosynthesis inhibitors such as anti-inflammatory drugs.

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Hypolipemic effects of soysterol, pantethine and dl-α-tocopheryl nicotinate (α-TN) were investigated on hyperlipemia induced in male Sprague-Dawley rats by ingestion of a cholesterol diet (HCD) containing 0.5% of cholesterol for 12 days. The test drugs were dissolved in olive oil and administered by gavage in a dose of 200 mg/2 ml/kg daily for 12 days. Lipid levels in the serum and in the liver were measured after 6 and 12 days of treatment. The treatment for 6 days of soysterol significantly inhibited the increase in serum total cholesterol (s-TC) and triglyceride (s-TG) induced by HCD. In addition to the increase in serum total lipid, free cholesterol and phospholipid (s-PL) induced by HCD were also inhibited by this treatment. Soysterol prevented the decrease of cholesterol in high density lipoprotein (HDL-C) and the increase in s-TC induced by HCD, resulting in a significant reduction of the atherogenic index, s-TC-HDL-C/HDL-C (atherogenic index using HDL-C). The treatment for 12 days of soysterol markedly inhibited the increase in serum lipid levels as compared treatment to the 6 day. There was a significant reduction of atherogenic index using HDL-C and phospholipid in high density lipoprotein (HDL-PL, s-PL-HDL-PL/HDL-PL). Soysterol inhibited increases in liver total lipid as induced by HCD in the treatment for 12 days. The treatment for 6 days of pantethine significantly inhibited the increase of s-TC, s-TG and s-PL, but had no effect on the decrease in HDL-C and HDL-PL induced by HCD. The decrease in HDL-C and HDL-PL was markedly prevented by the treatment of pantethine for 12 days. Inhibitory effects of pantethine on atherogenic index were also obtained. Pantethine had no effect on liver lipid levels. α-TN had no effect on the increase in serum and liver lipid levels induced by HCD. A histoligical study of the liver showed that soysterol inhibited fat-degeneration.

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Effects of Bromovincamine (BV) on cerebral noradrenaline (NA) and 5-hydroxytryptamine (5-HT) contents, and glucose metabolism in the brain were studied using stroke-prone spontaneously hypertensive (SHR-SP), stroke-resistant spontaneously hypertensive (SHR), age-matched normotensive Wistar Kyoto (WKR) and Wistar rats. In the SHR-SP which have a low level of NA in the hypothalamus, a continuous administration of BV for 1 week induced a normalization of the hypothalamic NA content. Under the same experimental conditions, a tendency toward normalization of hypothalamic NA was also observed in SHR. 5-HT contents in the cerebellum, striatum, hypothalamus, midbrain and hippocampus of SHR showed a significant increase following a single injection of BV. Similarly, 5-HT contents in the cerebellum and cerebral cortex of Wistar, WKR and SHR showed a significant increase following a continuous administration of BV for 1 week. Both in vitro and in vivo administration of BV significantly inhibited the high concentration of K⁺ evoked glucose consumption in cerebral cortical slices from SHR, WKR and Wistar rats, whereas glucose consumption in cerebral cortical slices from SHR determined in the absence of high concentration of K⁺ increased significantly following continuous in vivo administration of BV. The present results suggest that BV may be an useful drug for improving abnormal cerebral metabolisms of NA, 5-HT and glucose.

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The mechanisms of hyperglycemia induced by an oral administration of As₂O₃ were investigated in treated and non-treated rats. The highest level of blood sugar appeared 4 hours after an oral administration of As₂O₃ 15 mg/kg. As₂O₃-induced hyperglycemia was inhibited with bilateral splanchnicotomy, adrenalectomy or adrenodemedullation. As₂O₃-induced hyperglycemia was accelerated with bilateral vagotomy. As₂O₃-induced hyperglycemia was moderately inhibited by depressing the central nervous system activity with barbital sodium. As₂O₃-induced hyperglycemia was not affected with ephedrine but was inhibited with nicotine, drugs which accelerate catecholamine release of the adrenals. Pretreatment with hexamethonium, torazoline, propranolol or atropine which obstruct the release of catecholamine in adrenals inhibited As₂O₃-induced hyperglycemia. Hepatic glycogen levels decreased 2 hours after As₂O₃ 15 mg/kg administration and returned to normal levels in about 24 hours. These findings indicate that As₂O₃-induced hyperglycemia was not the result of direct effects of As₂O₃ on the adrenals but rather was due to effects on the central nervous system.

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Changes in tension of spiral strips of saphenous, femoral and external carotid arteries and veins were measured isometrically. DEM stimulated 6 preparations in almost the same concentration ranges (pD₂ values were 8.64 to 8.40). However, the dose-response curves for DEM indicated variations in responsiveness among the different arteries and veins. Compared with norepinephrine (NE) (1) the intrinsic activity of DEM was 0.002 on saphenous arteries, 0.05 on saphenous veins, 0.03 on femoral arteries, 0.18 on femoral veins, 0.13 on external carotid arteries and 0.13 on external carotid jugular veins. Thus DEM contracted more potently the venous strips from the hind limbs. In femaral and external carotid arteries, antagonism of serotonin by DEM or methysergide was investigated. DEM displaced the dose-contractile response curves for serotonin in a noncompetitive manner, and the antagonistic response of DEM to serotonin was about 8 times more effective in external carotid arteries (pD'₂ value=6.96) than in femoral arteries (pD'₂ value=6.05). Methysergide, unlike DEM, antagonized the response to serotonin in a competitive manner at low doses but in a noncompetitive manner in high doses, and was fairly equal in antagonizing response to serotonin in external carotid arteries (pA₂ value= 9.59, pD'₂ value=4.73) and femoral arteries (pA₂ value=9.14, pD'₂ value=4.63). The present results suggest that the therapeutic value of DEM in the treatment of orthostatic hypotension is due to its selective venoconstrictive effect in the lower extermities and in the treatment of migraine headache to its selective anti-serotonin activity on the external carotid arteries.

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