Control mechanisms for total renal blood flow (RBF) or regional blood flow were reviewed. Physiological and experimental conditions will usually cause simultaneous activation of several control mechanisms. The many interactions and secondary effects through release of intrarenal hormones, i.e., the renin-angiotensin system, prostaglandin and the kallikrein-kinin system, complicate the picture even more; but they also make it easy, and tempting, to construct various feedback control systems for renal hemodynamics. 1. There is no functional evidence for renal vasodilator nerves, while both pre- and postglomerular resistance vessels are supplied by adrenergic constrictor nerves. Nervous vasoconstrictor tone is absent or low under basal conditions, but may be activated by a number of afferent stimuli. 2. Intrarenal distributions of adrenergic alpha and beta-receptor are homogeneous and beta-receptor may be selectively located in the afferent arterioles. On the other hand, the distribution of dopamine and acetylcholine receptor is not uniform, and they are distributed more in the inner cortex than in the outer cortex. 3. The renal arterioles are highly sensitive to the vasconstrictor action of angiotensin II and to the vasodilator action of prostaglandin E₂ and bradykinin. Under basal conditions, there seems to be no resting “angiotensin vasoconstrictor tone” and “bradykinin vasodilator tone”, whereas salt depletion and certain types of renal hypertension may be associated with sustained renal vasoconstriction caused by angiotensin II. 4. Autoregulation tends to keep RBF and GFR constant at varying arterial pressure. There is no direct evidence for a metabolic autoregulation of RBF and for a contribution of intrarenal humoral factors for autoregulation. Thus, in spite of only indirect evidence, a Bayliss mechanism is still an attractive hypothesis, and would in fact seems to satisfy more experimental observations than any other mechanism.

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Single administration of FM-100 (50, 200 mg/kg, i.p.), cimetidine (200, 800 mg/kg, i.d.), pirenzepine (5, 20 mg/kg, i.d.) and ASS (20, 80 mg/kg, p.o.) dose-depenently prevented ulcer formation in pylorus-ligated rats. FM-100 and pirenzepine dose-dependently decreased the volume of gastric juice with a slight increase in the pH, but scarcely influenced pepsin activity. The inhibitory effect of cimetidine on gastric secretion was characterized by an elevation in the pH of the gastric juice. ASS at 80 mg/kg, showing antiulcerogenic activity, had a weak antacidic effect on gastric juice without affecting the volume and pepsin activity.
By the combination of FM-100 (50 mg/kg, i.p.) with cimetidine (200 mg/kg, i.d.), pirenzepine (5 mg/kg, i.d.) or ASS (20 mg/kg, p.o.), the preventive effects of these drugs on ulcer formation was augmented; and the combined administration of FM-100 with cimetidine or pirenzepine also enhanced the inhibitory effects of these drugs on gastric secretion.

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The mechanism for the expectorant effect of S-carboxymethylcysteine (S-CMC) was investigated histologically and histochemically using isolated canine trachea. Following S-CMC treatment, the number of total glycoprotein-containing goblet cells (GC) did not change. The numbers of acid glycoprotein (AGP)-, neutral glycoprotein (NGP)-, and sulphated glycoprotein (SGP)-containing GC were also unaltered in a concentration range of 10^-7 to 10^-4M. On the other hand, the ratio of the acinar inner diameter of submucosal glands (SG) to the tracheal wall thickness significantly increased with 10^-5 and 10^-4M S-CMC, and the thickness of the acini of SG significantly decreased with 10^-4M S-CMC. Although the ratio of the numbers of AGP-to NGP-containing glandular cells and AGP content in the cells did not change, the number of SGP-containing glandular cells significantly decreased with 10^-4M S-CMC, and SGP content in the cells significantly decreased concentration-dependently High concentrations (10^-5 and 10^-4M) of S-CMC produced increases in total saccharide, protein and Nacetylhexosamine concentrations in the incubation fluid. These findings suggest that S-CMC has a selective secretagogic action on SG, and an action which alters the composition of AGP, a chief viscous factor, in the mucous granules of SG. The expectorant effect of this agent may, at least in part, be ascribable to these actions.

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Cysteine ethylester (10 ?? 100 mg/kg, p.o.) augmented the production of hemolytic plaque-forming cells (HPFC) to sheep red blood cells and lipopolysaccharide in the spleen of mice. It showed no effect, however, on the HPFC production to trinitrophenylated polyvinylpyrrolidone; and it had no activity as a polyclonal B cell activator like lipopolysaccharide. Cysteine ethylester at a concentration of 3 μM or more potentiated the phagocytosis of yeast by the peritoneal polymorphonuclear leukocytes of rats. This activity was less potent than that of levemisole and D-penicillamine. It also potentiated the reduction of nitroblue tetrazolium (NBT) by blood leukocytes prepared from guinea pigs and a human being. This activity was more potent than that of levamisole and D-penicillamine. Furthermore, cysteine ethylester at doses showing an immunopotentiating activity protected irradiated mice from death by spontaneous infection. These findings suggest that this drug may have a capacity to potentiate the host defense mechanisms.

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It has been demonstrated that suloctidil [erythro-1-(4-isopropylthiophenyl)-2-n-octylaminopropanol] has a protective effect against cerebral hypoxia to elongate the survival time of mice subjected to normobaric hypoxia (96% N₂+4% O₂ gas mixture). In this study, further experiments were done to elucidate the mechanism of protection against cerebral hypoxia with a variety of experimental models. Pretreatment (30 min) with suloctidil (12.5-50 mg/kg, i.p.) increased the number of gasping in the decapitated head of mouse as a complete ischemic model. Pyrithioxine (25, 50 mg/kg, i.p.) or cinnarizine (50, 100 mg/kg, i.p.) did not increase the gasping number. In the histotoxic anoxia with KCN (4 mg/kg, i.v.) in mice, suloctidil showed 30.8% and 46.2% survival rates at the doses of 25 and 50 mg/kg, i.p., respectively. Concerning this result, it has been revealed that suloctidil did not have any methemoglobin formation liability in rats (unpublished). Pyrithioxine did not show such protection following the injection of 12.5-50 mg/kg, i.p.. Suloctidil (3.0-50 mg/kg, i.p.) and pyrithioxine (3.0, 10 mg/kg, i.p.) significantly prolonged the survival time of mice subjected to hypobaric hypoxia (210 mmHg). In this cerebral hypoxia model, suloctidil kept glucose at a significantly higher level and lactate at a lower level in the brain of mice that were administered this drug than the control group. ATP was kept at higher level after suloctidil than the control under hypobaric hypoxia. Taking these evidences together, it can be concluded that suloctidil exerts its cerebral anti-hypoxic effect through cerebral glucose metabolism coupled with oxidative phosphorylation to yield the high energy substance ATP in a variety of models tested in this study. The fact obtained in this study, together with increase in cerebral blood flow by suloctidil, may also elucidate the protective effect of suloctidil against cerebral hypoxia.

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Slow reacting substance of anaphylaxis (SRS-A) and slow reacting substance (SRS) were released from actively sensitized guinea-pig lung with bovine serum albumin and from rat peritoneal exudate cells with ionophore A23187, respectively. FPL55712 markedly inhibited the contraction induced by SRS-A and SRS in guinea-pig ileum which was treated with atropine (10^-7g/ml), mepyramine (10^-6g/ml), and cyproheptadine (10^-7g/ml). Tranilast and isoproterenol markedly suppressed the release of SRS-A in a dose-dependent manner; the concentrations of these drugs that gave 50% inhibition (IC50) were 1.1×10^-4M and 8.3×10^-9M, respectively. Although the inhibitory effect of tranilast (10^-3M) was not affected in the presence of propranolol (3×10^-6M), the inhibitory effect of isoproterenol was greatly diminished by propranolol. Also, tranilast markedly suppressed the release of SRS in a dose-dependent manner, its IC50 being 6.4×10^-5M. However isoproterenol slightly inhibited the release of SRS. Disodium cromoglycate did not suppressed the release of SRS-A at all, and it suppressed SRS release a little. Tranilast inhibited the contraction induced by leukotriene C₄ (0.5 ng/ml) and D₄ (1 ng/ml) in guinea-pig trachea in a dose-dependent manner; the IC50 values were 2.2×10_-4M and 2.0×10_-4M, respectively, for these inhibitions. These results suggest that the inhibition of SRS-A release and SRS-A-induced contraction of smooth muscle by tranilast participates in the anti-asthmatic effect of tranilast, and its inhibitory mechanism is different from that of isoproterenol.

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The effects of brovanexine (BvX) on secretory activities of tracheal secretory cells and on behavior of mucus glycoprotein in these cells were investigated histologically and histochemically using the biopsy technique. When BvX was given at 10 or 20 mg/kg intraduodenally to anesthetized dogs, the thickness of the acini of submucosal glands (SG) and the ratio of the acinar inner diameter to the tracheal wall thickness (A^IWR) markedly increased dose-dependently after 2 to 6 hr. The numbers of goblet cells (GC) and glandular cells showing a stain index B&P with a combination of alcian blue (AB) at pH 2.5 or pH 1.0 and periodic acid-Schiff (PAS) were reduced dose-dependently after 1 to 6 hr, while the number of cells with a stain index R were increased. Both the BvX-induced histological changes in SG and histochemical changes in GC and SG reached a peak after 4 hr. These histological and histochemical changes were also found for the BR-227-, a metabolite of BvX, and bromhexine (BH)-treated groups. BR-227 or BH-induced histological changes were to the same degree as those induced by BvX, but BvX or BR-227-induced histochemical changes were slighter than those induced by BH. The total number of GC stained positively with a combination of AB at pH 2.5 and PAS was unaffected by BvX or BH treatment, while BR-227 tended to decrease it. These findings suggest that BvX both has a secretagogic action selectively on SG and a mucolytic action toward acid glycoprotein in granules of secretory cells in vivo, and these actions are durable.

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The effects of suloctidil, an antispasmodic agent, on the femoral, renal, superior mesenteric, common carotid and vertebral blood flows were compared with those of papaverine and cinnarizine using electromagnetic flow meters in pentobarbital anesthetized dogs. In ix. administration, the peripheral vasodilating action of suloctidil, papaverine and cinnarizine dose-dependently occured from the dose of 0.1 mg/kg, and the order of their potencies in blood flow increase was vertebral ?? femoral ?? common carotid ?? mesenteric artery. However, the renal blood flow decreased byi.v. administration of suloctidil and papaverine. I.a. administration (1-100 μg/kg) of suloctidil, papaverine and cinnarizine dose-dependently increased femoral and common carotid blood flows. I.a. administered suloctidil and papaverine caused a transient increase of renal blood flow followed by a slight decrease. Suloctidil-induced increase of femoral blood flow was not affected by the pre-treatment with atropine, propranolol or diphenhydramine. Thus, suloctidil may cause direct vasodilation to increase regional blood flow, and its influence on the various blood flows is roughly similar to those of papaverine and cinnarizine.

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The effects of traxanox, an anti-allergic drug, on the cardiovascular system were studied in both anesthetized dogs and cats and in isolated heart preparations from guinea-pigs. In anesthetized dogs, a very small dose of traxanox (0.01 mg/kg, i.v.) had no effect, but 0.1 ?? 30 mg/kg caused an increase in respiratory rate, hypotension, bradycardia, a transient decrease followed by an increase in renal blood flow, and a decrease in femoral blood flow. These effects were abolished by vagal block, indicating they are mediated via vagal afferents. In contrast, oral administration of traxanox (100 mg/kg) had no effect on the blood pressure or heart rate of anesthetized dogs. In anesthetized cats, traxanox (3 and 30 mg/kg, i.v.) caused a slight increase in blood pressure, but showed no effect on respiratory rate and heart rate. Both traxanox and theophylline (10^-4M) caused increases in the beat rate of the atria and the contractile force of the papillary muscle in isolated preparations from guinea-pigs, and they potentiated the positive chronotropic and inotropic responses induced by isoproterenol. On the other hand, in anesthetized and vagotomized dogs, traxanox (3 and 10 mg/kg, i.v.) affected neither the left ventricular contractile force nor the hypotension and positive inotropic and chronotropic responses produced by isoproterenol. Administration of theophylline alone (3 and 10 mg/kg, i.v.) caused hypotension and increases in contractile force and heart rate, but it did not enhance the responses produced by isoproterenol. At doses of 1 and 10 mg/kg (i.v.), traxanox had little effect on either pressor or chronotropic responses to norepinephrine, epinephrine, DMPP and stellate cardiac nerve stimulation. The same doses of traxanox slightly reduced the depressor and chronotropic responses to isoproterenol, acetylcholine and vagus nerve stimulation. These findings suggest that traxanox had no effect on the cardiovascular systems of the animals studied in the dose range (1 ?? 5 mg/kg, p.o.) showing anti-allergic activity.

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The effect of traxanox on SRS-A release was examined in vivo and compared with that of disodium cromoglycate (DSCG). Intravenous antigen challenge produced an intense anaphylactic bronchoconstriction that showed a peak time of 5 min in egg albumin-sensitized guinea pigs pretreated with three agents, mepyramine (2.5 mg/kg, i.v.), indomethacin (1 mg/kg, i.v.) and propranolol (0.05 mg/kg, i.v.). This bronchoconstriction was almost completely inhibited by additional pretreatment with an SRS-A antagonist, FPL 55712 (2.5 mg/kg, i.v.). A lipoxygenase inhibitor, BW755C (10 mg/kg, i.v.), also significantly inhibited this reaction. These results indicate that this anaphylactic bronchoconstriction is due to the release of endogenous SRS-A. In this model, traxanox (5 and 10 mg/kg, i.v.) showed a dose-related inhibition, but DSCG (10 mg/kg, i.v.) did not. FPL 55712 (1 mg/kg, i.v.) administered at the peak time of the bronchoconstriction caused a relaxation. Traxanox, on the other hand, failed to relax this reaction. In IgE-mediated rat passive peritoneal anaphylaxis (PPA), traxanox (0.01 ?? 10 μg/rat, i.p.) inhibited the release of SRS-A and histamine dose-dependently. This inhibitory effect was about 10 ?? 20 times as potent as that of DSCG. In addition, both traxanox (0.1 μg/rat, i.p.) and DSCG (1 μg/rat, i.p.) showed a synergistic effect in combination with isoproterenol (0.01 μg/rat, i.p.) and an additive effect with theophylline (100 μg/rat, i.p.) in inhibiting the release of SRS-A in rat PPA. These results suggest that traxanox inhibits the release of SRS-A in vivo, so that it may be clinically effective in treating patients with allergic bronchial asthma.

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