Imidazoline derivatives, clonidine and guanfacine, were reviewed with respect to their effect on blood pressure. Excitation of the central alpha-adrenoceptors induced by clonidine or guanfacine produced a simultaneous decrease in peripheral sympathetic tone, hypotension and bradycardia. Both ponto-medullary regions and the hypothalamus are important action sites for these two drugs. With respect to the effects of clonidine or guanfacine on central alpha-adrenoceptors, two possibilities were investigated. First, we presumed that the excitation of central alpha-adrenoceptors induced by these two drugs appears to be located at postsynaptic sites. Thus, the alpha₂-subtype was considered. Secondarily, stimulation of the central presynaptic alpha₂ receptor produced by clonidine or guanfacine could not be excluded completely. It has been reported that after abrupt cessation of guanfacine, a withdrawal syndrome infrequently occurs which is moderate as compared with that caused by the abrupt cessation of clonidine. In comparison with clonidine, the characteristics of guanfacine pharmacokinetics, including its large volume of distribution, long biological half life and long duration of action, appear to be associated with the infrequent occurrence of withdrawal syndrome after guanfacine cessation.

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The analgesic effects of pirprofen on bradykinin-induced flexor reflexes in rats and rabbits were investigated in comparison with those of indomethacin and ibuprofen by oral administrations. The bradykinin-induced flexor reflexes in rats were suppressed by pirprofen at 10 mg/kg ?? 200 mg/kg, the effect reaching plateau at over 30 mg/kg. Suppression at the dose of 200 mg/kg was 56%. A similar dose-dependent curve was obtained for ibuprofen at 30 mg/kg ?? 300 mg/kg. On the other hand, indomethacin exerted dose-dependent inhibition at 1 mg/kg ?? 10 mg/kg without a tendency to reach the plateau effect within this dose range. Suppression at the dose of 10 mg/kg was 83%. The ED50 values of pirprofen, indomethacin and ibuprofen were 68 mg/kg, 3.3 mg/kg and 94 mg/kg, respectively. On the bradykinin-induced flexor reflexes in rabbits, pirprofen showed 60% suppression at the dose of 10 mg/kg, of which the effects were roughly equivalent to those of indomethacin and ibupropofen at the same dosage. These results indicate that there is a spiecies difference concerning the three drug activities on bradykinin-induced flexor reflexes between the rat and the rabbit.

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In order to clarify the role of prostaglandins (PGs) in the activity of cholinergic neurones other than the ileal myenteric plexus, the effects of indomethacin (IND) and PGE₂ on the contractile responses and the release of acetylcholine (ACh) induced by electrical stimulation were investigated in isolated guinea-pig phrenic nerve-diaphragm and chicken parasympathetically innervated oesophagus preparations. In the guinea-pig phrenic nervediaphragm preparations, IND at 56 μM did not affect the twitch responses induced by direct or indirect electrical stimulation. PGE₂ at 1 μg/ml augumented the twitch responses induced by direct or indirect stimulation of submaximal, but not of supramaximal intensity. The amounts of ACh released from the phrenic nerve by electrical stimulation were unaffected by IND (56 μM). PGE₂ (0.01-1 μg/ml) inhibited the ACh release by the nerve stimulation of high frequency (50 Hz) in a concentration-dependent manner. The inhibitory effect of PGE₂ was less clear on the ACh release by lower frequency (1 Hz). Neither IND nor PGE₂ affected the ACh release induced by 40 mM-K⁺. In the chicken parasympathetically innervated oesophagus preparation, IND (2.8 ?? 5.6 μM) augmented the twitch responses induced by the nerve stimulation at a frequency of 0.017 Hz, but not those produced by train pulse (5 sec at a frequency of 1 or 10 Hz). This augmentation was reversed by the application of PGE₂ at 10 ng/ml. PGE₂ at 10 ng/ml produced a transient inhibition of the twitch responses induced by 0.017 Hz or train pulses. IND (2.8 μM) significantly increased the ACh release evoked by the parasympathetic nerve stimulation at a frequency of 10 Hz. This increase was reversed by the application of PGE₂ at 10 ng/ml. The ACh release by the nerve stimulation at a frequency of 1 Hz was slightly increased by IND (2.8 μM). PGE₂ at 10 ng/ml significantly decreased the ACh release evoked by the nerve stimulation at a frequency of either 1 or 10 Hz. The results indicate that in the guinea-pig phrenic nerve-diaphragm and chicken parasympathetically innervated oesophagus preparations, PG has both neurotropic and musculotropic actions. Thus, it inhibits the release of ACh evoked by the electrical nerve stimulation acting on the nerve on one hand and augments the twitch responses acting directly on the muscle cell on the other. Since IND did not affect the electrically evoked release of ACh from the phrenic nerve, whereas it affected the release from chicken parasympathetic nerve, it is suggested that endogenous PGs are physiologically less important in regulating the activity of motor nerve.

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General pharmacological properties of cinobufagin (CB), isolated from Senso, were compared with those of digitoxin (DT). Decrement of spontaneous movement, inhibition of writhing, prolongation of hexobarbital-induced hypnosis, muscle relaxation, inhibition of acetic acid-induced capillary permeability, hypothermia, antipyretic effect in mice; excitation of respiration in rabbits; nerve blocking action in the isolated sciatic nerve of frogs; cardiotonic effect in the isolated atria of guinea pigs; contraction of the isolated ileum of rabbits and guinea pigs; contraction of the aorta of guinea pigs; and relaxation of the isolated trachea of guinea pigs were common properties observed after separate application of CB and DT. Membrane stabilizing effect in erythrocytes of rats and inhibition of propulsive motility of the small intestine in mice were observed only after the application of CB. Inhibition of gastric juice secretion, antiinflammation on carrageenin- or dextran-induced edema, diuresis in rats, mydriasis in mice and potentiation of transmission in the neuromuscular junction of rats were observed only after the application of DT. After oral administration, the onset of the effects of CB (30 min) was faster than that of DT (3-4 hr), and the duration of the effects of CB (1-2 hr) was shorter than that of DT (>24 hr).

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In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.

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The angiotensin converting enzyme (ACE) activity in tissues and plasma renin activity (PRA) were measured in 2-kidney, 1-clip renal hypertensive rats (2K-RHR) and normotensive rats after a single and 3-weeks oral administrations of ACE inhibitors such as MK-421 and captopril. In the single dose study, MK-421 (1 and 3 mg/kg) and captopril (3 and 10 mg/kg) inhibited the ACE activities in kidney, aorta and plasma in a dose-dependent fashion. The inhibition of ACE activity in kidney or aorta was observed for a longer time than that in plasma. PRA took a time course reversal to that of plasma ACE activity. In the 3-weeks repeated dose study, the ACE activity in kidney and aorta was strongly inhibited after the administration of each ACE inhibitor, while there was no significant change in lung ACE activity at any time point examined. The plasma ACE activity markedly elevated after the administration of each agent. PRA significantly increased after the administration of either agent, while the plasma angiotensin II level was significantly inhibited. These results indicate that the inhibition of the ACE activity in blood vessel or kidney correlate well with the antihypertensive activity in 2K-RHR after a single and repeated administration of both ACE inhibitors, but not well with the inhibition of plasma ACE activity.

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Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of verapamil hydrochloride and propranolol hydrochloride in anesthetized open-chest dogs. Intravenous injection of 5-ISMN (3 mg/kg) considerably lowered systolic blood pressure (SBP). Especially, stroke volume (SV), cardiac output (CO), cardiac work (CW) and systolic right ventricular pressure (SRVP) were significantly decreased. 5-ISMN also produced a continuous reduction in mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (MPCWP) and mean right atrium pressure (MRAP), while heart rate (HR) and total peripheral resistance (TPR) were not altered significantly. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered diastolic blood pressure (DBP). Verapamil also caused a significant decrease in HR, CW and TPR and a slight decrease in SRVP and MPCWP. However, SV was significantly increased, and slight increases in MPAP and MRAP were also observed. Propranolol (0.5 mg/kg, i.v.) greatly decreased HR together with CO, CW, SRVP and MPAP and slightly decreased MPCWP, while it caused a considerable increase in SV and a slight increase in TPR. The finding that administration of 5-ISMN resulted in reduction of pre-load and after-load suggests the possibility that this drug might decrease venous return and thereby reduce myocardial oxygen requirements.

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The anti-anoxic effect of sufoxazine was investigated in various cerebral anoxia models with mice, in comparison with those of various cerebroactive drugs. Sufoxazine reduced dosedependently the duration of coma induced by a sublethal dose of KCN (1.8 mg/kg, i.v.), significantly stimulating recovery from the coma at 5 mg/kg, i.p. and 30 mg/kg, p.o. It also protected against a lethal dose of KCN (2.5 mg/kg, i.v.). Sufoxazine prolonged the survival time of mice subjected to hypobaric and normobaric hypoxia. Dihydroergotoxin and ifenprodil gave similar protection in the KCN-induced anoxia models, but produced adverse effects in the hypoxia models. Calcium hopantenate exerted similar but weak protection only at a dose as high as 300 mg/kg, i.p. These findings suggest that sufoxazine has an anti-anoxic action superior to those of the other cerebroactive drugs used.

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