General pharmacological properties of the human corticotropin-releasing hormone corticorelin (human).

General pharmacological effects of the human corticotropin-releasing hormone, corticorelin (human) (CAS 86784-80-7), on the central nervous system, somatic nervous system, autonomic nervous system and smooth muscle, respiratory and circulatory system, digestive system and miscellaneous organs were investigated. 1. The central nervous system: Corticorelin (human) had little effect on hexobarbital-induced sleeping-time, maximal electroshock-induced convulsion, acetic acid-induced writhing, rota-rod performance. Corticorelin (human) at doses of more than 10 micrograms/kg i.v. induced flush of skin and pilo-erection, at doses of more than 30 micrograms/kg i.v. decreased body temperature, delayed expression of perphenazine-induced catalepsy and indicated hunched posture, and at the dose of 100 micrograms/kg i.v. induced the rise of awake-level and decrease of the total power of EEG, and decreased the spontaneous motor activity. 2. The somatic nervous system: Corticorelin (human) did not cause muscle relaxation in mice and had little effect on neuromuscular transmission in rats. No local anesthetic activity of corticorelin (human) was exhibited through inhibition of the corneal reflex in guinea pigs. 3. The autonomic nervous system and smooth muscle: Corticorelin (human) had no effect on the contraction of isolated ileum of guinea pigs induced by histamine and acetylcholine, and on the contraction of isolated trachea of guinea pigs induced by histamine, and the pupil diameter of rabbits. Corticorelin (human) at doses more than 30 micrograms/kg i.v. decreased spontaneous motility and contractile force of uterus of non-pregnant rabbits. 4. The respiratory and circulatory system: Corticorelin (human) had no effect on the contraction of isolated aorta of rats induced by norepinephrine. Corticorelin (human) at doses of more than 3 micrograms/kg i.v. decreased the blood pressure, increased heart rates and slightly increased the number of respiration in dogs. However, corticorelin (human) had no effect on ECG and femoral blood flow in dogs. 5. The digestive system: Corticorelin (human) at doses of more than 0.3 microgram/kg i.v. increased duodenal motility and contractile force, at doses of more than 1 microgram/kg i.v. increased colonic contractile force transiently and increased antral motility. Corticorelin (human) at doses of more than 3 micrograms/kg i.v. caused diarrhea and at doses of more than 30 micrograms/kg i.v. inhibited small intestinal propulsion in mice. Corticorelin (human) at dose of 100 micrograms/kg i.v. showed an inhibition of the gastric juice secretion and decreased the excretion of Na+, Cl- and H+ in rats. Corticorelin (human) produced slight gastric damages only at the highest dose of 100 micrograms/kg i.v.(ABSTRACT TRUNCATED AT 400 WORDS)

[Effects of terazosin on the blood pressure responses to tilting in conscious animals: comparison with prazosin].

Inhibitory effects of terazosin on the compensatory blood pressure responses to tilting were studied in conscious rabbits and spontaneously hypertensive rats (SHR). In rabbits, doses which reduced the mean blood pressure by 15 mmHg were 330 micrograms/kg, i.v., for terazosin and 42 micrograms/kg, i.v., for prazosin, while those which depressed the blood pressure responses to tilting by 30 mmHg were 180 micrograms/kg, i.v., for terazosin and 54 micrograms/kg, i.v., for prazosin. In SHR, almost equal decreases in the mean blood pressure (about 30%) were observed by 1 mg/kg prazosin, p.o., 20 mg/kg hexamethonium, i.p., 3 mg/kg hydralazine, p.o., or 3 mg/kg nicardipine, p.o. In these conditions, prazosin and hexamethonium markedly depressed the blood pressure responses to tilting, whereas hydralazine and nicardipine showed little effect. The results with these antihypertensive drugs closely paralleled the established orthostatic profiles seen clinically. In this SHR tilting model, when the mean blood pressure was reduced by 15%, prazosin significantly depressed the tilting reflexes; however, terazosin produced no depression. Considering the dose ratio of terazosin to prazosin for antihypertensive effects and inhibitory effects on the tilting reflexes, the orthostatic liability of terazosin was about 3 times as low as that of prazosin. On the basis of these results, it is expected that terazosin causes less orthostatic hypotension than prazosin in clinical use.

Effect of MCI-176, a new calcium antagonist, on the calcium induced contraction of isolated porcine coronary arteries.

Calcium antagonistic activity of MCI-176, a new calcium antagonist, was compared with those of diltiazem and nifedipine in isolated depolarized porcine coronary arteries. MCI-176, diltiazem and nifedipine competitively inhibited calcium contraction of the large coronary arteries, and their pA2 values were 7.49, 6.89 and 9.55, respectively. Similar competitive inhibition by MCI-176, diltiazem and nifedipine of calcium contraction was also observed in the small coronary arteries, and their pA2 values were 7.38, 6.83 and 9.91, respectively. Although calcium antagonistic activity of nifedipine was several hundreds times more potent than MCI-176 and diltiazem, the action of nifedipine, unlike MCI-176 and diltiazem, favored the small coronary arteries rather than the large coronary arteries.

[Alpha-adrenoceptor blocking action of terazosin].

alpha-Adrenoceptor blocking activities and vascular relaxation activities of terazosin, a new antihypertensive agent, were studied. Terazosin had no effect on Ba2+, serotonin, angiotensin II and Ca2+ induced contractions in the isolated rat aorta. Terazosin competitively inhibited norepinephrine (NE) and phenylephrine (PE) induced contractions of the isolated rat aorta, and their pA2 values were 9.28 and 8.74, respectively. The potency of terazosin in the NE induced contraction was about 0.11, 8 and 176 times more than prazosin, phentolamine and yohimbine, respectively. The potency of terazosin in the PE induced contraction was about 0.09, 6 and 60 times more than prazosin, phentolamine and yohimbine. Terazosin (i.v.) competitively inhibited the PE induced pressor response. The "pA2" values of postsynaptic alpha-adrenoceptor blocking activity was 5.22, and its potency was about 0.05, 5 and 62.5 times more than prazosin, phentolamine and yohimbine, respectively. Terazosin (0.3 mg/kg, i.v. or less) did not show any significant effect on clonidine induced bradycardia during electrical stimulation of cardiac sympathetic nerve, whereas prazosin (0.3 mg/kg), phentolamine (0.1 mg/kg) and yohimbine (0.1 mg/kg) antagonized the effect of clonidine by 37%, 80.6% and 63.3%, respectively. Terazosin, 0.3 and 1 mg/kg, p.o., antagonized the PE (3 micrograms/kg, i.v.) induced pressor response in conscious unrestrained rats. This effect lasted for 8 hr in the case of 0.3 mg/kg and lasted for 12 hr in the case of 1 mg/kg. Thus, it is strong suggested that the antihypertensive effect of terazosin is based on the postsynaptic alpha-adrenoceptor blocking action.

Coronary dilator effect of MCI-176, a new calcium channel blocker, in dogs.

Effects of MCI-176, 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopropox y-4 (3H)-quinazolinone hydrochloride, on coronary and aortic blood flows, mean blood pressure and heart rate were investigated in comparison with those of diltiazem in anesthetized dogs. MCI-176, like diltiazem, dose-dependently increased coronary and aortic blood flows and decreased mean blood pressure. In producing these effect MCI-176 was slightly but significantly more potent than diltiazem. Heart rate tended to increase with MCI-176, whereas it tended to decrease with diltiazem.

[Cardiovascular effects of MY-5116 and MY-1250].

The effects of MY-5116, isoamyl 5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c]quinoline-2-carboxylate, an anti-allergic drug, and MY-1250, an active metabolite of MY-5116, on the cardiovascular system were studied in dogs, rats and guinea pigs. Orally administered MY-5116 (300 mg/kg) had no effect on the cardiovascular system in anesthetized dogs and conscious rats. In anesthetized dogs, MY-1250 and disodium cromoglycate (DSCG) caused hypotension, bradycardia and reduction of respiration rate from the doses of 3 and 10 micrograms/kg, i.v., respectively. Both drugs showed a tachyphylaxic phenomena which was crossed with each other. MY-1250-induced cardiovascular effects were abolished by bilateral vagotomy. MY-1250 (3-30 micrograms/kg, i.v.) caused a decrease of carotid blood flow, a transient decrease followed by a slight increase of renal blood flow, and a transient increase followed by a slight decrease of femoral blood flow in anesthetized dogs. MY-1250 had no effect on sympathetic ganglion, but increased the contractile force of isolated left atria from guinea pigs at 10(-5) g/ml and increased its rate at 10(-4) g/ml. These positive inotropic and chronotropic effects were not influenced by reserpinization. MY-1250 had no effect on the norepinephrine-induced dose-response curve in isolated rat aorta.

A device for indirect measurement of blood pressure in conscious dogs.

A technique for indirect measurement of blood pressure by a combination of commercially available apparatuses was devised. There were good correlations in both of systolic and diastolic blood pressures measured by the indirect and direct methods.

[Effect of suloctidil on the contractions of isolated rat aortic strips induced by norepinephrine and CaCl2].

The mode for the antispasmodic action of suloctidil was examined using aorta strips of rats in vitro. Both 10 microM suloctidil and 0.1 microM verapamil non-competitively inhibited the norepinephrine (NE)-induced contraction, of which pD'2 values were 4.61 +/- 0.41 and 6.16 +/- 0.22, respectively. Prazosin at 1 nM competitively inhibited the NE-induced contraction, and its pA2 value was 9.84 +/- 0.15. In the depolarized aorta, suloctidil competitively inhibited the CaCl2-induced contraction at the concentrations of 0.1 and 1.0 microM, of which the pA2 value was 5.96 +/- 0.26. However, 10 microM suloctidil inhibited the CaCl2-induced contraction in a non-competitive manner, and its pD'2 value was 5.01 +/- 0.14. The pA2 values for papaverine, verapamil and cinnarizine were found to be 5.23 +/- 0.10, 7.53 +/- 0.09 and 7.11 +/- 0.11 in CaCl2 induced contraction, respectively. In a Ca2+ free medium, 1 microM NE caused a transient contraction, which was maximum (23.8 +/- 2.2% of that in a normal solution) at 0.4 min after the application of NE. Subsequent application of 2.5 and 10 mM CaCl2 evoked a gradual contractile response, of which the maximum was 103.1 +/- 4.2% and 133.8 +/- 10.3% of that in a normal solution, respectively. Initial phasic contraction induced by NE in a Ca2+ free medium was not affected by 10 microM suloctidil nor by 0.1 microM verapamil, while this contraction was significantly suppressed by 1 nM prazosin. The tonic contraction, however, induced by re-application of CaCl2 was significantly suppressed by 10 microM suloctidil, 0.1 microM verapamil and 1 nM prazosin. Furthermore, 1.0 microM suloctidil and 0.1 microM verapamil significantly suppressed the 45Ca uptake into the depolarized aorta 5 and 10 min after the addition of 45CaCl2. On the contrary, suloctidil had no influence on the phosphodiesterase activity prepared from the aorta of rats even at 10 microM, whereas 1.0 microM papaverine inhibited the enzyme activity. It is concluded that suloctidil and verapamil inhibit the contractions of the isolated rat aorta induced by NE and CaCl2 through the inhibition of the influx of Ca2+ without affecting the intracellular Ca2+ release.

[Effect of suloctidil on the dynamics of the peripheral artery of the dog].

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 i.v. administration, the peripheral vasodilating action of suloctidil, papaverine and cinnarizine dose-dependently occurred from the dose of 0.1 mg/kg, and the order of their potencies in blood flow increase was vertebral greater than or equal to femoral greater than or equal to common carotid much greater than mesenteric artery. However, the renal blood flow decreased by i.v. administration of suloctidil and papaverine. I.a. administration (1-100 micrograms/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.

[Effect of suloctidil on cerebral venous outflow in the dog (author's transl)].

The effects of intravenous administration of suloctidil [erythro-1-(4-isopropylthiophenyl)-2-n-octylamino-propanol], (MY 103) on cerebral venous outflow (VOF), blood gases, cerebral metabolic rate of oxygen (CMRO2) and other hemodynamic parameters were studied and effects compared to those of cinnarizine and papaverine, in gallamine immobilized dogs. MY103 and papaverine at doses 0.1-1.0 mg/kg, i.v. caused significant increases in VOF by 6.1-38.3% and 12.1-26.1% respectively. The changes in VOF persisted for 1.4 min and 0.5 min in mean following 1.0 mg/kg, i.v. of MY103 and papaverine, respectively. Cinnarizine also increased VOF by 10.0 and 18.7% at doses 0.3 and 1.0 mg/kg i.v. The duration of VOF changes by cinnarizine 1.0 mg/kg, i.v., 2.4 min (mean), was no longer than the duration seen with the same dose of MY103 or papaverine. Mean blood pressure (MBP) decreased dose dependently with these drugs and consequently the cerebral vascular resistance (CVR) decreased 8.6-40.2% with MY103, 13.6-25.0% with cinnarizine and 16.1-39.5% with papaverine administration, respectively. MY103 and papaverine at a dose of 1.0 mg/kg i.v. did not affect pH, Pco2 and Po2 in arterial blood, but these two drugs did show a tendency to lower Pco2 and elevate Po2 in cerebral venous blood. CMRO2 was not significantly affected by MY103 or papaverine. It is suggested that cerebral vasodilation may be the mechanism for VOF increase following MY103 administration.

Vasodilation produced by prostacyclin (PGI2) and 9(O)-thiaprostacyclin (PGI2-S) in the canine femoral circulation.

The action of 9(0)-thiaprostacyclin (PGI2-S) was compared with that of prostacyclin (PGI2) and papaverine in the femoral circulation of dogs. PGI2-S, injected into the dog femoral artery in a dose of 0.1 microgram or higher, produced marked vasodilation in the femoral artery without any change in blood pressure. The potentcy of PGI2-S was one tenth that of PGI2, and was a hundred times that of papaverine. The stability of PGI2-S in neutral solution was forty times that of PGI2.

Effects of ethyl adenosine-5'-carboxylate on the heart and coronary circulation.

Using the canine heart-lung preparation supported by a donor, the effects of ehtyl adenosine-5'-carboxylate (EAC) on the heart and coronary circulation were studied and compared with those of adenosine. EAC produced qualitatively similar effects to adenosine in this preparation. Aminophylline inhibited the effects of EAC as well as those of adenosine. Dipyridamole did not potentiate the effects of EAC, while it produced a definite potentiation of the effects of adenosine.