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Intracerebroventricular injections of capsaicin at 100–500 nmol elicited dose-dependent decreases in urine outflow volume in anesthetized, hydrated rats. The capsaicin (500 nmol)-induced antidiuresis was inhibited by pretreatment with CP96345 (30 nmol, a neurokinin-1-receptor antagonist), but not by that with phenoxybenzamine (20 nmol, an alpha-adrenoceptor antagonist), timolol (100 nmol, a beta-adrenoceptor antagonist) or atropine (300 nmol, a muscarinic antagonist) into the hypothalamic supraoptic nucleus (SON). Intravenous injections of d(CH2)5-D-Tyr(Et)VAVP (50 μg/kg, a vasopressin-receptor antagonist) completely blocked the antidiuresis. In intra-SON microdialysis experiments, acetylcholine concentration in the perfusate of the capsaicin-injected rats was not different from that of the vehicle-injected rats. These findings suggested that capsaicin stimulated substance P release in the SON and caused the antidiuresis as a result of the increased release of vasopressin into the circulation from the neurohypophysis mediated through neurokinin-1 receptors in the SON.

We have investigated opioid mechanisms concerning regulation of urine production in the hypothalamic supraoptic nucleus (SON). In this study, the effect of [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), a potent selective mu-opioid agonist, microinjected into the SON of anesthetized hydrated rats, on the urine outflow rate was examined. DAMGO caused a dose-dependent decrease in the urine outflow rate with no significant changes in blood pressure nor heart rate. The ED50 value for the antidiuresis was calculated to be 0.055 nmol from the dose-response curve. The antidiuresis elicited by DAMGO (0.1 nmol) was partially inhibited by intra-SON pre-injection of naloxone (3 nmol), a relatively mu-selective opioid antagonist, and timolol (100 nmol), a beta-adrenoceptor antagonist, but not by intra-SON pre-injection of phenoxybenzamine (20 nmol), an alpha-adrenoceptor antagonist, nor atropine (300 nmol), a muscarinic antagonist. Intravenous injection of d(CH2)5-D-Tyr(Et)VAVP (16.7 micrograms), a vasopressin receptor antagonist, did not influence the DAMGO-induced antidiuresis. These findings suggest that antidiuresis mediated through mu-opioid receptors in the SON involves beta-adrenoceptors in the nuclei, but does not involve an increase in vasopressin release.

We tried to produce a new ulcerative colitis model in rats by topical administration of sulfhydryl blockers. After male SD rats were fasted for 24 hr, 100 microliters of 3% N-ethylmaleimide (NEM) or iodoacetamide (IA) was introduced into the colon via a Nelaton's catheter. Both NEM and IA caused severe diarrhea with rectal bleeding and decreased body weight for about 7 days. At autopsy, adhesions and dilatation of the colon and severe mucosal lesions were observed. Both the weight and myeloperoxidase activity of the colon increased markedly. Maximum changes were observed within 1-3 days followed by gradual recovery, but even on day 21, some abnormalities were still observed. The ulceration and inflammation of the colon were confirmed by histological studies. Antiinflammatory drugs such as indomethacin inhibited the inflammation of the colon by NEM, but aggravated the ulceration. These results revealed that sulfhydryl blockers instilled into the colon caused ulcerative colitis in the rat. This model may be useful in studies on the pathogenesis of ulcerative colitis and the evaluation of drugs for therapy. Furthermore, it was suggested that antiinflammatory drugs may delay the healing of colonic ulcers.

We investigated the effects of angiotensin II (Ang II), microinjected into the supraoptic (SON) and paraventricular (PVN) nuclei of rats, on the urine outflow rate and underlying mechanisms. Ang II produced antidiuretic effects in a dose-dependent manner with ED50 values of 0.1 and 0.05 nmol in the SON and PVN, respectively. [Sar1, Ile8]Ang II at 0.1 nmol diminished the Ang II (0.5 nmol)-induced antidiureses in the SON more markedly than in the PVN. A high dose of [Sar1,Ile8]Ang II, 1 nmol, completely inhibited the effects in both the nuclei. In addition, the Ang II (1 nmol)-induced antidiuretic effects were partially inhibited by phenoxybenzamine (80 nmol) in the SON and by phenoxybenzamine, timolol (100 nmol) and propranolol (100 nmol) in the PVN. The microinjection of Ang II (1 nmol) into both the nuclei, after pretreatment with a vasopressin V1V2-antagonist, d(CH2)5-D-Tyr(Et)VAVP (i.v.) significantly increased the urine outflow rate. These findings suggest that 1) Two mechanisms account for the Ang II receptor-mediated antidiureses resulting from an increase in vasopressin release: direct stimulation on vasopressin-containing neurons and indirect stimulation on them through alpha-adrenoceptors in the SON and alpha- and beta-adrenoceptors in the PVN; 2) The Ang II-induced antidiuretic effect in the SON is slightly less potent than that in the PVN; and 3) Ang II receptors in the nuclei may possibly produce the diureses through mechanisms that are not presently understood.

The effects of D-Ala2-D-Leu5-enkephalin (DADL, a delta-opioid agonist), microinjected directly into the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, on urine outflow rate, urinary osmotic pressure, blood pressure, heart rate, respiratory rate and rectal temperature were investigated in water-loaded and ethanol-anesthetized rats. The microinjection of DADL into both the nuclei decreased urine outflow rate in a dose-dependent manner with an increase in urinary osmotic pressure, but did not change the other recorded parameters. The DADL-induced antidiuretic effect in the SON was inhibited by naloxone, but not by atropine, phenoxybenzamine, timolol nor a vasopressin antagonist, d(CH2)5-D-Tyr(Et)VAVP. The effect in the PVN was inhibited by naloxone, atropine, timolol and d(CH2)5-D-Tyr(Et)VAVP, but not by phenoxybenzamine. These results suggest that DADL causes antidiuretic effects mediated through opioid receptors in both the SON and PVN, and the underlying mechanisms are different between them. Involvement of delta-opioid receptors in the DADL-induced antidiureses was discussed.

alpha 1-Adrenoceptors in the rat prostate were characterized by a binding assay using the newly synthesized radioligand [3H]-YM617 (5-[2-[[2[ethoxyring(n)-3H](o-ethoxyphenoxy)ethyl]amino]prop yl]-2-methoxybenzenesulfonamide HCl) and an in vitro assay. Specific [3H]-YM617 binding in the rat prostate was saturable and of high affinity (KD = 61.5 +/- 5.9 pM) with 23.2 +/- 6.9 fmol/mg of protein as the maximal number of binding sites (Bmax). alpha-Adrenoceptor agonists and antagonists inhibited the binding of the radioligand with the following order of effectiveness: YM617 > prazosin = bunazosin > WB4101 > 5-methylurapidil = phenoxybenzamine > phentolamine > S(+)-isomer of YM617 > yohimbine > norepinephrine > phenylephrine > methoxamine. alpha 1-Adrenoceptors in the rat prostate preferred the R(-)-isomer of YM617 to the S(+)-isomer. Preincubation with chlorethylclonidine (CEC; 10(-5) M, 10 min) just slightly changed the Bmax value for [3H]-YM617 without changing the KD value in the prostate; however, CEC reduced the Bmax in the aorta. In the isolated tissue, pretreatment with CEC (10(-5) M, 10 and 30 min) time-dependently shifted to the right the dose-response curve for phenylephrine and decreased the maximal contraction of aortas induced by phenylephrine, but did not shift or decrease those of prostates. The present results indicate that the alpha 1-adrenoceptors in the rat prostate are mainly CEC-insensitive (alpha 1A), whereas those in the aorta are CEC-sensitive (alpha 1B).

The mechanisms for the antidiuretic effects of dynorphin (DYN), an endogenous kappa-agonist, microinjected into the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei were investigated. DYN decreased the urine outflow rate dose-dependently from 5 to 20 nmol in the SON and PVN, and it increased vasopressin release. Microinjection of des-Tyr-DYN (a non-opioid peptide) into the SON produced antidiuretic effects with similar potency to that of the DYN-induced effects. However, in the PVN, the effects of des-Tyr-DYN were very markedly weaker than those of DYN. The DYN-induced antidiureses in the SON were partially inhibited by phenoxybenzamine, timolol and atropine, but not by naloxone. Those in the PVN were partially inhibited by naloxone, timolol and atropine, but not by phenoxybenzamine. Synthetic specific kappa-agonists, U50, 488H and Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro- Arg-Leu-Arg-Gly 5-aminopentylamide (DAKLI), microinjected into the PVN also produced antidiuretic effects in a dose-dependent manner. The order of antidiuretic potency was DAKLIDYNU50,488H, which was the same as that of kappa-receptor binding affinity. The DAKLI-induced antidiureses in the PVN were not inhibited by naloxone. These results suggested that DYN caused antidiureses by vasopressin release, through adrenergic and cholinergic mechanisms in the SON and PVN. Only the DYN-induced effects in the PVN were mediated, at least partially, through opioid receptors, perhaps the kappa-subtype.

Exposing mice to 24 and 4 degrees C in alternate 1 hr periods in the day time and maintaining 4 degrees C at night for several days decreases the tail clamp pressure required to evoke pain behavior. This model is referred to as SART (specific alternation rhythm of temperature) stress. An extract from inflamed skin of rabbits inoculated with vaccinia virus (neurotropin) clearly normalized the hyperalgesia in this SART stress model. To clarify the mechanism of the hyperalgesia in SART mice and the mode of the antinociceptive action of neurotropin in this model, the influence of systemically administered neurotransmitter related drugs was studied. 1) Neurotropin, 5-hydroxytryptophan and L-dihydroxyphenylalanine significantly normalized the decrease in nociceptive threshold, and muscimol tended to inhibit it in nociceptive threshold in SART stressed mice. 2) Haloperidol, phenoxybenzamine, reserpine, bicuculline, scopolamine, physostigmine and naloxone alone did not influence the nociceptive threshold in SART stressed mice. 3) The antinociceptive effect of neurotropin was significantly attenuated by p-chlorophenylalanine, haloperidol and phenoxybenzamine; and it was completely inhibited by reserpine. 4) Naloxone, bicuculline, scopolamine and physostigmine had no influence on the antinociceptive effect of neurotropin. These results suggest that hypofunction mainly of the monoaminergic systems contributes to hyperalgesia in SART stressed mice and that neurotropin produces the antinociceptive effect by restoring these neural functions.

Our previous study has demonstrated that unilateral microinjection of norepinephrine (NE) into the right supraoptic nucleus (SON) of anesthetized hydrated rats elicited dose-dependent decreases in the urine outflow rate. This was antagonized by pretreatment with phenoxybenzamine (an alpha-antagonist) and timolol (a beta-antagonist) in the same SON. In the present study, we examined the effects of NE, microinjected into the right, left and bilateral SON, on the urine outflow rate in order to investigate neural connections between the bilateral SON. NE administered by those three routes dose-dependently decreased the urine outflow rate. The order for the antidiuretic potency was as follows: the effect elicited by the intrabilateral-SON microinjection > the intra-left-SON microinjection = the intra-right-SON microinjection. The antidiuresis of NE microinjected into the right SON was inhibited by an electrolytic left-SON lesion and by pretreatment with phenoxybenzamine (20 nmol) and timolol (100 nmol), but not by atropine (300 nmol) in the left SON. These findings suggest adrenergic neural connections from the right to left SON, contributing to the regulation of urine production. Furthermore, there is a possibility that stimulation of endogenously-released NE in the bilateral SON is amplified through these neurons and elicits more potent effects than those produced in either the right or left nucleus.

We examined the possible existence of excitatory cholinergic innervation in isolated rabbit portal vein. Longitudinal strips of the vein in the presence of both phenoxybenzamine, an alpha-adrenoceptor antagonist, and NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, exhibited a small contraction in response to transmural electrical stimulation (ES). The contractile response to ES was augmented by physostigmine, an anticholinesterase agent, and inhibited by atropine. These findings indicate the existence of an excitatory cholinergic innervation in addition to the known adrenergic and non-adrenergic, non-cholinergic innervations in the rabbit portal vein.

Phenylephrine displacement curves for the specific binding of [3H]prazosin in the membrane fraction prepared from rabbit thoracic aorta showed high- and low-affinity sites with slope factors significantly less than unity. The irreversible alpha 1B-antagonist phenoxybenzamine shifted the binding sites to single high affinity sites with a slope factor close to unity in the presence of the metabolically stable GTP analog GTP gamma-S. These results indicate that phenoxybenzamine may have affected selectively the low affinity site to phenylephrine in the presence of GTP gamma-S.

Scatchard analyses of 3H-prazosin binding in rat brain membranes showed biphasic curves, which identified the presence of alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 0.1 microM phenoxybenzamine. On the other hand, 3H-prazosin binding in rat spleen membranes resulted in linear curves that were identical to the binding curve for the alpha 1High-affinity site in the brain. The displacement potencies of alpha 1-adrenergic antagonists were characterized by 3H-prazosin binding to alpha 1High-affinity sites in the rat spleen and brain and alpha 1Low-affinity sites in the brain in the presence of 0.1 microM of phenoxybenzamine. The affinities of WB-4101, phenoxybenzamine, phentolamine, chlorpromazine, labetalol and nifedipine for brain alpha 1High-affinity sites were significantly higher than those in the spleen. The affinities of most ligands for alpha 1Low-affinity sites were significantly lower than those for both alpha 1High-affinity sites in the brain and spleen, but chlorethylclonidine was significantly selective for alpha 1Low-affinity sites, and bunazosin, dibenamine and 5HT had the same affinities for the alpha 1Low- and both alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat brain and that a different alpha 1High-subtype, exists in the rat spleen.

Pilocarpine, a partial agonist, activates propylbenzilylcholine mustard (PrBCM)-sensitive cholinoceptors in the guinea pig ileal longitudinal muscle, while carbachol, a full agonist, predominantly activates PrBCM-resistant ones. Carbachol behaves as a partial agonist in the preparation treated with phenoxybenzamine and mainly activates PrBCM-sensitive cholinoceptors, as phenoxybenzamine preferably blocks PrBCM-resistant ones. The receptor occupancy-response curve for carbachol became a rectangular hyperbola, while pilocarpine showed a linear relation. After occlusion of cholinoceptors with phenoxybenzamine, carbachol showed a linear receptor occupancy-response relation, suggesting that its contraction mechanisms after occlusion of cholinoceptors resemble those for pilocarpine. Both the agonists induced an increase in cytosolic Ca2+ concentration [( Ca2+]i) and tension development in a concentration-dependent manner under the conditions used herein. The slopes of the regression lines between [Ca2+]i and tension development for pilocarpine in the untreated preparation and for carbachol in the preparation treated with phenoxybenzamine were significantly steeper than that for carbachol in the untreated preparation, suggesting that carbachol in the phenoxybenzamine-treated preparation and pilocarpine induced a greater tension for a given increase in low [Ca2+]i than did carbachol. Thus an activation of PrBCM-sensitive cholinoceptors might enhance the Ca2+-sensitivity of the contractile elements.

Intravenous administration of beta-CCM (methyl-beta-carboline-3-carboxylate) at doses ranging from 0.3 to 10 mg/kg dose-dependently inhibited muricide in olfactory bulbectomized rats. beta-CCM elicited a decrease of locomotor activity at doses ranging from 0.3 to 3 mg/kg, and it impaired rotarod performance at doses of 1 and 3 mg/kg. The inhibition of muricide induced by beta-CCM was antagonized by intraperitoneal administration of Ro15-1788 at 10 mg/kg or diazepam at 3 mg/kg. However, the hypolocomotor activity and impairment of rotarod performance induced by beta-CCM were not antagonized by diazepam at 3 mg/kg. These results indicated that beta-CCM exerts an inhibitory effect on muricide through benzodiazepine receptors and this inhibitory effect was not solely caused by its sedative or motor incordinating activity at the dose ranges used in this study.

To characterize the alpha 1-adrenoceptors in the dog aorta and the rat brain and to assess the antagonistic potencies of various chemicals inclusive of newly synthesized ones, radioligand binding assays were performed, and the potencies thus obtained were compared with those obtained from pharmacological observations. Reproducible binding to and displacement from the dog aorta of 3H-prazosin were observed. The rank orders of the inhibition of 3H-prazosin binding to the membrane preparations of the aorta expressed as IC50 (the concentration of drugs inhibiting 50% of maximal specific binding of 3H-prazosin) were: prazosin greater than YM09538 greater than phentolamine greater than yohimbine greater than phenoxybenzamine greater than labetalol greater than S-596 greater than dibenamine greater than K-351 greater than propranolol greater than hydralazine greater than N-696 for alpha-blockers and I-epinephrine greater than clonidine greater than I-norepinephrine greater than phenylephrine greater than I-isoproterenol for agonists. IC50 values of phenoxybenzamine, labetalol, dibenamine and K-351 obtained in the brain preparations were higher than those obtained in the preparation of the aorta. There was a good correlation (r = 0.90) between the IC50 values obtained in the dog aorta and in the rat brain, suggesting that the alpha 1-adrenergic receptors in the dog aorta and the rat brain resemble each other. Good correlations (aorta, r=0.97 and brain, r=0.94) were also observed between IC50 values derived from the binding assay in the aorta or the brain and the pA2 values obtained as regards to the contractile response of the rat aorta to phenylephrine. Thus, this method could be useful for the assessment of newly synthesized chemicals as alpha-adrenergic antagonists.

Effects of methionine-enkephal n (ME) and 2-D-alanine-5-methionine-enkephalinamide (DAMEA) microinjected into the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, which contain neurons synthesizing and releasing antidiuretic hormone, upon the outflow and the osmotic pressure of urine and the other visceral functions were studied in a rat which was loaded with water and anesthetized with ethanol. These opioid peptides when microinjected into the SON or PVN induced potent antidiuretic effects in dose-dependent and time-dependent manners with no significant effects on the other visceral functions. The approx. ED50 values for DAMEA were 1.3 (in the SON) and 0.7 (in the PVN) nmol, and the values for ME were 110 (in the SON) and 60 (in the PVN) nmol. The antidiuretic effects showed slow onset and long duration, with a minimal urine' outflow at approx. 0.5 hr after microinjection and an approx. 2 hr-duration. The effects induced by the opioid peptides were inhibited by pretreatment with naloxone or atropine, without effects of pretreatment with alpha- or beta-adrenoceptor antagonists, suggesting that the antidiuretic effects were mediated through an opioid receptor having low sensitivity to naloxone and also possibly mediated through a muscarinic receptor which was stimulated probably by the ACh released by the opioid peptides.

Vasodepressor mechanism of lycorenine (an alkaloid of Lycoris radiata Herb.) was investigated in anesthetized rats. Lycorenine (1--10 mg/kg i.v.) produced dose-related decreases in blood pressure and heart rate and tachyphylaxis developed with repeated injections. In the blood-perfused rat hindquarters, lycorenine (62.5--500 micrograms i.a.) produced dose-related decreases both in mean blood pressure and in perfusion pressure, and the lycorenine-induced decrease in perfusion pressure was abolished by phenoxybenzamine or hexamethonium. Lycorenine (more than 1 mg/kg i.v.) blocked the pressor response to sympathetic nerve stimulation, but failed to block the tachycardia induced by sympathetic nerve stimulation. Lycorenine (7.5 or 15 mg/kg i.v.) reduced the spontaneous splanchnic nerve activity. Lycorenine when given intracerebroventricularly produced decreases in blood pressure and heart rate only in large doses (over 500 micrograms). The maximal bradycardia induced by lycorenine was abolished by bilateral vagotomy. It is suggested that lycorenine may produce a decrease in blood pressure as the result of alpha-adrenergic blockade in conjunction with the reduction of the spontaneous sympathetic nerve activity, and produce bradycardia by modifying vagal activity.

Mechanical responses produced in isolated chicken rectum by nerve stimulation were subjected to a pharmacological analysis to determine the nerves involved. Stimulation of Remak's nerve caused biphasic responses, consisting of an initial, short-lasting contraction and a subsequent, long-lasting relaxation. A similar pattern of responses was observed following coaxial stimulation of intramural nerves. The contraction was unaffected by atropine and hyoscine, and also insensitive to α-adrenoceptor blockers. The relaxation was reduced in duration but not in amplitude by β-adrenoceptor blockers, and still observed in preparations from reserpinized animals. These results suggest the presence of non-cholinergic excitatory innervation and nonadrenergic inhibitory innervation in the chicken rectum. Changing the stimulating sites and sectioning some of the side branches of Remak's nerve extending to the gut revealed that the excitatory nerve fibers appear to reach the rectal wall preferentially via the lower side branches. The smooth muscle of the dorsocaudal region appears to receive more excitatory innervation, since the largest contraction was found in muscle strips taken from the rectal wall where the side branches terminated when field stimulation was applied to the anal end of these strips.

Contractile responses to substance P, physalaemin and eledoisin, three members of the tachykinin family, were compared and characterized in rabbit iris sphincter smooth muscle. Eledoisin and physalaemin were approximately 5 times more potent than substance P, and the maximum responses to substance P and physalaemin were about 85 percent of those to eledoisin and carbachol. The contractile responses to the three tachykinins were not affected by tetrodotoxin (3 X 10(-6) M) and atropine (10(-6) M). The contractions induced by substance P and physalaemin were well sustained even after they were thoroughly washed out, whereas the eledoisin-induced contraction was rapidly ceased by removing the agonist from the bathing medium. The sustained contraction evoked by substance P or physalaemin was strongly dependent on extracellular calcium ions. Phenoxybenzamine (2 X 10(-5) M, 10 min) selectively attenuated the response to eledoisin, but not substance P or physalaemin, and concomitant incubation with excess eledoisin (10(-7) M) significantly prevented the inhibitory effect of phenoxybenzamine. The difference between responses to eledoisin and to the other peptides, substance P and physalaemin, may suggest the existence of two different receptor subtypes for tachykinins in rabbit iris sphincter smooth muscle.

We investigated the correlation between restraint stress-induced alteration of antibody responses and adrenal hormones. Adrenalectomy (Adx) blocked both the suppression of antibody response against T cell-dependent (TD) antigen and the enhancement of that against T cell-independent (TI) antigen in stressed mice. Adx also inhibited the atrophy of both thymus and spleen caused by restraint. Pre-treatment of metyrapone, an inhibitor of adrenocortical steroid biosynthesis, had an effect that was similar to, but far weaker than that of Adx on stressed mice. The pre-administration of phenoxybenzamine, an alpha-adrenergic blocking agent, to mice prevented both the inhibition of antibody response to TD antigen and the decrease in spleen cell number of restrained mice. A similar effect was observed in mice pre-treated with 6-hydroxydopamine, an adrenergic neuron degenerating agent. However, no effects of these two agents were observed on the enhancement of antibody response to TI antigen. The suppressive effect of the antibody response to TD antigen was augmented by the pre-administration of propranolol, a beta-adrenergic blocking agent. These results suggest that the suppression of the function of T cells in restrained mice are attributed to the released adrenocortical and adrenal medullary hormones and activated sympathetic nervous system and that the enhancement of B cell function is due to the adrenocortical hormones.

An investigation was made of monoamine-related agents on the Straub tail reaction (STR) due to central excitatory effect of morphine (10 mg/kg). Apomorphine (10 mg/kg) showed a tendency to enhance the STR, and L-dopa (150 mg/kg) and methamphetamine (5 and 10 mg/kg) produced a significant increase in the STR. Phenoxybenzamine and propranolol induced the inhibition of the STR to a large extent. Diethyldithiocarbamate (250 mg/kg) and disulfiram (200 and 400 mg/kg) had no influence on the STR. α-Methyl-p-tyrosine (100 and 400 mg/kg) reduced the STR. L-5-Hydroxytryptophan [L-5-HTP] (100 mg/kg) inhibited the STR significantly. Isocarboxazid (50 mg/kg), nialamide (50 and 100 mg/kg) and tranylcypromine (10 and 25 mg/kg) did not influence the STR. On the contrary, biochemical investigations showed that morphine (10 and 20 mg/kg) decreased the 5-hydroxytryptamine (5-HT) content of the lumbosacral cord significantly, although no alteration of 5-HT content occurred in various sites of the brain, compared to a vehicle-treated group. Morphine (10 and 20 mg/kg) did not act on the dopamine or norepinephrine content of various sites of the brain and spinal cord. Our results suggest that the STR is, at least to some extent, the result of an increase in catecholaminergic activity and/or a decrease in tryptaminergic activity in the central nervous system of mice.

Interactions of several muscarinic drugs with their receptors were studied in the ciliary body smooth muscles of the rabbit. The ciliary body smooth muscles responded to carbachol, a muscarinic full agonist, with concentration-dependent contractions, and the pD2 value of carbachol was 5.16 +/- 0.05. Atropine, a competitive antagonist of muscarinic receptors, produced a parallel shift to the right in the concentration-response curves for carbachol. Pilocarpine which is a well-known partial agonist on muscarinic receptors in most smooth muscles did not cause any contraction in this tissue. The drug, however, behaved as a competitive antagonist on the muscarinic receptors in the ciliary body smooth muscles. The pA2 values of atropine and pilocarpine versus carbachol obtained from the Schild plot are 8.97 +/- 0.25 and 5.17 +/- 0.09, respectively. On the other hand, arecoline and oxotremorine acted as a partial agonist in this tissue. The intrinsic activity, and pD2 and pA2 values were 0.41 +/- 0.02, 4.93 +/- 0.05 and 5.32 +/- 0.05 for arecoline respectively, and were 0.26 +/- 0.02, 5.64 +/- 0.08 and 6.12 +/- 0.16 for oxotremorine, respectively. The pA2 values of these drugs were significantly larger than the corresponding pD2 values of the drugs. The values of the negative log molar dissociation constant of carbachol, arecoline and oxotremorine estimated by the method of partial irreversible blockade of spare receptors with 3 X 10(-6) M phenoxybenzamine were 4.53 +/- 0.08, 5.20 +/- 0.09 and 6.02 +/- 0.06, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

In primary 2-day cultured bovine adrenocortical cells, adrenaline stimulated the steroidogenesis, while the effect of adrenaline did not appear in the freshly isolated cells. Thus the primary 2-day cultured cells were used to study the effect of adrenaline on steroidogenesis. Adrenaline showed the steroidogenesis-stimulating effect at concentrations higher than 10(-9) M, and the maximum effect was obtained between 10(-6) M and 10(-5) M in the primary 2-day cultured cells. The maximum effect of adrenaline was 50-70% of that of adrenocorticotropic hormone (ACTH). Noradrenaline, isoproterenol and phenylephrine also stimulated the steroidogenesis. However, the order of the potency was isoproterenol much greater than adrenaline = noradrenaline much much greater than phenylephrine. Propranolol and alprenolol inhibited the effect of adrenaline, but phenoxybenzamine and phentolamine did not inhibit the effect. Moreover, adrenaline stimulated the cyclic AMP production dose-dependently at concentrations higher than 10(-8) M. These results suggest that there are steroidogenesis-linked adrenergic receptors in primary 2-day cultured bovine adrenocortical cell membrane and that the steroidogenesis-stimulating effect of adrenaline occurs through the beta-adrenergic receptor.

Recent electrophysiological and anatomical studies on transmission between the sympathetic nerve and smooth muscle have confirmed the important role of a chemical substance acting in a manner similar to the chemical substance concerned with transmission between somatic nerve and skeletal muscle. A low frequency stimulation of the hypogastric nerve produced junction potentials on the smooth muscle of the vas deferens (1) and seminal vesicle (2) in the guinea-pig. The junction potentials may be due to the release of noradrenaline from the sympathetic nerve terminals, and this conjecture is supported by the following evidence. 1) The junction potentials were strongly depressed by pretreatment or intravenous injection of reserpine (3, 4), 2) The junction potentials were also depressed by guanethidine, bretylium and high doses of various α-blocking agents, such as phenoxybenzamine, phentolamine and yohimbine (5), 3) The intravenous injection of noradrenaline induced a burst of action potentials in smooth muscle which was associated with tetanic contraction (6), 4) Many investigators (7, 8) have demonstrated pharmacologically that the nature of the contractile response of the vas deferens to hypogastric nerve stimulation was probably of sympathetic origin, 5) The guinea-pig vas deferens and seminal vesicle contain a large amount of noradrenaline and also abundant noradrenaline containing fibers which have been observed among the smooth muscle cells (9, 10). On the other hand, it is well known that monoamine oxidase (MAO) and catecholO-methyl transferase (COMT) degrade noradrenaline to deaminated and methylated metabolites. However, there are a few inconsistent results concerning the effect of MAO inhibitor on the contractile response of the guinea-pig vas deferens to hypogastric nerve stimulation. For instance, Kamijo et al. (11) and Brown and Gillespie (12) have assumed that MAO inhibitors do not potentiate the effect of catecholamine released by nerve smonoamine oxidase and catechol-O-methyl transferase on the junction potential recorded from the guinea-pig seminal vesicle in response to hypogastric nerve stimulatiotimulation, whereas Bhargava et al. (13) have observed that MAO inhibitors, such as pheniprazine and tranylcypromine, and a COMT inhibitor, pyrogallol, potentiated the contractile response of the guinea-pig vas deferens to hypogastric nerve stimulation. The present study was, therefore, undertaken to examine the effect of inhibition of monoamine oxidanse and catechol-O-methyo transferase on the iunction potential recorded from the guinea-pig seminal vesicle in response to hypogastric nerve stimulation.

The pulmonary circulatory changes caused by adrenergic drugs using several techniques have been demonstrated by many investigators. The pulmonary arterial pressure and the pulmonary resistance increase with epinephrine, levarterenol and phenylephrine (1-4). Isoproterenol reduces the pulmonary arterial pressure (5, 6). Methoxamine causes either no change in pulmonary arterial pressure (7) or a significant pulmonary hypotension (4, 8). On the other hand, the idea of an adrenergic receptive mechanism was introduced by Langley (9, 10) and the receptor concept was reported by Dale (11) describing two kinds of receptors in the general circulation: receptors having an action resulting in excitation and receptors having an action resulting inhibition of the effector cells. But these two kinds of receptors do not exist in all the places of the body both together, sometimes, only one kind of receptor can be found in some places. We have classified the adrenergic receptors in several organs of the body using several adrenergic drugs and the adrenergic blocking agents (12-16). We have attempted to demonstrate in this paper the kind of adrenergic receptor existing in the pulmonary circulation since no references exist on this problem, even though many investigators have observed the action of adrenergic drugs in the pulmonary circulation, using a limited lung circulation technique and maintaining as normal a circulation as possible.

Although noradrenaline (NA) is well known for its pressor effect, it has been shown to produce a depressor response in hypothermic cats and dogs (1, 2) ; the mechanism of the latter effect has, however, not yet been clearly elucidated. This effect has been attributed to its ganglion blocking action (1) as well as to the parasympathetic over-activity resulting from the altered state of the higher autonomic center during hypothermia (2). It was, therefore, the object of this study to investigate further the mechanism of this depressor response to NA during hypothermia.

In the previous paper (1), the present authors reported a new perfusion method, in which the kidney of a recipient dog with intact innervation was perfused with the donor's blood using an artificial heart-lung apparatus. That method revealed a good response of renal vessels to various vasoactive substances as well as good hemodynamic conditions for about one hour, following by a gradual increase of renal vascular resistance. Such an increase in renal vascular resistance of the perfused dog kidney was also observed by several investigators (2-5), who used perfusion methods somewhat different from the authors' method. But the mechanism for the increase has been left unclarified. In the present study, it was observed that renin was liberated from the perfused kidney, and angiotensin was produced due to interaction of renin and its substrate in the perfusion circuit. The angiotensin thus formed constricted renal vessels, resulting in an increase in renal vascular resistance.

Although there have been divergent conclusions concerning the cardiac effects of the adrenergic blocking agents, it is generally agreed that no adrenergic blocking agent specifically inhibits the chronotropic and inotropic responses to adrenergic stimuli in the mammalian heart (1). It has been found that phenoxybenzamine, a potent adrenergic blocking agent, increases the concentration of noradrenaline and ' adrenaline in urine and plasma of dogs in barbiturate anesthesia (2, 3). Holzbauer and Vogt (4), and Gey and Pletcher (5) have shown that the intravenous injection of 20 to 25 mg/kg of chlorpromazine little affects on noradrenaline content of the hypothalamus in the cat and of the brain in the rat. On the other hand, Malhotra and Prasad (6) have recently shown that the intravenous injection of 2 to 5 mg/kg of chlorpromazine greatly increases the content of noradrenaline in the central nervous system such as hypothalamus, hippocampus, frontal cortex and midbrain in the dog, while the same procedure of 10 to 25 mg/kg significantly decreases the content of the amine in these structures. Graham (7) has demonstrated that the pressor responses of the atropinized dog to a series of 2-halogenoethylamines are blocked by pretreatment of the animal with reserpine. Benfey (8) has shown that the positive inotropic, chronotropic and hypertensive effects of phenoxybenzamine are prevented by pretreatment of dogs with reserpine or guanethidine. The inhibitory effects of the adrenergic blocking agents such as phenoxybenzamine, dibenamine, chlorpromazine, regitine, piperoxane, yohimbine and dihydroergotamine as well as guanethidine on the action of butyrylcholine and tyramine, and the potentiating effects of these adrenergic 'blocking agents on the action of noradrenaline in the isolated atrium of the guinea-pig have been presented by Ben-fey and Greeff (9). From the results cited above it seems that the effects of the adrenergic blocking agents have something in common with that of reserpine. If the adrenergic blocking agents affect the content of noradrenaline in the atrial muscle fibers, it is expected that the drugs may give some specific effects on the transmembrane potentials of the atrium.

Among Oriental peoples the panacean use of Panax ginseng persists today as it has for centuries. Physicians in some areas of the Near East dispense this substance in powder, pill and tincture form and adhere to beliefs in its curative and “tonic” properties [Schultz (1)]. This widespread popularity and use have prompted a number of studies to determine possible pharmacological foundations for its continued employment. Evidence has been advanced to indicate that ginseng stimulates the central nervous system and respiration [Petkov (2)], stimulates gastric and intestinal motility [Yoon (3)], corrects nutritional disorders [Myerhoff (4)], and blocks the hyperglycemic response to adrenaline [Kondo (5)]. Regarding the actions of ginseng on mean arterial blood pressure, the reports of Kim (6), Petkov (2), Hwang (7) and Park (8) indicate that the primary effect of ginseng is depressor followed by pressor in a variety of intact animals. Since the physiological basis of this response is uncertain, we have attempted, with modern instrumentation, to determine the extent of cardiac and/or vascular participation in the blood pressure response to ginseng administration.

The inhibitory effects of α-receptor blocking agents such as dibenamine, yohimbine and chlorpromazine on the transmembrane potentials in the atria isolated from intact and reserpinized rabbits were reported previously (1-3). Although acetylcholine (ACh) as well as adrenaline and noradrenaline could restart the atrial action potential which had been ceased by the application of the adrenolytics, the restarting effect of ACh showed considerable differences from that of catecholamines. It was described by several investigators that positive inotropic and chronotropic responses of catecholamines in the mammalian heart were not prevented by α-receptor blocking agents (4) but were antagonized by dichloroisoproterenol (DCI), a β-receptor blocking agent (5, 6). In the isolated heart preparations, the stimulating effect of ACh was blocked by the pretreatment with DCI or by the full reserpinization of the animals (7-10). These results proposed the assumption that the stimulating effect of ACh derived from endogenously released catecholamine. However, as already confirmed in the previous report (2), the evidence that the addition of ACh could restart the action potential which had been ceased by the pretreatment of α-receptor blocking agents even in the reserpinized rabbit was against the afcre-mentioned assumption. In order to elucidate whether the stimulating effect of ACh derives from endogenously released catecholamine or not, the effects of ACh and catecholamine on the transmembrane potentials of the heart should be observed in relation to β-receptor blocking effects of DCI. The present experiments have been designed to compare the effects of DCI and phenoxybenzamine, an α-receptor blocking agent, on the atrial and ventricular transmembrane potentials in the isolated rabbit's heart, and to elucidate the correlation between the actions of DCI and ACh or catecholamines. Further, the effects of DCI and phenoxybenzamine on the conduction time and the effective refractory period of the ventricle have been comparatively studied.

Hukovic (1) was the first to suggest the existence of the cholinergic fibers in the sympathetic nerve of the rabbit's atria. He showed that stimulation of the sympathetic nerve in the isolated reserpinized heart produced the negative chrono and inotropic effects which were potentiated by eserine and abolished by atropine. A series of experiments in this laboratory (2-5) have excluded an essential role of the heart catecholamine on initiation and maintenance of the spontaneous contraction and action potential of the rabbit's atria. Recently, Misu (6, 7) and Misu and Takaori (8) in this laboratory have demonstrated that the atrial action potentials abolished by the concentration of 10-5 of dibenarnine, chlorpromazine and yohimbine, are restarted by adrenaline as well as by acetylcholine, and that noradrenaline mainly shortens the repolarization phase of the potential, while acetylcholine serves to restore the depolarization phase. This suggests a modulating role of the endogenous noradrenaline in the rhythmic contraction or action potential of the heart, and led us to study the effects of catecholamine-relating drugs on the atrial responses to cholinergic stimulation.

A new compound, 6-(2-bromoethyl)-10, 11-methylenedioxy-5,6,7,8-tetrahydrodibenz [c,e] azocine (DA-VIII-MBr) was found to have a more selective α-adrenergic blocking action than dibenamine or phenoxybenzamine. From dose-response curves for adrenaline and 5-hydroxytryptamine (5-HT) obtained in strips of rat aorta before and after incubation with each of the three blocking agents, the fractions of receptors remaining active for adrenaline and 5-HT, respectively, were estimated. After blockade with DA-VIII-MBr the receptors for adrenaline were blocked considerably, but those for 5-HT were little affected. Dibenamine blocked the receptors to adrenaline and 5-HT almost equally. The effective dose of phenoxybenzamine for adrenaline receptors was less than one hundredth that of dibenamine or DA-VIII-MBr, but specificity for these receptors was intermediate between those of dibenamine and DA-VIII-MBr. The structure of DA-VIII-MBr is an analog of apogalanthamine and its nitrogen atom bears the 2-halogenoethylamine group in part of an eight membered ring.

Reserpine injected intravenously during infusion with dopamine brought about sympathomimetic effects, but a second injection of reserpine after 120 minutes did not elicit such effects. This pressor effect was eliminated by phenoxybenzamine and this positive chronotropic effect by propranolol. Reserpine induced similar but weak sympathomimetic effects after cocaine, while it induced no changes in blood pressure and heart rate after infusion with noradrenaline. Meanwhile, pressor response to dopamine was potentiated 24 hours after reserpine and was further potentiated after additional infusion with noradrenaline. The sympathomimetic actions induced by the concurrent administration of reserpine and dopamine may be attributable to a facilitation of those indirect mechanisms, principally of endogenous catecholamine release.

Oxygen uptake and amylase output in rat submandibular gland slices were measured by utilizing adrenergic agonists. Adrenaline, noradrenaline and isoproterenol significantly stimulated the oxygen uptake and amylase output. In the presence of propranolol or phenoxybenzamine, adrenaline-stimulated oxygen uptake was obviously blocked. Adrenaline-stimulated amylase output was inhibited by propranolol, but was not inhibited by phenoxybenzamine. The increase in oxygen uptake by nornol-stimulated oxygen uptake and amylase output were strongly inhibited by propranolol. The oxygen uptake due to isoproterenol was little affected by phenoxybenzamine. These results suggest that the increase in oxygen uptake seen with adrenergic agonists is mediated by both alpha- and beta-receptors, and that the amylase output is evoked through the stimulation of beta-receptors.

Thirty-min treatment of guinea-pig taenia caecum with 300 nM propyl-benzilylcholine mustard (PrBCM) shifted the concentration-response curve for carbachol to the right with a reduction of the maximum contraction, but 90-min treatment did not result in further inhibition. Under these conditions, pilocarpine hardly contracted the preparations, and it competitively antagonized carbachol. Muscarinic agonists might interact with two types of receptor mechanisms and carbachol elicited a stimulus from both types, whereas pilocarpine did so predominantly from the PrBCM-sensitive one.

When studying some of the properties of 5-hydroxytryptamine (5HT) receptors in the rat uterine muscle using phenoxybenzamine (PBZ) as an antagonist it was found that the specific receptors for 5HT in the smooth muscle were selectively blocked by PBZ; a period of 20-minute exposure to the antagonist was required for maximal effect. The blockade produced was of long duration and the recovery of response was relatively slow; it was incomplete throughout the 4-hour observation period. A concentration of 1 X 10(-8) g/ml PBZ produced a parallel shift of the dose-response effects while higher concentrations reduced both the slope and maximal response. The reasons for such a shift were discussed. 5HT produced a rapid onset and offset of effect suggesting that the site of 5HT receptor is on the surface of the cell membrane. Moreover, 5HT could protect its own receptor against PBZ blockade.

Sympathomimetic amines epinephrine and isoproterenol were administered to dogs, rabbits and pigeons, and effects on blood glucose and blood lactic acid levels were studied. Alpha and beta adrenergic receptor blocking drugs were employed to block the metabolic effects of the amines to elucidate the exact receptor status regarding the metabolic actions of sympathomimetic amines on carbohydrate metabolism. The results suggest that the receptors associated with hyperglycemic response vary depending on the species. In dogs, receptors are of beta type while in rabbits and pigeons both alpha and beta type of receptors appear to play a role. The hyperlactacidemic response, however, is associated with beta receptors in all animals studied herein.

Postsynaptic alpha-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxybenzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo alpha-adrenoreceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The alpha-blocking effect of E-643 was reversible. E-643 protected alpha-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the alpha-adrenoceptors.

Influences of several alpha-adrenoceptor antagonists on the triphasic time response curves of phenylephrine, which are characterized by an initial increasing phase followed by a declining phase and then a second increasing phase, were investigated in the guinea pig left atria pretreated with sotalol (5 x 10(-5) M) and driven at 0.2 Hz. Phenoxybenzamine (10(-6) M) blocked both the positive and the negative inotropic effects and resulted in disappearance of the characteristic pattern, although lower concentrations (10(-8)--10(-7) M) preferentially attenuated the positive phase. Phentolamine (10(-7)--6 x 10(-6) M) and yohimbine (10(-6)--10(-5) M) preferentially inhibited the negative phase and potentiated the positive inotropic effect, thus changing the pattern to a biphasic or a monophasic one. Prazosin depressed concentration-dependently the positive inotropic effect and blunted the triphasic pattern (10(-9)--10(-8) M) or altered the pattern to a biphasic one (10(-7) M). In the presence of 10(-6) M prazosin, only the negative inotropic effect was observed to subsist. This negative inotropic effect was antagonized by 3 x 10(-6) M phentolamine. The present results suggest that there may exist two distinct types of postsynaptic alpha-adrenoceptors in the left atria of guinea pigs, one type mediating the positive inotropic effect and the other type mediating the negative inotropic effect.

Tranylcypromine (TCP), a monoamine oxidase inhibitor, induced a hyperpyrexia in rats which had been given repeated doses of LiCl. This hyperpyrexia was not prevented by the pretreatment with α-adrenergic blockers (phenoxybenzamine and phentolamine), β-adrenergic blocker (DL-propranolol), histamine blockers (promethazine and diphenhydramine), anticholinergic agent (atropine), inhibitors of prostaglandin synthesis (acetylsalicylic acid and sodium salicylate). Among the dopamine (DA) blockers tested, chlorpromazine, thioridazine, fluphenazine, perphenazine and haloperidol, all of which are reported to inhibit the DA-sensitive adenylate cyclase, prevented the hyperpyrexia. On the other hand, sulpiride and metoclopramide, which are reported not to inhibit the DA-sensitive adenylate cyclase, were without effects on the hyperpyrexia. The hyperpyrexia was potentiated by injection of theophylline, a nucleotide phosphodiesterase inhibitor. The cyclic AMP level in the caudate nucleus was significantly increased only when TCP produced the hyperpyrexia in the LiCl-pretreated rats. The cyclic AMP level in the hypothalamus remained unchanged. These results suggest that DA produced the hyperpyrexia by mediation of the cyclic AMP in the caudate nucleus, but not in the hypothalamus.

Scopolamine-induced locomotor activation was studied in comparison with the responses to apomorphine and methamphetamine in mice. The responses to scopolamine and methamphetamine were markedly depressed by the pretreatment with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, while the activation response to apomorphine was not affected. p-Chlorophenylalanine did not affect the response to scopolamine. Phenoxybenzamine reduced the responses to scopolamine and methamphetamine, but did not affect the apomorphine response. Propranolol did not affect the responses to the three agonists, scopolamine, apomorphine and methamphetamine. Antipsychotic drugs haloperidol and pimozide reduced the responses to the three agonists. Haloperidol was especially effective in this regard. These results suggest the involvement of catecholamine in the locomotor activation produced by scopolamine. In the rotational behaviour model which is sensitive to dopamine receptor stimulating agents, effects of the three agonists were studied. Scopolamine produced the ipsilateral rotation in mice with unilateral striatal 6-hydroxydopamine-induced lesions. Methamphetamine induced the ipsilateral rotation, while apomorphine produced the contralateral rotation. The rotations induced by three agaonists were suppressed by pimozide. The results indicate the participation of dopamine in the scopolamine-induced rotational behaviour in mice.

Small tracking electrodes were inserted into the cat locus coeruleus (LC), and the effects of LC stimulation were determined on the transcallosal potential (TCP) evoked in cerebral cortex on the same side. LC stimulation at 8 volts inhibited TCP amplitude an average of 11%. Rostral LC placements appeared most effective. LC stimulation, without drugs, did not affect the peak latency of the TCP. dl-Propranolol and FLA-63 blocked LC inhibition of the TCP and also increased TCP amplitude per se. Propranolol first increased the latency of the TCP during LC stimulation, then decreased decreased it, while also prolonging the latency of the TCP per se. Phenoxybenzamine increased rather than blocked the LC inhibitory effect and also increased TCP amplitude. dl-Erythro-DOPS slightly increased the LC inhibitory effect, and substantially increased TCP amplitude. dl-Threo-DOPS produced somnolence in unanesthetized animals, led to increased norepinephrine levels in cortex and brain stem, and caused cortical potentials to fluctuate widely. A midbrain lesion of the dorsal ascending NE bundle blocked the LC inhibitory effect. LC stimulation alone, or in combination with evoked cortical stimulation, did not affect the interstimulus electrocorticogram or the heart rate. In the transcallosal system of the cortical regions studied, the LC appears to play mainly an inhibitory role.

A difference in alpha-adrenoceptor mechanisms in vasa deferentia isolated from 3 weeks old and 40 weeks old rats were studied by analysis of the concentration-response curve of norepinephrine and Scatchard plot of specific [3H]-prazosin binding to microsomal fractions. The efficacy of norepinephrine and capacity of the maximum binding sites of [3H]-prazosin estimated in 40 weeks old rats were larger than those in the 3 weeks old rats, while there was no difference in the affinity of norepinephrine estimated in the 3 weeks old rats and in the 40 weeks old rats. The increase of efficacy for norepinephrine in the vas deferens from the 40 weeks old rats is due to the increase in the total concentration of alpha-adrenoceptors.

The fibrinolysis induced by intraperitoneal injection of adrenaline in the rat was inhibited by prior intraperitoneal injection of very low doses of α-adrenergic blocking agents. For example, 5 μg/kg of phenoxybenzamine or 10 μg/kg of phentolamine was sufficient to prevent almost completely the fibrinolysis induced by 1 mg/kg of adrenaline. These α-blockers also inhibited the fibrinolysis induced by serotonin and bisobrin, but a much higher dosage was required. Phenoxybenzamine did not inhibit the adrenaline-induced fibrinolysis when the drug was injected after the injection of adrenaline. No inhibitory effect was observed with β-blockers. dichloroisoproterenol, pronethalol and practolol, even at a dose of 10 mg/kg, although propranolol at a dose of 3 mg/kg did exert an inhibitory effect. The involvement of peritoneal blood vessels in adrenaline-induced fibrinolysis is suggested.