[Two types of depersonalization--reconsideration from a descriptive-phenomenological view point].

The term depersonalization has been vaguely used in clinical contexts and there is confusion over its nosological positioning. Although the syndrome has been assigned a niche of its own in the European psychiatric taxonomy, the American's Diagnostic and Statistical Manual of Mental Disorders (DSM-III, IV) labeled it under the term Dissociative Disorder. The latter, which does not agree with the classical theory of Janet, seems to have no basis on traditional psychopathology and is not derived from any dissociative theories. In this paper the descriptive characteristics of depersonalization are discussed with regard to the features of "observing self" and the relationship between experiences and selves, according to which the authors distinguish two types of depersonalization: an "excessive-self-reflecting type" and an "absorbed-in-experience type". Whereas the former coinsides with the typical depersonalization neurosis, in which excessive self-reflection plays an important role in reducing the sense of reality, in the latter over-absorption in some situations leads the patient to construct a wall to block out reality. We suggest that in making a distinction between these two types, the psychopathology of depersonalization will be better clarified.

Dietary nucleotides modulate antigen-specific type 1 and type 2 t-cell responses in young c57bl/6 mice.

Mice fed a nucleotide-free (NF) diet have impaired antibody (Ab) responses. The mechanisms responsible for this effect are not understood but may be related to specific changes in T-cell functions. The objective of this study was to examine the effects of dietary nucleotides on serum immunoglobulin-G (IgG) subclass Ab levels and T-cell cytokine production by cells from the lymph nodes draining the site of antigen challenge. C57BL/6 (B6) mice were fed an NF diet or the same diet supplemented with nucleotides (NS diet; 4.74 g nucleotides/kg). Keyhole limpet hemocyanin (KLH; 25 microg/dose), a T-dependent protein neoantigen, was given with incomplete Freund's adjuvant. We administered KLH at 3, 6, and 9 wk to determine primary and secondary responses. Anti-KLH IgG subclass Ab levels were measured 3 wk after the first KLH challenge and 2 wk after the last KLH challenge. T-cell responses in lymph nodes draining the site of KLH challenge were assessed 5 d after the primary and 14 d after the final KLH challenge. We measured mRNA expression and production of interferon-gamma and interleukin-5, type-1 and type-2 T-cell cytokines, respectively. Anti-KLH IgG2a and IgG2b Ab levels were higher in the NS diet group than in the NF diet group after the last KLH challenge. The NS diet group had higher interferon-gamma production and mRNA expression than did the NF diet group after the first KLH challenge. Because increased levels of interferon-gamma and IgG2a/IgG2b Ab reflect a shift toward type-1 responses to antigen stimuli, our results show that dietary nucleotides preferentially enhance type-1 responses to KLH given with incomplete Freund's adjuvant.

[Sequence of time and relation with others in borderline personality disorder].

In order to present some new psychopathological explanations on borderline personality disorder, the authors made a study on 3 borderline patients who could reflectively state their experiences of changes in the sequence of time and the relation with others. The following characteristics are considered to be most important: 1) They needed someone under their noses who always kept his/her eyes upon them. And as soon as they thought that he/she was in close relation with them, his/her intensions toward them were taken as already concluded (or determined) ones in their subjective experiences. 2) Every-time they found that others' intentions were apart from the determined ones, strong rage was evoked in them, because they felt that they were betrayed by others. Thus, their painful experiences were produced successively. 3) Consequently, they took the whole past as congregation of painful experiences, so that they struggled to cut the linkage of the present and the past. For that purpose, they tried to plunge head-long into momentary experiences. But to complete the purpose, they intensified their dependence on others' intentions again as previously stated. This vicious cycle itself is thought to be the significant framework of borderline personality disorder.

Effects of nucleotides on learning and memory in a Morris water maze test in normal and basal forebrain-lesioned rats.

The effects of nucleotides on learning and memory were studied in normal and basal forebrain-lesioned rats using a Morris water maze test. Chronic oral administration of a nucleotide mixture (500 mg/kg), containing an equal weight of the disodium salts of adenosine 5'-monophosphate, guanosine 5'-monophosphate, inosine 5'-monophosphate, cytidine 5'-monophosphate, and uridine 5'-monophosphate facilitated learning acquisition in normal rats. In basal forebrain-lesioned rats, administration of the nucleotide mixture showed a tendency to improve learning acquisition and memory retrieval. In the biochemical studies, no significant changes were observed in brain choline and acetylcholine levels by treatment with the nucleotide mixture at the doses tested in both normal and basal forebrain-lesioned rats. The nucleotides did not affect the monoaminergic systems in normal rats, but did cause some changes in these systems in basal forebrain-lesioned rats. The present studies indicate that nucleotides ameliorate learning and memory processes in normal rats, but not in basal forebrain-lesioned rats, and they also modulate the activity of the central monoaminergic systems under certain conditions.

The effects of hyperoxic injury and antioxidant vitamins on death and proliferation of human small airway epithelial cells.

Previously it was reported that hyperoxia induced death of the human lung adenocarcinoma cell line (A549 cells) by necrosis, not by apoptosis. This study examined proliferation and death of untransformed human small airway epithelial (SAE) cells in normoxia or hyperoxia in comparison with A549 cells. We tested the hypothesis that SAE cells respond differently to hyperoxic injury than do A549 cells. We measured total cell number and viability, thymidine incorporation (SAE cells only), lactate dehydrogenase (LDH) release, and apoptotic changes as markers for cell proliferation and death. Protective effects of antioxidant vitamins also were examined in SAE cells. In normoxia, subconfluent SAE cells had less apoptosis and fewer detached cells, but higher thymidine incorporation than did near-confluent cells. Hyperoxia suppressed thymidine incorporation and augmented apoptosis in both subconfluent and near-confluent SAE cells. Hyperoxia decreased the total cell number only in subconfluence, whereas SAE cell viability declined with hyperoxia in near confluence, but not in subconfluence. For SAE cells, necrosis assessed by LDH release was minimal in all conditions and was not augmented by hyperoxia in SAE cells. In contrast, normoxic A549 cells proliferated more rapidly than did SAE cells with a large number of cells detached during the culture. A549 cells underwent necrotic cell death under confluent or in hyperoxic conditions, but had much less apoptotic cell death. In SAE cells, vitamin E partially prevented the decline of thymidine incorporation with hyperoxia in subconfluence and protected against apoptotic changes with hyperoxia in both subconfluent and near-confluent conditions. Vitamin C prevented apoptosis with hyperoxia only in near-confluent SAE cells. Thus, SAE cells maintained balanced apoptosis and cell proliferation that were altered by cell density and hyperoxia and demonstrated very little necrosis with hyperoxia. Although A549 cells underwent cell death mainly by necrosis, they also were influenced by cell density and hyperoxia. Cell density also determined specific antioxidant vitamin protection in SAE cells.

Differential vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, in the isolated rat femoral artery and vein.

The vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, was investigated in the isolated rat femoral artery and vein. Exposure to YT-146 resulted in preferential vasodilatation; the vein was completely dilated at YT-146 concentrations as low as 10(-7) M; in contrast, a concentration of YT-146 greater than 10(-4) M was necessary to induce complete relaxation in the femoral artery. 2-[p-(2-Carboxyethyl)-phenethylamine]-5'-N-ethylcarboxamidoadenosine (CGS 21680) also evoked stronger dilation in the vein than in the artery. The vasodilatory action of N6-cyclopentyladenosine (CPA) was much weaker in the vein than that of YT-146. YT-146-induced vasodilation in the artery was antagonized by neither 10(-7) M 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) nor 3 x 10(-6) M (E)-8-(3,4-dimethoxystylyl)-1,3-dipropyl-7-methylxanthine (KF17837), while the vasodilation in the vein was only antagonized by KF17837, suggesting that the vasodilation may involve adenosine A2 receptor activation in the vein. However, the present study did not provide evidence of a link between adenosine agonist-induced vasodilation and adenosine A2 receptor activation in the artery. The addition of 10(-4) M N omega-nitro-L-arginine partially reversed YT-146-induced vasodilation in the artery, but not in the vein. The reversal of YT-146-induced vasodilation by N omega-nitro-L-arginine in the artery was attenuated by the addition of 10(-3) M L-arginine. Removal of the endothelium decreased YT-146-induced vasodilation in the artery, but not in the vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats.

1. We examined the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the impairment of endothelium-dependent relaxation caused by acetylcholine (ACh) in the aorta of streptozotocin-induced diabetic rats, by using N omega-L-nitro-arginine methylester (L-NAME) and tetraethylammonium chloride (TEA) to inhibit nitric oxide (NO) and EDHF, respectively. 2. ACh-induced relaxation of the aorta decreased in diabetic rats. In contrast, sodium nitroprusside-induced relaxation was the same in diabetic rats and control rats. 3. Treatment with 5 x 10(-7) M L-NAME resulted in a right shift of the dose-response curves of ACh-induced relaxation in the aorta. The shift was greater in the control aorta. 4. Treatment with 5 x 10(-4) M TEA resulted in a similar right shift in both the control and diabetic aorta. 5. Therefore, while endothelium-derived NO appears to contribute to the impairment of ACh-induced endothelium-dependent relaxation in the aorta of diabetic rats, EDHF does not.

Simultaneous measurement of vasodilation and changes in cyclic nucleotides in the perfused mesenteric arterial bed of the rat.

We examined the relationship between relaxation responses of the mesenteric arterial bed and the levels of cAMP and cGMP released from the rat mesenteric arterial bed. Perfusions of mesentery preparations with 1 microM acetylcholine, 0.1 microM calcium ionophore A23187, and 1 microM sodium nitroprusside all produced complete and long-lasting relaxation and increased the levels of cAMP as well as cGMP in the effluent. In endothelium-denuded preparations, acetylcholine did not elicit either vasorelaxation or an increase in cAMP and cGMP levels. Perfusion of the endothelium-denuded preparation with 1 microM sodium nitroprusside evoked complete relaxation and a marked increase in cGMP levels but not cAMP levels. Isoproterenol (1 microM) produced complete relaxation and an increase in cAMP levels, but did not affect cGMP levels either in the preparation with or in that without endothelium. Acetylcholine (0.001-1 microM) relaxed the preparation and increased cAMP and cGMP levels in the effluent in a dose-dependent manner. The acetylcholine-induced relaxation was reversed by 45% following perfusion with 10 microM methylene blue, and both the cAMP and cGMP levels were decreased. L-NG-Monomethyl arginine (L-NMMA) (100 microM), a nitric oxide synthase inhibitor, completely reversed the relaxation induced by 0.1 microM acetylcholine and reduced the elevated cGMP levels. Indomethacin (1 microM) reduced the acetylcholine-induced cAMP release, but did not alter the vasorelaxation in response to acetylcholine. We propose a novel method for the simultaneous measurement of vasodilation and changes in cAMP and cGMP levels released from the rat mesenteric arterial bed. We conclude that this method may provide information about the function of the endothelium of resistance vessels.

Changes in endothelium-dependent relaxation and levels of cyclic nucleotides in the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats.

The influence of diabetes on the function of vascular endothelium was examined with respect to the role of nitric oxide (NO) in the regulation of blood pressure (BP) in vivo, the vascular relaxation, and levels of cAMP and cGMP in the effluent of the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. An intravenous injection of 100 mg/kg N omega-nitro-L-arginine methylester (L-NAME) caused hypertension in both diabetic rats and controls. However, the degree of hypertension in the diabetic rats was significantly lower than that in the controls. Acetylcholine (ACh)-induced vasorelaxation of the perfused mesenteric arterial bed decreased in diabetic rats. At the same time, the levels of cAMP and cGMP in the effluent of the diabetic rats were also lower than in the controls. These data indicate that NO formation is involved in the regulation of BP in rats, and is decreased in diabetic rats, due to an impairment of the vascular endothelium, including the endothelium of resistance vessels.

Nucleosides and nucleotides. 112. 2-(1-Hexyn-1-yl)adenosine-5'-uronamides: a new entry of selective A2 adenosine receptor agonists with potent antihypertensive activity.

Chemical modifications of the potent A2 adenosine receptor agonist 2-(1-hexyn-1-yl)adenosine (7, 2-HA) at the 5'-position have been carried out to find more potent and selective A2 agonists. These analogues were evaluated for adenosine A1 and A2 receptor binding affinity in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR). Among the series of compounds, 2-(1-hexyn-1-yl)adenosine-5'-N-cyclopropyluronamide (16d) had the most potent affinity to the A2 receptor with a Ki of 2.6 nM, which is essentially the same as that of the parent agonist, 2-HA. However, the most selective agonist for the A2 receptor was 2-(1-hexyn-1-yl)adenosine-5'-N-methyluronamide (16b) with a Ki of 11 nM and a 162-fold selectivity. The N-alkyl substituents of 5'-uronamide derivatives did not seem to potentiate the A2 binding affinity but drastically reduced the A1 affinity compared with the parent 2-HA. Therefore, the A1/A2 selectivity was consequently increased. Other 5'-deoxy-5'-substituted derivatives of 2-HA such as the chloro (20), carboxamide (27, 28), sulfonamide (29), urea (30), and thiourea (22) analogues were also prepared. Among these nucleosides, no active compounds with potent or selective affinities to both receptors were found except 20. Although glycosyl conformations and sugar-puckering of these nucleosides were studied by 1H NMR spectroscopy, there were no positive correlations between active and inactive agonists. 2-(1-Hexyn-1-yl)adenosine-5'-uronamide (16a) and 16d had a potent hypotensive effect at ED30 values of 0.18 and 0.17 micrograms/kg, respectively, upon iv administration to anesthetized SHR.

Nucleosides and nucleotides. 107. 2-(cycloalkylalkynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effects.

Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length of the alkynyl side chain and bulkiness of the terminal cycloalkyl substituents in terms of binding activity and cardiovascular effects. All the 2-CAAs had a preferential affinity for A2 receptors. Of these derivatives, 2-(3-cyclopentyl-1-propyn-1-yl)adenosine (10b) exhibited the most selective affinity for A2 receptors (Ki ratio: A1/A2 = 70) on the basis of receptor binding. In the C-2 binding region of adenosine, compounds often have potent and/or selective A2 activity from introduction of an acetylenic group at the C-2 position followed by one methylene residue further followed by a hydrophobic substituent such as a cycloalkyl ring at the terminal position of the alkynyl side chain. Intravenous injection of 10b up to 100 micrograms/kg had a potent hypotensive effect without a marked decrease in heart rate in anesthetized SHR. Compounds 10j-s, with a hydroxyl group in the C-3" position of the alkynyl side chain, had a potent affinity for both A1 and A2 receptors, but they were not highly selective for A2 receptors. These compounds caused a marked bradycardia upon intravenous administration in anesthetized SHR. Oral administration of 10b (0.1-1 mg/kg) had a potent and long-lasting antihypertensive effect in conscious SHR.

Influences of cyclooxygenase inhibitors on the cataleptic behavior induced by haloperidol in mice.

Haloperidol administered intraperitoneally, and prostaglandin F2 alpha (PGF2 alpha) and PGE2 intraventricularly induced dose-dependent cataleptic behavior in mice. The cataleptic behavior induced by haloperidol was inhibited dose-dependently by oral pretreatment with aspirin and indomethacin, inhibitors of PGs synthetase. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole 3 acetic acid (5-HIAA) were elevated by haloperidol, although dopamine (DA) and 5-hydroxytryptamine (5-HT) levels did not change. The increase of DOPAC level in striatum induced by haloperidol was significantly suppressed by aspirin, but not in brain stem. The alteration of DOPAC level by aspirin correlated with the behavioral response. These results suggest that central prostaglandin synthesis may participate in the development of cataleptic behavior, which might also involve alteration of brain catecholaminergic activity.

Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus.

To investigate the influence of diabetes mellitus on the responsiveness of the vascular smooth muscle, the effects of various vasoactive agents on the reactivity of the vascular smooth muscle from diabetic animals have been undertaken, focusing on the functional changes in the endothelium, alpha-adrenoceptors, beta-adrenoceptors, voltage-dependent Ca(2+)-channels, receptor-operated Ca(2+)-channels, phosphatidylinositol turnover and potassium channels. Among the functional changes, it is a common phenomenon that decreases in acetylcholine-induced production of cyclic GMP are due to the attenuation of release of endothelium-derived relaxing factor through an impairment of endothelium; this observation was found in both rats and rabbits with diabetes mellitus. These functional changes in diabetes may be responsible for the vascular complications such as coronary heart disease, cerebrovascular disease, and an acceleration in atherosclerosis.

Nucleosides and nucleotides. 103. 2-Alkynyladenosines: a novel class of selective adenosine A2 receptor agonists with potent antihypertensive effects.

The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium-catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide in N,N-dimethylformamide containing triethylamine gives 2-alkynyladenosines (5a-r). An economical synthetic method for the preparation of 9-(2,3,5-tri-O-acetyl-1-beta-D-ribofuranosyl)-6-chloro-2-iodopurine++ + (2), which is a precursor of 4a, is also included. Several transformation reactions of 2-(1-octyn-1-yl)adenosine (5e) and 2-(1-ethyn-1-yl)adenosine (9) and a similar cross-coupling reaction of 6-chloropurine derivative 11 and 8-bromoadenosine (13) with 1-octyne are also reported. Many of these 2-alkynyladenosines tested for A1 and A2 adenosine receptor binding activities in rat brain are selective for the A2 adenosine receptor. Among them, 2-(1-hexyn-1-yl)adenosine (5c) has the highest affinity for both A1 and A2 receptors with Ki values of 126.5 and 2.8 nM, respectively. The structure-activity relationship of this series of compounds including 6- or 8-alkynylpurine nucleosides and 2-alkyl- and 2-alkenyladenosines is discussed in terms of potency at both receptor subtypes. Additionally, we describe how hypotensive activity and heart rate decrease brought on by 5 and some other compounds with spontaneously hypertensive rats are proportional to the order of the potency to both A1 and A2 binding affinities. Thus, 2-alkynyladenosines are interesting and promising as antihypertensive agents that should be considered for further detailed preclinical evaluation.

Effects of chronic diabetes on vascular responses of basilar artery and aorta from rabbits with alloxan-induced diabetes.

The influences of chronically diabetic states on contraction and relaxation responses of the isolated basilar artery and aorta to various vasoactive agents were examined in alloxan-induced diabetic rabbits with 2 years duration. There were no significant differences in the reactivities of basilar artery to norepinephrine (NE), 5-hydroxytryptamine (5-HT) and KCl between age-matched control and diabetic rabbits. Maximal contractions of aorta with endothelium in response to NE and 5-HT were significantly enhanced in case concentration-response curves for NE and 5-HT-induced contractions in the aorta without endothelium from diabetic rabbits were not different from those from age-matched control rabbits. Acetylcholine-induced relaxations in both the basilar artery and aorta from diabetic rabbits were significantly attenuated compared with those from age-matched control rabbits. However, no differences were observed in concentration-response curves for sodiumnitroprusside-induced relaxations in both the basilar artery and aorta between diabetic rabbits and age-matched control rabbits. These results indicate that chronic diabetes induces an specific enhancement in the contractile responses to NE and 5-HT in aorta and an attenuation in the endothelium-dependent relaxation in both the basilar artery and aorta. These results further demonstrated that the cerebral artery is resistant to diabetes of 2 years duration as compared with the peripheral artery.

Pharmacological profile of the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146) in the cardiovascular system.

We investigated the cardiovascular effects of 2-octynyladenosine (YT-146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4 micrograms/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at h hypotensive doses. Orally given YT-146 (0.1 - 1 mg/kg) produced a potent and long-lasting antihypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadenosine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long-acting hypotensive agent having less cardiac depressant activity.

Attenuation of depressor response induced by platelet activating factor and acetylcholine in streptozotocin-induced diabetic rats.

The in vivo and in vitro effects of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine) and acetylcholine (ACh) on vascular relaxation responses were examined in streptozotocin-induced diabetic rats. Intravenous injection of PAF and ACh (0.03 to 10 micrograms/kg) decreased the mean blood pressure in both control and diabetic rats in a dose-dependent fashion. Initial blood pressure in diabetic rats did not significantly differ from that in control rats. However, depressor responses induced by PAF and ACh in diabetic rats were attenuated more than those in control rats. In perfused mesenteric arterial bed preconstricted with methoxamine (10(-5) - 10(-4) M), PAF (10(-11) -3 x 10(-10) M) produced a concentration-dependent relaxation. However, this relaxation was significantly attenuated in the diabetic preparation compared with the control preparation. ACh also produced a concentration-dependent vasodilation in perfused mesenteric arterial bed. The concentration-response curve for the relaxation of the mesenteric arterial bed to ACh in diabetic preparation was shifted to the right compared with that in control preparation. A pretreatment with oxyhaemoglobin (10(-6) M) also shifted the concentration-response curves for relaxation to ACh in both control and diabetic preparation to the right. There was no difference in relaxation induced by sodium nitroprusside between the diabetic and the control preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive effect of 2-alkynyladenosines and their selective affinity for adenosine A2 receptors.

We examined the affinity for adenosine receptors and the antihypertensive effects of 2-alkynyladenosines, especially 2-hexynyladenosine (2-H-Ado) and 2-octynyladenosine (2-O-Ado). The order of decreasing affinity of 2-H-Ado, 2-O-Ado, and other agonists tested for A1 receptors was N6-cyclopentyladenosine (CPA) greater than N6-cyclohexyladenosine (CHA) greater than N6-R-phenylisopropyladenosine (R-PIA) greater than 2-chloroadenosine (CADO) = 5'-N-ethylcarboxamideadenosine (NECA) greater than N6-S-phenylisopropyladenosine (S-PIA) greater than 2-H-Ado greater than 2-O-Ado greater than 2-phenylaminoadenosine (CV-1808), and that for A2 receptors was 2-H-Ado greater than 2-O-Ado = NECA greater than CADO greater than CV-1808 greater than R-PIA greater than CPA greater than CHA greater than S-PIA. The Ki values of 2-H-Ado and 2-O-Ado for [3H] NECA binding to A2 receptors were 4.1 and 12.1 nM, respectively, and those for [3H]CHA binding to A1 receptors were 146 and 211 nM, respectively: the affinity of 2-H-Ado and 2-O-Ado for A2 receptors was about 36- and 17-fold higher than their affinity for A1 receptors. Injection of 2-H-Ado and 2-O-Ado (0.03-100 micrograms/kg) decreased the blood pressure of anaesthetized spontaneously hypertensive rats (SHR). A slight decrease in heart rate was observed after i.v. injection of 100 micrograms/kg 2-H-Ado and 2-O-Ado. A potent and long-lasting antihypertensive effect was also observed after oral administration of 2-H-Ado and 2-O-Ado to conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in vascular responses to vasoactive agents of basilar artery and aorta from rabbits with alloxan-induced diabetes.

Responses of the basilar artery and aorta to vasoactive agents in alloxan-induced diabetic and age-matched control rabbits were examined. There were no significant differences in the reactivity of the basilar artery to norepinephrine (NE), 5-hydroxytryptamine (5-HT), and K+ between age-matched control and diabetic rabbits. The maximal contraction of the aorta with endothelium in response to NE was significantly enhanced in the case of the aorta from diabetic rabbits. Pretreatment with 10(-6) M methylene blue or removal of the endothelium enhanced the contractile response of aorta to NE from control rabbits and, after such treatment, the concentration-response curve to NE was almost identical to that of aorta from diabetic rabbits. Basal levels of cyclic GMP but not cyclic AMP in the diabetic aorta with endothelium were significantly lower than those in the control aorta with endothelium. These results demonstrate that the cerebral artery is resistant to diabetes mellitus within 10 weeks as compared with the peripheral artery. The enhancement in the contractile response of aorta to NE in diabetic rabbits is due to the attenuation of the spontaneous release of endothelium-derived relaxing factor, through an impairment of the function of endothelial cells.

Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes.

To investigate the influence of diabetes mellitus on vascular relaxation response, acetylcholine (ACh)-induced relaxation and production of cyclic GMP and cyclic AMP in aortic rings with endothelium were compared between alloxan-induced diabetic and control rabbits. ACh-induced relaxation was significantly attenuated in the aortic rings of diabetic rabbits. Concentration-response curve for ACh-induced relaxation in the aortic rings of control rabbits was shifted to the right by the pretreatment with hemoglobin, and this concentration-response curve was almost identical to that in the aorta from diabetic rabbits. Sodium nitroprusside (SNP)-induced relaxation in the aortic rings without endothelium from diabetic rabbits was similar to that in the aortic rings without endothelium from control rabbits. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were markedly lower in diabetic rabbits than those in control rabbits. On the other hand, there were no differences in basal and ACh-induced production of cyclic AMP between diabetic and control aorta. These results suggest that impairment of endothelium but not guanylate cyclase activity may be occurred in the aorta of diabetic rabbits. This impairment leads to the decrease in production of cyclic GMP through the attenuation of endothelium-derived relaxing factor (EDRF) release, and this may be responsible for the decreased endothelium-dependent relaxation of ACh.