Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion

Summary Defibrotide is known to enhance prostacyclin (PGI₂) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10^–7 or 100 g/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10^–7 or 100 g/ml, markedly restored the vasodilation to acetylcholine 10^–7 nmol/l to 1 mol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 g/1). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of (PGI₂) release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10–100 g/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.Supported in part by Research Grant No. HL-25575 from the National Heart, Lung and Blood Institute of the NIH Send offprint requests to A. M. Lefer at the above address     

Intelligence and temperament as protective factors for mental health. A cross-sectional and prospective epidemiological study

The Sjöbring system of personality dimensions measuring intellectual capacity, activity, impulsivity and sociability was used to study possible salutogenic (i.e. causes of health) effects. The study comprised 590 subjects investigated in 1947, 1957, 1972 and 1988–1989 in the Lundby project, an epidemiological study in Sweden. Psychiatric diagnoses were made in 1947, 1957 and 1972. Mental health was estimated in 1988–1989 using the concept love well, work well, play well and expect well. The Sjöbring dimensions were clinically assessed in 1972. Both in the concurrent study in 1972 and in the prospective study in 1988–1989 super capacity (high intellectual function), super validity (high activity level) and super solidity (low impulsivity) were statistically associated with lower frequencies of certain psychiatric diagnoses and a higher frequency of positive mental health. These variables are proposed to increase coping capacity, and therefore increase stress resilience.     

Selective attenuation of neuropeptide-Y-mediated contractile responses in blood vessels from patients with diabetes mellitus

Vascular smooth muscle contractile responses to neuropeptide Y, ,ß-methyleneATP and noradrenaline were studied in circular segments of isolated vessels with intact endotheliumin vitro from 12 patients with diabetes mellitus type 2 (NIDDM) and 12 control subjects. The dilatory effect of acetylcholine was used to test the function of the endothelium. Subcutaneous arteries and veins (diameter 0.1–1.1 mm) were obtained during surgery. There was no difference in contractile responses to noradrenaline or ,ß-methyleneATP between diabetic and control vessels. The contractile response to neuropeptide Y, however, was markedly reduced in the diabetic group. The maximal contractile effect (46.0 ± 14.0%,p < 0.05) but not the sensitivity to neuropeptide Y was significantly less in diabetic veins compared to control (107.5 ± 19.6%). Thus, the attenuation of neuropeptide Y responses was present in humans as previously observed in alloxan-induced diabetes mellitus in rabbits. There was no difference in the dilator effect of acetylcholine between the diabetic and the control group in any of the vessel types, indicating that the difference in vascular reactivity to neuropeptide Y was not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of neuropeptide Y, a co-transmitter of the peripheral sympathetic nervous system, is selectively attenuated in diabetes mellitus.     

Up-regulation of β1-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments

Quantitative receptor autoradiography was used to study the effects of the selective serotonin reuptake inhibitors citalopram and fluoxetine and the tricyclic antidepressant imipramine on the regulation of ₁-adrenergic receptors in the rat brain. Rats were treated with saline, citalopram (10 mg kg^–1), fluoxetine (10 mg kg^–1), or imipramine (15 mg kg^–1) SC once daily for 14 days. [¹²⁵I]Iodocyanopindolol binding to ₁-adrenergic receptors was found to increase significantly in the caudate-putamen and the somatosensory areas of the frontal cortex after both citalopram and fluoxetine treatments. Imipramine treatment elicited a marked decrease in ₁ binding in the outer laminae of the cingulate cortex, as well as in the motor and somatosensory areas of the frontal cortex. In a separate experiment, rats were treated with saline, citalopram (2.5, 10 and 20 mg kg^–1) or fluoxetine (2.5, 10 and 20 mg kg^–1) SC once daily for 14 days. The effects of citalopram and fluoxetine on ₁ receptors in the somatosensory cortex and caudate-putamen were replicated. These results demonstrate that chronic administration of selective serotonin reuptake inhibitors, in contrast to imipramine, can cause a regional up-regulation of ₁-adrenergic receptors in the rat brain.     

Catecholamines modulate growth and differentiation of human preosteoclastic cells

Using a clonal cell line of human osteoclast precursors (FLG 29.1 cells), that after treatment with 12-O-tetradecanoyl phorbol 13-acetate (TPA) show many functional characteristics of osteoclasts, we demonstrated that catecholamines act as inducers of osteoclast maturation in vitro and as stimulators of osteoclast activity via the binding to 24hq1/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂ adrenergic receptors. Scatchard analysis of¹²⁵I-labelled iodocyano-pindolol to untreated (undifferentiated) or TPA-treated (differentiated) FLG 29.1 cells revealed the presence of a single high-affinity site with aK _d value around 24 pM and 8 pM respectively and with superimposable binding capacity (1.18 fmol/mg protein). Catecholamines increased in a dose-dependent fashion the intracellular cyclic AMP (cAMP) accumulation in both undifferentiated and TPA-treated FLG 29.1 cells. Pretreatment of untreated and TPA-treated FLG 29.1 cells with propranolol inhibited the catecholamine effect on cAMP accumulation, while pretreatment with clonidine had no effect. Catecholamines also reduced cell proliferation, increased tartrate-resistant acid phosphatase (TRAcP) activity, interleukin 6 (IL-6) production, multinuclearity and response to salmon calcitonin (sCT) in undifferentiated FLG 29.1 cells. In differentiated FLG 29.1 cells only IL-6 release was induced by catecholamine treatment. These findings support a potential role for catecholamines in modulating osteoclast differentiation and mature osteoclast activity.     

Ubiquitinated neurites are associated with preamyloid and cerebral amyloid β deposits in patients with hereditary cerebral hemorrhage with amyloidosis Dutch type

Summary Here ditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D) is characterized clinically by recurrent strokes and pathologically by deposition of amyloid (A) in cerebral vessel walls and, to a lesser extent, in the neuropil. Distinct from Alzheimer's disease, amyloid formation in HCHWA-D is not associated with neurofibrillary changes. Since a central issue in the pathophysiology of Alzheimer's disease and related conditions is the role of A in the neurodegencrative process, we investigated HCHWA-D brains for the presence of neuritic abnormalities using antibodies to ubiquitin and to phosphorylated neurofilaments. The study showed that amyloid deposits in the vessel walls and in the neuropil were surrounded by abnormal ubiquitinated neurites, suggesting that A deposition induces neuritic changes.Supported by the Italian Ministry of Health. Department of Social Services, and by N.I.H. Grants AG05891 and AG08721 (to B.F.)     

Are the disparate pharmacological profiles of competitive and un-competitive NMDA antagonists due to different baseline activities of distinct glutamatergic pathways? (Hypothesis)

Summary In superfused mouse striatal slices preincubated with [³H] dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [³H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H₃ agonist R-(–)--methylhistamine; it was not affected by the H₁ antagonist dimetindene and the H₂ antagonist ranitidine but abolished by the H₃ antagonist thioperamide. Tritium overflow evoked by Ca²⁺ ions (introduced into Ca²⁺free, K⁺-rich medium containing tetrodotoxin) was not affected by histamine 10 mol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H₃ receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H₃ receptor-mediated inhibition of dopamine release.