Acute reversible reduction of PGI2 platelet receptors after iloprost infusion in man

Platelet sensitivity to PGI2 and platelet PGI2 receptors were investigated in eight subjects with peripheral artery disease (stage IV according to Fontaine) treated for 14 consecutive days with six hour iv infusion of Iloprost (Schering, FRG) 2 ng/Kg/min. Platelet studies were performed on the 1st, the 2nd, the 7th and the 14th day of therapy, immediately before infusion (between 8.00 and 9.00 a.m.), at the end and 6 and 18 hours (the following morning) after the end of the infusion. Platelet sensitivity to PGI2 was assessed by determining the PGI2 inhibitory dose 50(ID 50) on platelet aggregation induced by 5 μM ADP. PGI2 platelet receptors were investigated by a direct radioligand binding assay.

PGI2 ID 50 after the infusion was significantly higher than that at baseline(p<0.01) and six hours later the baseline sensitivity was restored. After the six hour Iloprost iv infusion a significant reduction in the number of high affinity PGI2 platelet receptor (HAR) was observed (p<0.005) without any change in their affinity for the ligand. Six hours after the end of the infusion the number of the HAR was still significantly reduced (p<0.05). The following morning the receptor number of HAR was restored. The baseline values of PGI2 HAR, when reassessed after seven and fourteen days of treatment, were not significantly different from those recorded on the first day of therapy. These data indicate that the reduction of platelet PGI2 sensitivity following short-term Iloprost infusion is rapidly reversible and is related to a contemporary down-regulation of PGI2 platelet receptors. However the observed decrease of the number of PGI2 receptors, in the absence of any changes in affinity for the ligand, seems unable to explain the reduced biological effects so that the existence of other post-binding alterations could be postulated.     

Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors

Methylenedioxymethamphetamine (MDMA) produced a significant hyperthermia in rats which was antagonized in a competitive manner by the selective 5-HT2 antagonist, MDL 11,939. The 5-HT antagonist also blocked MDMA-induced neurotoxicity as assessed by the decline in regional 5-HT concentrations observed 1 week later. These two effects of MDL 11,939 were dissociated at higher doses of MDMA where the antagonist still provided virtually complete protection against the neurochemical deficits but only partially attenuated the hyperthermic response. In contrast to the effect of the 5-HT2 antagonist, haloperidol did not alter MDMA-induced hyperthermia but did antagonize its long-term neurochemical effects. Similarly, coadministration of the selective 5-HT uptake inhibitor, MDL 27,777, did not affect the hyperthermia produced by a high dose of MDMA but completely prevented the depletion of 5-HT. When the MDMA-induced hyperthermia was prevented by temporarily maintaining animals at reduced ambient temperature, the neurochemical changes normally observed 1 week later were also blocked. Although these results demonstrate that the drugs tested do not antagonize MDMA-induced neurotoxicity by interfering with its effect on body temperature, they do indicate that MDMA-induced hyperthermia may contribute to the development of the drug's long-term neurochemical effects.     

Defective coronary prostaglandin modulation in anginal patients

In order to investigate whether coronary vasodilating prostaglandins (PGI2 and PGE2) have a role in the pathophysiology of myocardial ischemia, 26 patients with angina pectoris and 23 control subjects (nonischemic patients) were studied by assessing coronary hemodynamics and prostaglandin formation in relation to sympathetic stimulation. Following a cold pressor test (CPT), coronary prostaglandin output markedly increased (p less than 0.001) and coronary vascular resistance (CVR) decreased (p less than 0.001) in all control subjects. In contrast, in anginal patients prostaglandins in the coronary sinus were undetectable and after CPT prostaglandin output did not increase, whereas CVR paradoxically increased (p less than 0.001). In control subjects the inhibition of coronary prostaglandin formation (by ketoprofen [1 mg/kg intravenously] or by aspirin [15 mg/kg intravenously]) caused a paradoxical increase of CVR following CPT (p less than 0.001). In anginal patients the inhibition of prostaglandins further exaggerated the increase of CVR after CPT (p less than 0.001). These results indicate that coronary vasodilating prostaglandin PGI2 and PGE2 play a role in modulating coronary vascular response to sympathetic stimulation induced by CPT. Their defective production in anginal patients may be responsible for the paradoxical increase in CVR following sympathetic stimulation.     

ACE DD genotype: an independent predisposition factor to venous thromboembolism

BACKGROUND: The renin angiotensin system affects haemostasis through different mechanisms; data on the possible role of angiotensin-converting enzyme I/D polymorphism in the pathogenesis of deep venous thrombosis are conflicting, and no information is available regarding the A1166C polymorphism of the angiotensin type 1 receptor gene. In order to investigate this issue, angiotensin-converting enzyme and AT1R polymorphisms were genotyped in 336 consecutive venous thromboembolism patients and 378 controls. MATERIALS AND METHODS: Haemostasis-related risk factors have been evaluated by routine tests. Factor V Leiden, Factor II (G20210A), angiotensin-converting enzyme (I/D), and angiotensin type 1 receptor (A1166C) polymorphisms have been identified by molecular analysis. RESULTS: We documented a significant association between angiotensin-converting enzyme DD genotype and venous thromboembolism (OR=2.19 95%CI 1.51-3.17 adjusted for acquired and haemostasis-related risk factors, P<0.0001); in patients with haemostasis-related risk factors, angiotensin-converting enzyme DD genotype modified the risk of venous thromboembolism in hyperhomocysteinaemic and Factor V Leiden patients and was associated with the risk of recurrent venous thromboembolism (OR=1.83 95%CI 1.06-3.17 P=0.03). In patients without haemostasis-related risk factors the angiotensin-converting enzyme DD genotype was still an independent predictor of venous thromboembolism (OR=3.29 95%CI 2.17-4.98 adjusted for acquired risk factors, P<0.0001). No significant association between the angiotensin type 1 receptor CC genotype and venous thromboembolism was found. CONCLUSIONS: This study shows that angiotensin-converting enzyme DD genotype represents a susceptibility marker of thrombosis in subjects apparently without predisposing factors and traditional thrombophilic alterations, and increases the risk of venous thromboembolism in subjects in whom a thrombogenic condition occurs. Moreover, angiotensin-converting enzyme DD genotype may be considered a new predisposing factor to venous thromboembolism recurrence.     

Paradoxical role of CD16+CCR2+CCR5+ monocytes in tuberculosis: efficient APC in pleural effusion but also mark disease severity in blood

The role of CD16(-) and CD16(+) Mo subsets in human TB remains unknown. Our aim was to characterize Mo subsets from TB patients and to assess whether the inflammatory milieu from TB pleurisy modulate their phenotype and recruitment. We found an expansion of peripheral CD16(+) Mo that correlated with disease severity and with TNF-α plasma levels. Circulating Mo from TB patients are activated, showing a higher CD14, CD16, and CD11b expression and Mtb binding than HS. Both subsets coexpressed CCR2/CCR5, showing a potential ability to migrate to the inflammatory site. In tuberculous PF, the CD16(+) subset was the main Mo/MΦ population, accumulation that can be favored by the induction of CD16 expression in CD16(-) Mo triggered by soluble factors found in this inflammatory milieu. CD16(+) Mo in PF were characterized by a high density of receptors for Mtb recognition (DC-SIGN, MR, CD11b) and for lipid-antigens presentation (CD1b), allowing them to induce a successful, specific T cell proliferation response. Hence, in tuberculous PF, CD16(+) Mo constitute the main APC population; whereas in PB, their predominance is associated with the severity of pulmonary TB, suggesting a paradoxical role of the CD16(+) Mo subset that depends on the cellular localization.