Increased prostacyclin metabolites and decreased red cell deformability in patients with systemic sclerosis and raynauds syndrome

doi:10.1016/0262-1746(85)90029-0

Prostaglandins, Leukotrienes and Medicine

Volume 17, Issue 1, January 1985, Pages 1-9

Prostaglandins, Leuk...

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Abstract

Patients with systemic sclerosis (SS) often suffer from Raynaud's Syndrome (RS). As prostacyclin (PGI₂) is of benefit in the treatment of RS in SS, we have measured endogenous stable metabolites of PGI₂ (PGI₂m)in 42patients with Raynaud's Phenomenon (RP) of varying aetiology (15 SS patients, 15 patients with Raynaud's Disease (RD) but no other symptoms, and 12 other RS patients with probable connective tissue disorder). Results were compared with 15 matched controls. Since abnormally rigid red blood cells (RBC) may occur in SS, we also measured RBC deformability (filtration technique). Results show that the SS group have significantly elevated PGI₂m levels compared to patients with RD alone and normal controls. In addition, SS patients have more rigid RBC. If all 42 patients with RS were analysed, a significant correlation between PGF and RBC filtration was obtained. The cells of SS patients are resistant to the effects of PGI₂ and it would appear that as a compensatory mechanism, production of PGI₂ is increased. Treatment with exogenous PGI₂ may overcome this resistance and improve microcirculatory flow. The more rigid RBC in SS may also be related to the increased endogenous PGI₂. These results may have important clinical implications and allow new therapeutic approaches.

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Cited by (31)

Long-term administration of beraprost, an oral prostacyclin analogue, improves pulmonary diffusion capacity in patients with systemic sclerosis
2002, Prostaglandins Leukotrienes and Essential Fatty Acids
The objective of this study was to assess the effect of beraprost sodium, an oral prostacyclin analogue, on pulmonary function in patients with systemic sclerosis. Seventeen patients, with systemic sclerosis and predicted percent values of carbon monoxide diffusion capacity (%DLCO) of less than 95, received beraprost sodium for at least 12 months. Conventional testing for pulmonary function was performed at 12-month intervals and changes were evaluated with special reference to DLCO. Twelve patients completed the treatment. Nine patients showed improvement in DLCO (12.1±2.3 to 15.5±4.4 ml/min/mmHg, P<0.006) and 10 patients showed an increase in %DLCO (66.6±11.9 to 87.7±23.2%, P<0.004). Total lung capacity, vital capacity and forced expiratory volume remained unchanged. This study showed that DLCO levels in patients with systemic sclerosis improved after the administration of beraprost sodium, probably due to the decrease in pulmonary vascular resistance accompanied by increased cardiac output.
From Raynaud's Phenomenon to Systemic Sclerosis (Scleroderma): Lack or Exhaustion of Adaptation?
1998, Advances in Organ Biology
This chapter focuses on ischemia–reperfusion and its importance to the evolution and maintenance of systemic sclerosis (SSc). The chapter presents a hypothesis on a possible lack or exhaustion of adaptation of endothelial cells to reperfusion–injury to explain the evolution of Raynaud's phenomenon (RP) to SSc. SSc is a multisystem disease leading to fibrosis of the skin and internal organs. In the large majority of SSc patients before the onset of fibrosis, the disease affects the microcirculatory endothelium generating vascular tone instability—that is RP. RP is characterized by episodes—in particular when exposed to cold, of finger blanching (white) followed by ischemia (blue) and hyperemia (red). This phenomenon may take place many times during the day, is prevalent during the winter, and may attenuate during the summer. In SSc, the vasoconstrictive phenomenon may be divided into two phases: (1) at first, functional phase, when the vessel is still able to accommodate and may thus close and open generating the classic triad of RP (blanching, cyanosis, and redness); and (2) a second, organic phase, when the profound alteration of the vessel wall (hypertrophic intima and media) does not allow vessel accommodation, and the initial blanching of RP is replaced by chronic cyanosis.
Microcirculatory functions in systemic sclerosis: Additional parameters for therapeutic concepts?
1993, Journal of Investigative Dermatology
To study the functional reactivity of the cutaneous microcirculation in progressive systemic sclerosis (PSS), hyperemic responses after arterial occlusion (3 min) and during local heating (42°C) were investigated with simultaneous measurements of red blood cell flux and cutaneous oxygen tension (pcuO2) of the skin in female patients (n = 19) with PSS and in healthy female controls (n = 15). Additionally, serum levels of 6-keto-prostaglandin 1α (PGF1α), a stable metabolite of prostacyclin, were compared to the microcirculatory data, and both were used to evaluate further a standardized therapy with 10-d intravenous calcitonin (100 IU/d) infusion in six PSS patients. In PSS, the initial mean PcuO2 value was significantly reduced and was inversely proportional to flux and to PGF1α levels, whereas the flux and PcuO₂ responses to the above hyperemic stimuli showed significant reductions, revealing a pattern of “hyperemic hypoxia” probably due to exhausted functional reserves of cutaneous perfusion. During calcitonin infusion significant rises in pcuO2 and temporarily in PGF1α and flux were found. After 10 d of therapy, increased pcuO2 was associated significantly with decreased flux, indicating a shifting of blood from deeper regulatory vessels to the sub-epidermal capillaries. Both clinical improvement and the results of microcirculatory measurements demonstrate a beneficial effect of calcitonin on the cutaneous microcirculation in PSS patients, possibly due in part to a short-term increase in release of endogenous prostacyclin from the vascular endothelium during the infusion. The disturbed reactivity of the dermal vessels in PSS is important for the evaluation of therapeutic concepts and stresses, together with the elevated PGF1α plasma levels, vascular factors in the pathogenesis of PSS.
Nitric oxide from polymorphonuclear leukocytes modulates red blood cell deformability in vitro
1993, European Journal of Pharmacology
We confirmed that iloprost is very potent in preserving the deformability of rabbit red blood cells (RBC). Incubation of RBC with a small number (up to 1.2 × 10⁶ cells/ml) of polymorphonuclear leukocytes (PMNs) caused a gradual decline in RBC deformability. The addition of PMNs up to 2.8 × 10⁶ cells/ml increased RBC deformability but, at higher concentrations both in the presence and absence of a neutrophil activating cytokine (interleukin-8; IL-8), PMNs reduced the deformability of RBCs. In the presence of a small number of PMNs, the deformability of RBC was increased by nitric oxide (NO) donors, such as sydnonimine (SIN-1) or sodium nitroprusside, and reduced by the NO synthase inhibitor, N^G-monomethyl-L-arginine. We suggest that the deformability of RBC is modulated by PMNs via the release of NO and that the NO concentration is of critical importance in this modulatory mechanism. No seems to preserve or enhance RBC deformability within a certain range of concentrations, but these effects are reversed or eliminated at both too low and too high concentrations.
Eicosanoids and rheumatology: Inflammatory and vascular aspects
1989, Prostaglandins, Leukotrienes and Essential Fatty Acids
Eicosanoids are not only involved in inflammation but also are important in the maintenance of blood vessel tone and blood flow. This may be relevant in the rheumatological disorders of vasculitis and RS. Although little work has been carried out in vasculitis, the beneficial effects of the natural and synthetic antiplatelet vasodilator PGs in RS are well documented. Less well tested has been the effects of manipulation of AA metabolism.
It should be remembered however that many patients with Raynaud's Phenomenon do not have an associated rheumatological disorder. Conservative management with vasodilators such as the calcium channel blockers may be very successful (119). At the present time PG treatment should be reserved for patients with severe RS, particularly those whose raynaud's is complicated by digital ulceration.
Serum from patients with Raynaud's phenomenon inhibits prostacyclin production
1987, Journal of Investigative Dermatology
Prostacyclin (PGI₂) and PGE₂, the predominant cyclooxygenase products of endothelial cells are potent vasodilators. An inability to produce appropriate concentrations of these prostanoids may be a factor in the pathogenesis of the digital vasospasm experienced by patients with Raynaud's phenomenon (RP). The effect of sera from normal subjects, patients with primary RP, and patients with RP in association with systemic sclerosis (SS) on the production of PGI₂ and PGE₂ by cultured human endothelial cells was investigated. All sera produced a dose-dependent inhibition of 6-keto-PGF_1α, but both the 10% and 20% sera from patients with RP and SS produced a significantly greater inhibition than control sera. The mean production of 6-keto-PGF_1α expressed in ng/10⁴ cells was 2.278 (normal), 1.9311 (RP), and 2.1824 (SS) after incubation with 1% serum for 24 h. This decreased to 1.3647, 0.5927, and 0.4171, respectively following incubation with 20% sera for 24 h. This represented a 44% (normal), 76% (RP), and 83% (SS) inhibition of 6-keto-PGF_1α production compared with serum free media. Similar results were obtained after 1 h incubation experiments. There was a nonsignificant decrease in mean PGE₂ production following similar incubations with 1% and 20% sera for 24 h. These results suggest that factor(s) present in the sera of patients with RP may reduce the ability of endothelial cells to synthesize or release the vasodilator and antiaggregatory prostanoid PGI₂.

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Increased prostacyclin metabolites and decreased red cell deformability in patients with systemic sclerosis and raynauds syndrome

Abstract

Progressive systemic sclerosis: kidney involvement

Clinical Rheumatic Diseases

Raynauds syndrome: current trends

British Journal of Rheumatology

Prostaglandin E1 infusions for vascular insufficiency in progressive systemic sclerosis

Annals of the Rheumatic Diseases

Successful treatment of Raynauds syndrome with prostacyclin

Thrombosis & Haemostasis

Therapy of Raynauds phenomenon by intravenous infusion of prostacyclin

British Journal of Dermatology

Effect of cooling on prostacyclin mediated inhibition of platelet aggregation

Clinical Science

Abnormalities of T lymphocyte subsets in patients with progressive systemic sclerosis (PSS, scleroderma)

Journal of Laboratory and Clinical Medicine

Absence of prostaglandin stimulated increase in acute phase proteins in systemic sclerosis

Lancet

Urinary prostaglandins in scleroderma

Raynaud's phenomenon, histamine and prostaglandins

The Lancet

Altered behaviour of erythrocytes in scleroderma

Clinical Science

A sensitive radio-immunoassay for 6-keto-PGF1α: preliminary observations on circulating concentrations

Prostaglandins in Medicine

Prostaglandin E₁ infusions for vascular insufficiency in progressive systemic sclerosis

A sensitive radio-immunoassay for 6-keto-PGF_1α: preliminary observations on circulating concentrations