Big Endothelin in Patients with Complicated Plasmodium falciparum Malaria

Abstract

Plasma concentrations of big endothelin-1 were determined by ELISA in 18 patients with complicated Plasmodium falciparum malaria in Bangkok. Before therapy, elevated levels were recorded (21 +/- 12 vs. 2.9 +/- 1.1 pmol/L in age- and sex-matched healthy subjects; P < .001). Even 7 days after therapy, elevated concentrations were seen (25 +/- 14 pmol/L). Plasma endothelin levels were correlated with levels of tumor necrosis factor-alpha (r = .632, P < .01), and a negative correlation with platelet counts was seen (r = .783, P < .005). No relation between plasma endothelin concentrations and parasitemia, fever, or other indices of severe infection (hypotension, renal, hepatic or pulmonary impairment, cerebral malaria) existed. During and after complicated malaria, increased levels of plasma endothelin could contribute to malarial pathology or reflect endothelial damage or both.

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

“…This is in keeping with evidence in human and murine CM showing vascular dysfunction attributable to low nitric oxide (NO) bioavailability 34 and potentially other vasoconstrictive mechanisms. [35][36][37] Third, leukocyte adhesion in brain vessels acted as barriers for blood flow by decreasing luminal diameters and directly blocking capillaries. These dynamic observations provided by intravital microscopy support the long-disputed argument in favor of a role for microvascular sequestration in contributing to impaired CBF and ischemia in CM.…”

“…8,18 Definitive evidence of cerebral vasoconstriction in human CM is lacking, although histological findings suggestive of arteriolar spasm have been described in both human and murine CM, 54 and raised serum levels of vasoconstrictive factors such as endothelin-1 have been associated with human and murine CM. [35][36][37] It is also noteworthy that TNF-␣, which is believed to play an important role in murine and human CM pathogenesis, 19,40 has been shown to induce constriction of pial arterioles in piglets 55 as well as vasoconstriction and reduction of cerebral blood volume in rats via an endothelin-dependent pathway. 56 The apparent contradictory data regarding cerebral hemodynamics during human CM may arise from the heterogeneity of presentations of human CM.…”

Transdermal Glyceryl Trinitrate as an Effective Adjunctive Treatment with Artemether for Late-Stage Experimental Cerebral Malaria

“…In vivo studies of the retinal microcirculation of CM patients revealed vascular obstruction, hypoperfusion and intravascular filling defects (8). Endothelial dysfunction in CM has been demonstrated, with low nitric oxide (NO) bioavailability (9), elevated plasma levels of cell-free hemoglobin (10), asymmetric dimethylarginine (11), endothelin 1 (12), and angiopoietins (13), and spastic constriction of cerebral arterioles (14).…”

Endothelin-1 and its role in the pathogenesis of infectious diseases

“…Clinical and experimental data indicate that ET-1 is involved in the pathogenesis of sepsis [8, 47, 50], viral and bacterial pneumonia [9, 10], Rickettsia conorii infections [11], Chagas disease [13, 48], and severe malaria [15, 17, 51, 52]. ET-1 is associated with vasospasms, vascular damage, blood brain barrier (BBB) permeability, cardiovascular remodeling, and inflammation [19, 20, 46, 53, 54].…”