endothelin-1 and Cyanosis

Secondary erythrocytosis results in increased shear stress in cyanotic congenital heart disease (CCHD), which may modify the balance between vasodilators and vasoconstrictors and affect systemic endothelial function. Because no data are available on systemic vasomotion, systemic endothelial function and nitric oxide (NO) availability were investigated in CCHD patients.. Responses to arterial endothelium-dependent (acetylcholine [Ach]) and -independent (sodium nitroprusside [SNP]) vasodilation, NO synthase blockade (NG-monomethyl-L-arginine [L-NMMA]), endothelin-1 (ET-1), and ET-1 receptor blockade by BQ-123 in 11 CCHD patients (O2 saturation <90%; mean+/-SD, 79+/-1%; mean+/-SD age, 39+/-2 years) were compared with those in 10 age-matched healthy referents by using forearm venous occlusion plethysmography. Resting forearm blood flow (FBF) was lower in CCHD patients than in referents (2.4+/-0.2 versus 3.5+/-0.4 mL.min(-1).100 mL(-1) of forearm volume [FAV], P<0.05). Although the response to SNP was similar in both groups (CCHD, 2.0+/-0.3 to 8.3+/-1.0; referents, 3.6+/-0.7 to 11.9+/-1.2 mL.min(-1).100 mL(-1) of FAV; P>0.1), the response to Ach was markedly reduced in CCHD (maximal increase in FBF, 2.8+/-0.8 versus 37.5+/-4.4 mL.min(-1).100 mL(-1) of FAV; P<0.0001). l-NMMA was less effective in CCHD (decrease in FBF, 25+/-6% versus 40+/-4%; P<0.05). ET-1 caused less vasoconstriction in the CCHD group (-25+/-9% versus -51+/-7%, P<0.05), but the response to BQ-123 was similar in both groups (32+/-9% versus 27+/-9%).. Systemic endothelial dysfunction is evident in CCHD patients as shown by strikingly reduced endothelial vasodilation to Ach. The response to exogenous ET-1 is reduced, possibly because of elevated endogenous ET-1 levels, but the effects of endogenous ET-1 on arterial tone are not enhanced, as indicated by the similar response to ET-1 blockade.

Topics: Acetylcholine; Adult; Antihypertensive Agents; Cyanosis; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Heart Defects, Congenital; Hemoglobins; Humans; Microcirculation; Nitroprusside; omega-N-Methylarginine; Oxygen; Peptides, Cyclic; Polycythemia; Vasoconstriction; Vasodilation; Vasodilator Agents

Cyanotic congenital heart disease is associated with functional limitation and vascular events. The nature and extent of endothelial dysfunction in cyanotic adults is poorly understood. We sought to characterise endothelial function in this setting.. A total of fourteen adults with cyanotic congenital heart disease (40±3 years) together with age- and sex-matched healthy controls underwent assessment of nitric oxide-dependent vascular responses, including flow-mediated dilatation of the brachial artery and dynamic vessel analysis of the retina in response to flickering light. Plasma levels of the endothelium-derived vasoconstrictor endothelin-1 and the nitric oxide antagonist, asymmetric dimethylarginine, were measured. Circulating endothelial progenitor cells were assessed by flow cytometry.. Flow-mediated dilatation was significantly lower in cyanosed adults than controls (4.0±0.8 versus 7.2±1.0%, p=0.019, n=11 per group). Retinal arterial and venous dilatory responses were also impaired (2.9±0.8 versus 5.0±0.6%, p=0.05 and 3.4±0.3 versus 5.2±0.7%, p=0.04, n=13). Serum levels of endothelin-1 and asymmetric dimethylarginine were higher in cyanosed adults (3.0±0.6 versus 1.1±0.1 pg/ml, p=0.004 and 0.68±0.05 versus 0.52±0.02 μmol/L, p=0.03, n=11). Endothelial progenitor cells (CD34+CD45dimCD133+KDR+) were reduced in those with chronic cyanosis (17±4 versus 40±6 per million white blood cells, p=0.005, n=11).. Endothelial function is impaired in the systemic arteries and retinal vessels in adults with cyanotic congenital heart disease, suggesting a widespread endotheliopathy. Diminished numbers of endothelial progenitor cells might potentially contribute to these observations.

Topics: Adult; Arginine; Brachial Artery; Case-Control Studies; Cell Count; Cyanosis; Endothelial Cells; Endothelial Progenitor Cells; Endothelin-1; Female; Flow Cytometry; Heart Defects, Congenital; Humans; Male; Middle Aged; Nitric Oxide; Retinal Artery; Retinal Vein; Risk Factors

To assess endothelin-1 (ET-1) response to cold stimulation in essential acrocyanosis (EA), the authors measured ET-1 plasma concentrations in 6 patients with EA (6 women, age range seventeen to thirty-seven years) and in 6 controls (5 women, 1 man, age range twenty-one to thirty-seven years) before and after cold challenge by unilateral hand immersion in water bath at 13 degrees C for five minutes. The contralateral upper limb was considered as control. Blood samples were simultaneously drawn from an antecubital vein in the cooled side and in the contralateral upper limb at baseline, at the end of cooling, and at ten and ninety minutes after cooling was begun. Plasma ET-1 was determined by a radioimmunoassay system. Results are mean +/- SD. Baseline ET-1 was higher in patients with EA (5.1 +/- 0.3 pmol/L) than in controls (1.9 +/- 0.1 pmol/L, P < 0.001). After hand cooling, ET-1 in the cold-exposed upper limb rose in patients with EA to a peak value of 7.2 +/- 0.7 pmol/L, which was greater than that observed in healthy subjects (2.7 +/- 0.4 pmol/L, P < 0.001). The absolute increase in ET-1 plasma concentrations from baseline to peak value was significantly higher in patients with EA than in controls (2.1 +/- 0.3 vs 0.8 +/- 0.2 pmol/L, respectively, P < 0.001). In patients with EA, but not in controls, the rise in ET-1 plasma concentrations was still detected ninety minutes after cooling. The same time course of the plasma ET-1 concentrations was observed in the noncooled upper limb, but the increases in ET-1 at different times after cold stimulus were smaller than in the cold-challenged upper limb in both groups (P < 0.001). In conclusion, the results demonstrate that in patients with EA, baseline plasma levels of ET-1 are enhanced and are further increased by cooling until ninety minutes after cold challenge. This rise in plasma ET-1 could contribute to potentiating and prolonging cold-induced vasoconstriction/vasospasm and/or could be a marker for endothelial damage in EA.

Topics: Adolescent; Adult; Cold Temperature; Cyanosis; Endothelin-1; Female; Humans; Vascular Diseases; Vasoconstriction