Pathogenic Mechanisms of Pulmonary Arterial Hypertension: Homeostasis Imbalance of Endothelium-Derived Relaxing and Contracting Factors.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs.

Histamine as an Endothelium-Derived Relaxing Factor in Aged Mesenteric Lymphatic Vessels.

BACKGROUND: Knowledge of the mechanisms by which aging affects contracting lymphatic vessels remains incomplete; therefore, the functional role of histamine in the reaction of aged lymphatic vessels to increases in flow remains unknown. METHODS AND RESULTS: We measured and analyzed parameters of lymphatic contractility in isolated and pressurized rat mesenteric lymphatic vessels (MLVs) obtained from 9- and 24-month Fischer-344 rats under control conditions and after pharmacological blockade of nitric oxide (NO) by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 µM) or/and blockade of histamine production by α-methyl-DL-histidine dihydrochloride (α-MHD, 10 µM). We also quantitatively compared results of immunohistochemical labeling of the histamine-producing enzyme, histidine decarboxylase (HDC) in adult and aged MLVs. Our data provide the first demonstration of an increased functional role of histamine as an endothelial-derived relaxing factor in aged MLVs, which appears in parallel with the abolished role of NO in the reactions of these lymph vessels to increases in flow. In addition, we found an increased expression of HDC in endothelium of aged MLVs. CONCLUSIONS: Our findings provide the basis for better understanding of the processes of aging in lymphatic vessels and for setting new important directions for investigations of the aging-associated disturbances in lymph flow and the immune response.

Role of Endothelium -Derived Relaxing Factor in the Pathogenesis of Coronary Artery Spasm and Its Relationship with Ethanol

Isometric tension recording was performed in the transverse strips of porcine coronary arteries and rabbit aorta to observe the effects of the endothelium and endothelium-derived relaxing factor(EDRF) on vasomotor tone and to test the hypothesis that alcohol may have the deleterious effect on endothelium-dependent vasorelaxation. Tension-development by vasoconstrictor was markedly attenuated in the endothelium-intact strips compared to the endothelium denuded strips. Administration of hemoglobin(10-5M) to inhibit the action of EDRF increased tension selectively in the endothelium-infarct strips, which is suggestive of basal EDRF secretion. Nitro L-arginine(10-5M). an analogue of L-arginine(10-4M) partially reversed the inhibitory effect of nitro L-arginine. Ethyl alchol inhibited bradykinin-induced endothelium-dependent vasorelaxation of porcine coronary artery in dose dependent manner. These data suggest that the protective effect of vascular endothelium to the action of vasoconstirctor can be explained by exercise of basal EDRF release and damaged endothelium would be a great risk of induction of vasospasm. Also we believe that there is a relationship of competive inhibition between L-arginine. a precursor of EDRF, and its analogues on the action of EDRF and alcohol intake would be hazardous to the patients with coronary artey disease because its inhibitory action on endothelium-dependent vasorelaxation may evoke myocardial ischemia.

Contractile and Inhibitory Effects of McN-A-343 and Acetylcholine on Isolated Arteries

Effect of acetylcholine(ACh) and McN-A-343 on porcine coronary artery and rabbit thoracic aorta were investigated in isolated preparations with or without intact endothelium. In the porcine coronary artery, ACh produced concentration dependent contraction which was greater in rings without the endothelium than in intact endothelial rings, but McN-A-343 did not alter the basel tension in both tissues. ACh relaxed contraction induced by 5-hydroxytryptamine(5-HT) in only intact endothelial rings, while NcN-A-343 inhibited the 5-HT induced tension in both preparations dose dependently. Carbachol elicited a prominent contraction in both tissues. The carbacol-induced tension was markedly inhibited by McN-A-343 in either rings with or without endothelium, while ACh contracted further the tension. ACh and McN-A-343 did not after the KCi induced tension, but clearly potentiated the contraction induced by Bay K 8644 in intact endothelial rings. In rabbit thoracic aorta, ACh elicited contraction in a concentration-dependent fashion which was potentiated by removal of endothelium, but McN-A-343 did not affect the basal tension of both rings. ACh inhibited the 5-HT-induced contraction in only intact endothelial ring, but McN-A-343 did not change the contraction of both rings. Conclusively, ACh produces endothelium-dependent relaxation in both arteries, while McN-A-343 elevated endothelium-independent inhibition to 5-HT or carbachol-induced tension.