The ductus arteriosus (DA), a fetal arterial connection between the main pulmonary artery and the descending aorta, normally closes immediately after birth. The DA is a normal and essential fetal structure. However, it becomes abnormal if it remains patent after birth. Closure of the DA occurs in two phases: functional closure of the lumen within the first hours after birth by smooth muscle constriction, and anatomic occlusion of the lumen over the next several days due to extensive neointimal thickening in human DA. There are several events that promote the DA constriction immediately after birth: (a) an increase in arterial oxygen tension, (b) a dramatic decline in circulating prostaglandinE2 (PGE2), (c) a decrease in blood pressure within the DA lumen, and (d) a decrease in the number of PGE2 receptors in the DA wall. Anatomical closure of the DA is associated with the formation of intimal thickening, which are characterized by (a) an area of subendothelial deposition of extracellular matrix, (b) the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer, and (c) migration into the subendothelial space of undifferentiated medial smooth muscle cells. In addition to the well-known vasodilatory role of PGE2, our findings uncovered the role of PGE2 in anatomical closure of the DA. Chronic PGE2-EP4-cyclic AMP (cAMP)-protein kinase A (PKA) signaling during gestation induces vascular remodeling of the DA to promote hyaluronan-mediated intimal thickening and structural closure of the vascular lumen. A novel target of cAMP, Epac, has an acute promoting effect on smooth muscle cell migration without hyaluronan production and thus intimal thickening in the DA. Both EP4-cAMP downstream targets, Epac and PKA, regulate vascular remodeling in the DA.
In this review, we demonstrate the basic properties, modulation of, and pathological changes in voltage-dependent K+ (Kv) channels that are expressed in pulmonary arterial smooth muscle cells (PASMCs). Pulmonary Kv channels are thought to play a crucial role in the maintenance of resting membrane potentials, and therefore the vascular tone of the pulmonary arteries. Although the molecular identity of pulmonary Kv channels is not clear, Kv1.1, Kv1.2, Kv1.5, Kv2.1, Kv9.3, and Kv3.1 subtypes are expressed in PASMCs. In addition, resistant PASMCs contain greater amount of Kv channels as compared to conduit PASMCs. This heterogenetic expression of Kv channels is consistent with regional differences in the contractile response to hypoxia. Similar to other K+ channels, pulmonary Kv channels can also be modulated by several vasoconstrictors concomitant with the activation of protein kinase C (PKC). Alterations in Kv channel function have several additional and interrelated consequences, including the regulation of cell proliferation and apoptosis, which ultimately lead to pulmonary vascular remodeling. Increased pulmonary vasoconstriction in pulmonary arterial hypertension is attributable to decreased expression and activity of Kv channels in smooth muscle cells. Kv channels play a central role in the maintenance of cellular homeostasis and ion channels, and consequential signaling cascades. Therefore, Kv channels are potential therapeutic targets for the treatment of pulmonary vascular disease.
Mentha pulegium is common known as “poleo” and used for the treatment of diarrhea, headache and cough in Mexican traditional medicine. Organic extracts from aerial parts were evaluated to determine their spasmolytic action on rat isolated ileum test. Hexanic (HEMp), dichloromethanic (DEMp) and methanolic (MEMp) extracts induced a concentration-dependent (0.97 to 1000 μg/mL) antispasmodic effect on spontaneous contractions. DEMp was the most active extract; therefore, spasmolytic mechanism was investigated. This extract (200 μg/mL) induced a significant depression on cumulative concentration-response curve for carbachol and serotonin (P<0.05). Besides, extract decreased and shifted to the right KCl- and CaCl2-induced contraction curves. Moreover, pre-incubation with chlorpromazine (0.001 mM) shifted to the left the relaxant curve. Pre-treatment with L-NAME (1 mM), papaverine (0.01 mM), teophylline (0.01 mM), TEA (1 mM) and glybenclamide (0.1 mM) did not produced any changed of the relaxant curves of DEMp. Findings indicate that dichloromethanic extract of M. pulegium induced its spasmolytic effect through Ca2+-influx blockade, which may explain its traditional use against diarrhea.
The Anti-diarrhoeal effect of aqueous extract of Rubia tinctorum L. (Rubiaceae) roots in rodents was examined. At doses 300, 600 and 800 mg/kg aqueous extract protected rats, in a dose-dependent fashion, against castor oil-induced diarrhoeal dropping by 37, 59 and 64% respectively. Furthermore, it has significantly inhibited by 41% the gastrointestinal transit of charcoal in mice at 800 mg/kg dose of extract. These data suggest that Rubia tinctorum showed antidiarrhoeal activity by inhibiting intestinal motility which was concordant with its use in traditional medicine.