Vascular pharmacology
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Vascular pharmacology · Nov 2002
ReviewRole of Ca2+ signaling in the regulation of endothelial permeability.
The vascular endothelial cell forms a semipermeable barrier between blood and interstitium. Inflammatory mediators such as thrombin and histamine induce vascular leakage defined as increased endothelial permeability to plasma proteins and other solutes. Increased endothelial permeability is the hallmark of inflammatory vascular edema. ⋯ In addition, TRPC4(-/-) mice LEC exhibited lack of actin stress fiber formation and cell retraction in response to thrombin activation of proteinase-activated receptor-1 (PAR-1) in endothelial cells. The increase in lung microvascular permeability in response to thrombin receptor activation was inhibited in TRPC4(-/-) mice. These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling the increase in endothelial permeability.
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Vascular pharmacology · Nov 2002
ReviewTargets for pharmacological intervention of endothelial hyperpermeability and barrier function.
Many diseases share the common feature of vascular leakage, and endothelial barrier dysfunction is often the underlying cause. The subsequent stages of endothelial barrier dysfunction contribute to endothelial hyperpermeability. Vasoactive agents induce loss of junctional integrity, a process that involves actin-myosin interaction. ⋯ Sometimes, a controlled, temporal, and local increase in permeability can also be desired, for example, with the aim to enhance drug delivery. Therefore, vessel leakiness is also being exploited to enable tissue access of liposomes, viral vectors, and other therapeutic agents that do not readily cross healthy endothelium. This review discusses strategies for targeting signaling molecules in therapies for diseases involving altered endothelial permeability.
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Vascular pharmacology · Mar 2002
Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.
The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. ⋯ From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.
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Pulmonary hypertension is a hemodynamic abnormality that is common to a variety of conditions. In obliterative pulmonary hypertension, vascular remodeling leads to an obliterative process involving the small muscular pulmonary arteries, thereby increasing pulmonary vascular resistance (PVR) and the pulmonary artery pressure (PAP). This process can be triggered by a defect in the function of K+ channels or by alveolar hypoxia. ⋯ Vasoconstriction causes elevation of intravascular pressure and elastic stretch of the SMCs, both of which have been shown to play a role in pulmonary arterial cellular growth and synthetic activity, creating a vicious cycle of cellular hypertrophy, proliferation, and vascular remodeling. Dysfunction of K+ channels has also been linked to decreased apoptosis in pulmonary arterial SMCs, a condition that contributes further to the medial hypertrophy of the arterial walls and vascular remodeling. The goal of this article is to review the current understanding of the function of K+ channels and their contribution to the pathophysiology and cellular mechanisms involved in the development of pulmonary hypertension.