New approaches to the treatment of pulmonary hypertension: from bench to bedside

Abstract

Pulmonary hypertension (PH) is a severe, life-threatening disease for which there are no effective curative therapies. A diverse group of agents such as prostacyclins, endothelin antagonists, phosphodiesterase inhibitors, calcium channel blockers, diuretics, inotropic agents, and anticoagulants are used to treat PH; however, none of these agents have a marked effect upon survival. Among the new agents that promise treatment of PH are rho-kinase inhibitors and soluble guanylate cyclase stimulators. Although these new classes of agents have beneficial effects in experimental animal models and clinical studies, they are not selective in their actions on the pulmonary vascular bed. This manuscript reviews the actions of rho-kinase inhibitors and soluble guanylate cyclase stimulators on the pulmonary vascular bed. It is our hypothesis that these new agents may be more effective than current therapies in the treatment of PH. Moreover, new methods in the delivery of these agents to the lung need to be developed so that their main effects will be exerted in the pulmonary vascular bed and their systemic effects can be minimized or avoided.

Figure 1

Chemical structures of the Rho-kinase inhibitors which are currently available. Fausdil has been used in clinical studies in Japan and USA.

Figure 2

Diagram drawing showing interactions of receptor and store-operated calcium channels and of Rho-kinase in activation of myosin light chain (MLC₂₀) in vascular smooth muscle (VSM). Phosphorylation of MLC₂₀ and resultant VSM contraction are primarily determined by the balance between myosin light chain kinase (MLCK) that induces VSM contraction, and MLC phosphatase (MLCP) that induces VSMC relaxation. Increases in intracellular Ca²⁺ concentrations, Ca²⁺ entry (Bay K-8644, a Ca²⁺channel opener), and from receptor-operated calcium channels (G protein coupled receptor due to agonist interactions with ET-1, endothelin-1; 5-HT, serotonin; AII, angiotensin II; NE, norepinephrine; or TxA₂, thromboxane A₂) with subsequent Ca²⁺ release from the sarcoplasmic reticulum (SR), increase intracellular Ca²⁺-calmodulin complex that stimulates MLCK and induces VSM contraction. In the resting state, RhoA/GDP exists in the cytosol. However, with activation of certain trimeric G proteins, RhoA/GDP migrates and is changed to RhoA/GTP (now active) on the membrane of the VSM cell where it interacts with Rho-kinase to initiate increased phosphorylation of MLCP (active) to MLCP-P (inactive). MLCP opposes the action of MLCK. MLCP, myosin light chain phosphatase (active); MLCP-P, myosin light chain phosphatase (inactive); PLC, phospholipase C; IP₃, inositol triphosphate. Modified from Nagaoka T, Fagan KA, Gebb SA, et al.: Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171:494–499.

Figure 3

Bar graphs comparing decreases in pulmonary and systemic arterial pressure and increases in cardiac output in response to IV injections of SB-772077-B in L-NAME treated animals. The IV injections of L-NAME in doses of 5 to 25 mg/kg produced a significant increase in pulmonary and systemic arterial pressures. n indicates number of experiments. * indicates significantly different from baseline. Modified from Dhaliwal JS, Badejo AM, Jr., Casey DB, et al.: Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin- 2-yl)-1,2,5-oxadiazol-3-amine], a novel aminofurazan-based Rho kinase inhibitor. J Pharmacol Exp Ther 2009;330:334–341 [117].

Figure 4

Effect of IV injections of SB-772077-B on pulmonary and systemic arterial pressures and cardiac output in monocrotaline treated rats. The responses to SB-772077-B were measured on day 29 after treatment with the plant alkaloid in an IV dose of 60 mg/kg. Modified from Dhaliwal JS, Badejo AM, Jr., Casey DB, et al.: Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin- 2-yl)-1,2,5-oxadiazol-3-amine], a novel aminofurazan-based Rho kinase inhibitor. J Pharmacol Exp Ther 2009;330:334–341 [117]