Review ArticlesPhysiologic basis for the treatment of pulmonary hypertension☆
Section snippets
Regulation of pulmonary artery tone
Many of the current therapeutic approaches aim at restoring or boosting endogenous vasodilator mechanisms or suppressing vasoconstrictor mechanisms of the pulmonary vessels. In comparison, our exploitation of the mechanisms controlling vascular remodeling is limited. After birth, where mechanical forces and oxygen tensions change dramatically both in lung tissue and in the vessels, there are considerable phenotypic changes in the pulmonary artery SMCs, including their electrophysiologic
Balance between vasoconstrictive and vasodilative mechanisms
Pulmonary vascular tone is mainly determined by the SMC cytoplasmic calcium balance. This is controlled by (1) the membrane potential, controlling the L-type calcium channels and thus the cellular calcium influx; (2) the release of calcium from intracellular stores (IP3 pathway) and the associated activation of store depletion-activated calcium currents3; and (3) calcium pumps that shift cytosolic calcium into the sarcoplasmic reticulum (Ca++ sequestration) and the extracellular space (calcium
Endothelial function in pulmonary arteries
The endothelium represents a barrier against extra-vasation of blood plasma and has important anti-thrombotic and vasodilator functions. However, it is also the site of endothelin and plasminogen activator inhibitor-1 production, and it is capable of oxygen radical production. Moreover, it can express adhesion molecules that initiate leukocyte and platelet adhesion. The endothelium of the small pulmonary arteries may play a key role in modulating growth and remodeling of vessels after birth.
Vasoconstrictive mechanisms
The capillary pressure in the lung is regulated in a way that prevents complete collapse of the apical area vessels and severe congestion in the basal zones. This regulation mechanism presumably predominantly involves postcapillary tone,37 but the underlying cellular events are currently not understood. The so-called “Kitajew-reflex,” a pre-capillary vasoconstriction secondary to capillary pressure increase, has been postulated for many years, stemming from the clinical observation that most
Interaction of ventilation and pulmonary arterial tone
In addition to oxygen-mediated effects, ventilation per se can affect pulmonary vascular tone (Fig 5).Hyperventilation has been demonstrated to reduce elevated pulmonary arterial pressure in
Role of phosphodiesterases
The second messengers for the vasodilator signals are rapidly degraded by constitutive PDEs. PDE isozymes inactivate the cyclic nucleotides cGMP and cAMP by cleaving the 3′-phosphoester bond to form the inactive 5′-nucleotide monophosphate products (Fig 6).
Future development
Despite considerable progress, our knowledge of the mechanisms controlling pulmonary vascular tone and remodeling is still incomplete. This applies to both endogenous vasodilator and vasoconstrictor mechanisms. For instance, the means by which exercise decreases the resting pulmonary vascular resistance 3-fold to 5-fold are not completely understood. The same applies for the impressive active vasodilatation of the pulmonary vessels that occurs after birth. The endogenous vasoconstrictor
Acknowledgements
We thank Ralph Wiedemann and H. Ardeschir Ghofrani for stimulating discussions and Mary-Kay Steen-Müller, MD, for carefully reviewing the manuscript.
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2018, Advanced Drug Delivery ReviewsCitation Excerpt :Prostacyclin, also known as prostaglandin I2 (PGI2), is synthetized from the prostaglandin endoperoxide PGH2 by prostacyclin synthase, an enzyme which is present in smooth muscle cells and vascular endothelial cells [42, 43]. The arachidonic acid derivate PGI2 acts predominantly through the G-protein coupled IP receptor which stimulates adenyl cyclase to raise intracellular levels of cyclic adenosine monophosphate (cAMP), thereby activating cAMP-regulated protein kinases A-dependent cell signaling pathways [13, 44, 45]. Prostacyclin is chemically unstable and degrades rapidly to the stable, but biologically inactive 6-keto-prostaglandin F1α; half-life of prostacyclin in blood is only about 3 min [46–48].
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2018, Heart Failure ClinicsCitation Excerpt :Epoprostenol is a synthetically derived prostaglandin I2 (prostacyclin) analogue that has a breadth of action on multiple molecular pathways. In addition to a vasodilating effect on vascular smooth muscle, epoprostenol has also been reported to have antiproliferative, antiplatelet, and antiinflammatory effects.79 Epoprostenol improves symptoms, 6-minute walk distance, and hemodynamics in patients with PAH, and is the only treatment that has been shown to reduce mortality (based on a prespecified secondary analysis from a single randomized controlled trial).80
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2016, Progress in Pediatric CardiologyCitation Excerpt :Factors, released from the endothelium, that affect the potassium channel include nitric oxide (NO), endothelium-derived hyperpolarizing factor, prostaglandin I2. In a hypoxic environment, potassium efflux in the SMC is inhibited, thus allowing calcium inflow, and inducing pulmonary vasoconstriction [13,14]. NO, endothelin, and prostacyclin pathways have become targets for current PH treatments.
Serum levels of tumor necrosis factor-related apoptosis-inducing ligand correlate with the severity of pulmonary hypertension
2015, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :Recently, the levels of C-reactive protein (CRP)—a marker for systemic inflammation and tissue damage—have been reported to correlate with the severity and mortality of PH [33]. Moreover, we observed that the serum levels of CRP were elevated in patients with PH, although we failed to detect an overt correlation between serum CRP levels and sTRAIL levels in PH. Furthermore, prostacyclin has potent anti-inflammatory and antiproliferative effects [34] and can inhibit the mitogen-activated protein kinase (MAPK) pathway and reduce TNF-α, IL-1, IL-2, and IL-10 levels [35], which may further reduce sTRAIL secretion, as observed in the present study. PAH is histologically characterized by endothelial and vascular smooth muscle cell proliferation, medial hypertrophy, and in situ thrombosis.
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2022, Journal of Cardiothoracic Surgery
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Reprint requests: Horst Olschewski, MD, Medical Clinic II, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany.