Review Articles
Physiologic basis for the treatment of pulmonary hypertension

https://doi.org/10.1067/mlc.2001.119329Get rights and content

Abstract

J Lab Clin Med 2001;138:287-97

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).

. Effects of ventilation and hyperventilation on pulmonary artery tone. →, Activating factor; —|, inhibiting factor. The relative importance of the depicted factors has not been defined, but lung distension seems to be one of the key factors, explaining most of the vasodilatory effects of hyperventilation.

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).

. Regulation of the PDEs. →, Activating factor; —|, inhibiting factor; thickness of gray arrows depicts the cleavage capacity for cyclic nmonophosphates of the respective PDE type; PDE, PDE types 1 to 5, cleaving cAMP and cGMP; 5-AMP,

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.

References (88)

  • T Wisenbaugh et al.

    Pulmonary hypertension is a contraindication to beta-blockade in patients with severe mitral stenosis

    Am Heart J

    (1993)
  • HM Thomas et al.

    Inhibition of hypoxic pulmonary vasoconstriction by dipheny-leneiodonium

    Biochem Pharmacol

    (1991)
  • NS Chandel et al.

    Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing

    J Biol Chem

    (2000)
  • Y Ishii et al.

    Hyperventilation stimulates the release of prostaglandin I2 and E2 from lung in humans

    Pro-staglandins

    (1990)
  • SJ Skinner et al.

    The effects of mechanical stretching on fetal rat lung cell prostacyclin production

    Prostaglandins

    (1992)
  • VC Manganiello et al.

    Diversity in cyclic nucleotide phosphodiesterase isoenzyme families

    Arch Biochem Biophys

    (1995)
  • C Lugnier et al.

    Characterization of cyclic nucleotide phosphodiesterases from cultured bovine aortic endothelial cells

    Biochem Pharmacol

    (1990)
  • HL Reeve et al.

    A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent

    Am J Physiol

    (1998)
  • SH Abman

    Abnormal vasoreactivity in the pathophysiology of persistent pulmonary hypertension of the newborn

    Pediatr Rev

    (1999)
  • SS McDaniel et al.

    Capacitive Ca2+ entry in agonist-induced pulmonary vasoconstricition

    Am J Physiol

    (2001)
  • R Schubert et al.

    Iloprost activates KCA channels of vascular smooth muscle cells: role of cAMP-dependent protein kinase

    Am J Physiol

    (1996)
  • DJ Hartshorne et al.

    Myosin light chain phosphatase: subunit composition, interactions and regulation

    J Muscle Res Cell Motil

    (1998)
  • A Olschewski et al.

    Basic electrical properties of in situ endothelial cells of small pulmonary arteries during postnatal development

    Am J Respir Cell Mol Biol

    (2001)
  • T Busch et al.

    Nasal, pulmonary and autoinhaled nitric oxide at rest and during moderate exercise

    Intensive Care Med

    (2000)
  • A Fischer et al.

    Evidence for an esophageal origin of VIP-IR and NO synthase-IR nerves innervating the guinea pig trachealis: a retrograde neuronal tracing and immunohistochemical analysis

    J Comp Neurol

    (1998)
  • O Sitbon et al.

    Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension

    Eur Resp J

    (1998)
  • RA Cohen et al.

    Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery

    Proc Natl Acad Sci

    (1997)
  • WB Campbell et al.

    Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors

    Circ Res

    (1996)
  • M Feletou et al.

    Endothelium-derived hyperpolarizing factor

    Clin Exp Pharmacol Physiol

    (1996)
  • AC Resende et al.

    Role of non-nitric oxide non-prostaglandin endothelium-derived relaxing factor(s) in bradykinin vasodilation

    Braz J Med Biol

    (1998)
  • G Edwards et al.

    K+ is an endothelium-derived hyperpolarizing factor in rat arteries

    Nature

    (1998)
  • RL Jones et al.

    Prostanoid action on the human pulmonary vascular system

    Clin Exp Pharmacol Physiol

    (1997)
  • RA Coleman et al.

    International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes

    Pharmacol Rev

    (1994)
  • CR Kennedy et al.

    Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor

    Nat Med

    (1999)
  • WF Jackson et al.

    Prostacyclin-induced vasodilation in rabbit heart is mediated by ATP-sensitive potassium channels

    Am J Physiol

    (1993)
  • M Dumas et al.

    Role of potassium channels and nitric oxide in the effects of iloprost and prostaglandin E1 on hypoxic vasoconstriction in the isolated perfused lung of the rat

    Br J Pharmacol

    (1997)
  • L Walch et al.

    Prostanoid receptors involved in the relaxation of human pulmonary vessels

    Br J Pharmacol

    (1999)
  • M Nguyen et al.

    The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth

    Nature

    (1997)
  • H Sinzinger et al.

    Antimitotic actions of vasodilatory prostaglandins: clinical aspects

    Agents Actions

    (1997)
  • K Schrör et al.

    Roles of vasodilatory prostaglandins in mitogenesis of vascular smooth muscle cells

    Agents Actions

    (1997)
  • S Fukumoto et al.

    Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation

    Circ Res

    (1999)
  • R Friedman et al.

    Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension

    Circulation

    (1997)
  • DJ Crutchley et al.

    Effects of prostacyclin analogues on human endothelial cell tissue factor expression

    Arterioscler Thromb

    (1993)
  • S Della Bella et al.

    Differential effects of cyclo-oxygenase pathway metabolites on cytokine production by T lymphocytes

    Prostaglandins Leukot Essent Fatty Acids

    (1997)
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