calcium channel blockers and pulmonary hypertension

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From the Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada,

and t h e Department of Clinical Pharmacology,

University Hospital, Lund, Sweden.

Calcium Channel Blockers and Pulmonary Hypertension

Karl-Erik Anderson

Abstract

In vascular smooth muscle from the pulmonary circulation, potassium evoked contractions are abolished in calcium-free medium and by calcium channel blockers (CCB). Noradrenaline, histamine, and serotonin induced contractions are partly resistant. Pulmonary arterial hypertension may occur both as a primary disorder and secondary to cardiac and pulmonary diseases; in both types there may be a component of pulmonary arterial vasoconstriction. In animal models, hypoxic pulmonary hypertension is counteracted by CCBs, nifedipine being particular ef- fective. In patients with this disorder, CCRs also seem able to lower pulmonary arterial pressure and vascular resistance, but no controlled trials documenting their clinical efficacy have been performed. This is valid also for primary pulmonary hypertension, where some of the CCBs may have clinical value.

K e y words: calcium, calcium channel blockers, pulmonary hypertension.

Introduction

The ability of calcium channel blockers to inhibit contraction in vascular smooth muscle has made them potential alterna- tives of treatment of disorders where vascular hyperactivity is believed to be an essential pathogenetic factor. This is the case in pulmonary arterial hyper-

tension. This short review summarizes some effects of calcium channel blockers on vascular smooth muscle from the pulmonary circulation. In addition, clinical experiences w i t h calcium channel blockers in the treatment of various forms of pulmonary hypertension is discussed.

Effects on the pulmonary circulation

1. Effects on pulmonary vascular smooth muscle.

Animal vessels. The rabbit main pulrnon- ary artery is often used a s a model of vascular smooth muscle in studies on contractile mechanisms, membrane potential, and calcium fluxes (for review, see HAEUSLER 1983). In isolated preparations of this vessel, potassium induced contractions are completely dependent on extracellular calcium, and exposure to calcium-free medium for 20 rnin. abol- ishes such contractions. Potassium up to 40 m M was shown to cause a concentration-related increase in calcium influx (HAEUSLER 1983). This in f lux could be concentration dependently inhibited by verapamil. It was suggested that high extracellular potassium promoted calcium influx sufficient to trigger contraction through voItage-dependent calcium channels sensitive t o blockade with calcium entry blockers.

CARRIER and HOWELL (1982) found that in the rabbit pulmonary artery, both

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noradrenaline and histamine produced contraction in calcium-free medium. Maximum contractile force was reduced, but not the EC50 values for t h e drugs. In the same preparation, the contraction induced by low concentrations of noradrenaline (< 10-6M) was associated with a modera t e depolariza t ion ( H A EUSLER 1978). High noradrenaline concentrations (> 1 0 - 6 M ) caused contractions without further depolarization. The maximal depolarization induced by noradrenaline was accompanied by a t least half maximal contraction. The same amount of depolarization induced by potassium caused contraction of threshold magnitude. I t was therefore concluded (HAEUSLER 1983) that the noradrenaline induced depolarization would be insufficient to open the voltage-dependent calcium channels. HAEUSLER (1972) showed that in the rabbit pulmonary artery t h e contraction induced by noradrenaline was less sensitive t o inhibition by calcium entry blockers than that evoked by potassium. There- fore, activator calcium for noradrenaline induced contraction probably appears to come mainly from intracellular sources. As far as extracellular calcium contributes, it may enter the cell through calcium channels operated by a-adreno- ceptors (HAEUSLER 1983).

Human vessels. The importance of extracellular calcium for the maintenance of tone and for agonist-induced contraction in human pulmonary smooth muscle has not been established. MIKKELSEN e t al. (1983) found that calcium-free medium within 20 min. abolished the response to potassium. A t this time t h e preparations still responded to histamine and serotonin. Potassium-induced contraction were more effectively relaxed by t h e drug than contractions induced by histamine or serotonin.

2. Pulmonary arterial hypertension.

Pulmonary hypertension, encountered in t h e newborn (GERSONY 1984) or in adults, has many potential causes. I t way occur as a primary disorder of the pulmonary arteries, or it may be secondary to a variety of cardiac and pulmonary diseases (GERSONY 1984, RICH and H K U N D A G E 1984, ROUNDS and H I L L 1984). in both primary and secondary

hypertension it is believed that there is a component of constriction of the pulmonary arterial bed (HARRIS and ::BATH 1977, WAGENVOORT and WA- GENVOORT 19771, but except for hypoxic lung disease (see, K E N N E D Y et al. 19851, the stimulus for vasoconstriction is unknown. Vasodilators are currently being tested as a treatment of these patients, but even if some of the drugs have been shown to decrease the pulmonary artery pressure, it remains to be proved that they improve survival or cause regression of the disease. Occasional case reports have documented a marked reduction in both pulmonary arterial pressure and vascular resistance, and clinical improvement . However, controlled clinical trials are lacking, and in general long-term therapy has not been successful (FISH- M A N and PIETRA 1980, K U L I K and LOCK 1984, ROUNDS and HILL 1984). One reason for th i s may be lack of potent vasodilator drugs with a t least some se- lectivity for t h e pulmonary circulation.

a) HypoJnc pulmonary hypertension Animal models. McMURTRY et al. (1976) studied the role of transmembrane calcium influx in pulmonary vasoconstriction induced by hypoxia in t h e isolated, blood-perfused rat lung. They found that the hypoxic pressor response could be effectively inhibited by verapamil and SKF 525 , but that responses evoked by prostaglandin Fg, and angiotensin II could not. These results were found to support the idea that hypoxia directly depolarizes the smooth muscle cell; and initiates calcium influx. Other investigators have suggested that alveolar hypoxia depolarizes perivascular mastcells, causing cal- c ium inf lux and release of vasoactive mediators which produce vasocontriction (see, K E N N E D Y et al. 1985).

The findings of McMURTRY et al. (1976) have been confirmed by other investigators. In several species it has been demonstrated that hypoxic vasoconstriction can be inhibited by calcium entry blockers such as verapamil, diltiazem, nifedipine, and nisoldipine, both acutely and in long-term experiments (DAVIDSON et al. 1978, KENTERA et al. 1979, SUG- GETT and BARER 1980, K E N N E D Y and SUMMER 1982, Y O U N G e t al. 1983, A R - CHER e t al. 1985, see K E N N E D Y et al.

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1985). In the conscious rat, STANBROOK et al. (1984) compared the ability of verapamil, nifedipine and hydralazine to reduce the development of hypoxic hypertension. After one month of treatment, all drugs reduced pulmonary hypertension, the calcium entry blockers more effectively than hydralazine. Nifedipine was able to reverse established hypoxic pulmonary hypertension, causing a reduction of right ventricular hyperthrophy and medial thickening (STANBROOK et al. 1984).

Man. In normal man, NAEIJE et al. (1982) found that nifedipine did not abolish hypoxic pulmonary vasoconstriction, nor did it induce pulmonary vasodilatation a t nor m oxic conditions. Investigating patients with pri m ary hypertension, GUAZZI e t al. (1982) showed that nifedipine administration reduced both systemic and pulmonary vascular resistance. The per cent decrease was related to the base-line of resistance in both circula- tions. SIMONNEAU et al. (1981) demonstrated in hypoxemic patients with pulmonary hypertension secondary to chronic obstructive lung disease that nifedipine had a pulmonary vasodilating action. MU- RAMOTO et al. (1981) also found nifedipine to acutely reduce both pulmonary arterial pressure and pulmonary vascular resistance in patients wi th stable, chronic obstructive pulmonary disease. There was no change in arterial oxygen tension and an increases in cardiac output. STURANI et al. (1983) found similar effects treating patients w i t h oral nifedipine for 6 to 9 weeks. However, MELOT e t al. (1984) reported deleterious effects of nifedipine on pulmonary gas exchange in patients with chronic obstructive pulmonary disease. This was probably a con- sequence of loss of hypoxic regulation of t h e pulmonary circulation.

Not only nifedipine but also verapamil seem to be able to lower pulmonary arterial pressure. In patients with pulmonary hypertension given intravenous verapamil pulmonary arterial pressure was reduced by 24% (REUBEN and K U A N 1980).

CCBs, particularly nifedipine, thus seem to be able to lower pulmonary artery pressure and resistance in patients w i t h hypoxic pulmonary hypertension. How- ever, no controlled clinical trials have

been performed, and their long-term clinical efficacy remains to be established.

b) Primary pulmonary hypertension LOCKHART and REEVES (1984) pointed out that i f sustained or paroxystic pulmonary vasoconstriction contributes to the increase in pulmonary vascular resistance and/or promotes the develop- m e n t of irreversible damage to the pulmonary vessels, prolonged vasodilator treatment could be expected to favour- ably alter t h e course of pulmonary hypertension. So far t h i s has not been shown to be the case, and the experiences w i t h calcium entry blockers have given vari- able results.

L A N D M A R K e t al. (1978) found in 9 patients wi th primary pulmonary hypertension that verapamil caused a smell decrease in mean pulmonary arterial pressure, did not change pulmonary vascular resistance and decreased cardiac index. CREVEY e t al. (1982) reported similar responses to intravenous diltiazem. PACKER e t al. (1983) reported that nifedipine decreased pulmonary arterial pressure and vascular resistance in 5 patients with primary pulmonary hypertension, but mean right arterial pressure increased and cardiac output decreased. Similar findings were made in 7 patients with primary pulmonary hypertension treated with verapamil (PACKER et ai. 1984). The drug decreased both mean arterial pressure and vascular resistance, but there was a pronounced decrease in right ventricular stroke work index and an increase in right ventricular filling pressure. In one patient these cardiodepressant effects were sufficient to produce severe hypotension and cardiac arrest.

On the other hand, it was reported that diltiazem had a sustained beneficial effect in a patient w i t h primary pulmonary hypertension treated for 11 months ( K A M B A R A e t al. 1981). In 7 patients with primary pulmonary hypertension, OLIVARI et al. (1984) showed that nifedipine produced a significant and persistent decrease of mean pulmonary arterial pressure and pulmonary vascular resistance, both a t rest and during exercise. Treatment for up to 1 0 months produced symptomatic improvement in 6 out of

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7 pa t ien ts , a n d hemodynamic improve- m e n t in 3 out of 4 s tudied pa t ien ts . Also o t h e r inves t iga tors h a v e found nifedipine to c a u s e both s y m p t o m a t i c and hemodynamic improvement in s o m e cases last- ing f o r m o r e t h a n six months (CAMERINI et al. 1980, DE FEYTER et al . 1983, DOUGLAS 1983, RUBIN et al. 1983, SAI- T O et al. 1983, WISE 1983, FISHER et al. 1984). Also a n o t h e r dihydropyridine, fe lodipine was r e p o r t e d to produce symp- t o m a t i c and h e m od yna m i c improvement las t ing f o r m o r e t h a n 3 months in 2 pa- t i e n t s (ARNMAN et al. 1984).

It c a n n o t b e excluded t h a t calcium e n t r y blockers , par t icu lar ly dihydropyrid- ines, c a n be of value in t h e t r e a t m e n t of pr imary pulmonary hypertension. How- ever , as is t h e case in hypoxic pulmonary hypertension control led cl inical trials d e m o n s t r a t i n g t h e long-term e f f i c a c y and p o t e n t i a l h a z a r d s of t h e treatment are still lack ing (cf . PACKER 1985).

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calcium channel blockers and pulmonary hypertension

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