calcium channel blockers in hypoxic pulmonary hypertension

Calcium Channel Blockers in Hypoxic Pulmonary Hypertension

THOMAS P. KENNEDY, M.D. JOHN R. MICHAEL, M.D. WARREN SUMMER, M.D. Baltimore, Maryland

Hypoxia is the major cause of pulmonary hypertension and right ventricular hypertrophy in chronic obstructive pulmonary disease, cystic fibrosis, kyphoscoliosis, chronic mountain sickness, and the obesity-hypoventilation and sleep apnea syndromes. Pulmonary hypertension develops in these patients because the long-standing vasoconstriction produced by hypoxia causes muscular hypertrophy of the pulmonary arteries and arterioles. These pathologic changes may regress if alveolar hypoxia is corrected and hypoxic pulmonary vasoconstriction is continuously inhibited. Intermittent inhibition of hypoxic pulmonary vasoconstriction does not reverse these pathologic changes. Since patient noncompliance with oxygen therapy makes it difficult to achieve continual relief of alveolar hypoxia, a drug that inhibits hypoxic vasoconstriction may be useful. Experimental findings indicate that hypoxic pulmonary vasoconstriction requires calcium influx and can be inhibited by certain slow-channel calcium blockers. Studies also demonstrate that slow-channel calcium antagonists can attenuate the pulmonary hypertension and right ventricular hypertiophy produced in rats by chronic hypoxia. Recently, two studies have shown that nifedipine inhibits hypoxic pulmonary vasoconstriction in patients with chronic obstructive pulmonary disease. If further studies demonstrate that these short-term effects are sustained, certain slow- channel calcium blockers may become a useful adjuvant to low-flow oxygen therapy in the treatment of hypoxic pulmonary hypertension.

In the past decade, the use of vasodilators has revolutionized the treatment of systemic hypertension and congestive heart failure. Systemic vasodilators reduce the impedance or afterload to left ventricular ejection, improving left ventricular ejection fraction and cardiac output. As an ex- tension of this concept, investigators have recently used vasodilators in patients with pulmonary hypertension in an attempt to reduce right ventricular afterload and improve right ventricular function. Most investigators have used vasodilators to treat primary pulmonary hypertension [l-l 41, pulmonary hypertension caused by congenital heart disease [5,15,16],

. recurrent pulmonary emboli [5,14,16], or interstitial lung disease [17-l 61. Debate still exists over the utility of vasodilator therapy in these disease

From the Divisions of Occupational and Pulmonary processes [19-241. The presence of irreversible obliterative vascular Medicine, Johns Hopkins Hospital, Baltimore, Maryland. Requests for reprints should be ad-

changes probably accounts for the inconsistent response to vasodilators

dressed to Dr. Thomas P. Kennedy, Johns Hopkins in these disorders. Hospital, Brady 415, 601 North Wolfe Street, Balti- In contrast, pulmonary hypertension due to chronic hypoxia represents more, Maryland 21205. the most common and potentially reversible form of pulmonary hyperten-

18 February 22, 1985 The Amerlcen Journal of Medicine Volume 78 (suppl 28)

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Arterial Oxygen Saturation ( %) Figure 1. The relation between the mean pulmonary arterial pressure and the systemic arterial oxygen saturation in a group of normal subjects breathing (solid circles) room air 12 to 14 percent oxygen (open circles). Reproduced from 1371 by permission of the American Heart Association, inc.

sion. Chronic hypoxia is the leading cause of pulmonary hypertension in chronic bronchitis and emphysema [25], cystic fibrosis [26], kyphoscoliosis [271, chronic mountain sickness [28], and the obesity-hypoventilation and sleep apnea syndromes [29]. This review will focus on the potential role of calcium channel blockers in the treatment of hypoxic pulmonary hypertension.

PATHOPHYSIOLOGY OF HYPOXIC PULMONARY VASOCONSTRICTION

In 1946, Von Euler and Liljestrand [30] first demonstrated that alveolar hypoxia causes pulmonary vasoconstriction. Other investigators have subsequently observed hypoxic pulmonary vasoconstriction in numerous species [31-351 including man [36]. Figure 1 depicts this response in man. In this study, when subjects breathed a gas mixture con- taining 12 to 14 percent oxygen, their average pulmonary artery pressure increased from 14 to 19 mm Hg [37]. Hy- poxia appears to vasoconstrict small pulmonary arterioles and perhaps alveolar vessels [38,39]. Normally, hypoxic pulmonary vasoconstriction helps match blood flow and ventilation, diverting blood flow away from poorly ventilated areas [38,40-421. When only a small area of lung is hypoxic, this response maximizes arterial oxygen saturation by reducing blood flow to the poorly ventilated lung segments without increasing pulmonary artery pressures. However, when a large portion of the lung is hypoxic, as is the case in patients with moderately severe chronic obstructive pulmonary disease, a large fraction of the vascu- lature may constrict, thereby increasing pulmonary artery pressure [43,44].

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-KENNEDY ET AL

Whereas acute hypoxia causes pulmonary hypertension, which is quickly reversed when hypoxia is relieved, chronic alveolar hypoxia causes pathologic changes that maintain pulmonary hypertension even in the absence of hypoxia [45]. In patients with chronic alveolar hypoxia, increased muscle develops in the muscular pulmonary arteries and new muscle appears in arterioles that are normally without smooth muscle [28,46-491. Experimen- tal studies also indicate that in rats exposed to chronic hypoxia, increased muscle develops in the pulmonary arteries, resulting in pulmonary hypertension and right ventricular hypertrophy [50]. Recent studies in humans and rats indicate that prolonged inhibition of hypoxic pulmonary vasoconstriction will reverse these pathologic changes [5t-521. Sime et al [53] measured pulmonary artery pressure and pulmonary vascular resistance during rest and exercise in 11 Peruvian military recruits who had lived their entire lives at 14,000 feet above sea level. These subjects were restudied after they had lived at sea level for two years. When studied at high altitude, all subjects had increased pulmonary vascular resistance during rest and exercise. After two years at sea level, the subjects’ pulmonary vascular resistance had dramatically decreased toward normal values (Figure 2). Other clinical studies indicate that if patients with hypoxic pulmonary hypertension living at high altitudes move to sea level, their electrocardiographic signs of right ventricular hypertrophy disappear within three to six months [28]. Experi- mental studies in rats also demonstrate that continuous inhibition of hypoxic vasoconstriction will lead to the rever-

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Figure 2. The relationship between mean pulmonary artery pressure and cardiac output at rest and during exercise in natives living at 500 feet (solid square) and in natives living at high-altitudes before” (open circle) and after (solid circle) two years at sea level. Y = regression equation for each line. Regression coefficients: Highlanders, at 14,900 feet (open circle) r = 0.8580; at 500 feet (solid circle) r = 0.8617. Lowlanders, at 500 feet (solid square) r = 0.6740. (p < 0.007 in all cases). Reproduced with permission from j53].

February 22, 1985 The Amerlcen Journal of Medicine Volume 78 (suppl 2B) 19


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Figure 3. Mean right ventricular pressure (f/W) in control rats, rats exposed to chronic hypoxia, rats exposed to chronic hypoxia followed by continuous normoxia, and rats exposed to chronic hypoxia followed by intermittent normoxia for eight and 16 hours per day. Reproduced with permission from 1521.

sal of the hemodynamic and pathologic changes produced by chronic hypoxia [51,52,54].

Continuous oxygen use reduces pulmonary artery pressure and pulmonary vascular resistance in patients with chronic obstructive pulmonary disease and pulmonary hypertension, but these parameters often remain elevated even after prolonged low-flow oxygen therapy [55]. Pul- monary vascular resistance may remain elevated because ambulatory patients fail to use their oxygen continuously, thus allowing an intermittent hypoxic stimulus that maintains the vascular muscle contraction and hypertrophy. Even in the Nocturnal Oxygen Therapy Trial, patients randomly assigned to receive continuous oxygen used it only 18 hours a day [56]. Kay et al [51,52] compared the efficacy of intermittent versus continuous inhibition of hypoxic vasoconstriction in chronically hypoxic rats with pulmonary hypertension and right ventricular hypertrophy [51,52] (Figure 3). As shown in Figure 3, mean right ventricular pressure returned toward control values in hypertensive rats treated with continuous normoxia, whereas mean right ventricular pressure remained elevated in the group treated with eight or 16 hours of normoxia per day. A regression of right ventricular hypertrophy was observed in the animals treated with continuous normoxia, whereas hypertrophy persisted in the rats treated with normoxia for only eight or 16 hours per day (Figure 4). Thus, continuous inhibition of hypoxic pulmonary vasoconstriction appears necessary for maximal hemodynamic and pathologic improvement.

These studies suggest that regression of pulmonary hypertension and right ventricular hypertrophy in patients with hypoxic lung disease may require continuous inhibition of the hypoxic pressor response. Because patients find it difficult to use oxygen 24 hours a day, a drug that

blocks hypoxic pulmonary vasoconstriction might be useful as an adjuvant to low-flow oxygen therapy.

In the past decade, our understanding of hypoxic pulmonary vasoconstriction has increased greatly, even though the underlying mechanism remains unknown. The following mechanisms have been proposed: sympathetic neural activation, mediation of vascular tone by an oxygen receptor on smooth muscle membranes, or the release of histamine, serotonin, prostaglandins, or leukotrienes [38- 44,57-64]. Currently, two major explanations exist for how hypoxia produces pulmonary vasoconstriction. Some investigators believe that alveolar hypoxia directly depolarizes the vascular smooth muscle cell membrane, thereby increasing calcium influx and causing smooth muscle contraction. Support for this theory comes from experimental work demonstrating that in isolated pulmonary arteries, hypoxia decreases the resting transmem- brane potential, increases calcium influx, and causes contraction [65]. Other investigators propose that alveolar hypoxia depolarizes perivascular mast cells, thereby causing calcium influx and the release of vasoactive me- diators that produce the vasoconstriction [66,671. Support for this thesis comes from the demonstration that cromo- lyn, a calcium blocker [68], inhibits mast cell degranulation and hypoxic pulmonary vasoconstriction [69].

In both theoretic models, calcium influx is necessary for hypoxic pulmonary vasoconstriction to occur, since both mast cell mediator release and vascular smooth muscle contraction require calcium influx [70,71]. Mcfvlurtry et al [72] first demonstrated that verapamil, a slow-channel calcium antagonist, abolishes the pulmonary pressor re-

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Figure 4. Ratio of weight of right ventricle (RV) to left ventricle and interventricular septum (LV+S) in control rats, rats exposed to chronic hypoxia, rats exposed to chronic hypoxia followed by continuous normoxia, and rats exposed to chronic hypoxia followed by intermittent normoxia for eight and 16 hours per day. Reproduced with permission from 1521.

20 February 22,198S The American Journal of Medlclne Volume 78 (suppl 26)


sponse to hypoxia (Figure 5). In their study, verapamil was more effective in inhibiting hypoxic pulmonary vasoconstriction than angiotensin II or prostaglandin Fza. Other experimental studies also suggest a role for calcium influx in the sustained pulmonary hypertension present in chronically hypoxic animals. Haack et al (731 demonstrated that the pulmonary arterial smooth muscle of chronically hypoxic rats has an increased intracellular concentration of calcium. Subsequently, Voelkel et al [74], in a study of chronically hypoxic rats, found that hypoxic pulmonary vasoconstriction could be augmented by increasing the calcium concentration of the perfusate. To- gether, these studies indicate that hypoxic pulmonary vasoconstriction requires calcium influx, and that changes in calcium influx markedly affect the degree of hypoxic vasoconstriction.

ANIMAL STUDIES OF CALCIUM CHANNEL BLOCKERS IN HYPOXIC PULMONARY HYPERTENSION

Considerable experimental evidence exists to show that calcium channel blockers inhibit hypoxic pulmonary vasoconstriction. McMurtry et al [72,75,76] have demonstrated in rats, dogs, and cattle that intravenous verapamil strikingly attenuates the increase in pulmonary artery pressure caused by hypoxia. Verapamil and nifedipine have also been studied in chronically hypoxic rats in which they attenuated, but did not completely prevent, the pulmonary hypertension and right ventricular hypertrophy caused by chronic hypoxia [77-811.

Nifedipine also prevents hypoxic pulmonary vasoconstriction in pigs, a species known for its marked response to hypoxia [82]. In our study, we perfused pig lungs in

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Figure 5. Relative susceptibilities of hypoxia and prostaglandin F,,-induced pressor responses to inhibition by verapamil in isolated rat lung. Reproduced with permission from [72].

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Figure 6. Hypoxic pressor response (AP,,,) in perfused pig lungs in control (n = 5) and nifedipine-treated (n = 5) animals as a function of dose of nifedipine. APpa, is determined as the difference between Ppal (mean pulmonary artery pressure at a blood flow of 1.0 liters per minute) during normoxia and the immediately subsequent Ppal values during hypoxia. Each open circle represents APpal k 1 SEM. l p c 0.025; jp < 0.01; #p -C 0.001. Reproduced with permission from [82].

situ while the lungs were ventilated with alternating periods of hyperoxia (inspired alveolar oxygen tension, (PAo,) = 200 mm Hg) or normoxia (inspired PAo, = 50 mm Hg). Using this model, we studied the steady-state relationship between pulmonary artery pressure and blood flow during hyperoxia and hypoxia. Hypoxia produced pulmonary vasoconstriction, increasing the slope of the pressure-flow curve. Nifedipine (given as a 0.1, 1, or 10 pglkg bolus into the pulmonary artery) caused a dose- dependent inhibition of hypoxic pulmonary vasoconstriction (Figure 6).

HUMAN STUDIES OF CALCIUM CHANNEL BLOCKERS IN HYPOXIC PULMONARY HYPERTENSION

Several investigators have studied the effect of slow- channel calcium antagonists on hypoxic pulmonary vasoconstriction. Naeije et al [83] found that in eight normal volunteers, 20 mg of sublingual nifedipine failed to attenuate the pulmonary vasoconstriction produced by inhaling 12.5 percent oxygen. Brown et al [84] studied the effects of verapamil in 10 patients with chronic obstructive pulmonary disease in whom hypoxia was induced by breathing 12 to 14 percent oxygen. In their study, low doses of verapamil (0.1 mg/kg bolus followed by infusion of 0.005 mg/kg per minute) blunted, but did not entirely block, the increase in pulmonary artery pressure seen during exercise when the patients were hypoxic. Pulmonary vascular

February 22, 1985 The American Journal of Medicine Volume 78 (suppl 28) 21


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Figure 7. Effect of nifedipine on pulmonary vascular resistance index (PVRI) in six clinically stable patients with hypoxic pulmonary hypertension. P = placebo; N = nifedipine; RA rest = patients studied at rest breathing room air; RA exercise = patients studied during supine bicycle ergometric exercise (25 watts) breathing room air; 0, rest = patients studied at rest breathing low-flow supplemental oxygen; O2 exercise = patients studied during supine bicycle ergometric exercise (25 watts) breathing low-flow sup- plementaloxygen. ‘p < 0.05; tp < 0.01; #p < 0.001. Repro- duced with permission from [87].

resistance was not significantly decreased because of substantial inter-individual variability.

Other groups have found that slow-channel calcium antagonists reduce pulmonary artery pressure and pulmonary vascular resistance in patients with hypoxic pulmonary hypertension. Simmoneau et al [85] studied nifedipine in. 13 patients with chronic obstructive pulmonary disease and acute respiratory failure and hypoxemia (851. One hour after nifedipine was administered (20 mg, sub- lingually), pulmonary artery pressure decreased at rest from 34 2 4 to 31 2 4 mm Hg (mean + SEM), while cardiac output rose from 7.0 -t 0.5 to 7.8 ? 0.5 liters per minute, causing a 37 percent decrease in pulmonary vascular resistance from 5.0 + 0.5 to 3.4 IT 0.4 mm Hg/liter per minute. Kastonos et al [88] briefly reported on six patients with chronic DbSttIJCtiVe pulmonary disease and hypoxic pulmonary hypertension treated with nifedipine. The two patients with the most severe chronic obstructive pulmonary disease (forced expiratory volume in one second, FEV,, 18 percent of predicted) had an increase in pulmonary vascular resistance because nifedipine decreased right ventricular filling pressure and cardiac output. In four of the six patients, nifedipine decreased mean pulmonary artery pressure from 41 to 34 mm Hg (17 percent) and increased cardiac output from 5.6 to 6.6 liters per minute (17 percent), thereby decreasing pulmonary vascular resistance from 8.7 to 6.3 mm Hglliter per minute (28 percent). Changes in Pao, after nifedipine were not reported, but oxygen delivery rose from 784 to 895 ml per minute (14 percent).

We have recently studied the effect of nifedipine on hypoxic pulmonary vasoconstriction in six clinically stable patients (five with chronic obstructive pulmonary disease and one with kyphoscoliosis) using a randomized, double- blind, crossover study design [871. All subjects with chronic obstructive pulmonary disease met the entrance criteria for the Nocturnal Oxygen Therapy Trial [56]. The mean FEV, of our patients was 0.69 2 0.2 I and the mean Pao, while breathing room air 49 2 7 mm Hg. Subjects were studied both at rest and during supine bicycle exercise at a work load of 25 watts while breathing room air or their usual low-flow supplemental oxygen. The effect of nifedipine on pulmonary vascular resistance under these four treatment conditions is summarized in Figure 7. Compared with placebo, 40 mg of oral nifedipine lowered the pulmonary vascular resistance index by 26 percent at rest and by 44 percent during exercise while patients breathed room air. When patients breathed their usual low-flow oxygen, nifedipine produced an additional decrease in the pulmonary vascular resistance index of 18 percent at rest and 27 percent during exercise.

The demonstration that nifedipine exerts an additional pulmonary vasodilator effect when combined with low- flow oxygen differs from the finding of Simmoneau et al [85], who reported that nifedipine did not produce further pulmonary vasodilation when added to oxygen at rest. However, they studied the acute effect of a single 20 mg sublingual dose given with high-flow oxygen (mean PAO, = 277 mg Hg) on hemodynamic values at rest. No exercise studies were performed. In contrast, we studied the effect of multiple doses (40 mg) of nifedipine given with the patient’s usual low-flow oxygen (mean P&,, = 74 mm Hg) during both rest and exercise [87]. The amount of oxygen given in Simmoneau’s study may have achieved maximal pulmonary vasodilation, explaining the failure to observe an additional fall in pulmonary vascular resistance with nifedipine. Our study more closely approxi- mates the conditions under which patients would be likely to receive the combination of oxygen and nifedipine.

One potential adverse effect of blocking the hypoxic pressor response might be a significant decrease in systemic arterial oxygen content. Simmoneau et al found that nifedipine lowered the mean Pao, of their patients breathing room air from 42 IT 2 to 38 !I 2 mm Hg [85]. In our study, nifedipine lowered mean Pao, from 51 + 3 mm Hg to 47 + 2 mm Hg at rest while patients breathed room air. This produced a small decrease in arterial oxygen content from 19 ? 1 to 18 IT 1 volumes percent. Nifedipine did not affect Pao, during exercise while patients breathed room air. While patients breathed low-flow oxygen, nifedipine lowered Pao, from 74 2 7 to 61 IT 4 mm Hg at rest and from 64 & 3 to 56 * 3 mm Hg during exercise without significantly reducing arterial oxygen content. At rest or during exercise while breathing room air or oxygen, nifedipine

22 February 22,1985 The American Journal of Medlclne Volume 78 (ruppl28)


strikingly increased oxygen delivery by increasing cardiac output. These two studies indicate that in patients with hypoxic pulmonary hypertension the predominant effect of nifedipine is to improve oxygen delivery both at rest and during exercise (Figure 8).

QUESTIONSFORFUTURERESEARCH

Although preliminary data suggest that slow-channel calcium antagonists may be helpful in the therapy of hypoxic pulmonary hypertension, many unsolved questions remain. Are the Acute Effects Sustained? Attenuation of the early hemodynamic benefits of vasodilator therapy in left ventricular failure has been reported for long-acting ni- trates [88], hydralazine [89], and prazosin [go]. In some instances, tolerance can be minimized by increasing drug dosage or by temporarily interrupting therapy, as has been seen with prazosin [91]. Whether tolerance to vasodilators occurs in hypoxic pulmonary vasoconstriction is at present unknown, but it has been observed in primary pulmonary hypertension [92]. Is Exercise Tolerance Improved? The right ventricular response to exercise, as measured by nuclear angiocardi- ographic assessment of ejection fraction, is frequently abnormal in patients with moderately severe chronic obstructive pulmonary disease [93]. Since right ventricular function is quite sensitive to changes in afterload, calcium channel blockers might improve right ventricular function by decreasing right ventricular afterload. Slow-channel calcium antagonists might also increase exercise tolerance if their combined vasodilator and bronchodilator effects improved the matching of ventilation and perfusion during exercise, thereby increasing the efficiency of ventilation [94-971. Do Slow-Channel Calcium Antagonists Vary in Their Specificity and Potency for the Pulmonary Circula- tion? The specificity and potency of slow-channel calcium blockers vary in different vascular beds [98]. This may be true in the pulmonary circulation. The suggestion that nifedipine attenuates hypoxic pulmonary vasoconstriction in man to a greater degree than verapamil requires further investigation [84-871. What Are the Overall Effects of Slow-Channel Calcium Antagonists on Gas Exchange, Oxygen Delivery, and Oxygen Consumption? Whether calcium channel antagonists will ultimately be useful in patients with hypoxic pulmonary hypertension will depend partly on the net effect of these agents on cardiac output, arterial oxygen content, and oxygen delivery during rest and exercise. Formal exercise studies are needed to delineate the effect of calcium channel blockers on gas exchange and oxygen consumption during exercise. Different calcium channel blocking agents may have different effects on peripheral oxygen consumption, as indicated by a report that diltia-

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Figure 8. Effect of nifedipine on oxygen delivery in six patients with hypoxic pulmonary hypertension. P = placebo; N = nifedipine; RA rest = patients studied at rest breathing room air; RA exercise = patients studied during supine bicycle ergometric exercise (25 watts) breathing room air; O2 rest = measurements at rest breathing low-flow supplemental oxygen; O2 exercise = measurements during supine bicycle ergometric exercise (25 watts) breathing low-flow supplemental oxygen. *p < 0.05; tp C 0.01. Reproduced with permission from 1871.

zem stimulates, verapamil inhibits, and nifedipine does not affect the oxygen consumption of vascular smooth muscle [99]. Will Calcium Channel Antagonists Decrease Morbid- ity or Mortality in Patients with Hypoxic Pulmonary Hypertension? This is the most important question and the most difficult to answer. There are, at present, no data to suggest that treating pulmonary hypertension in patients with chronic obstructive pulmonary disease pro- longs life and decreases symptoms or complications of chronic obstructive pulmonary disease. However, drugs that are effective in lowering pulmonary hypertension are so new that long-term studies have not yet been performed.

CONCLUSIONS

In this review, we have attempted to outline the pathology of hypoxic pulmonary vasoconstriction with special atten- tion to the role of hypoxia in causing pulmonary hypertension and right ventricular hypertrophy in chronic obstructive pulmonary disease and other common forms of lung disease. Recent animal and human studies indicate that hypoxic pulmonary vasoconstriction can be attenuated by certain slow-channel calcium antagonists, leading to the possibility that hypoxic pulmonary hypertension might be treated with a combination of low-flow oxygen and calcium channel blockers. Although this possibility is promising, a number of important questions remain to be answered about the role of calcium channel blockers in the therapy of hypoxic pulmonary hypertension.



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calcium channel blockers in hypoxic pulmonary hypertension

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