Calcium Channel Blockers, Postural Vasoconstriction and Dependent Oedema in Essential Hypertension

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Journal of Human Hypertension (2001) 15, 455–461  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension

R Pedrinelli, G Dell’Omo and M Mariani Dipartimento Cardiotoracico, Universita’ di Pisa, Italy

Treatment with calcium channel blocker (CCB)s, dihy- hyperfiltration consequent to gravitational stimuli, and dropyridines and others, is frequently complicated by consistent evidence shows attenuation of this response dependent oedema in the absence of sodium retention by L-type calcium channel blockers. Interference with or cardiac failure, a bothersome side effect of unclear the postural reflex control of skin blood flow may there- aetiology. The present paper reviews our own and other fore contribute to dependent oedema, although cannot work dealing with the antagonism exerted by such entirely explain its development. Attenuation of postural drugs on postural vasoconstriction, a mechanism trig- vasoconstriction may amplify the fluid hyperfiltration gered by limb venous congestion during orthostasis induced by CCBs through other mechanisms, such as and controlled through a local sympathetic axo-axonic imbalanced intracapillary pressure or enhanced vascu- reflex and increased myogenic tone in response to lar permeability, which are the main factors determining changes in transmural pressure. By stabilising capillary net fluid filtration into the interstitial compartment. pressure, postural vasoconstriction counteracts fluid Journal of Human Hypertension (2001) 15, 455–461

Keywords: calcium channel blockers; postural vasoconstriction; skin blood ﬂow; hypertension, essential; angiotensin converting enzyme inhibitors

Introduction stitial spaces and that returned to the circulation through the lymphatics) results from a balanced Leg and ankle swelling is a frequent occurrence interplay among four main determinants5 such as: while taking calcium channel blockers (CCBs), not (1) intracapillary pressures and flow rates; (2) only dihydropyridines (DHP)1 but also verapamil2 3 plasma and interstitial oncotic pressures; (3) intrin- and diltiazem. This troublesome side effect sic capillary permeability; and (4) lympathic drain- presents as leg and ankle swelling in the absence of 4 1 age of interstitial fluid. sodium retention or cardiac failure and may reach In normal conditions, net fluid filtration is main- the stage of pitting oedema, thereby requiring dis- tained constant even on changing from the supine continuation of an otherwise highly effective antihy- to the standing position, when arterial and venous pertensive therapy. This review will focus on the pressures in the foot increase in direct proportion to antagonism exerted by CCBs on cutaneous postural the change in height of the column of blood between vasoconstriction, and the possible contribution of the heart and foot. A similar increase in capillary this pharmacological interference to the development of dependent oedema during treatment with pressure would increase net fluid filtration and rap- CCBs. idly result in interstitial oedema unless a precise modulation of pre- and post-capillary resistance and oncotic pressure concurred to maintain capillary A synoptic view of the postural control pressure.6 The importance of postural vasoconstric- of capillary filtration in human skin tion was highlighted by the studies of Henriksen7 Net capillary fluid filtration (ie, the difference who demonstrated that, on lowering the leg, subcut- between the amount of fluid filtered into the inter- aneous blood flow in the foot fell as a result of an increase in vascular resistance, a mechanism termed the veno-arteriolar reflex. Henriksen et al7 also Correspondence: Prof Roberto Pedrinelli, Dipartimento Cardiotor- showed that in chronically sympathetic enervated acico, Universita` di Pisa, 56 100 Pisa, Italy E-mail: r.pedrinelliȰint.med.unipi.it limbs, in which the veno-arteriolar response was Received 10 October 2000; revised 15 January 2001; accepted 31 absent, venous pressure elevation caused a linear January 2001 increase in capillary filtration rate, whereas in the Calcium channel blockers and dependent oedema R Pedrinelli et al 456 In summary, posturally induced pre-capillary vasoconstriction, by limiting the rise in capillary pressure, reducing microvascular blood flow and thereby increasing plasma colloid osmotic pressure at the microvascular interface and reducing capillary wall permeability, contributes to prevent subcutaneous oedema development in the dependent limb. It is important in this context also to mention the anatomical and functional heterogeneity of skin microvasculature. In fact, most of the human skin is Figure 1 Schematic representation of a nutritive segment of the perfused by low flow, high resistance nutritive capil- human skin microcirculation (E, epidermis, D, dermis; S, subcut- laries15 but areas such as the pulp of the fingertip aneous tissue). The diagram shows ascending arterioles, descending venules and capillary plexuses forming microcircu- or the toe are rich in arterioles, venules and artero- latory units (mu). venous anastomoses with low resistance and high flow.16 These vascular areas, which are extremely 17 opposite intact limb, the capillary filtration rate reactive to thermal stimulation, are primarily under the systemic sympathetic control while myo- increased by only a portion of that predicted by 18 changes in hydrostatic pressure.8,9 This autoregulat- genic mechanisms predominate in nutritive areas. ory vasoconstrictor mechanism consists of two main Nutritive cutaneous microcirculation, to which the components: (1) a locally-evoked sympathetic axo- following discussion applies, is organised as two axonic reflex triggered by limb venous conges- horizontal plexuses. One is situated 1–1.5 mm tion;7,10 and (2) an acute arteriolar reaction to below the skin surface, and the other is at the der- increasing transmural pressure,11 the so-called mal-subcutaneous junction. Ascending arterioles myogenic response.12 Experimental studies have and descending venules are paired as they connect shown that myogenic responses result from cell the two plexuses. From the upper layer, arterial membrane depolarisation, opening of L-type DHP- capillaries endowed with sphincter-like smooth sensitive voltage-gated channels and extracellular muscle cells arise to form dermal papillary loops, 19 calcium ion entry into the cell (see Davis and Hill12 the so-called microcirculatory units (Figure 1). for a review). The behaviour of capillary flow heav- From the above considerations, it is clear that the ily influences even other determinants of capillary behaviour of skin blood flow is important for the filtration such as plasma oncotic pressure and capil- understanding of the pathogenesis of CCB-mediated lary permeability. Plasma oncotic pressure, in fact, dependent oedema, although reliable determi- rises progressively in the dependent stationary foot nations of this parameter are not easy to obtain in and brakes further fluid filtration,13 a process that man. Laser Doppler flowmetry (LDF),20,21 however, can only occur if microvascular blood flow is low, as allows recording the sudden changes in foot skin allowed by effective pre-capillary vasoconstriction. blood flow evoked by posture,10,22–24 without Capillary permeability, on the other hand, was entailing local heating of skin, injection trauma, or shown to increase as a function of increased flow venous occlusion, all of which may disturb local and shear stress through the vessel, possibly with vasomotor reflexes (Figure 2). When performed the mediation of nitric oxide production (see Michel under strictly standardised experimental con- and Curry14 for a review). ditions, LDF is satisfactorily reproducible and pro-

Figure 2 Laser Doppler ﬂowmetry (LDF) at the heart (H) level and during dependency (D, leg dangling 50 cm below the heart level for 10 min). Postural vasoconstriction is deﬁned as the percent postural changes of LDF [(H-D)/H × 100]. Data expressed in perfusion units, PU (1 PU = 10 mV measured on the analogue output). Final results are computer-derived smoothed averages of recordings during the 2 min preceding foot lowering, and the 2 last minutes of foot dependency (for further details see Iabichella24).

Journal of Human Hypertension Calcium channel blockers and dependent oedema R Pedrinelli et al 457 calcium antagonism since both DHPs and verapamil slow extracellular calcium ion fluxes,29,30 but belong to structurally different classes and act on distinct calcium-channel receptors.35 Furthermore, non-CCB vasodilators, such as doxazosin, losartan and captopril (Figure 3), left postural vasoconstriction undis- turbed in spite of a degree of microvascular dilation comparable to that induced by calcium channel 24,31 ␣ blocking drugs. In particular, doxazosin, an 1- adrenoceptor blocker36 (Figure 3), did not modify the postural vasoconstrictor responses of skin blood flow. The data confirmed the independence from ␣- Figure 3 Box-and-Whisker plot* of the postural change [(Heart- adrenergic vasoconstriction of cutaneous autoregu- Dependent)/Heart × 100] in skin blood flow at the dorsum of the lation at the dorsum of the foot, a site representative foot during treatment with CCB and non-CCB vasodilators. Fig- of nutritive capillary perfusion.18 Therefore, a more ures between brackets indicate the number of patients per treat- likely target of calcium channel blockade was the ment group; baseline include values of the overall sample. For myogenic component of the reflex control of skin the sake of clarity, negative signs indicate a reduction in flow (readapted from Iabichella et al24 and Pedrinelli et al31). (*Box- blood flow, an extracellular calcium-dependent and-Whisker plot: The central box encloses the middle 50% of vasoconstrictor response evoked by changes in the data; the vertical line inside the box represents the median transmural pressure independently from neural, and the mean is plotted as a cross. Horizontal lines (whiskers) metabolic and hormonal influences.12 Gustafsson et extend from each end of the box and cover four interquartile 37 ranges.) al reached the same conclusions in evaluating the effect of calcium antagonists on the vasoconstriction induced by a rapid increase in transmural pressure vides a tool for the evaluation of pharmacological in the cat hindleg. The lack of effect of angiotensin interference on skin vasomotion, an aspect scarcely II-type 1 specific receptor blockade through losar- studied insofar, particularly in essential hyperten- tan38 as well as angiotensin converting enzyme sion. (ACE) inhibition by enalapril39 (Figure 3) also seemed to exclude the involvement of angiotensin CCBs antagonise postural II or increased bradykinin levels in maintaining or assisting the postural increase in skin pre-capillary vasoconstriction resistance (Figure 3). Dependent ankle swelling relieved by periods of supine rest is the frequent complaint of patients on Attenuated postural vasoconstriction CCBs. That consistent behaviour suggests a permissive role of gravitational factors in promoting and fav- and dependent oedema ouring oedema formation, and allows to postulate an To evaluate the extent to which attenuation of vaso- interference of CCBs with postural vasoconstriction, constriction in response to orthostasis explains similar with other vasoconstrictor responses25–27 dependent oedema by CCBs, we correlated the inhi- dependent on extracellular calcium influx into vas- bition of skin vasoconstrictor responses with objec- cular smooth muscle cells.28 In agreement with this tive measures of ankle swelling and also character- expectation, two DHP CCBs such as nifedipine and ised the dose-response profile of that vasomotor amlodipine,29,30 as well as the unrelated phenylal- interference. To this end, LDF experiments were car- kylamine derivative verapamil,29 were able to ried out in hypertensive patients treated with amlo- reduce postural vasoconstriction at the dorsum of dipine at 5 mg o.d. for 2 weeks, a dosage that was the foot24,31 (Figure 3), a result in agreement with doubled to 10 mg during the 2 final weeks of the several other reports32–34 (Table 1). Attenuation of study.31 The extent of gravitational fluid extrava- postural vasoconstriction was probably the result of sation was indirectly assessed by measuring leg

Table 1 Clinical and experimental studies addressing the effect of various CCBs on postural vasoconstriction

Author Species Site Drug Relationship with ﬂuid extravasation

Gustafsson et al37 Cat Hindleg D, F, N, Ni, V Not examined Williams et al33 Diabetic, hypertensive man Foot N Not examined Gustafsson et al32 Normal man Forearm F Permissive action Belcaro et al34 Hypertensive man Foot N Reduced vasoconstriction in those with clinically evident dependent oedema labichella et al24 Hypertensive man Foot V, N, A Not examined Pedrinelli et al31 Hypertensive man Foot A Permissive action

A, amlodipine; D, diltiazem; F, felodipine; N, nifedipine; Ni, nimodipine; V, verapamil.

Journal of Human Hypertension Calcium channel blockers and dependent oedema R Pedrinelli et al 458 weight, an accurate and highly reproducible surro- Mechanisms of oedema gate measure of dependent fluid extravasation (see Pedrinelli et al31 for further technical details). That If attenuated postural vasoconstriction by CCBs is to study showed a subtle and dose-dependent fluid be seen as an amplifying rather than a causal mech- accumulation in response to both doses of amlodip- anism of oedema, other factors such as capillary ine (Figure 4b), indicating that CCB-mediated hypertension and increased microvascular per- dependent oedema should not be merely considered meability, may set the main stage for hyperfiltration. as a side effect, but rather the extreme clinical The occurrence of capillary hypertension is sup- expression of a specific pharmacological action. A ported by animal studies showing a preferential next significant finding was to show evidence of dilation of skeletal precapillary vessels and the affer- 40 subclinical oedema with amlodipine treatment at ent glomerular arteriole by CCBs. In man, forearm 5 mg o.d., ie a dose that preserved the function of the infusion of felodipine increased skin blood flow and reflex postural control of skin blood flow (Figure 4a). caused net fluid filtration from blood to tissue, an Thus, net fluid filtration increased independently effect due to the more pronounced inhibition of vas- from any interference with the reflex control of skin cular tone in pre-capillary resistance vessels than in 32 blood flow by CCBs. However, an attenuated veno- post-capillary ones. Haemodynamic effects at the arteriolar reflex could have favoured dependent microcirculatory level may perhaps explain also 41 fluid accumulation and accelerated fluid extrava- both the decreased prevalence of ankle swelling 42 sation, a possibility suggested by our high-dose and the reduced fluid extravasation in patients and 43 amlodipine studies in which limb weight increased rats on combined ACE inhibitor and CCB treat- further when postural vasomotion was impaired ment. In our experience as well, enalapril reduced (Figure 4a, b).31 Previous studies also described the dependent fluid extravasation due to amlodipine ankle oedema in nifedipine-treated patients charac- administration, and this modulating action was dis- terised by attenuated cutaneous vasoconstriction on sociated from the changes in skin precapillary resist- standing,34 while Gustafsson et al32 reported oedema ance associated with lowering one extremity below 31 amplification by the felodipine-mediated antagon- heart level. A complex interplay may perhaps ism of the myogenic component of forearm vaso- occur at the microcirculatory level between inhi- contriction. bition of precapillary resistance vessels by amlodip- ine44 and preferential venous dilation by enalapril,45 with a resulting limited rise in capillary pressure. Increased permeability is a second potential mechanism underlying dependent oedema by CCBs, since both nifedipine46 and diltiazem47 increased microvascular permeability of the venular side of the rat microcirculation. Earlier work also showed extravasation of plasma protein-bound Evans blue dye into the kidney, skeletal and cardiac muscle during nicardipine and lacidipine administration.48–50 The loss of intravascular fluid in that experimental model was accompanied by haemoconcentration,50 a trend observed even in some nifedipine-treated hypertensive patients.51 Case reports of acute non- haemodynamic pulmonary oedema with nifedipine in primary pulmonary hypertension52 or periorbital oedema during nifedipine and diltiazem53,54 are consistent with an increased permeability in response to calcium channel blockade. As outlined above, however, the two possibilities are not alternatives since increased capillary flow may per se augment vascular permeability,14 suggesting that both may represent a consequence of the same phenomenon, ie, an unbalanced relationship between pre- and post-capillary pressures (Table 2).

Clinical implications Figure 4 Box-and-Whisker plot (see Figure 3) of postural changes The recognition of cutaneous postural vasocostric- in skin blood ﬂow [(Heart-Dependent)/Heart × 100] at the dorsum tion as a target for several clinically used CCBs has of the foot ((a) for the sake of clarity, negative signs indicate a reduction in ﬂow), and changes in leg weight from baseline (b) relevant clinical and research implications, includ- during amlodipine (AMLO), 5 and 10 mg UID, and recovery from ing the following. First, a reduced postural vaso- drug effect (from Pedrinelli et al31 with permission). constriction by CCBs may contribute relatively more

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