Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension

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1 (2001) 15, Nature Publishing Group All rights reserved /01 $ 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, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment. (2001) 15, Keywords: calcium channel blockers; postural vasoconstriction; skin blood flow; hypertension, essential; angiotensin converting enzyme inhibitors Introduction Leg and ankle swelling is a frequent occurrence while taking calcium channel blockers (CCBs), not only dihydropyridines (DHP) 1 but also verapamil 2 and diltiazem. 3 This troublesome side effect presents as leg and ankle swelling in the absence of sodium retention 4 or cardiac failure 1 and may reach the stage of pitting oedema, thereby requiring discontinuation of an otherwise highly effective antihypertensive therapy. This review will focus on the antagonism exerted by CCBs on cutaneous postural vasoconstriction, and the possible contribution of this pharmacological interference to the development of dependent oedema during treatment with CCBs. A synoptic view of the postural control of capillary filtration in human skin Net capillary fluid filtration (ie, the difference between the amount of fluid filtered into the inter- Correspondence: Prof Roberto Pedrinelli, Dipartimento Cardiotoracico, Università di Pisa, Pisa, Italy r.pedrinelli int.med.unipi.it Received 10 October 2000; revised 15 January 2001; accepted 31 January 2001 stitial spaces and that returned to the circulation through the lymphatics) results from a balanced interplay among four main determinants 5 such as: (1) intracapillary pressures and flow rates; (2) plasma and interstitial oncotic pressures; (3) intrinsic capillary permeability; and (4) lympathic drainage of interstitial fluid. In normal conditions, net fluid filtration is maintained constant even on changing from the supine to the standing position, when arterial and venous pressures in the foot increase in direct proportion to the change in height of the column of blood between the heart and foot. A similar increase in capillary pressure would increase net fluid filtration and rapidly result in interstitial oedema unless a precise modulation of pre- and post-capillary resistance and oncotic pressure concurred to maintain capillary pressure. 6 The importance of postural vasoconstriction was highlighted by the studies of Henriksen 7 who demonstrated that, on lowering the leg, subcutaneous blood flow in the foot fell as a result of an increase in vascular resistance, a mechanism termed the veno-arteriolar reflex. Henriksen et al 7 also showed that in chronically sympathetic enervated limbs, in which the veno-arteriolar response was absent, venous pressure elevation caused a linear increase in capillary filtration rate, whereas in the

2 456 Figure 1 Schematic representation of a nutritive segment of the human skin microcirculation (E, epidermis, D, dermis; S, subcutaneous tissue). The diagram shows ascending arterioles, descending venules and capillary plexuses forming microcirculatory units (mu). opposite intact limb, the capillary filtration rate increased by only a portion of that predicted by changes in hydrostatic pressure. 8,9 This autoregulatory vasoconstrictor mechanism consists of two main components: (1) a locally-evoked sympathetic axoaxonic reflex triggered by limb venous congestion; 7,10 and (2) an acute arteriolar reaction to increasing transmural pressure, 11 the so-called myogenic response. 12 Experimental studies have shown that myogenic responses result from cell membrane depolarisation, opening of L-type DHPsensitive voltage-gated channels and extracellular calcium ion entry into the cell (see Davis and Hill 12 for a review). The behaviour of capillary flow heavily influences even other determinants of capillary filtration such as plasma oncotic pressure and capillary permeability. Plasma oncotic pressure, in fact, rises progressively in the dependent stationary foot and brakes further fluid filtration, 13 a process that can only occur if microvascular blood flow is low, as allowed by effective pre-capillary vasoconstriction. Capillary permeability, on the other hand, was shown to increase as a function of increased flow and shear stress through the vessel, possibly with the mediation of nitric oxide production (see Michel and Curry 14 for a review). 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 perfused by low flow, high resistance nutritive capillaries 15 but areas such as the pulp of the fingertip or the toe are rich in arterioles, venules and arterovenous anastomoses with low resistance and high flow. 16 These vascular areas, which are extremely reactive to thermal stimulation, 17 are primarily under the systemic sympathetic control while myogenic mechanisms predominate in nutritive areas. 18 Nutritive cutaneous microcirculation, to which the following discussion applies, is organised as two horizontal plexuses. One is situated mm below the skin surface, and the other is at the dermal-subcutaneous junction. Ascending arterioles and descending venules are paired as they connect the two plexuses. From the upper layer, arterial capillaries endowed with sphincter-like smooth muscle cells arise to form dermal papillary loops, the so-called microcirculatory units 19 (Figure 1). From the above considerations, it is clear that the behaviour of skin blood flow is important for the understanding of the pathogenesis of CCB-mediated dependent oedema, although reliable determinations of this parameter are not easy to obtain in man. Laser Doppler flowmetry (LDF), 20,21 however, allows recording the sudden changes in foot skin blood flow evoked by posture, 10,22 24 without entailing local heating of skin, injection trauma, or venous occlusion, all of which may disturb local vasomotor reflexes (Figure 2). When performed under strictly standardised experimental conditions, 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 Iabichella 24 ).

3 Figure 3 Box-and-Whisker plot* of the postural change [(Heart- Dependent)/Heart 100] in skin blood flow at the dorsum of the foot during treatment with CCB and non-ccb vasodilators. Figures between brackets indicate the number of patients per treatment group; baseline include values of the overall sample. For the sake of clarity, negative signs indicate a reduction in flow (readapted from Iabichella et al 24 and Pedrinelli et al 31 ). (*Boxand-Whisker plot: The central box encloses the middle 50% of the data; the vertical line inside the box represents the median and the mean is plotted as a cross. Horizontal lines (whiskers) extend from each end of the box and cover four interquartile ranges.) vides a tool for the evaluation of pharmacological interference on skin vasomotion, an aspect scarcely studied insofar, particularly in essential hypertension. CCBs antagonise postural vasoconstriction Dependent ankle swelling relieved by periods of supine rest is the frequent complaint of patients on CCBs. That consistent behaviour suggests a permissive role of gravitational factors in promoting and favouring oedema formation, and allows to postulate an interference of CCBs with postural vasoconstriction, similar with other vasoconstrictor responses dependent on extracellular calcium influx into vascular smooth muscle cells. 28 In agreement with this expectation, two DHP CCBs such as nifedipine and amlodipine, 29,30 as well as the unrelated phenylalkylamine derivative verapamil, 29 were able to reduce postural vasoconstriction at the dorsum of the foot 24,31 (Figure 3), a result in agreement with several other reports (Table 1). Attenuation of postural vasoconstriction was probably the result of 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 undisturbed in spite of a degree of microvascular dilation comparable to that induced by calcium channel blocking drugs. 24,31 In particular, doxazosin, an 1 - adrenoceptor blocker 36 (Figure 3), did not modify the postural vasoconstrictor responses of skin blood flow. The data confirmed the independence from adrenergic vasoconstriction of cutaneous autoregulation at the dorsum of the foot, a site representative of nutritive capillary perfusion. 18 Therefore, a more likely target of calcium channel blockade was the myogenic component of the reflex control of skin blood flow, an extracellular calcium-dependent vasoconstrictor response evoked by changes in transmural pressure independently from neural, metabolic and hormonal influences. 12 Gustafsson et al 37 reached the same conclusions in evaluating the effect of calcium antagonists on the vasoconstriction induced by a rapid increase in transmural pressure in the cat hindleg. The lack of effect of angiotensin II-type 1 specific receptor blockade through losartan 38 as well as angiotensin converting enzyme (ACE) inhibition by enalapril 39 (Figure 3) also seemed to exclude the involvement of angiotensin II or increased bradykinin levels in maintaining or assisting the postural increase in skin pre-capillary resistance (Figure 3). Attenuated postural vasoconstriction and dependent oedema To evaluate the extent to which attenuation of vasoconstriction in response to orthostasis explains dependent oedema by CCBs, we correlated the inhibition of skin vasoconstrictor responses with objective measures of ankle swelling and also characterised the dose-response profile of that vasomotor interference. To this end, LDF experiments were carried out in hypertensive patients treated with amlodipine at 5 mg o.d. for 2 weeks, a dosage that was doubled to 10 mg during the 2 final weeks of the study. 31 The extent of gravitational fluid extravasation was indirectly assessed by measuring leg 457 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 al 37 Cat Hindleg D, F, N, Ni, V Not examined Williams et al 33 Diabetic, hypertensive man Foot N Not examined Gustafsson et al 32 Normal man Forearm F Permissive action Belcaro et al 34 Hypertensive man Foot N Reduced vasoconstriction in those with clinically evident dependent oedema labichella et al 24 Hypertensive man Foot V, N, A Not examined Pedrinelli et al 31 Hypertensive man Foot A Permissive action A, amlodipine; D, diltiazem; F, felodipine; N, nifedipine; Ni, nimodipine; V, verapamil.

4 458 weight, an accurate and highly reproducible surrogate measure of dependent fluid extravasation (see Pedrinelli et al 31 for further technical details). That study showed a subtle and dose-dependent fluid accumulation in response to both doses of amlodipine (Figure 4b), indicating that CCB-mediated dependent oedema should not be merely considered as a side effect, but rather the extreme clinical expression of a specific pharmacological action. A next significant finding was to show evidence of subclinical oedema with amlodipine treatment at 5 mg o.d., ie a dose that preserved the function of the reflex postural control of skin blood flow (Figure 4a). Thus, net fluid filtration increased independently from any interference with the reflex control of skin blood flow by CCBs. However, an attenuated venoarteriolar reflex could have favoured dependent fluid accumulation and accelerated fluid extravasation, a possibility suggested by our high-dose amlodipine studies in which limb weight increased further when postural vasomotion was impaired (Figure 4a, b). 31 Previous studies also described ankle oedema in nifedipine-treated patients characterised by attenuated cutaneous vasoconstriction on standing, 34 while Gustafsson et al 32 reported oedema amplification by the felodipine-mediated antagonism of the myogenic component of forearm vasocontriction. Mechanisms of oedema If attenuated postural vasoconstriction by CCBs is to be seen as an amplifying rather than a causal mechanism of oedema, other factors such as capillary hypertension and increased microvascular permeability, may set the main stage for hyperfiltration. The occurrence of capillary hypertension is supported by animal studies showing a preferential dilation of skeletal precapillary vessels and the afferent glomerular arteriole by CCBs. 40 In man, forearm infusion of felodipine increased skin blood flow and caused net fluid filtration from blood to tissue, an effect due to the more pronounced inhibition of vascular tone in pre-capillary resistance vessels than in post-capillary ones. 32 Haemodynamic effects at the microcirculatory level may perhaps explain also both the decreased prevalence of ankle swelling 41 and the reduced fluid extravasation in patients 42 and rats 43 on combined ACE inhibitor and CCB treatment. In our experience as well, enalapril reduced the dependent fluid extravasation due to amlodipine administration, and this modulating action was dissociated from the changes in skin precapillary resistance associated with lowering one extremity below heart level. 31 A complex interplay may perhaps occur at the microcirculatory level between inhibition of precapillary resistance vessels by amlodipine 44 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 nifedipine 46 and diltiazem 47 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 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 nonhaemodynamic pulmonary oedema with nifedipine in primary pulmonary hypertension 52 or periorbital oedema during nifedipine and diltiazem 53,54 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). Figure 4 Box-and-Whisker plot (see Figure 3) of postural changes in skin blood flow [(Heart-Dependent)/Heart 100] at the dorsum of the foot ((a) for the sake of clarity, negative signs indicate a reduction in flow), and changes in leg weight from baseline (b) during amlodipine (AMLO), 5 and 10 mg UID, and recovery from drug effect (from Pedrinelli et al 31 with permission). Clinical implications The recognition of cutaneous postural vasocostriction as a target for several clinically used CCBs has relevant clinical and research implications, including the following. First, a reduced postural vasoconstriction by CCBs may contribute relatively more

5 Table 2 Flow diagram summarising the possible sequence of events triggered by CCBs with preferential arteriolar vasodilating activity on the forces controlling fluid transfer at the capillary membrane CCBs with preferential arteriolar vasodilating activity Increased capillary pressure and flow Increased capillary permeability Fluid hyperfiltration and dependent oedema Attenuation of postural vasoconstriction Augmented dependent oedema to the development of dependent oedema in diabetic patients 23,55 or arteriopaths 56 with an already impaired postural autoregulation. In this kind of subject, CCB-mediated ankle swelling may develop more frequently and at lower dosages than in subjects with an intact veno-arteriolar response, a possibility to be explored in the future. Secondly, the whole body of knowledge dealt with in this review refers to L-type CCBs, and no studies have investigated the effect of T-type channel blockade. 57 Perhaps, the postural defence mechanisms of cutaneous microcirculation might be less sensitive to T- than L-type channel blockade, thus generating less dependent oedema. This hypothesis is consistent, to some extent, with some preliminary clinical evidence obtained with mibefradil, the prototype T- type CCB 58 although more definite information awaits the availability of clinically safer drugs belonging to that same class. Lastly, most of the L- type CCBs tested so far, possess a preferential vasodilating affinity for pre-capillary vessels. 32,40,44,47 This pharmacological profile is not universal, though: DHP CCBs, such as lercanidipine and manidipine, were recently shown to cause a similar degree of relaxation in pre- as in post-capillary renal vessels. 59 That same peculiar behaviour might also extend to the postural control of cutaneous microcirculation thus preserving more efficiently intracapillary pressures and perhaps engendering less fluid extravasation, a purely speculative hypothesis at this time. Conclusions A consistent body of evidence indicates an interference by several L-type CCBs with the local vasoconstrictor reflexes that protect dependent vascular regions from excessive fluid filtration, likely through a preferential impairment of the myogenic component of that mechanism. 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