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 con- verting 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 develop- ment 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 capil- lary wall permeability, contributes to prevent subcu- taneous 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 capto- pril (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