(Hypertension. 1997;29:751-756.)
© 1997 American Heart Association, Inc.
Articles |
Calcium Channel Blockers Blunt Postural Cutaneous Vasoconstriction in Hypertensive Patients
the Reparto di Medicina Interna, Laboratorio Microcircolatorio, Azienda Ospedaliera Pisana (M.L.I., E.M.), I Clinica Medica (G.D., R.P.), Universita di Pisa (Italy).
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Abstract |
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The aim of this work was to test whether calcium channel blockers interfere with skin vasoconstrictor reflexes that minimize postural increases in capillary pressure and avoid fluid extravasation and eventually subcutaneous edema. Studies were conducted in 23 untreated mild to moderate essential hypertensives; drugs, either calcium channel blockers or not, were given for 2 weeks according to a crossover, sequence-randomized design. Skin blood flow was measured by laser Doppler flowmetry in two skin areas: (1) the dorsum of the foot, where arteriovenous anastomoses are poorly represented, and (2) the plantar surface of the great toe, where those anastomoses are predominant. Determinations were obtained both with the foot at heart level and with it placed passively 50 cm below the heart level; percent flow changes from the horizontal to the dependent position were the measure of postural vasoconstriction. Two dihydropyridine derivatives, amlodipine (10 mg UID) and nifedipine (60 mg UID), and verapamil (240 mg BID), a chemically unrelated compound, diminished to similar extents the postural fall in skin blood flow at the dorsum of the foot. Blockade of
1-adrenergic and AT-1 subtype angiotensin II receptors by doxazosin (4 mg UID) and losartan (50 mg UID), respectively, exerted no effect. Postural skin blood flow responses at the plantar surface of the great toe were unmodified during the pharmacological trials. Thus, calcium channel blockers of different chemical origins antagonized postural skin vasoconstriction at the dorsum of the foot. The data indicate altered postural capillary blood flow regulation, since arteriovenous anastomoses are anatomically absent at this site; the effect was independent of either 1-adrenoceptor or angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may result in net filtration of fluid to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema during treatment with calcium antagonists.
Key Words: hypertension, essential • calcium channel blockers • edema, ankle • blood flow, skin • vasoconstriction, postural
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Introduction |
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Precapillary resistance in the skin of the foot rises when one stands, thereby limiting the increase in capillary pressure resulting from gravitational increases in transmural pressure.1 2 This vasoconstrictor mechanism is triggered by limb venous congestion and operates both through a locally evoked sympathetic axoaxonic reflex1 2 with some minor participation of central mechanisms2 and through local myogenic factors.3 The postural vasoconstrictor response protects subcutaneous tissue from fluid extravasation during dependency and eventually dependent edema.1 Its derangement, as in patients with peripheral vascular disease4 and insulin-dependent diabetes mellitus,5 reduces precapillary vasoconstriction and sets the stage for development of subcutaneous edema.4 6 Scarce evidence7 exists about the behavior of skin reflexes in human essential hypertension, and possible interferences by antihypertensive drugs are practically unknown. By modulating extracellular calcium influx through voltage- and receptor-operated channels into vascular smooth muscle cells, CCBs alter a wide spectrum of vasoconstrictor functions in humans8 9 and therefore may modulate local subcutaneous antiedema protective mechanisms as well. To test this possibility, we treated essential hypertensive patients with vasodilators with and without calcium channel blocking properties. Skin blood flow was measured through laser Doppler flowmetry, a noninvasive method that is able to register the sudden changes in skin blood flow evoked by posture2 5 10 without entailing local heating of skin, injection trauma, or venous occlusion, all of which may disturb local vasomotor reflexes.
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Methods |
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Patients
Twenty-three patients (18 men, 5 women; age range, 33 to 70 years) with uncomplicated stage I to II mild essential hypertension diagnosed by exclusion of secondary causes through history, physical examination, routine blood chemistry, and laboratory examinations were recruited for the study. All subjects had ankle/brachial systolic BP ratios >1.0; none complained or showed evidence of venous disease. Patients were off treatment (CCBs and/or ACE inhibitors) for 1 month at the moment of the first basal determination.
Experimental Protocol
The studies were performed between 2 and 8 PM and at least 2 hours after the last food, drink, or smoking. Drugs were taken at 8 AM, and measurements were obtained 6 to 12 hours from last dosing. Patients were at ease with the attending medical staff and lay supine for at least 30 minutes in a quiet, climatized room (22°C to 24°C) at constant barometric pressure (range, 756 to 768 mm Hg) and humidity (range, 35% to 41%). Laser Doppler flowmetry was performed at (1) the dorsum (first intermetatarsal space) and (2) the plantar surface of the great toe of the right foot. Systolic, diastolic (Korotkoff phase V), and mean (diastolic+1/3 pulse pressure) BPs (indirect method, supine position) were measured at the dominant arm during each phase of the protocol. The reported BP values represent the averages of several determinations.
The general structure of the study consisted of the measurement of LDFs and their percent postural changes [(H-D)/Hx100] at the heart (H) level and during dependency (D, leg dangling 50 cm below the heart level). Data were obtained at baseline and during drug treatment administered at maximal or near-maximal recommended doses for a period of 2 weeks, ie, a time interval sufficient to reach a steady state. When two drugs were crossed over in the same patient, the drug sequence was randomized and a 2-week washout period was allowed to reestablish baseline conditions.
Three series of experiments were carried out. Series 1 (7 patients, 5 men; age, 51±6 years) evaluated the effect of amlodipine (10 mg UID), a dihydropyridine CCB,11 crossed over with doxazosin (4 mg UID), an arteriolar vasodilator with selective 1-adrenoceptor blocking properties.12
Series 2 (6 patients, 4 men; age, 58±7 years) consisted of the crossover evaluation of nifedipine (60 mg UID, sustained-release formulation) and the phenylalkylamine verapamil (480 mg BID, sustained-release formulation) to compare the microcirculatory effects of another dihydropyridine congener with those of a chemically unrelated CCB.13
Series 3 (10 patients, 7 men; age, 58±9 years) investigated the effect of losartan (50 mg UID), an AT-1–specific angiotensin II receptor blocker,14 in the light of past evidence that the renin-angiotensin system may augment the increase in systemic vascular resistances associated with postural changes.15
Laser Doppler Velocimeter
Skin blood flow was recorded with a laser Doppler flowmeter (Periflux 4001 Master, Perimed Ltd). The device contains a solid-state low-power diode laser (1 mW at the probe tip; wavelength, 780 nm) that delivers a laser light to a cutaneous surface of 
1 mm2 at a depth of 1 mm via flexible graded-index fiberoptic light guides. The laser light strikes moving red blood cells and is reflected with a shift in frequency, whereas nonmoving structures cause no shift in frequency.16 17 The reflected light is guided from the tissue surface through a second fiberoptic light guide, mixed, and analyzed in real time by an analog processor that provides a continuous output of the instantaneous mean Doppler frequency in the photocurrent identified by a square-law detector; the digitized signal was fed into a computer for on- and off-line analysis. Before each study, the instrument was made null for a condition of no flow by placement of the laser probe in the calibration clip on a surface containing no mobile structures and was calibrated into a colloidal suspension of latex particles moving with Brownian motion. Biological zero (ie, the LDF recorded under no-flow conditions) was not subtracted, because the precise nature of this measurement is still undetermined.10 18 Time constant and sampling frequency were set at 0.03 seconds and 16 Hz, respectively. Double-sided adhesive disks were attached to the probes, which were then applied to the skin of the dorsal surface of the right foot and the plantar surface of the right big toe. Laser Doppler measurements at the former site reflect mainly nutritional capillary blood flow, because shunt flow is poor at this site.19 Conversely, the plantar surface of the right big toe is heavily endowed with AV anastomoses, and measurements at this site represent predominantly shunt blood flow.18 Results (expressed in PU, where one PU=10 mV measured on the analog output) were computer-derived smoothed averages (Perisoft, Perimed Ltd) of skin blood flow recordings during the 2 minutes preceding foot lowering and at minutes 9 and 10 of foot dependency, when the parameter was invariably constant in all patients. In our hands, the average intraindividual variabilities of the percent postural changes in skin blood flow recorded at precisely the same measuring point and 48 hours apart from each other were 14% and 7% (variation coefficients of triplicate measurements obtained in n=6 healthy subjects) for the dorsum and great toe, respectively.
Statistics
Descriptive statistics were medians and range for skewed data and mean±SD otherwise. Statistical analysis was based on the comparison of parameters during drug treatment versus the preceding basal values. Wilcoxon's test was used for paired comparisons of LDF, since data were nonnormally distributed. Two-way ANOVA was used to analyze differences in mean BP values among groups, followed by a multiple-range test to evaluate differences between means. A value of P<.05 was the limit for statistical significance.
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Results |
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Basal BP and fluximetric parameters were comparable among the three experimental groups (Table
s 1 through 3), as well as between the first and second baselines in the two series with drug crossovers (Tables 1 and 2).
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Blood Pressure
All treatments decreased BP, either systolic, diastolic, or both (Table
s 1 through 3). The mean percent drop in mean BP did not differ significantly among the various drug regimens (amlodipine, -7.1%; doxazosin, -4.2%; nifedipine, -5.6%; verapamil, -8.6%; and losartan, -6.8%).
LDF at the Dorsum of the Foot
During amlodipine, skin blood flow did not change significantly at rest and tended to increase on dependency (Table 1); therefore, postural vasoconstriction was reduced (P<.001; Table 1, Fig 1). Conversely, both resting and dependent flows tended to increase during doxazosin (Table 1), so that postural vasoconstriction did not change (Table 1, Fig 1). A representative tracing showing the opposite behavior of fluximetric data during treatment with the two different drugs is shown in Fig 2.
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Unchanged skin blood flow at rest, less reduction on dependency, and decreased percent postural decrement characterized treatment with both nifedipine and verapamil (Table 2).
The percent attenuations of the vasoconstrictor response by amlodipine, nifedipine, and verapamil did not differ significantly (Fig 1).
Losartan did not change microcirculatory parameters (Table 3, Fig 1).
LDF at the Plantar Surface of the Great Toe
Supine, dependent skin blood flow fluxes and percent postural changes were unchanged during the different drug interventions (Tables 1 through 3, Figs 2 and 3).
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Discussion |
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The main and original finding of this study is the blunted postural vasoconstriction of skin blood flow during treatment with amlodipine, nifedipine, and verapamil. Nonspecific vasorelaxation could not explain that effect because microvascular regulation was preserved during treatment with non-CCB vasodilators such as doxazosin and losartan given at doses equieffective on BP. Since the dihydropyridine derivatives and the chemically unrelated verapamil behaved similarly, the microcirculatory action of the drugs was probably related to extracellular calcium antagonistic properties; however, any generalization on this point is impossible because of the heterogeneous activity of CCBs in humans (eg, Reference 20). The mechanism of the blunted postural vasoconstriction of skin blood flow is not immediately evident, but it may be better understood on the basis of the coexistence of the reduced vasoconstriction at the dorsum of the foot with the maintained responses at the plantar surface of the great toe. To reconcile this apparent contradiction, one has to take into account that laser Doppler flowmetry measures flow in both superficial capillaries and at least part of slightly deeper shunt flow element.18 21 Therefore, the technique becomes a function of capillary flow where AV anastomoses are few, such as at the dorsum of foot,19 and of shunt flow where the latter predominate, such as at the plantar surface of the great toe.18 Anatomic heterogeneity of the cutaneous vascular bed in the foot has physiological implications for skin blood flow control, since AV anastomoses are mainly under sympathetic drive,22 whereas precapillary arterioles seem to be preferentially regulated by the intrinsic myogenic tone.3 22 Accordingly, one is led to conclude that the blunted postural vasoconstriction at the dorsum of the foot reflected preferential precapillary arteriolar modulation by CCBs, because AV shunts are scarce at this level.18 Furthermore, the mechanism of action of amlodipine, nifedipine, and verapamil was probably independent of sympathetic modulation, because precapillary arterioles operate by and large independently of autonomic stimuli.22 This latter conclusion is also supported by other pieces of evidence. In fact, dihydropyridine and phenylalkylamine calcium channel antagonist classes exerted divergent effects on forearm arteriolar responsiveness to intra-arterial norepinephrine23 and sympathetic outflow.24 Yet, irrespective of their pharmacological classes, all CCBs appeared similarly active in this study. By logical inference, one might postulate modulation by CCBs of myogenic tone, an extracellular calcium–dependent process8 that has been suggested to take part in the autoregulation of skin blood flow.2 3 Rather strong support for this hypothesis is offered by the previous demonstration of reduced transient vasoconstriction in response to a rapid increase in transmural pressure in the hindleg of the anesthetized cat by calcium antagonists.25 Some inferential support also comes from the present negative results of the losartan series, performed on the basis of previous evidence showing a role for the renin-angiotensin system in augmenting the postural increase of vascular resistances.15 However, this mechanism does not seem to assist the postural increase in skin precapillary resistance and shunt flow associated with lowering of one extremity below heart level. The lack of effect of selective
1-adrenoceptor blockade through doxazosin12 at both the dorsum of the foot and the plantar surface of the great toe was rather unexpected in the light of the previous demonstration of abolished vasoconstrictor response during either nonselective -adrenoceptor blockade through intra-arterial phentolamine infusion1 or local lignocaine infiltration.2 One might postulate a postural vasoconstrictor mechanism dependent primarily on postsynaptic 2-adrenoceptors previously identified in forearm,26 skin vessels,27 and in vitro isolated human subcutaneous arterioles.28 Were this the case, however, CCBs should have been active against these putative 2-mediated postural vasoconstrictor stimuli, as they were against selective 2-adrenoceptor agonists both at the forearm level29 and in subcutaneous arterioles.30 We cannot exclude the possibility that doses >4 mg might be able to antagonize sympathetic postural vasoconstriction at the foot, although little seems to be gained in terms of antihypertensive efficacy.31 Possibly, -adrenergic receptor subtypes other than those conventionally recognized may operate that physiological mechanism32 ; however, this is a highly speculative hypothesis that needs appropriate experimental testing.
The clinical and physiopathological significance of our findings derives from the present knowledge about the physiological role played by the local vasoconstrictor skin reflexes in humans.1 2 When one changes from the supine to the standing position, 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 rapidly result in interstitial edema unless compensatory increases in precapillary and postcapillary resistances and oncotic pressure concurred to maintain capillary pressure.33 This concept was supported by the studies by Henriksen,1 in which it was demonstrated that when the leg was lowered, subcutaneous blood flow in the foot fell as a result of an increase in vascular resistance, a mechanism called the venoarteriolar reflex. The same author showed that in chronically sympathetic enervated limbs, in which the venoarteriolar response was absent, venous pressure elevation caused a linear increase in capillary filtration rate, whereas in the opposite intact limb, the capillary filtration rate increased by only a portion of that predicted by changes in hydrostatic pressure.34 35 Another important determinant of capillary filtration is plasma oncotic pressure, which rises progressively in the dependent stationary foot and brakes further fluid filtration.36 Such an increase in colloid osmotic pressure can occur only if microvascular blood flow is low, as allowed by effective precapillary vasoconstriction. In summary, posturally induced precapillary vasoconstriction, by limiting the rise in capillary pressure, reducing microvascular blood flow, and thereby increasing plasma colloid osmotic pressure at the microvascular interface, appears to be central to the prevention of interstitial edema in the dependent limb. On the basis of these concepts, we hypothesize that interference by CCBs with skin postural vasoconstrictor mechanisms may alter the balance of Starling's forces, resulting in net filtration of fluid from the intravascular to the extravascular compartment. At its extreme, derangement by CCBs of the control mechanism of cutaneous capillary flow might lead to ankle edema without consistent fluid retention, a typical and not yet elucidated complication of treatment with calcium antagonists, including verapamil, when given at fully antihypertensive doses.37 In contrast to CCBs, this undesirable side effect is not listed among those induced by other classes of vasodilators. It might not be simply chance that 1-adrenoceptor and AT-1 subtype angiotensin II receptor antagonists such as doxazosin and losartan, respectively, left intact the postural responsiveness of skin blood flow. More studies are needed, however, to substantiate our hypothesis about the genesis of pretibial edema during calcium antagonist treatment, with particular regard to data correlating inhibition of skin vasoconstrictor responses with objective measures of ankle swelling. A complete evaluation of the dose-response profile of the vasomotor interference by CCBs will also be important, because the information gathered in this study relates only to the effects of single, relatively high dosages.
In conclusion, dihydropyridine and phenylalkylamine calcium channel antagonists antagonized postural skin vasoconstriction at the dorsum of the foot, indicating interference with postural capillary blood flow regulation in essential hypertensive patients. The effect was independent of either 1-adrenoceptor or AT-1 subtype angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may alter the balance of Starling's forces, resulting in net filtration of fluid from the intravascular to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema without consistent fluid retention during treatment with calcium antagonists.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to thank the local representatives of the Italian subsidiaries of Bayer, Knoll, Merck Sharp & Dohme, Roerig, and Pfizer for the kind gift of drugs.
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Footnotes |
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Reprint requests to Dr Roberto Pedrinelli, I Clinica Medica, Universita di Pisa, Pisa, Italy. E-mail r.pedrinelli@int.med.unipi.it
Presented in abstract form at the Meetings of the American Society of Hypertension, New York, NY, May 15-17, 1996; the International Society of Hypertension, Glasgow, UK, June 24-27, 1996; and the European Society of Cardiology, Birmingham, UK, August 26-29, 1996.
Received July 22, 1996;
first decision August 15, 1996;
first decision October 10, 1996;
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