Calcium Channel Blockers Blunt Postural Cutaneous Vasoconstriction in Hypertensive Patients

Abstract

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 alpha1-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 alpha1-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.

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

“…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 [25][26][27] 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 [32][33][34] (Table 1). Attenuation of postural vasoconstriction was probably the result of 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.…”

“…Attenuation of postural vasoconstriction was probably the result of 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.…”

“…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][23][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- vides a tool for the evaluation of pharmacological interference on skin vasomotion, an aspect scarcely studied insofar, particularly in essential hypertension.…”

Amlodipine, Enalapril, and Dependent Leg Edema in Essential Hypertension

“…6 We have recently shown impaired postural skin blood flow control in patients with essential hypertension who were treated with calcium channel blockers (CCBs). 7 This pharmacological effect may contribute to ankle and/or pretibial edema in the absence of fluid retention, 8 a frequent, bothersome, and still not completely understood collateral effect of calcium antagonist drugs. 9 To test this hypothesis, we evaluated the relation between changes in postural skin vasomotion and objective measures of ankle swelling during treatment with graded doses of amlodipine, a dihydropyridine CCB.…”

Fluid Matters in Choosing Antihypertensive Therapy: A Hypothesis That the Data Speak Volumes

“…Verapamil increases plasma volume, 15 and it blunts postural cutaneous vasoconstriction in the lower extremities, as do amlodipine and nifedipine. 49 One placebo controlled study found that the prevalence of edema in patients with hypertension who were treated with verapamil was 3% compared with 5% in the placebo group. 50 Other non-placebo-controlled studies have found a 1% to 14% frequency of edema in subjects treated with verapamil.…”