F. T. M. Huysmans

Oedema formation with the vasodilators nifedipine and diazoxide : direct local effect or sodium retention ?

Objective To determine whether the common side effect of ankle oedema with arteriolar vasodilators such as the calcium entry blocker (CEB) nifedipine and the potassium channel opener (PCO) diazoxide is the direct result of peripheral vasodilation or merely a consequence of renal sodium retention. Design In 12 healthy sitting volunteers we studied for 3 h the effects of 20 mg nifedipine, 150 mg diazoxide intravenously, 25 mg captopril and placebo on oedema formation and sodium excretion. Conclusions Foot swelling was determined with a new accurate device (coefficient of variation 0.30%), which uses Archimedes principle to measure water displacement induced by immersion of the foot. Blood pressures were recorded with a Hawksley random-zero sphygmomanometer. Results All of the active drugs decreased diastolic blood pressure (captopril by 9 ± 2%, nifedipine by 4 ± 3% and diazoxide by 2 ± 2%, compared with an increase of 5 ± 2% with placebo). Foot volume increased acutely after administration of nifedipine (by 2.6 ± 0.4%), whereas it remained stable with placebo and the other drugs. Administration of captopril and nifedipine induced increases of fractional sodium excretion (by 20 ± 9% and 40 ± 20%, respectively) in contrast to the decreases with placebo and diazoxide (by 13 ± 11% and 24 ± 10%, respectively). Only administration of nifedipine induced significant, albeit small, increases in haemoglobin and serum albumin levels. Conclusions Administration of nifedipine increased foot volume and natriuresis simultaneously, thereby supporting the hypothesis that development of ankle oedema with CEB is a local phenomenon at the site of vasodilation. The absence of a similar increase in foot volume with diazoxide administration should be interpreted with caution because of the rather minor effect of this dose of diazoxide on blood pressure. However, it could be indicative of a different mechanism of oedema formation with PCO.

Haemodynamic, Hormonal, and Diuretic Effects of Felodipine in Healthy Normotensive Volunteers

SummaryFelodipine and placebo were infused in a double- blind, crossover study in 10 healthy normotensive volunteers. Compared with placebo, felodipine caused a significant decrease in diastolic blood pressure and forearm vascular resistance, while there was no change in systolic blood pressure. The rises in heart rate, plasma renin activity and plasma nor- adrenaline (norepinephrine) concentration further demonstrated the vasodilating activity of felodipine. Plasma aldosterone, adrenaline (epinephrine) and antidiuretic hormone concentrations were similar after a 90- minute infusion of felodipine or placebo. The response of plasma aldosterone levels to exogenous adenocorticotrophic hormone showed evidence of a slight blunting during felodipine infusion. Felodipine had a marked diuretic effect, probably secondary to an increase in natriuresis, which might be due to a direct tubular effect of the drug.

Diazoxide infusion in severe hypertension and hypertensive crisis.

Prompted by reports of hypotension with myocardial ischemia after bolus injection, we restudied the efficacy of diazoxide infusion (5 mg/kg, rate, 15 mg/min) in 35 hypertensive patients. In 20 patients with chronic hypertension, mean arterial pressure of 138 mm Hg was 110 (after 30 min) and 121 (after 8 hr). In 15 patients with hypertensive crisis, there was a fall from 159 to 126 (in 30 min) and 133 mm Hg (after 8 hr), similar to findings in 12 patients with hypertensive crisis treated with a 300‐mg bolus injection (159, 130, 140 mm Hg). In the latter, the maximal systolic blood pressure decrease was greater (56 mm Hg, reached in 4 min) than in the 15 patients with hypertensive crisis treated by slow infusion (38 mm Hg in 28 min). Thus, infusion of diazoxide causes a gradual decline of blood pressure and is, in contrast to current opinion, also an effective treatment in hypertensive crisis.

The Natriuretic Effect of the Dihydropyridine Calcium Antagonist Felodipine: A Placebo-Controlled Study Involving Intravenous Angiotensin II in Normotensive Volunteers

Changes in systemic and renal hemodynamics and in the renin-angiotensin system caused by infusion of the calcium antagonist felodipine were investigated in a placebo-controlled study with 12 normotensive volunteers before and during a graded infusion of angiotensin II (AII). In spite of a fall in blood pressure through vasodilatation, felodipine had a natriuretic effect. There was only a transient rise in effective renal plasma flow (ERPF), whereas glomerular filtration rate (GFR) did not change. Urinary sodium excretion remained elevated when ERPF had normalized. Urinary potassium excretion did not change. AII-induced reductions in ERPF, GFR, and sodium excretion were abolished by felodipine. Felodipine also partly antagonized the rise in plasma aldosterone levels caused by AII. We conclude that the natriuretic effect of dihydropyridine calcium antagonists is probably not caused by a single mechanism, but may be dependent on changes in renal hemodynamics together with a diminished sodium reabsorption at multiple tubular sites. Interference with AII-mediated renal mechanisms and an impairment of the action of aldosterone may contribute to this natriuretic effect as well.

Ankle edema formation during treatment with the calcium channel blockers Lacidipine and Amlodipine: a single centre study.

All studies suggesting a lower incidence of edema on lacidipine than on amlodipine are based on subjective scoring. Therefore, we have compared edema formation on two dihydropyridine calcium channel blockers, using an accurate method for quantitative assessment of foot volume. In a randomized study, we treated 62 patients with essential hypertension for 12 weeks starting with either lacidipine 4 mg o.d. (n = 30) or amlodipine 5 mg o.d. (n = 32). At 6 weeks, the doses were increased to that maximally allowed (lacidipine 6 mg, n = 18; amlodipine 10 mg, n = 12) if trough diastolic blood pressure response was insufficient (>90 mmHg and decrease < 10 mmHg). Edema, scored visually, occurred more frequently (p = 0.02) on amlodipine (15/32) than on lacidipine (6/30); this was confirmed by an increase of foot volume above the 95% upper limit of normal variation in 15 patients on amlodipine and in only five patients on lacidipine (p = 0.01). In the whole group of patients, both the increases of foot volume and the decreases of blood pressure just failed to be significantly different between amlodipine and ]acidipine (foot volume, +3.3+/-1.0% on amlodipine and +1.2+/-0.5% on lacidipine, p = 0.08; mean arterial pressure, -11+/-1% on amlodipine and -8+/-1% on lacidipine, p = 0.052). In patients requiring dose increase, the increase of foot volume on amlodipine was more pronounced (p < 0.05), and the antihypertensive effect was larger (p < 0.05) than on lacidipine. In conclusion, our data show a higher incidence of edema on amlodipine than on lacidipine, which has to be explained at least partly by a comparably higher dose c.q. a larger antihypertensive effect of amlodipine. Other mechanisms might have contributed to these differences and need to be explored.

Haemodynamic Effects of Intravenous Felodipine in Normotensive and Hypertensive Subjects

SummaryThe effects of intravenous administration of a new calcium antagonist, felodipine, were studied in healthy subjects and hypertensive patients. Felodipine infused at a rate of 0.01 mg/min in 10 normotensive volunteers caused gradual haemodynamic and hormonal changes compatible with a direct vasodilatory mechanism of action; it also had a diuretic and natriuretic effect. When infused at a mean dose of 0.02 mg/kg body weight over 20 to 120 minutes in 7 patients with a hypertensive emergency, felodipine caused a rapid reduction in blood pressure with a maximal fall in mean arterial pressure of 30.4 ± 7.3% (mean ± 1 SD) in 30 minutes. No serious side effects were observed. The haemodynamic effectiveness of an infusion rate of 0.01 mg/min was confirmed in a pilot study of 5 patients with refractory hypertension. On the basis of these findings, a schedule for the treatment of acute hypertension with intravenous felodipine is proposed.

Combined intravenous administration of diazoxide and beta-blocking agent in acute treatment of severe hypertension or hypertensive crisis

Twenty-nine patients with severe hypertension (n = 14) or hypertensive crisis (n = 15) were treated with diazoxide infusion and intravenous injection of a beta blocker. In 13 patients diazoxide was administered first. It gradually reduced mean arterial pressure (MAP) by 16.1 +/- 2.1% (mean +/- SEM), and increased heart rate (HR) by 27.3 +/- 4.1% and plasma renin activity (PRA) by 48.9 +/- 13.0%. Beta blockade thereafter lowered MAP by only 1.2 +/- 1.9% despite reductions of HR by 35.6 +/- 2.2% and of PRA by 17.1 +/- 5.9%. In 16 other patients a beta blocker, when given first, reduced MAP by 3.5 +/- 1.2%, HR by 18.9 +/- 1.8%, and PRA by 24.2% +/- 4.4%. Diazoxide infusion thereafter gradually reduced MAP further by 21.9 +/- 1.9% and raised HR and PRA to pretreatment levels. No complications were observed. Beta blockade before diazoxide infusion effectively prevents a rise in HR above control levels while its acute effect on blood pressure is negligible. It is advisable to use this combined treatment in all situations where the occurrence of tachycardia might be dangerous.

Foot volume increase on nifedipine is not prevented by pretreatment with diuretics.

Objective Despite their natriuretic effects, dihydropyridine calcium-channel blockers (CCBs) often induce ankle oedema, probably due to vasodilation in the dependent legs. Since concomitant administration of frusemide does not prevent the acute increase in foot volume on nifedipine, we investigated whether diuretic pretreatment attenuates foot swelling on CCBs. Methods In four separate experiments, 10 healthy volunteers received: (i) 20 mg of nifedipine without active pretreatment (pretreatment with placebo only); (ii) 20 mg of nifedipine after 5 days’ treatment with amiloride 5 mg twice daily; (iii) 20 mg of nifedipine after 5 days’ treatment with chlorthalidone 50 mg once daily; and (iv) no active drugs (pretreatment with placebo and placebo in place of nifedipine) as the control. Foot volumes were measured using an accurate water displacement technique (intra-individual coefficient of variance 0.27%). Results Amiloride and chlorthalidone pretreatment induced marked volume depletion, with a 2–3% reduction in body weight, a 5–10% increase in haematocrit and a 14–23% increase in plasma colloid osmotic pressure. In addition, the mean ± SEM foot volume after both chlorthalidone (1282 ± 37 ml) and amiloride (1289 ± 40 ml) was lower than without pretreatment (1315 ± 38 ml) (P < 0.05). Neither amiloride nor chlorthalidone significantly influenced the acute increase in foot volume on nifedipine. However, due to pretreatment effects, the foot volume after nifedipine was higher (P < 0.05) without pretreatment (1356 ± 36 ml) than after amiloride (1318 ± 38 ml) or chlorthalidone (1319 ± 37 ml). Amiloride significantly attenuated the natriuretic effect of nifedipine, whereas chlorthalidone prevented the nifedipine-induced rise in colloid osmotic pressure and haematocrit. Conclusions Diuretic pretreatment and the concomitant volume depletion did not prevent acute foot swelling on nifedipine, although the absolute foot volume remained lower after such pretreatment. Therefore diuretics mitigate the oedema of CCBs, but do not directly interfere with oedema formation.

Acute Effects of Nifedipine in Renal Transplant Recipients Treated With Cyclosporine or Azathioprine

Cyclosporine (CsA) impairs renal function, probably by preglomerular vasoconstriction. Vasodilating substances may therefore be of benefit to ameliorate CsA-induced renal dysfunction. We studied the acute effects on blood pressure and renal function of the dihydropyridine calcium antagonist nifedipine (10 mg orally) in 20 CsA-treated renal transplant patients. In addition, we compared the effects of nifedipine when given immediately before and 4 weeks after elective conversion from CsA to azathioprine. Compared with placebo (n = 14), administration of nifedipine led to a significant decrease in blood pressure and a strong natriuretic and diuretic response. Despite the reduction in blood pressure, glomerular filtration rate improved from 60 +/- 20 (mean +/- SD) to 69 +/- 24 mL/min/1.73 m2 (P < 0.001) and renal plasma flow (RPF) increased from 260 +/- 87 to 338 +/- 120 mL/min/1.73 m2 (P < 0.001). The combination of a decreased blood pressure with an increased RPF was reflected in a sharp decrease in renal vascular resistance (0.34 +/- 0.18 units v 0.23 +/- 0.10 units; P < 0.001). The conversion from CsA to azathioprine by itself led to significant increases in glomerular filtration rate (62 +/- 15 mL/min/1.73 m2 v 76 +/- 18 mL/min/1.73 m2; P < 0.05) and RPF (280 +/- 86 mL/min/1.73 m2 v 334 +/- 66 mL/min/1.73 m2; P < 0.05). During treatment with azathioprine an effect of nifedipine on glomerular filtration rate and RPF was no longer observed, although the natriuretic effect was similar on both occasions. The decrease in renal vascular resistance was larger during treatment with CsA than during treatment with azathioprine (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dihydropyridine calcium antagonists on rabbit renal Na,K-ATPase activity in vitro

Dihydropyridines are reported to have a stimulatory effect on vascular smooth muscle Na,K-ATPase activity in vitro. We studied the effects of the dihydropyridine calcium antagonists nimodipine, nitrendipine, nisoldipine, niludipine, nifedipine and felodipine (10(-5) M) on purified Na,K-ATPase isolated from rabbit kidney outer medulla. We were unable to detect an effect of the drugs on the enzyme activity, either under optimal or suboptimal substrate conditions. Likewise, Na,K-ATPase activity, partly inhibited by the addition of ouabain (10(-6) M), Ca2+ (10(-3) M) or arachidonic acid (4 x 10(-5) M), was not influenced by the dihydropyridines. The absence of a stimulatory effect of dihydropyridines on renal Na,K-ATPase is in agreement with the known diuretic and natriuretic effects of the drugs in normotensive and hypertensive men.