Verapamil increases serum ionized calcium and serum phosphate in patients with post-surgical hypoparathyroidism.

The calcium homeostasis in eight patients with postoperative hypoparathyroidism was examined before and after 2 weeks of administration of verapamil in an oral dose of 80 mg three times daily. Serum ionized calcium increased during verapamil treatment (from mean +/- SD of 1.10 +/- 0.06 to 1.24 +/- 0.38 mmol l-1; P less than 0.05), as well as total serum calcium corrected for protein (from 2.11 +/- 0.13 to 2.18 +/- 0.13 mmol l-1; P less than 0.05). During treatment with verapamil there was an increase in serum phosphate (from 1.08 +/- 0.15 to 1.19 +/- 0.20 mmol l-1 P less than or equal to 0.05) and in the urinary excretion of phosphate (P/creatinine ratio from 1.22 +/- 0.69 to 1.83 +/- 0.97; P less than or equal to 0.05). The serum 1,25-dihydroxyvitamin-D3 and serum parathyroid hormone were below the detection limits both before and after verapamil treatment. There were no significant changes either of the intestinal absorption of calcium or of the urinary calcium excretion. Serum osteocalcin was insignificantly reduced after treatment (1.60 +/- 0.70 before treatment and 1.25 +/- 0.71 micrograms l-1 after treatment). Thus in patients with post-surgical hypoparathyroidism verapamil has effects on calcium and phosphorous homeostasis. Since calcium absorption was not influenced by verapamil, it is suggested that verapamil affects bone mineral metabolism.

In vivo interactions between beta-1 and beta-2 adrenoceptors regulate catecholamine tachyphylaxia in human adipose tissue.

Catecholamine tachyphylaxia was investigated in human s.c. adipose tissue in situ by using microdialysis. The tissue was dialyzed with adrenergic agents (10(-8) mol/l) and the glycerol concentration (lipolysis index) was determined. Perfusion with adrenaline caused a 3-fold rise in the glycerol concentration, which peaked at 30 min and then (within 1 hr) declined to a level 75% higher than base line; the latter elevation was constant for at least 2 hr. Noradrenaline or isoprenaline in the absence and presence of a selective beta-2 receptor antagonist, or the selective beta-1 adrenergic agonist dobutamine, caused a 2- to 2.5-fold transient lipolytic response which also peaked at 30 min but then (within 3 hr) declined to the base-line level. On the other hand, isoprenaline plus a selective beta-1 receptor antagonist or the beta-2 selective adrenergic agonist terbutaline caused a constant lipolytic effect for at least 3 hr. Noradrenaline or adrenaline plus a nonselective beta adrenergic antagonist as well as the alpha-2 selective adrenergic antagonist clonidine caused a sustained antilipolytic action for at least 3 hr. In conclusion, the adrenoceptor subtypes involved in lipolysis regulation in humans have different in vivo sensitivities to homologous desensitization. Beta-2 and alpha-2 adrenoceptors are resistant in this respect whereas activation of beta-1 adrenoceptors leads to rapid desensitization. However, simultaneous beta-1 and beta-2 receptor activation is accompanied by different degrees of tachyphylaxia, indicating regulatory in vivo interactions within this receptor family in human adipose tissue.

Verapamil increases serum alkaline phosphatase in hypertensive patients.

In rats, verapamil decreases intestinal absorption of calcium, increases serum parathyroid hormone (PTH), and induces osteopenia. In this prospective study, verapamil 80-120 mg three times daily was given for 2 months to 20 patients with hypertension, and the effects on calcium homeostasis were recorded. This dose of verapamil significantly reduced supine systolic and diastolic blood pressure (+/- SD) from 158/100 +/- 9/8 mmHg to 146/89 +/- 14/8 mmHg (P = 0.001). Serum alkaline phosphatase (ALP) increased significantly from 2.77 +/- 1.06 mu kat l-1 to 3.19 +/- 1.22 mu kat l-1 (P = 0.004), and isoenzymes of ALP of skeletal origin appeared after verapamil treatment. The excretion of sodium in the urine increased (Na/creatinine ratio 8.95 +/- 6.01 before and 13.16 +/- 8.26 after verapamil; P = 0.04), while the excretion of calcium, phosphate and potassium was not changed. PTH was slightly increased at the end of verapamil treatment (1.09 +/- 0.54 vs. 0.98 +/- 0.74 microgram l-1; P = 0.07), and s-1,25(OH)2D3 was also somewhat increased (22.3 +/- 14.4 vs. 17.6 +/- 4.9 ng l-1; P = 0.26). Serum Ca was not affected by verapamil (before verapamil 2.43 +/- 0.11 mmol l-1, after verapamil 2.40 +/- 0.12 mmol l-1; P = 0.28). The increase in serum ALP demonstrates that verapamil affects bone cell metabolism in man. This effect could be secondary to the enhancement of PTH secretion.

In situ studies of catecholamine-induced lipolysis in human adipose tissue using microdialysis.

The effects of catecholamines on lipolysis in situ were investigated in humans. Subcutaneous adipose tissue was microdialyzed with solvents containing adrenergic agents. Norepinephrine caused a rapid increase in the glycerol level in adipose tissue (lipolysis index) that was further increased by the alpha adrenoreceptor blocker phentolamine. At 10(-11) mol/l of norepinephrine caused a 100% stimulation of lipolysis (P less than .025). In the presence of phentolamine the lipolytic effects of catecholamines at 10(-12) mol/l was isoproterenol greater than epinephrine greater than norepinephrine. All these three lipolytic catecholamines caused a transient increase in the adipose tissue dialysate glycerol level, which peaked after 20 to 30 min of catecholamine exposure and then declined. The apparent tachyphylaxia could not be overcome by a gradual increase of the catecholamine concentration from 10(-12) to 10(-8) mol/l. However, the selective alpha-2 adrenoreceptor agonist clonidine caused a continuous and dose-dependent decrease in the dialysate glycerol level; the minimum effective concentration was 10(-9) mol/l. In conclusion, catecholamines have a lipolytic effect in situ at much lower concentrations than those in the circulation. This effect is transient and is related to beta adrenoreceptors. In additio, catecholamines have alpha adrenoreceptor-mediated effects on lipolysis in situ.

Adrenergic regulation of lipolysis in situ at rest and during exercise.

The adrenergic regulation of lipolysis was investigated in situ at rest and during standardized bicycle exercise in nonobese healthy subjects, using microdialysis of the extracellular space in subcutaneous adipose tissue. The glycerol concentration was about two times greater in adipose tissue than in venous blood. At rest, the glycerol concentration in adipose tissue was rapidly increased by 100% (P less than 0.01) after the addition of phentolamine to the ingoing perfusate, whereas addition of propranolol did not alter the adipose tissue glycerol level. Glycerol in adipose tissue and plasma increased during exercise and decreased in the postexercise period. Propranolol in the perfusate almost completely inhibited the increase in the tissue dialysate glycerol during the exercise-postexercise period. Phentolamine, however, was completely ineffective in this respect. During exercise, the lipolytic activity was significantly more marked in abdominal than in gluteal adipose tissue; this was much more apparent in women than in men. Thus, in vivo lipolysis in subcutaneous adipose tissue is regulated by different adrenergic mechanisms at rest and during exercise. Alpha-adrenergic inhibitory effects modulate lipolysis at rest, whereas beta-adrenergic stimulatory effects modulate lipolysis during exercise. In addition, regional differences in lipolysis are present in vivo during exercise, which seem governed by factors relating to sex.

Calcium absorption and excretion in patients treated with verapamil.

1. The effect of verapamil on the intestinal absorption of calcium was studied using a single isotope technique. Serum calcium and urinary excretion of calcium in the urine were followed in nine patients during treatment with verapamil for 2 months. 2. A dose of 80-120 mg (three times daily) resulted in a significant reduction of systolic and diastolic blood pressure. 3. There was no change in the intestinal calcium absorption (alpha) expressed as the fraction of given activity absorbed per hour (alpha = 0.82 +/- 0.19 vs alpha = 0.83 +/- 0.25; +/- s.d., NS) or of the excretion of calcium in urine (Ca/creatinine ratio 0.35 +/- 0.20 vs 0.31 +/- 0.33; NS). 4. Serum calcium was not significantly different before and during treatment (2.43 mmol l-1 +/- 0.10 vs 2.47 mmol l-1 +/- 0.14; NS). 5. This study demonstrates that verapamil, at doses recommended for clinical use, does not seem to affect the intestinal absorption of calcium, the serum calcium concentration or the excretion of calcium in urine.