Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension.

The aim of this study was to determine the dose-response characteristics of the calcium antagonist, mibefradil, and to evaluate its antihypertensive efficacy and safety in varying doses in patients with mild-to-moderate hypertension. Three hundred and three eligible patients were randomized to receive once-daily 6.25-, 12.5-, 25-, 50-, 100-, 150-, or 200-mg mibefradil doses or placebo for 4 weeks. Repeated blood pressure measurements and electrocardiographic recordings were obtained for the 24 h following the last dose of the placebo run-in period and for the first and last doses of randomized treatment. A statistically significant (P < .001 versus placebo) and clinically relevant drop in sitting diastolic blood pressure (SDBP) both at trough and at peak was observed in the 50-, 100-, 150-, and 200-mg mibefradil dose groups (trough placebo-corrected reductions: -4.9, -9.1, -9.9, and -11.9 mm Hg, respectively), with a significant dose-response relationship (P < .001) and high response rates. Trough/peak ratios for the placebo-corrected change from baseline to week 4 in SDBP were >85% for the 50- and 100-mg doses and 68% and 69% for the 150- and 200-mg doses, respectively. The full antihypertensive effect of mibefradil was achieved within 1 week of treatment. Reductions in sitting systolic blood pressure (SSBP) closely paralleled those in SDBP. The antihypertensive effect of mibefradil was associated with a slight dose-dependent decrease in heart rate and increase in the pulse rate (PR) electrocardiographic interval [corrected]. The appropriate therapeutic dose range of mibefradil in the management of mild-to-moderate essential hypertension is 50 to 100 mg.

Primary hepatic pheochromocytoma?

We report a case of a single intrahepatic pheochromocytoma in the absence of an adrenal lesion and no evidence of metastatic disease. The patient had strong clinical and biochemical evidence of a pheochromocytoma. A CT scan was abnormal but nondiagnostic for pheochromocytoma. An 123I-metaiodobenzyl guanidine (MIBG) scan was falsely negative, but an MRI scan showed a definitive hepatic abnormality. After confirmation of endocrine activity by venous sampling, the tumor was surgically removed. The patient's symptoms have resolved and her plasma catecholamine levels as well as her 24-h urine catecholamine excretion have normalized. The case shows an unusual location of an isolated pheochromocytoma and provides an example of a false negative I-123 MIBG scan.

The retail cost of antihypertensive therapy. Physician and patient as educated consumers.

The retail cost for antihypertensive medication in the Cincinnati area was examined using a questionnaire sent to 20 local pharmacies asking them to provide the cost to the patient for a 30-day supply of medication. Six pharmacies responded, providing a detailed list of drug prices. The price for a given drug varies considerably from pharmacy to pharmacy, with generics having the greatest variability. There are also large differences between agents within a drug class, leading to overlap between classes. Some diuretics and beta-blockers are more expensive than angiotensin-converting enzyme inhibitors or calcium-channel blockers. For some agents a dose increase costs nothing, whereas for others it dramatically increases the cost. The price structure for antihypertensive agents is complex. Without detailed and current information, a physician will find it difficult to estimate the cost of a given prescription.

Clonidine and PGE2 have different effects on Na+ and water transport in rat and rabbit CCD.

We examined the effects of prostaglandin E2 (PGE2) and the adrenergic agonist clonidine on osmotic water permeability (Pf), lumen-to-bath 22Na+ flux (Jl----b), and transepithelial voltage (VT) in isolated perfused cortical collecting ducts (CCD) from rats and rabbits. Although PGE2 inhibited arginine vasopressin (AVP)-dependent Jl----b and Pf in CCDs from deoxycorticosterone (DOC)-treated and untreated rabbits, 0.1-10 microM PGE2 had no inhibitory effect on any of these transport parameters in CCDs from DOC-treated rats in presence of AVP. On the other hand, clonidine (1 microM in bathing solution) reversibly inhibited AVP-dependent Pf, Jl----b, and VT in the rat CCD by 30-40%, and 0.3 microM yohimbine, a specific alpha 2-adrenoceptor antagonist, reversed these effects. However, we were unable to demonstrate any inhibitory effect of 1-10 microM clonidine on Pf, Jl----b, or VT in the rabbit CCD using a variety of protocols. These results are consistent with the pattern of inhibition of AVP-dependent adenosine 3',5'-cyclic monophosphate (cAMP) production in the rat and rabbit CCD in that PGE2 inhibits both transport and cAMP production in the rabbit but not the rat CCD, and clonidine inhibits both transport and cAMP production in the rat but not the rabbit CCD [D. Chabardès, C. Brick-Ghannam, M. Montégut, and S. Siaume-Perez, Am. J. Physiol. 255 (Renal Fluid Electrolyte Physiol. 24): F43-F48, 1988].

A comparison of demographic, behavioral, and ego function data in borderline and eating disorder patients.

Seven borderline personality and ten eating disorder patients were compared using demographic, descriptive/behavioral, and ego function measures on admission to an inpatient unit. Demographic and descriptive data analysis revealed areas of overlap, consistent with other reports of co-morbidity between the two groups. Ratings of intrapsychic function were made using Bellak's Ego Function Assessment profiles, and showed that the two groups shared deficits in the areas of impulse/affect control and sense of identity, but had otherwise easily distinguishable profiles. The authors feel that studying ego functioning is a useful way of assessing co-morbidity in borderline personality and eating disorder patients.

Stimulation of sodium transport by aldosterone and arginine vasotocin in A6 cells.

The effects of aldosterone and arginine vasotocin (AVT) on transepithelial Na+ transport of cultured A6 cells were investigated. All experiments were performed with cells grown on Millicell TM culture-plate inserts for a period of 2-4 weeks in defined, serum-free medium. Omitting fetal bovine serum 2 days after seeding the cells on filters did not influence potential difference (PD) development or the hormonal responses tested. The cell layers were placed in an Ussing chamber for short-circuit current (ISC) and transepithelial conductance (G) measurements. Base-line values were (n = 93): PD, 51.0 +/- 0.2 mV (apical side negative); ISC, 14.55 +/- 0.06 microA/cm2; G, 0.306 +/- 0.001 mS/cm2. ISC and G were higher in cells pretreated with 10(-7) M aldosterone for 24 h in the incubator, when compared to controls (ISC, 28 +/- 2 vs. 16 +/- 2 microA/cm2, G, 0.41 +/- 0.04 vs. 0.26 +/- 0.01 mS/cm2, n = 5) and both remained stable for at least 6 h. In cells not treated with aldosterone, 10(-7) M AVT increased ISC within 1 min after addition, producing a maximum ISC within 15 min which then declined to baseline levels over the next 5 h. Addition of AVT to aldosterone-pretreated cells resulted in a significantly greater peak increase in ISC than in non-pretreated cells (change in ISC compared to controls: 8.1 +/- 0.4 vs. 4.9 +/- 0.4 microA/cm2, n = 5, P less than 0.001), indicating a synergistic effect. A dose-response curve for amiloride obtained in the presence of AVT showed that amiloride completely inhibits ISC. Pretreatment of the A6 cells with aldosterone for 24 h shifted the amiloride dose-response curve to the right, as expressed in a doubling of the apparent Ki value (from 0.17 +/- 0.02 to 0.33 +/- 0.04 microM). In conclusion, A6 cells grown in defined, serum-free medium express a greater than additive synergism between aldosterone and AVT in stimulating transepithelial Na+ transport.

Sodium transport by rat cortical collecting tubule. Effects of vasopressin and desoxycorticosterone.

We have used rat cortical collecting tubules perfused in vitro to study the effects of antidiuretic hormone (ADH) and desoxycorticosterone (DOCA) on the unidirectional fluxes of sodium. We found that in the basal state, lumen-to-bath flux (Jlb) and bath-to-lumen flux (Jbl) of 22Na were approximately equal, 39.5 +/- 3.9 and 41.8 +/- 11.0 pmol X min-1 X min-1, respectively, resulting in no net flux. Addition of 100 microU/ml ADH to the bath produced a stable increase in Jlb to 58.3 +/- 4.7 pmol X min-1 X mm-1. Pretreatment of the animal with DOCA for 4 to 7 d (20 mg/kg per d) increased baseline Jlb to 81.6 +/- 8.7 pmol X min-1 X mm-1. Addition of ADH to a tubule from a DOCA-pretreated rat caused an increase in Jlb to 144.1 +/- 12.0 pmol X min-1 X mm-1 X Neither hormone had an effect on Jbl X Thus ADH produced a greater absolute and fractional increase in Jlb when the animal was pretreated with DOCA, and the ADH-induced increase over baseline was greater than the DOCA-induced increase. Both the ADH-and DOCA-induced stimulation of Jlb were completely abolished by 10(-5) M luminal amiloride, suggesting that the route of sodium transport stimulated by both hormones involves apical sodium channels. However, ADH and DOCA have very different time courses of action; ADH acted within minutes, while aldosterone and DOCA are known to require 90-180 min. The facilitating action of ADH on DOCA-induced stimulation of sodium transport may be important for maximal sodium reabsorption and for the ability to achieve a maximally concentrated urine.

Massive hemorrhage from a lumbar artery following percutaneous renal biopsy.

We report a case of severe lumbar artery bleeding following percutaneous renal biopsy. A 68-year-old man with a history of rheumatoid arthritis, gold therapy, and Staphylococcus aureus bacteremia underwent a percutaneous renal biopsy to evaluate nephrotic syndrome and renal insufficiency. Following the procedure, he developed signs of severe hemorrhage. A selective renal angiogram revealed an intrarenal bleeding site that was occluded by selective embolization. The patient failed to stabilize however, and repeat angiography was performed two days later. A lumbar artery was identified as a second bleeding site, and was also occluded by selective embolization. The bleeding was controlled, but the patient developed serious complications and died five days later.

Sustained response to vasopressin in isolated rat cortical collecting tubule.

The effect of arginine vasopressin (ADH) on water permeability and transepithelial voltage was examined in cortical collecting tubules from a specific pathogen-free line of male Sprague-Dawley rats (75-125 g body weight). Tubules were bathed in a medium resembling serum ultrafiltrate (310 mOsm/kg H2O) at 38 degrees C. Osmotic water permeability (Pf, micron/sec) was determined by the volume flow occurring with a hypo-osmotic perfusate (210-220 mOsm/kg H2O) and diffusional water permeability (Pd, micron/sec) was calculated from the lumen-to-bath flux of tritiated water using an isosmotic perfusate. In the absence of ADH, both Pf and Pd were low, 17 +/- 6 and 9.0 +/- 0.6 (SEM), respectively. ADH added to the bath at concentrations above 0.5 microunits/ml increased Pf, with a maximal response at 40 microunits/ml or greater. With 100 microunits/ml ADH, Pf and Pd were, respectively, 994 +/- 117 and 37.0 +/- 2.4. Without ADH, the transepithelial voltage was variable (range, -5.4 to +2.5 mV; mean, -1.9 +/- 0.4); however, with 100 microU/ml ADH, it hyperpolarized (lumen-negative) by 4.2 +/- 0.8 mV. In contrast to findings in the rabbit, both the hyperpolarization and the increased water permeability persisted for at least 3 hr. The higher water permeabilities are consistent with the shorter length of the cortical collecting tubule in the rat, and may reflect the importance of attaining osmotic equilibration within the cortex during maximal antidiuresis.

Urate uptake in membrane vesicles of rat renal cortex: effect of copper.

[2-14C]Urate uptake was studied in brush border and basolateral membrane vesicles of rat renal cortex. In the absence of copper, urate equilibrated without metabolism of transported urate. Exposure of the vesicles to copper significantly stimulated uptake, and in these vesicles uptake was also stimulated by NaCl or KCl gradients. Allantoin accumulated in these vesicles due to oxidation of transported urate. This oxidation is ascribed to a copper-stimulated, membrane-associated uricase since purified uricase and the membranes had similar Km values, both were inhibited by oxonic acid, and extramembranal uricase was not detected. Oxonic acid and pyrazinoic acid inhibited both uptake and enzyme activity. These findings suggest that urate uptake is carrier mediated and that uricase may play some role in transport. In addition, it appears that a significant loss of copper occurs during isolation of membrane vesicles that profoundly affects the characteristics of urate uptake. Those properties of the membrane that influence urate uptake, however, can be restored by exposure of the membranes to copper.