Max C. Reif

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.

Effects of candesartan cilexetil in patients with severe systemic hypertension

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.

Genetic Markers at the Leptin (OB) Locus Are Not Significantly Linked to Hypertension in African Americans

Increased body mass index (BMI) has been correlated with increased blood pressure in human populations. To examine the role of the leptin gene (OB) in essential hypertension in African Americans, we performed affected sib pair analysis on a set of 103 hypertensive African American sibships using four highly polymorphic markers at the human leptin locus. No evidence of linkage was detected between these markers and the phenotype of essential hypertension either in these sibships or in a severely obese subset of 46 sibships in which each sibling had a BMI > or = 85th percentile for the US population. Using BMI rather than hypertension as a quantitative trait, we found significant linkage for the marker D7S504 (P=0.029) but not for the other markers. Significance strengthened in the overweight subset of sibships for this marker (P=0.001), and there was a trend of lower P values for the other three markers. However, multipoint analysis with the use of all four markers simultaneously to estimate linkage between BMI and the leptin locus did not demonstrate a statistically significant relationship. Analysis of the coding region of the leptin gene (exons 2 and 3) by single-strand conformational polymorphism revealed a rare Ile-Val polymorphism at amino acid 45 but revealed no other alterations. These results suggest that the OB gene is not a major contributor to the phenotype of essential hypertension in African Americans, although a minor contribution to the phenotype of extreme obesity in this group cannot be ruled out.

Antihypertensive Efficacy of Candesartan in Comparison to Losartan: The CLAIM Study

An 8‐week, multicenter, double‐blind, randomized, parallel‐group, forced‐titration study was conducted to evaluate the antihypertensive efficacy of candesartan vs. losartan in 654 hypertensive patients with a diastolic blood pressure between 95 and 114 mm Hg from 72 sites throughout the U.S. Eligible patients were randomized to candesartan cilexetil 16 mg once daily, or losartan 50 mg once daily. Two weeks following randomization, patients doubled the respective doses of their angiotensin receptor blockers for an additional 6 weeks. At week 8, candesartan cilexetil lowered trough systolic/diastolic blood pressure by a significantly greater amount than did losartan (13.3/10.9 mm Hg with candesartan cilexetil vs. 9.8/8.7 mm Hg with losartan; p< 0.001). At the same period, candesartan cilexetil also lowered peak blood pressure by a significantly greater amount than did losartan (15.2 to 11.6 mm Hg with candesartan cilexetil vs. 12.6 to 10.1 mm Hg with losartan; p< 0.05). There were statistically significantly (p< 0.05) higher proportions of responders and controlled patients in the candesartan cilexetil group (62.4% and 56.0%, respectively) than in the losartan group (54.0% and 46.9%, respectively). Both treatment regimens were well tolerated; 1.8% in the candesartan cilexetil group and 1.6% in the losartan group withdrew because of adverse events. In conclusion, this forced‐titration study confirms that candesartan cilexetil is more effective than losartan in lowering blood pressure when both are administered once daily at maximum doses. Both drugs were well tolerated.

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.

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 patients 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.

Molecular physiology of urinary concentration defect in elderly population

It is estimated that by the year 2050 one in five Americans will be 65 years or older. This mandates the growing need for clinical and basic research in the field of geriatric medicine to understand age-related maladies. The most prominent abnormality in renal function in the aging population is the inability to handle water, frequently resulting in hypo- or hyperosmolar states, and the associated electrolyte imbalances. During the past decade, thanks to the advent of powerful molecular techniques, rapid strides have been made in the approaches employed to understand and dissect the physiology of renal function in general and the urinary concentration mechanism in particular. Using an integrated approach of clinical observations, experimental model systems, molecular analysis, and functional genomics, a more comprehensive picture of the interplay of physiological systems in the genesis of urinary concentration defect in the elderly is beginning to emerge. Much remains to be deciphered regarding the complex interactions between the role of environment, genetics, diet, pharmacological agents and the general effects of aging on kidney function. The emerging importance of socio-economic and quality of life issues surrounding geriatric medicine encourage public and private support and funding for research in the area of age-related diseases, especially as they are related to the kidney.