Spontaneously hypertensive rats (SHR) and nonnotensive Wistar-Kyoto ("WKY") rats are frequently employed in experimental studies of hypertension. Although both SHR and WKY rat strains have been presumed to be fully inbred, recent studies have revealed important biologic variability in WKY rats from different commercial sources. Genealogk evidence suggests that, in the United States, breeding stocks of WKY rats may have been distributed to major commercial suppliers as early as the F10 generation. To test the hypothesis that commercially available WKY rats are genetically heterogeneous, we performed deoxyribonucleic acid (DNA) "fingerprint" analysis on genomic DNA of WKY rats from two of the largest vendors in the United States, Taconic Farms and Charles River Laboratories. We found molecular evidence of genetic variability not only among WKY rats from two different breeding facilities, but also among WKY rats within a single breeding facility (Taconic Farms). Although some studies have suggested the possibility of biologic variability in SHR from different sources, preliminary studies have not revealed molecular evidence of genetic heterogeneity in SHR from these vendors. In demonstrating genetic variability in WKY rats from different sources, the current study provides compelling evidence that rats designated WKY do not constitute an inbred strain. Accordingly, the results of studies in which SHR and WKY rats are compared might vary because of genetic heterogeneity in "the WKY rat control strain." (Hypertension 1989; 13:188-192) T he spontaneously hypertensive rat (SHR), initially bred in Kyoto, Japan, is the most widely studied experimental model of human essential hypertension. 12 Over the past 2 decades, numerous investigators have studied the pathogenesis of spontaneous hypertension by comparing SHR with normotensive Wistar-Kyoto rats (the so-called "WKY" strain) with respect to an enormous variety of physiological and biochemical characteristics. 2 Although both SHR and WKY rat strains have been presumed to be fully inbred, 3 recent studies have revealed important biologic

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The spontaneously hypertensive rat (SHR) exhibits alterations in the renin-angiotensin-aldosterone system which are similar to those that characterize patients with "nonmodulating" hypertension, a common and highly heritable form of essential hypertension. Accordingly, we determined whether the inheritance of a DNA restriction fragment length polymorphism (RFLP) marking the renin gene of the SHR was associated with greater blood pressure than inheritance of a RFLP marking the renin gene of a normotensive control rat. In an F2 population derived from inbred SHR and inbred normotensive Lewis rats, we found the blood pressure in rats that inherited a single SHR renin allele to be significantly greater than that in rats that inherited only the Lewis renin allele. To the extent that the SHR provides a suitable model of "nonmodulating" hypertension, these findings raise the possibility that a structural alteration in the renin gene, or a closely linked gene, may be a pathogenetic determinant of increased blood pressure in one of the most common forms of essential hypertension in humans. (J. Clin. Invest. 1990Invest. . 85:1328Invest. -1332 hypertension.

A comparison of intravenous to intracarotid artery (ICA) administration of 14C-BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) was made in squirrel monkeys. Radioactivity was measured as soluble drug products and as RNA-, DNA-, and protein-bound radioactivity. The ICA administration of BCNU achieved 190% to 280% higher brain nucleic acid-bound drug levels than use of the intravenous route in the infused hemisphere and 130% to 280% higher levels than in the noninfused hemisphere. In addition, some brain regions directly subserved by the middle cerebral artery had bound drug levels four- to fivefold greater than those found in regions of noninfused brain. The data suggest that a need for BCNU dose reduction due to myelotoxicity may be an indication for ICA therapy in selected brain-tumour cases.

MATERIALS AND METHODSutero, fetal bilirubin is cleared by the placenta. At birth the neonatal liver must assume detoxification and elimination of bilirubin. The mechanisms responsible for development of bilirubin conjugation after birth are poorly understood. Evidence for substrate-dependent stimulation of bilirubin conjugation in heterozygous newborn Gunn rats has been reported by Thaler (8) but studies of bilirubin conjugation in human neonates have not been performed due to unavailability of adequate methods. The gestation age at which the capacity for bilirubin conjugation is acquired and the types of conjugates initially formed are unknown. A highly specific and sensitive method for the measurement of unconjugated bilirubin and bilirubin mono-and diester conjugates in biologic fluids has been developed in our laboratory (9, 10). By utilizing this procedure, we investigated the appearance of bilirubin conjugates in serum of human neonates during the period of physiologic jaundice.Collection of serum specimens. Forty-three serial serum samples obtained in the course of routine laboratory evaluation from 13 premature infants (six male, seven female) of 25-36 wk gestational age were compared with 25 samples from 11 fullterm newborns (six male, five female) of 37-41 wk gestational age during the first 3 days oflife. Birth weights for the premature infant group ranged from 590-3000 g while full-term infant's birth weights ranged between 2500-3900 g. Infants with evidence of hemolysis or liver disease were excluded from the study.For comparison, serum samples from 22 healthy adults, seven pregnant women at term and their corresponding infant's cord blood at delivery, 46 cord blood specimens obtained at unselected deliveries, and five cord blood specimens from neonates with intrauterine hyperbilirubinemia due to blood group incompatibility or hypoxia also were examined.All specimens were protected from light in containers wrapped in aluminum foil, and were assayed immediately or after storage in the light-shielded containers at -12°C for less than I wk.Analytical methods. All procedures were performed in dim light. The AM-HPLC method for analysis of serum bilirubins has been previously described (9, 10). About 60 mg of sodium ascorbate, 2-3 mg of disodium ethylene diamine tetraacetate, 4 ml of methanol, and 2 ml of methanol containing the internal standard xanthobilirubic acid methyl ester were mixed with 0.6 ml of serum. The mixture was treated with 6 ml of 2% (w/v) KOH in methanol and immediately vortex-mixed. After reaction for 60-90 s at 20-25°C, 6 ml of chloroform and 12 ml of g1ycine/ HCI buffer (004 M HCI brought to pH 204 with solid glycine) were added sequentially. Organic and aqueous phases were separated by brief centrifugation, the organic phase was transferred to a dry tube, and the extract evaporated to dryness under nitrogen at 30°C. The residue was stored under argon at -12°C and analyzed within I wk. 947 Abbreviation AM-HPLC, alkaline methanolysis-high-performance liquid chromatography ABSTRACf. Bi...