Regional blood flow measurements made by the radioactive microsphere technique were studied in conscious rats. A femoral arterial reference sample blood flow was measured directly, and at the same time indirectly by the combined use of direct Fick cardiac output and microsphere techniques. A significant correlation (r = .81, P less than .01) was obtained between direct and indirect blood flow values when 200--400 microspheres were trapped in the reference sample. When 100--200 microspheres were trapped, regional blood flow was 32% below true flow (P less than .01); and cardiac output, calculated by the reference sample method, was 57% greater than Fick cardiac output (P less than .01). When three consecutive Fick determinations and microsphere injections (20,000 per injection, 15 micrometer diam) were made in conscious rats, significant correlations were obtained among the first, second, and third regional blood flow measurements (r = .95, P less than .01). The results have demonstrated that cardiac output and reference blood flow can be measured with accuracy and precision in the conscious rat by the radioactive microsphere procedure.

No abstract

No abstract

No abstract

Body fluid volumes were examined in young spontaneously hypertensive rats (SHR) and in two strains of age-matched normotensive controls to ascertain whether expanded plasma volume (PV) or extracellular fluid volume (ECFV) was associated with onset of spontaneous hypertension. Mean arterial pressure (MAP) was measured in conscious male SHR, Wistar-Kyoto normotensive (WKY), and American Wistar normotensive (NR) rats 3 h after arterial cannulation. At age 10-14 days no differences in MAP or PV (determine with 125I-albumin) were found between SHR and WKY. At age 18-43 days, SHR had elevated MAP and a small but significant elevation in total body water volume (TBWV; wet weight minus dry weight) compared to WKY and NR; no differences among the three groups were found in PV or ECFV (estimated with inulin). These results provide no evidence that expanded PV or ECFV plays a role in the pathogenic mechanisms of spontaneous hypertension, but do not exclude the possibility of altered vascular compliance. The slightly elevated TBWV in SHR may be related to reduced body fat in SHR.

Influenza neuraminidase (NA) plays an important role in viral replication, and characterization of viruses resistant to NA inhibitors will help elucidate the role of active-site residues. This information will assist in designing better inhibitors targeted to essential active-site residues that cannot generate drug-resistant mutations. In the present study we used the benzoic acid-based inhibitor BCX-140 to select and characterize resistant viruses. BCX-140 binds to the NA active site in an orientation that is opposite that of a sialic acidbased compound, 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (GANA). Thus, the guanidino group of BCX-140 binds to Glu-276, whereas in GANA the guanidino group binds to Glu-119. We passaged influenza A/Singapore/1/57 (H2N2) in Madin-Darby canine kidney cells in the presence of BCX-140, and virus resistant to this inhibitor was selected after six passages. The NA of this mutant was still sensitive to inhibition by BCX-140. However, the mutant virus was resistant to BCX-140 in plaque and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Sequence analysis of hemagglutinin (HA) and NA genes revealed changes in both, although none were in the active site of the NA. Depending on the method of selection of the resistant virus, two types of changes associated with the sialic acid binding site were seen in the HA. One is a change in HA1 of Ala-133 to Thr, a residue close to the binding site, while the other change was Arg-132 of HA1 to Gln, which in HA1 of serotype H3 is a sialic acid contact (Asn-137). Binding studies revealed that both types of resistant viruses had reduced receptor binding affinity compared to that of the wild type. Thus, resistance to BCX-140 was generated by modifying the HA. NA active-site residue 276 may be essential for activity, and thus, it cannot be changed to generate resistance. However, drug-induced changes in the HA can result in a virus that is less dependent on NA activity for growth in cells and, hence, resistant to NA inhibitors.

No abstract

The results of this study demonstrate that the spontaneously hypertensive rat is sensitive to salt excess. The hypertensinogenic effect of salt was mediated through elevation of peripheral vascular resistance. The addition of DOCA aggravated the hypertension, mainly be elevating the cardiac output without appreciably decreasing peripheral vascular resistance. SHR'S EXPOSED TO 1% NaCl consumed more fluids and excreted more sodium and urine than control rats. Those exposed to 1% NaCl and DOCA had higher fluid consumptions and excreted more sodium than the other two groups. These effects of sodium in a neurogenic strain of hypertensive rats suggest a possible interplay between the neurogenic and salt-dependent components in the development and maintenance of hypertension. They also suggest that SHRs, like other hypertensive rat models, are salt sensitive.