Denervation of the kidney of SHR aged 6 weeks of age altered the pressure-GFR but not the pressure-flow relationship for these rats 4 weeks later. The results are compatible with there having been an increase in average preglomerular and a decrease in post-glomerular vessel lumen diameters. These changes suggest that the renal nerves affect the structural development of the renal vasculature in SHR.

Abstract-In 10-to 12-week-old Dahl salt-sensitive (DS) and salt-resistant (DR) rats fed a 0.3% salt diet (nϭ10 in each group), flow-pressure and pressure-glomerular filtration rate (F-P and P-GFR, respectively) relationships were established for maximally vasodilated perfused kidneys. From these relationships, 3 indices of vascular structural properties were estimated: slope of F-P (minimal renal vascular resistance reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of P-GFR (glomerular filtration capability against pressure), and threshold pressure for beginning filtration at P-GFR (preglomerular-to-postglomerular vascular resistance ratio). Thereafter, maximal renal vascular resistance was determined to assess wall-to-lumen ratios of the resistance vessels in half of each group. In the remainder, the kidneys were perfusion-fixed for histological analysis. Mean arterial pressure did not differ between the DS and DR rats. There were no significant differences in the slopes of F-P between the 2 groups. In contrast, the slope of P-GFR was significantly lower (33%) in DS rats than in DR rats, although the DS kidneys began filtering at a threshold pressure similar to that of the DR kidneys. Thus, in DS rats, there were no abnormalities in luminal dimensions at preglomerular and postglomerular vascular segments, but the kidney filtration capacity decreased at any given increase in pressure. Maximal vascular resistance was greater in DS than in DR rats, a finding compatible with the histological appearance, which showed vascular hypertrophy with little, if any, vascular narrowing in the interlobular arteries of DS rats. In conclusion, hypertrophic remodeling without vascular narrowing at preglomerular resistance vessels and structural defects in filtering at the glomeruli could occur in prehypertensive DS rats. (Hypertension. 2000;36:68-72.)Key Words: renal artery Ⅲ rats, Dahl Ⅲ kidney Ⅲ remodeling Ⅲ hypertension, sodium-dependent O n the basis of intrarenal hemodynamic data in various hypertensive animal models, it is recognized that in models of salt-induced hypertension, including Dahl saltsensitive (DS) rats and deoxycorticosterone-salt rats, intraglomerular pressure is elevated compared with models of spontaneous (ie, non-salt-induced) hypertension, such as the spontaneously hypertensive rat(s) (SHR). 1-6 Because intraglomerular hypertension plays an important role in the genesis of glomerular injuries, 7 it might be responsible for the early onset and rapid progression of hypertensive renal damages that are found in association with salt-induced hypertension in animals and humans. 8 -13 Accordingly, from the viewpoint of cardiovascular protection, it is clinically important to elucidate the precise mechanisms causing intraglomerular hypertension in salt-induced hypertension.In hypertension, it is well known that resistance vessels become thicker or encroach into the lumen (ie, vascular hypertrophy or vascular remodeling) in the kidneys as well as in other vascular beds...

To determine whether platelet response to mental stress is altered in essential hypertension, platelet aggregability and plasma beta-thromboglobulin were determined in 24 patients with essential hypertension (11 patients with World Health Organization (WHO) stage I and 13 patients with stage II) and 14 normotensive controls before and after a 10-min arithmetic stress (serial subtraction of 7 from 1000). In normotensive subjects, arithmetic stress did not affect primary aggregations to 1.0 micromol/L adenosine diphosphate (ADP) and to 2.5 micromol/L 5-hydroxytryptamine (5-HT), ADP threshold for biphasic aggregation and plasma beta-thromboglobulin level. In hypertensive patients with WHO stage I, these parameters were similar to those in normotensives before arithmetic stress, but the arithmetic stress test significantly increased primary aggregation to reagents and beta-thromboglobulin level, and decreased threshold of ADP for biphasic aggregation. In WHO stage II patients, platelet aggregability to reagents and beta-thromboglobulin level were already enhanced as compared with WHO stage I patients and normotensive subjects before arithmetic stress. However, the stress-induced changes in platelet function were less pronounced in WHO stage II patients compared with stage I patients. In conclusion, platelet aggregability and proaggregatory effect of mental stress differed depending on the severity of hypertension in patients with essential hypertension; the transient activation of platelet function during stress with no enhancement under the resting condition in the early phase of hypertension and the continuous activation of platelet function in the advanced phase with hypertensive organ damage.

To investigate effects of a reduction in nephron numberson renal structural properties in hypertension, either unilateral nephrectomy (UNX) or sham operation (SO) was performed at 5 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats ( n = 9 for each operation for each strain).2. At 10-12 weeks of age, flow-pressure (F-P) and pressureglomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. Kidneys were then perfusion fixed for histological analysis.3. In the SO groups, the slope of F-P (minimal renal vascular resistance, reflecting overall luminal dimensions of pre-and post-glomerular vasculature) was greater in SHR than in WKY rats. The threshold pressure for beginning filtration at P-GFR (preglomerular to post-glomerular vascular resistance ratio) was higher in SHR than in WKY rats, but the slope of P-GFR (glomerular filtration capacity) did not differ between the two strains. These results suggest that vascular narrowing occurred, especially in the preglomerular resistance vessels in the kidneys of SHR, although glomerular filtration capacity was normal.4. In UNX animals, the following results were obtained: (i) the slope of F-P was not affected in either strain; (ii) the pressure for beginning filtration at P-GFR was unchanged in WKY rats, but was decreased in SHR; (iii) the slope of P-GFR increased in WKY rats, but a compensatory adaptive increase was missing in SHR; and (iv) histologically, small increases in the luminal cross-sectional area of interlobular arteries and glomerular tuft area were observed in both strains. However, the increase in vascular lumen was more pronounced in SHR, whereas glomerular enlargement was greater in WKY rats. 5. These results suggested that UNX attenuates vascular narrowing of the preglomerular resistance vessels and glomerular structural adaptations to UNX (i.e. increased filtering capacity and glomerular enlargement) are impaired in SHR.

1 The role of the metalloendopeptidase EC 3.4.24.15 (EP 24.15) in peptide metabolism in vivo is unknown, in part reflecting the lack of a stable enzyme inhibitor. The most commonly used inhibitor, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB, K,= 16 nM), although selective in vitro, is rapidly degraded in the circulation to cFP-Ala-Ala, an angiotensin converting enzyme (ACE) inhibitor. This metabolite is thought to be generated by neutral endopeptidase (NEP; EC 3.4.24.11), as the Ala-Tyr bond of cFP-AAY-pAB is cleaved by NEP in vitro. In the present study, we have examined the role of NEP in the metabolism of cFP-AAY-pAB in vivo, and have tested a series of inhibitor analogues, substituted at the second alanine, for both potency and stability relative to the parent compound. ACE. Injection of 1 mg kg-' inhibitor resulted in plasma concentrations at 10 s of 23.5 ,uM (cFP-AAYpAB) and 18.0 giM (cFP-AVY-pAB), which fell 100 fold over 5 min. Co-injection of 1251I-labelled inhibitor revealed that 80-85% of the radioactivity had disappeared from the circulation within 5 min, and h.p.l.c. analysis demonstrated that only 25-30% of the radiolabel remained as intact inhibitor at this time. Both analogues were cleared from the circulation at the same rate, and both inhibitors blunted the pressor response to angiotensin I, indicative of ACE inhibition. 4 These results suggest that both NEP and other clearance/degradation mechanisms severely limit the usefulness of peptide-based inhibitors such as cFP-AAY-pAB. To examine further EP 24.15 function in vivo, more stable inhibitors, preferably non-peptide, must be developed, for which these peptide-based inhibitors may serve as useful molecular templates.