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Angiotensin-converting enzyme inhibitors are renoprotective in diabetes mellitus through their intrarenal hemodynamic effects. Alpha-1 blockade has variable pre- and postglomerular vasodilatory effects dependent upon the stimulation of the sympathetic nervous system. We tested the hypothesis that the two different classes of drugs have similar renal hemodynamic effects when the patients are examined in an upright position where the sympathetic nervous system is activated. Mean blood pressure (MAP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined in 28 hypertensive type-1 diabetic patients with variable degree of nephropathy treated for a mean period of 7.6 +/- 0.4 months with captopril (n = 13) or doxazosin (n = 15). Average treatment doses were 112 +/- 7 mg/day in the captopril group and 8 +/- 1 mg/day in the doxazosin group. Sitting MAP decreased from 118 +/- 3 to 106 +/- 4 mm Hg after captopril (p < 0.05), and from 117 +/- 4 to 110 +/- 3 mm Hg after doxazosin (p = 0.07). GFR and ERPF were unchanged in both groups. The filtration fraction (FF) decreased from 0.27 +/- 0.02 to 0.25 +/- 0.02 after captopril (p < 0.05) and from 0.26 +/- 0.01 to 0.25 +/- 0.01 after doxazosin (p = 0.08). Calculation of 95% confidence intervals of the difference between the post-treatment values as well as the difference between pre- and post-treatment values of MAP, GFR, ERPF and FF of the two drugs indicates no difference in renal hemodynamic response between the drugs. In conclusion, captopril and doxazosin have similar renal hemodynamic responses when the patients are examined in a situation where the sympathetic nervous system is stimulated, and this suggests that doxazosin has a renoprotective effect beyond the blood pressure-lowering effect.

Background/aims: To gain insight into the effect of arginine vasopressin (AVP) on renal hemodynamics in hypertensive rats, we investigated the vasoconstrictive response to AVP on total renal blood flow (RBF) and total and zonal glomerular filtration rate (GFR) in young and old spontaneously hypertensive rats (SHR). A hypothesis of increased AVP sensitivity in the juxtamedullary cortex of SHR was tested., Methods: Total RBF and total and zonal GFR were studied in 10- and 40-week-old SHR and normotensive Wistar-Kyoto rats (WKY). RBF was recorded by a flowmeter before infusion of AVP and immediately after injection of a bolus dose of 10 ng AVP. Whole kidney GFR and its intracortical distribution was measured by the tubular uptake of 125I- and 131I-labelled aprotinin before and during a continuous infusion of AVP 5 ng/min. Ligand binding measurements of preglomerular V1a receptors were performed in young and old rats., Results: RBF decreased by 43 +/- 3% in 10-week SHR (9.2 +/- 0.5 vs. 5.2 +/- 0.3 ml x min(-1) x g(-1)), significantly more than 10-week WKY where RBF decreased by 35 +/- 3% (9.6 +/- 0.7 vs. 6.5 +/- 0.5 ml x min(-1) x g(-1)) (p < 0.05). The effect of AVP on RBF was attenuated in 40-week-old rats where the decline in RBF was 29 +/- 5% in SHR and 23 +/- 4% in WKY (p > 0.05). GFR decreased by 6 +/- 3% (1.03 +/- 0.04 vs. 0.96 +/- 0.04 ml x min(-1) x g(-1), p < 0.05) in 10-week SHR and was unchanged in 10-week WKY (1.10 +/- 0.07 vs. 1.08 +/- 0.04 ml x min(-1) x g(-1), p > 0.10). GFR decreased by 11 +/- 10% in 40-week SHR and by 4 +/- 4% in 40-week WKY (p > 0.05). AVP infusion significantly increased filtration fraction in all groups except 40-week SHR, indicating that AVP has the strongest vasoconstrictive effect on postglomerular vessels. The intrarenal distribution of GFR was unchanged in the normotensive and hypertensive groups. V1a receptor density was upregulated in young SHR compared to young WKY (p < 0.05), but downregulated in old compared to young SHR (p = 0.05)., Conclusion: The results indicate that AVP sensitivity is not increased in the juxtamedullary cortex in SHR and the reduced vasoconstrictive effect in old SHR is due to a reduced density of V1a receptors., (Copyright 2001 S. Karger AG, Basel)

Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) is well maintained in the spontaneously hypertensive rat (SHR). In old SHR, the RBF autoregulation is dependent upon prostaglandins as well as the sympathetic nervous system. The purpose of this study was to examine the role of nitric oxide (NO) in the autoregulation of RBF and GFR in aging SHR (70 weeks) as compared with young SHR (10 weeks) and age-matched Wistar-Kyoto (WKY) rats using NO synthase (NOS) inhibition that has a minimal effect on the RBF. The autoregulation of RBF was examined using an adjustable aortic clamp above the renal arteries and an ultrasound Doppler flow probe on the left renal artery. The lower pressure limit of RBF autoregulation was examined before and after infusion of the NOS inhibitor N(G)-monometyl-L-arginine (L-NMMA; 500 microg. kg(-1).min(-1)). Separate groups were given a coinfusion of L-NMMA and L-arginine (5 mg.kg(-1).min(-1)) or Ringer solution. The autoregulation of the GFR was studied in continuously infused animals using the (125)I-iothalamate clearance. Measurements of the GFR were done at control blood pressure, at a renal arterial pressure 10 mmHg above the lower pressure limit of RBF autoregulation and at a renal arterial pressure of about 60-65 mmHg. In both SHR and WKY rats, infusion of L-NMMA increased the mean arterial blood pressure, and the RBF decreased in young SHR, while the RBF was unchanged in the WKY groups and aged SHR. The autoregulation of RBF was maintained in all animals. The GFR was unchanged in all groups after infusion of L-NMMA, and the autoregulation of GFR was well maintained in all groups except in the 70-week-old SHR. In these animals, the fractional compensation of GFR decreased from 0.95 to approximately 0 after infusion of L-NMMA, indicating that autoregulation of the GFR was lost during NOS inhibition. Coinfusion of L-NMMA and L-arginine normalized the GFR autoregulation in this group. The results indicate that in hypertensive rats with renal hypertensive damage, the GFR autoregulation is strongly NO dependent, as doses of L-NMMA that do not interfere with the RBF have an effect on the GFR autoregulation. As the GFR was unchanged during L-NMMA infusion, these observations suggest that postglomerular contraction during NOS inhibition may be involved in the regulation of GFR in 70-week-old SHR.

This study was designed to assess the renal capability to autoregulate total blood flow, glomerular filtration rate (GFR) and local GFR in outer, middle and inner cortical layers (OC, MC, IC) in the two-kidney, one-clip (2K-1C) renovascular hypertensive rat, with or without acute infusion of the angiotensin II receptor antagonist losartan (5 mg/kg, i.v.). Age-matched, sham-operated Wistar rats were used as controls. The hemodynamic study in all animals was performed 4 weeks after clipping. The clipping increased blood pressure significantly, whereas losartan reduced the renal arterial pressure (RAP) from 165+/-8 to 125+/-6 mm Hg (p < 0.01) in 2K-1C hypertensive rats and reduced the RAP from 107+/-2 to 101+/-1 mm Hg (p < 0.05) in normotensive animals. Renal blood flow (RBF), total and local GFR were decreased in the nonclipped kidney of 2K-1C hypertensive rats compared with sham-operated rats, but losartan significantly increased the RBF and GFR. RBF was well maintained in response to reduction in RAP in the nonclipped kidneys with and without losartan treatment. The capability of total GFR autoregulation was impaired in untreated 2K-1C hypertensive rats and losartan-treated sham-operated rats, whereas losartan completely abolished GFR autoregulation in the nonclipped kidney of 2K-1C hypertensive rats. Losartan impaired autoregulation of zonal GFR to the same extent in all three cortical layers of sham-operated rats, whereas in the nonclipped kidney of 2K-1C hypertensive rats losartan had a more pronounced effect on the superficial GFR autoregulation than in middle and inner cortex, indicating that angiotensin II plays a major role in regulating the GFR response to the acute changes of renal arterial pressure.

In this study we tested the hypothesis that mesangial cells participate in autoregulation of the glomerular filtration rate (GFR) in normotensive and hypertensive rats. Mesangial cell lesions were induced by intravenous administration of antithymocyte (anti-Thy 1.1) antibodies in spontaneously hypertensive rats (SHR) and in Wistar-Kyoto rats (WKY). Normal murine serum was injected in control rats. Hemodynamic measurements were performed 24 h after the infusion of the anti-Thy 1.1 antibodies. Renal blood flow (RBF) was measured by a transit time flowmeter (Transonic) and the GFR was measured as the uptake of 125 iodine-labeled aprotinin ([125]I-Ap) by proximal tubular cells at the control renal arterial pressure and (131)I-Ap at a pressure reduction close to the lower pressure limit of RBF autoregulation. RBF was unaltered and the autoregulatory capability was maintained in SHR and WKY after mesangial cell lesions. Mesangiolysis significantly reduced the total GFR in normotensive, but not in hypertensive animals. The fractional compensation of the GFR was attenuated in the outer cortical layer (p<0.05) in normotensive WKY. In SHRs the fractional compensation of the GFR was impaired in all cortical layers after mesangiolysis, slightly more in the outer than in the inner cortex. We conclude that mesangial cells may contribute to the autoregulation of GFR in hypertensive rats, but to a lesser extent in normotensive rats.