We have examined the effects of endothelin (ET) on the renal microcirculation by in vivo microscopy using the model of the split hydronephrotic rat kidney. ET, a potent vasoconstrictor peptide synthesized by vascular endothehal cells, showed marked and long-lasting effects on glomerular blood flow and vessel diameters in various segments of the renal vascular bed. Intravenously applied ET (100 ng/min/kg) increased systemic blood pressure from 123 ± 7 to 156 ± 4 mm Hg, decreased glomerular blood flow by 70%, and preferentially constricted larger preglomerular vessels, e.g. the arcuate artery. The competitive leukotriene antagonist FPL55712 significantly attenuated the vascoconstrictor response of the larger vessels. Local ET adminstration decreased glomerular blood flow in a dose-dependent manner (50% reduction at a concentration of 2.6 ± 0.7 · 10^-9M) and constricted smaller vessel segments, e.g. the afferent and efferent arterioles near the glomerulus. The constriction induced by ET was not significantly affected by the Ca²⁺ channel blocker nitrendipine (2.8 · 10^-6 to 1.1 · 10^-5M). We conclude that intravenous ET effects are probably mediated by leukotrienes, inducing constriction of larger renal vessels. Locally administered ET acts directly on the renal vasculature, especially on smaller vessels.

SUMMARY1. The renovascular effects of neuropeptide-Y (NPY) were examined in the split hydronephrotic rat kidney.2. Systemic infusion of low non-pressor doses of NPY (0-2 #g kg-' up to 5.0 jug kg-') produced a non-uniform pattern of vascular reactivity. In general, a significant constriction of the proximal and distal arcuate artery was seen at all doses. No constriction was seen at the interlobular artery or the larger part of the afferent arteriole. These segments initially dilated during the lower dose infusions. The very distal part of the afferent arteriole adjacent to the glomerulus and the proximal efferent arteriole responded in a similar way to the arcuate arteries.3. NPY, locally applied into the tissue bath at concentrations of 1 nmol 1-1 up to 25 nmol 1-1, produced non-uniform vascular reactions similar to those ofintravenously infused NPY. At the considerably higher local dosage of 1 14 ,umol I`, all vascular segments revealed vasoconstriction.4. NPY application did not attenuate effects of acetylcholine. This observation suggests that the mechanism of NPY-induced vasoconstriction does not rely upon antagonism of endothelium-derived vasodilatation.5. The pattern of vascular reactivity to NPY was substantially different from that known for the vasoconstrictors noradrenaline and angiotensin II in our preparation.

The technique of the split hydronephrotic kidney of anesthetized Wistar rats was used for the first time to study afferent and efferent arterioles of juxtamedullary (JM) glomeruli in vivo and to compare their behavior with that of the cortical glomeruli in female (F, 270 g body wt) and male (M, 400 g body wt) rats. The mean length of cortical efferent arterioles (F, 260; M, 380 microns) was less than 10% the length of JM efferent arterioles. Luminal diameters of the JM afferent arteriole (F, 17.1; M, 18.3 microns) and efferent arteriole (F, 25; M, 33.4 microns) were much larger than those of cortical arterioles (afferent: F, 9.1, M, 10.5 microns; efferent: F and M, 11.1 microns). In the hydronephrotic kidney, cortical glomerular blood flow (F, 17.5; M, 18.3 nl/min) is much reduced compared with the normal filtering kidney. This, however, is not true of JM glomerular blood flow (F, 120; M, 262 nl/min). During the reduction of renal perfusion pressure in females blood flow was autoregulated in cortical glomeruli within the pressure range of 110 to 80 mmHg; JM glomeruli failed to show any autoregulation. In males the glomerular blood flow was similarly autoregulated down to 90 mmHg in both cortical and JM nephrons. Local application of indomethacin to the kidneys from female rats reduced the glomerular flow rates by 30% but changed the autoregulatory behavior of cortical and JM glomerular blood flow so that it resembled that observed in untreated males. The data suggest that in females the autoregulatory response, particularly in JM glomeruli, is modified by prostaglandins.

Besides its beneficial effects in organ transplantation cyclosporin (CyA) exhibits nephrotoxic (and other) side effects. CyA nephrotoxicity is associated with a decrease in glomerular filtration rate. Two mechanisms of action have emerged. First, tubular destruction with secondary reduction in renal blood flow and glomerular filtration rate; second, decrease in renal blood flow with secondary interstitial fibrosis. We studied the effect of an acute infusion of CyA in the hydronephrotic rat kidney model, which lacks tubular structures completely. Hence, only the direct vascular effects of CyA were determined. Five groups (G) of rats were studied by television microscopy. G I (n = 7) received CyA (30 mg/kg, i.v.) dissolved in cremophore/plasma; G II (n = 5), time control 1, received cremophore/plasma instead of CyA; G III (n = 8), received CyA 30 mg/kg followed by 20 mg/kg CyA i.v. dissolved in an ethanol/tween solution; G IV (n = 3), time control 2 received ethanol/tween alone in the experimental period; in G V, CyA was applied locally onto the surface of the kidney with concentrations increasing from 10(-7) to 10(-5) M. CyA caused profound reduction in the diameter of arcuate arteries in groups I and III, in contrast to the time control groups II and IV. The vasoconstriction could be partially reversed by the calcium-channel blocker nitrendipine, and completely reversed with acetyl-choline. Glomerular blood flow decreased due to CyA and could not be completely normalized by either drug. Increasing the dosage from 30 to 50 mg/kg was not associated with further reduction in blood flow. Local application of CyA (G V) did not demonstrate vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

We microscopically examined the narrow segment of the efferent arteriole (NSEA) in the hydronephrotic kidney of rats in vivo. This segment is routinely found at the proximal efferent arteriole adjacent to the glomerulus and is characterized by a narrowing due to a cellular structure which bulges into the lumen. The existence of NSEA has been described in a previous study from our laboratory, but it was not examined in detail; its functional behavior in particular is still unknown. In the present study, we measured changes in luminal diameter of NSEA during reduction of renal perfusion pressure and in response to angiotensin II (Ang II), saralasin, and nitroprusside. The mean luminal diameter of NSEA at its narrowest point was 5.1 microns and its effective length was 8.4 microns. Reduction of renal perfusion pressure from 115 to 90, 70, and 40 mm Hg decreased NSEA diameter by 9, 15, and 23%, respectively. Topical application of saralasin (10(-5) M) or nitroprusside (10(-4) M) to the kidney dilated NSEA by 10 or 20%, respectively, and attenuated the pressure-dependent constriction of NSEA. Intravenous infusion of Ang II at rates of 50, 100, 200, and 400 ng/min/kg constricted NSEA lumen by 7, 15, 20, and 21%, respectively. The vascular bed of the hydronephrotic kidney was scanned morphologically, and a mathematical model was developed from these data. With this model, we could calculate the effect of segmental diameter changes on total renal resistance as well as flow and pressure at different vascular levels. NSEA contributed 4% to the total renal resistance and 20% to the efferent resistance under control conditions. Lowering of renal perfusion pressure increased the efferent arteriolar resistance up to 50% above the control value mainly as a result of constriction of NSEA. Our data indicate that efferent resistance increases at reduced renal perfusion pressure and leads to a stabilization of glomerular pressure. The rise of efferent resistance is mediated primarily by NSEA constriction, and the renin-angiotensin system is involved in this regulation.