Kate M. Denton

Differential neural control of glomerular ultrafiltration

1.u2002The renal nerves constrict the renal vasculature, causing decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Whether renal haemodynamics are influenced by changes in renal nerve activity within the physiological range is a matter of debate.

Renovascular Hypertension: Structural Changes in the Renal Vasculature

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.

Role of angiotensin II in renal wrap hypertension.

The role of angiotensin II in the development of renal wrap hypertension was studied in rabbits that underwent either bilateral renal cellophane wrap or sham operation. In half the rabbits, angiotensin II production was blocked by continuous administration of enalapril. Four weeks after renal wrapping, mean arterial pressure had risen by 48 +/- 5 mm Hg in untreated rabbits, but by only 25 +/- 4 mm Hg in enalapril-treated rabbits (p less than 0.01). Similar differences were also measured 6 weeks after wrapping. In untreated rabbits, plasma renin activity had increased fourfold 4 and 6 weeks after renal wrapping. There were no significant changes in blood pressure or plasma renin activity following sham operation. Compared with that in sham-operated rabbits, renal blood flow was reduced by 60% in the untreated rabbits 4 weeks after wrapping but by only 30% in the enalapril-treated wrapped rabbits (p less than 0.05). Renal vascular resistances were 5.5 +/- 1.7 mm Hg . ml-1 . min-1 and 1.2 +/- 0.1 mm Hg . min . ml-1 in the untreated wrapped and sham-operated rabbits respectively and 1.9 +/- 0.4 mm Hg . min . ml-1 and 0.8 +/- 1 mm Hg . min . ml-1 in the enalapril-treated wrapped and sham-operated rabbits. Renal wrapping did not alter filtration fraction in untreated rabbits, but markedly reduced it in enalapril-treated rabbits. These results suggest that angiotensin II had two major effects in rabbits after bilateral renal wrapping: it contributed substantially to the increase in blood pressure and caused renal vasoconstriction, primarily at a postglomerular site.

Neural control of renal medullary perfusion.

1.u2002There is strong evidence that the renal medullary circulation plays a key role in long‐term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF).

EFFECT OF ENDOTHELIN‐1 ON REGIONAL KIDNEY BLOOD FLOW AND RENAL ARTERIOLE CALIBRE IN RABBITS

1.u2002Medullary blood flow (MBF) is important in the long‐term control of arterial pressure. However, it is unclear which vascular elements regulate MBF.

Intrarenal haemodynamic and glomerular responses to inhibition of nitric oxide formation in rabbits.

1. The renal effects of inhibiting nitric oxide (NO) formation using N‐nitro‐L‐arginine (NOLA, 20 mg kg‐1) were examined using micropuncture techniques in pentobarbitone‐anaesthetized rabbits. 2. Renal vascular resistance doubled from 2.7 +/‐ 0.5 to 5.0 +/‐ 1.1 mmHg ml‐1 min‐1 after NOLA (P < 0.01), with similar percentage increases in both pre‐ (149 +/‐ 38%, P < 0.01) and postglomerular (158 +/‐ 42%, P < 0.01) resistance. 3. Glomerular capillary pressure rose from 33 +/‐ 1 to 40 +/‐ 1 mmHg after NOLA (P < 0.01) but despite this, glomerular filtration rate (GFR) and single nephron glomerular filtration rate did not significantly change. 4. Blood pressure increased 18 +/‐ 1 mmHg (P < 0.001) within 10 min of NOLA administration and remained near this level for the next 90 min. 5. The glomerular ultrafiltration coefficient (Kf) decreased significantly from 0.085 +/‐ 0.022 to 0.035 +/‐ 0.006 nl s‐1 mmHg‐1 (P < 0.05). 6. Urine flow and sodium excretion increased markedly (26 +/‐ 9 to 337 +/‐ 102 microliters min‐1 and 5 +/‐ 2 to 342 +/‐ 12 mumol min‐1 respectively, (P < 0.001)) and sodium fractional excretion rose from 1.0 +/‐ 0.3 to 8.0 +/‐ 2.2% (P < 0.01). 7. Thus, administration of NOLA to rabbits caused vasoconstriction of both pre‐ and postglomerular vessels, diuresis and natriuresis without significant change in GFR, and a reduction in Kf. The results suggest that NO may play an important role in the regulation of renal haemodynamics and glomerular function.

VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY

1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre‐ and postglomerular vascular resistance have been studied in anaesthetized rabbits.

Renal blood flow and glomerular filtration rate in renal wrap hypertension in rabbits.

Serial measurements of mean arterial pressure and glomerular filtration rate (GFR) were made in rabbits before and 10, 28 and 56 days after bilateral renal cellophane wrap (n = 8) or sham operation (n = 6). No significant changes were seen 10 days after renal wrap, but by 28 days GFR was reduced by 50 +/- 3% and mean arterial pressure had risen by 42 +/- 5 mmHg. No significant further changes occurred over the subsequent month. Changes in plasma renin activity after renal wrapping were not significantly different to those seen after sham operation. In a separate series of experiments, renal extraction ratio of para-aminohippurate (PAH), 28 days after renal wrap, averaged 63 +/- 4% (n = 6) compared to 83 +/- 2% (n = 5) after sham operation. Calculated renal blood flow of the hypertensive rabbits was only about 40% of that in the sham operated rabbits. Thus large reductions in GFR, renal blood flow and PAH extraction ratio occurred following bilateral renal wrapping and these changes may reflect compression of the kidney by the cellophane induced fibrous capsule. These reductions occurred concomitantly with the rise in arterial blood pressure.

Effects of activation of vasopressin-V1-receptors on regional kidney blood flow and glomerular arteriole diameters.

Objectives We tested whether vasoconstriction of juxtamedullary glomerular arterioles contributes to vasopressin V1-receptor-mediated reductions in medullary perfusion (MBF). Design and methods The left kidney of pentobarbitone anaesthetized rabbits was denervated, a perivascular flow probe placed around the renal artery and laser-Doppler flow probes positioned in the inner medulla and on the cortical surface. Rabbits then received a 30 min intravenous infusion of [Phe2,Ile3,Orn8]vasopressin (V1-AG; 30 ng/kg per min;n = 7) or its vehicle (n = 7). Kidneys were perfusion fixed at the final recorded mean arterial pressure (MAP) and filled with methacrylate casting material. Diameters of afferent and efferent arterioles were determined by scanning electron microscopy. Results V1-AG increased MAP (19 ± 3%) and reduced MBF (30 ± 8%) but not cortical perfusion or total renal blood flow. Vehicle-treatment did not significantly affect these variables. After vehicle- and V1-AG-treatment, juxtamedullary afferent arteriole luminal diameter averaged 15.35 ± 1.31 and 15.88 ± 1.86 μm, respectively (P = 0.92), while juxtamedullary efferent arteriole luminal diameter averaged 17.75 ± 1.86 and 18.36 ± 2.24 μm, respectively (P = 0.93). Conclusions V1-AG reduced MBF but did not significantly affect juxtamedullary arteriolar diameter. Our results therefore do not support a role for juxtamedullary arterioles in producing V1-receptor-mediated reductions in MBF, suggesting that downstream vascular elements (e.g. outer medullary descending vasa recta) might be involved.

Evidence for a renomedullary vasodepressor system in rabbits and dogs.

Renal perfusion was increased in anesthetized rabbits and dogs by using an extracorporeal circuit. When left kidney perfusion pressure was raised in rabbits (145-240 mm Hg), arterial pressure fell by 1 J4±0J0 mm Hg/min. Pretreatment of the rabbits with 2-bromoethylamine hydrobromide, which destroyed the renal medulla, abolished the fall in arterial pressure (-0.08 ±0.08 mm Hg/min) in response to increased renal perfusion pressure. In dogs (with blockade of autonomic ganglia by pentolinium, converting enzyme inhibition [captopril/ enalaprilat], and surgical renal denervation), increasing renal perfusion pressure to 170-220 mm Hg resulted in a fall in arterial pressure by 0.32±0.03 mm Hg/min (or by 28.9±3.1 mm Hg over a 90-minute period). Mean arterial pressure did not change significantly in identically prepared dogs not subjected to increased renal perfusion pressure, whereas pretreatment of dogs with bromoethylamine abolished the hypotensive response to increased renal perfusion pressure. Thus, the hypotensive response to increased renal perfusion was dependent on the presence of an intact renal medulla, but hypotension still occurred in the presence of converting enzyme inhibition, autonomic ganglion blockade, and renal denervation. The results provide in vivo evidence in two species that a vasodepressor factor from the renal medulla is released in response to increased renal perfusion.