Preglomerular Afferent Arteriole Research Articles

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

Age-related Changes in Renal Arterio-Arteriolosclerosis in Kidney Disease: Renal Biopsy-based Study

Calcium antagonists: current and future applications based on new evidence. Renal protective action of calcium channel blockers

Ca channel blockers have been widely prescribed as an antihypertensive agent in Japan, because the blood pressure (BP) lowering effect of it is strong among Japanese patients whose amount of salt intake is high and patients with chronic kidney disease (CKD) whose sodium sensitivity of BP is enhanced. In addition, it can maintain the perfusion pressure into important organs including kidneys despite lowered systemic BP, and can be used efficiently in combinations with many types of antihypertensive agents. On the other hand, most of Ca channel blockers dilate mainly preglomerular afferent arterioles, resulting in elevated glomerular capillary pressure. Therefore, renal protection by Ca channel blockers remains in debate. We will discuss the renal protective action of new Ca channel blockers, which can dilate postglomerular efferent arterioles.

Rapid non-genomic effects of aldosterone on the renal vasculature

There is increasing evidence for the importance of rapid non-genomic effects of aldosterone on the human vasculature including renal vessels. Arima and collegues by examining isolated perfused afferent and efferent arterioles from rabbit kidneys found a vasoconstriction in both. In another study the same group showed that endothelium-derived nitric oxide (NO) modulates the vasoconstrictor response to aldosterone in rabbit preglomerular afferent arterioles. Disrupting the endothelium as well as blockade of endothelial NO synthase (eNOS) augmented aldosterone-induced vasoconstriction in this study. Uhrenholt et al. found no effect of aldosterone alone to afferent arterioles but a suppression of depolarisation-induced vasoconstriction. After the blockade of eNOS the aldosterone effect was completely suppressed. In a clinical study in healthy male volunteers injection of aldosterone had no statistically significant effects. Co-infusion of the eNOS inhibitor N(G)-monomethyl- l-arginine ( l-NMMA) changed the effect of aldosterone on renal hemodynamics. Aldosterone in co-infusion with l-NMMA decreased renal plasma flow (RPF) much stronger than l-NMMA alone. Infusion of l-NMMA alone increased GFR whereas aldosterone/ l-NMMA lowered GFR slightly. Aldosterone co-infused with l-NMMA strongly increased renal vascular resistance (RVR). The increase was on top of the smaller increase that was induced by l-NMMA infusion. These data indicate that aldosterone acts via rapid non-genomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial nitric oxide synthase unmasks these effects. Therefore, rapid non-genomic aldosterone effects increase renal vascular resistance and thereby may mediate arterial hypertension if endothelial dysfunction is present.

Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole.

We have recently demonstrated that aldosterone causes nongenomic vasoconstriction by activating phospholipase C (PLC) in the preglomerular afferent arteriole (Af-Art). In the present study, we tested the hypothesis that endothelium modulates this vasoconstrictor action by releasing nitric oxide (NO). In addition, to study the post-PLC mechanism, we examined possible contributions of phosphoinositol hydrolysis products. Rabbit Af-Arts were microperfused at 60 mm Hg in vitro, and increasing doses of aldosterone (10(-10) to 10(-8) mol/L) were added to the bath and lumen. Aldosterone caused dose-dependent vasoconstriction (within 10 minutes); significant (P<0.01) constriction was observed from 5x10(-9) mol/L, and at 10(-8) mol/L, intraluminal diameter decreased by 29%+/-3% (n=9). Disrupting the endothelium augmented vasoconstriction; significant constriction was observed from 10(-10) mol/L, and at 10(-8) mol/L, the diameter decreased by 38%+/-2% (n=6). NO synthesis inhibition reproduced this augmentation (n=7). Pretreatment with chelerythrine (10(-6) mol/L), a protein kinase C (PKC) inhibitor, slightly attenuated the constriction; aldosterone at 10(-8) mol/L now decreased the diameter by 18%+/-3% (n=7). However, in Af-Arts treated with thapsigargin (10(-6) mol/L) or dantrolene (3x10(-5) mol/L), which blocks inositol 1,4,5-triphosphate (IP3)-induced intracellular calcium release, aldosterone at 10(-8) mol/L decreased the diameter by only 9%+/-1% (n=6) or 9%+/-2% (n=5), respectively. These results demonstrate that in the Af-Art endothelium-derived NO modulates vasoconstrictor actions of aldosterone that are mediated by the activation of both IP3 and PKC pathways. Such vasoconstrictor actions of aldosterone may contribute to the development or aggravation of hypertension by elevating renal vascular resistance in cardiovascular diseases associated with endothelium dysfunction.

Renal afferent and efferent arteriolar dilation by nilvadipine: studies in the isolated perfused hydronephrotic kidney.

Although calcium antagonists are believed to exert preferential vasodilator action on the renal preglomerular afferent arteriole, we recently demonstrated that efonidipine, a novel calcium antagonist, vasodilates both afferent and efferent arterioles. Nilvadipine also is reported to increase renal blood flow and reduce filtration fraction, suggesting indirectly afferent and efferent arteriolar vasodilation. No direct investigation, however, has been conducted examining the renal microvascular action of nilvadipine. We therefore characterized the renal microvascular reactivity to nilvadipine, by using the isolated perfused rat hydronephrotic kidney. The administration of angiotensin II (0.3 nM) caused marked vasoconstriction of afferent (from 13.5 +/- 0.6 to 9.2 +/- 0.6 microm, p < 0.01, n = 6) and efferent arterioles (from 11.5 +/- 1.0 to 7.4 +/- 0.7 microm, p < 0.01; n = 5). The subsequent addition of nilvadipine (10 nM, 100 nM, and 1 microM) caused 37 +/- 5%, 91 +/- 4%, and 95 +/- 8% reversal of afferent arteriolar constriction, respectively. Similarly, efferent arterioles manifested 59 +/- 12% reversal by 1 microM nilvadipine. Thus unlike nifedipine, which we previously reported to cause modest efferent arteriolar dilation (21 +/- 1% reversal at 1 microM), nilvadipine possesses the greater ability to dilate efferent arterioles (p < 0.01 vs. nifedipine), although both antagonists cause similar magnitudes of afferent arteriolar vasodilation. Variable effects on the efferent arteriole suggest the heterogeneity in the calcium antagonist with regard to the renal microvascular action of this agent.

Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole.

Although angiotensin II type 2 (AT2) receptor has recently been cloned, its functional role is not well understood. We tested the hypothesis that selective activation of AT2 receptor causes vasodilation in the preglomerular afferent arteriole (Af-Art), a vascular segment that accounts for most of the preglomerular resistance. We microperfused rabbit Af-Arts at 60 mmHg in vitro, and examined the effect of angiotensin II (Ang II; 10(-11)-10(-8) M) on the luminal diameter in the presence or absence of the Ang II type 1 receptor antagonist CV11974 (CV; 10(-8) M). Ang II was added to both the bath and lumen of preconstricted Af-Arts. Ang II further constricted Af-Arts without CV (by 74+/-7% over the preconstricted level at 10(-8) M; P < 0.01, n = 7). In contrast, in the presence of CV, Ang II caused dose-dependent dilation; Ang II at 10(-8) M increased the diameter by 29+/-2% (n = 7, P < 0.01). This dilation was completely abolished by pretreatment with an AT2 receptor antagonist PD123319 (10(-7) M, n = 6), suggesting that activation of AT2 receptor causes vasodilation in Af-Arts. The dilation was unaffected by inhibiting either nitric oxide synthase (n = 7) or cyclooxygenase (n = 7), however, it was abolished by either disrupting the endothelium (n = 10) or inhibiting the cytochrome P-450 pathway, particularly the synthesis of epoxyeicosatrienoic acids (EETs, n = 7). These results suggest that in the Af-Art activation of the AT2 receptor may cause endothelium-dependent vasodilation via a cytochrome P-450 pathway, possibly by EETs.

High glucose augments angiotensin II action by inhibiting NO synthesis in in vitro microperfused rabbit afferent arterioles

Preglomerular afferent arteriole (Af-Art) is a crucial vascular segment in the control of glomerular hemodynamics. We have recently reported that vascular reactivity of Af-Art is modulated by nitric oxide (NO). However, little is known about its reactivity under pathophysiological conditions such as diabetes, which is often accompanied by abnormal glomerular hemodynamics. In the present study, we examined the direct effects of high glucose, the hallmark of diabetes, on the vascular reactivity of Af-Art. Rabbit Af-Arts were microperfused for three hours with medium 199 containing either normal (5.5 mM; NG-Af-Arts) or high concentrations (30 mM; HG30-Af-Arts) of glucose, and then vascular reactivity was examined. Sensitivity to angiotensin II (Ang II) was significantly higher in HG30-Af-Arts than in NG-Af-Arts. Ang II began to cause significant constriction from 10(-9) M in NG-Af-Arts (18 +/- 3%, N = 6, P < 0.01) and from 10(-11) M in HG30-Af-Arts (9 +/- 2%, N = 6, P < 0.01). NO synthesis inhibition with 10(-4) M nitro-L-arginine methyl ester (L-NAME) increased the sensitivity to Ang II in NG-Af-Arts without affecting Ang II action in HG30-Af-Arts. In L-NAME-pretreated NG-Af-Arts, Ang II began to cause constriction from 10(-11) M (11 +/- 3%, N = 6, P < 0.01). Thus, pretreatment with L-NAME abolished the difference in sensitivity to Ang II between NG- and HG30-Af-Arts, suggesting impaired NO synthesis in HG30-Af-Arts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topography of nitric oxide synthesis by localizing constitutive NO synthases in mammalian kidney

Nitric oxide (NO) is generated from L-arginine by NO synthase (NOS). We have investigated the localization of constitutive NOS isoforms in rat, mouse, guinea pig, rabbit, pig, and human kidney. NADPH diaphorase (NADPH-d) reaction was used for histochemical detection of NOS enzyme activity, neuronal NOS (NOS I) and endothelial NOS (NOS III) were identified by specific antibody, and in situ hybridization was applied for NOS I mRNA detection. Strong presence of NOS I in macula densa (MD), previously detected in rat, was found in all species including humans. Additional NOS I-positive cells of the thick ascending limb (TALH) were defined. A clear-cut distinction between Tamm-Horsfall-protein-positive cells of the TALH and NOS I-positive cells of the TALH was shown. Ultrastructurally, NOS I was located in the cytosol. Intimate spatial relation between NOS I-positive cells and renin-containing preglomerular afferent arteriole suggests an effect of MD-derived NO on the juxtaglomerular granular cells. In the renal vasculature, both NADPH-d and NOS III were located in the endothelium of cortical and medullary vessels, whereas the muscle layer was unreactive. The glomerular arterioles showed stronger labeling in the efferent than in the afferent endothelium, and efferent endothelium selectively contained both NOS I and NOS III. The unique morphology of efferent endothelial cells indicates a particular role for NO in this vessel segment. At the capillary level, only the glomerular tuft showed NOS-positive endothelia. A subpopulation of renal nerves containing NADPH-d and NOS I was found in perivascular connective tissue and near pelvic epithelium. These results demonstrate a wide distribution of two constitutive NOS isoforms in the kidney of various animal species including humans. The distinct location of both isoforms in the cortex confirms that NO plays a crucial role in local glomerular signaling events.

Morphometric investigations on intrarenal vessels of streptozotocin-diabetic rats

We have investigated 975 different grazing sections of vessels in kidney preparations of 20 rats of the Wistar strain. Half of these genetically identical animals had an insulin-deficiency diabetes induced by injection of streptozocin. The kidneys were removed for investigation after 2 and 12 weeks duration of diabetes. The vessel cross-section, wall, lumen and endothelial surface area were determined in renal arteries, arterioles and preglomerular afferent arterioles in a blind experiment. Statistically detecteable changes were found in the diabetic vessels in the early stage of the diabetes. Preglomerular afferent arterioles showed a highly significant and increasing lumen dilatation commencing after 2 weeks. Diabetic arteries and arterioles developed narrower lumina. A significant thickening of the endothelium took place at the same time in both vessel types. All three vessel regions became smaller and had thinner walls than healthy vessels as the diabetes progressed. The findings on the afferent vessels indicate that haemodynamic effects on the glomerulus are to be expected. Familial diabetic gloermulopathy begins with a reversible hyperfiltration. However, the mechanism has not been clarified in the context of the diabetic metabolic disorder, and this change is probably the haemodynamic consequence of the substantial dilatation of the preglomerular afferent arterioles. With their renin-positive segment, these arterioles are the centre of intrarenal regulation. The increase of the capillary glomerular pressure associated with the dilatation of the preglomerular afferent arterioles is a crucial factor in the development of diabetic glomerulopathy.

Modulation of angiotensin II-induced vasoconstriction by endothelium-derived relaxing factor in the isolated microperfused rabbit afferent arteriole.

Although endothelium-derived relaxing factor (EDRF) has been studied extensively in large vessels, little is known about its role in the preglomerular afferent arteriole (Af-Art). We tested the hypothesis that EDRF, which is produced locally in the Af-Art, modulates arteriolar responses to angiotensin II (AII). A single rabbit Af-Art with its glomerulus intact was microperfused in vitro at 60 mmHg. When 0.1 microM AII was first applied, luminal diameter decreased by 49 +/- 7.0% (n = 9; P less than 0.0001); however, constriction waned, with the decrease becoming 15 +/- 3.5% at 1 min. After washing the Af-Art, repeated AII caused less constriction (13 +/- 4.0%; P less than 0.0002 vs. first application), showing tachyphylaxis. Pretreatment with Nw-nitro-L-arginine (N-Arg), which inhibits synthesis of nitric oxide (an EDRF), decreased basal diameter by 18 +/- 3.0% (n = 14; P less than 0.0001). N-Arg also augmented AII-induced constriction (86 +/- 6.8%; P less than 0.02 vs. nontreated Af-Art) and rendered it persistent (82 +/- 6.9% at 1 min). Even after pretreatment with N-Arg, repeated AII caused a weaker response, which was restored by washing with kidney homogenate rich in angiotensinase. In conclusion, this study provides evidence that local production of EDRF is an important determinant of the tone of the Af-Art. Our results suggest that the transient nature of AII-induced constriction of the Af-Art may be due to production of EDRF, while tachyphylaxis may be the result of long lasting receptor occupancy.

Renal vessel changes in diabetic KK-mice.

Glomerular hyperfiltration is thought to be of pathogenic importance in the structural abnormalities seen in diabetic nephropathy but its cause is not known. It has been suggested that the changes in the preglomerular vascular system may lead to a disturbance of glomerular blood flow in diabetes. We therefore examined the potential role of changes in the vascular system supplying the glomerulus in diabetic mice. The kidneys of 15 diabetic KK-mice (aged 2, 5 and 12 months) were studied and compared with those of 15 non-diabetic NMRI-mice. We determined vessel cross-sectional, wall and lumen areas of 408 small intrarenal arteries, 5,140 arterioles and 518 preglomerular afferent arterioles using a morphometric method. At 2 months, diabetic arteries and arterioles were considerably smaller than the controls, while preglomerular afferent arterioles were the same size. At 12 months, however, all diabetic vessels measured were much larger than the controls. This was chiefly due to an excessive increase in lumen area: in the diabetic arteries the mean (+/- SEM) lumen area at 12 months was 1,057 +/- 142 vs 616 +/- 72 sq mu in controls (P less than 0.001), in arterioles 176 +/- 7 vs 115 +/- 4 sq mu (P less than 0.001) and in preglomerular afferent arterioles (at 5 months) 131 +/- 8 vs 95 +/- 7 sq mu (P less than 0.001). The dilatation of small intrarenal arteries and arterioles in diabetic mice may result from progressive impairment of vasoconstriction and may be a cause of the glomerular hyperfiltration in diabetes.

The no-reflow phenomenon after canine renal preservation with medium 199

Twenty-four-hr renal preservation at hypothermic temperatures with pulsatile flow using either Medium 199 or a cryoprecipitate of plasma maintained a patent microcirculation prior to reestablishing blood flow. However, failed reflow of blood, the no-reflow phenomenon, occurred in kidneys preserved with Medium 199 within 4 hr after reimplantation into the host animal, as determined by the intra-arterial injection of carbon. The site of vascular obstruction in the renal microcirculation was documented to be within the glomerulus or in the preglomerular afferent arteriole. Renal preservation using a cryoprecipitate of plasma maintained a patent intrarenal vasculature after restoration of blood flow providing normal or near normal function.