A true champion of Hungarian kidney research and nephrology education--tribute to László Rosivall.

This article pays tribute to the tremendous achievements of Dr. László Rosivall in renal (patho)physiology research and nephrology education in Hungary on the occasion of his 60th birthday. For the past several decades Dr. Rosivall has been a charismatic leader of academic institutions, national and international societies, foundations in physiology, nephrology and hypertension, but the most important of his many contributions, is his role as a scientist. He earned his MD with Summa cum Laude at Semmelweis University (1973) and was invited immediately after that to join the laboratory of Hársing. He studied the distribution of intra-renal blood flow employing then state-of-the-art methods as well as developed his own technique at Semmelweis University and at the University of Bergen with Knut Aukland. This led to his PhD thesis and degree in 1980. An important determinant of his early basic scientific training and development was his postdoctoral research fellowship and later many visiting professorships in the Nephrology Research and Training Center (NRTC) at the University of Alabama at Birmingham, Birmingham, AL, USA between 1981 and 1983. Actually, this research fellowship not only impacted his own future career, but it also cleared the path for many other young Hungarian scientists who later trained with Dr. Rosivall and then at UAB. The early 1980s were the years of significant scientific discoveries and the NRTC team at UAB made important contributions by their studies on renal and glomerular hemodynamics, the renin-angiotensin system (12, 19, 22) and by the development of classic experimental techniques like renal micropuncture, microperfusion, and the juxtamedullary nephron preparation (3) that are still being used worldwide. When Dr. Rosivall joined UAB in the 1980s, the team at the NRTC included Drs. Navar, Bell, Inscho, Carmines, Casellas, and Oparil, among many others, who share their fond memories of working with Dr. Rosivall in this article.

[Sodium ion inhibits angiogenesis of cultured rat aortic and coronary rings]. / L'ion sodium inhibe les capacités angiogéniques in vitro d'explants d'aorte et d'artère coronaire de rat.

High sodium intake is associated with the development of cardiac hypertrophy in man and rats independently of the rise of blood pressure. In addition, the reduced capillary density observed in striated muscle of rats fed a high salt diet suggests that angiogenesis is altered. The aim of the present experiments was to investigate the angiogenic capacities of vascular rings isolated from the aorta and the coronary artery of rats. Vascular rings (external diameter of 1 669 +/- 9 and 323 +/- 26 microm for aorta and coronary artery. respectively) are cultured in a three-dimensional collagen type I lattice and a standard medium (DMEM+HAMF12) containing 152 mM of sodium. Sodium ion associated with chloride or citrate is added to the standard medium to achieve a final concentration of sodium of 160 and 176 mM. The role of sodium-proton exchanger is evaluated through the addition of amiloride to the culture medium. Sprouts formed from vascular explants are counted every second day until days 8 to 10. Kinetics of new vessels formation and the number of sprouts were similar in aortic and coronary rings (83 +/- 5 and 95 +/- 5 sprouts, respectively). Elevation of sodium chloride concentration inhibits by 50 to 80% the neo-vessels formation in both the aorta and the coronary artery. Anti-angiogenic effect of the high sodium medium was not affected when citrate was substituted to chloride. Amiloride (3.10(-5) M) reduced the number of sprouts formed in the standard medium; however, it counteracted the anti-angiogenic effect of elevated sodium concentration. These results indicate that high extracellular concentration of sodium and not chloride anion is accompanied by a deleterious effect on angiogenic capacities of cultured aortic and coronary artery rings through modifications of trans-membrane sodium exchanges.

Influence of irbesartan and enalapril on changes of renal function associated with the established phase of l-NAME hypertension.

OBJECTIVE: Reversibility of the systemic and renal alterations induced by N(omega)-nitro-L-arginine-methyl ester(L-NAME) was assessed by treatment with irbesartan and enalapril (30 and 10 mg/kg per 24 h, respectively) alone or in combination. DESIGN: L-NAME (20 mg/kg per 24 h) was given to rats for 6 weeks and treatments were administered during the last 2 weeks. Glomerular filtration rate and renal plasma flow [GFR and RPF per g of kidney weight (KW)] were determined using the clearance technique. RESULTS: Arterial pressure was similarly reduced by treatments. GFR was lower in L-NAME-treated rats than in controls (552 +/- 52 versus 1106 +/- 78 microl/min per g KW), whereas RPF was reduced to a larger extent, thus resulting in an increase in filtration fraction. GFR was normalized by irbesartan but not enalapril or the combination (1042 +/- 50, 790 +/- 79 and 725 +/- 38 microl/min per g KW, respectively). RPF returned to normal and filtration fraction fell markedly with the combination. All treatments reduced the lesions of preglomerular vessels and reversed L-NAME-induced albuminuria and cardiovascular hypertrophy. At a dose of 3 mg/kg per 24 h, irbesartan only reduced the lesions of the afferent arteriole. CONCLUSIONS: Through its effects on AT1 receptors, angiotensin II may play an important role in the maintenance of L-NAME hypertension and associated alterations. The lower GFR and filtration fraction observed with enalapril in the presence of irbesartan suggests the intervention of non-angiotensin II-mediated mechanism, and at the postglomerular level, in the effect of angiotensin-converting enzyme (ACE) inhibitors.

Advanced glycosylation end-products and NO-dependent vasodilation in renal afferent arterioles from diabetic rats.

Systemic pressor responses to acetylcholine (ACh) are reduced in DM, an effect thought to be related to quenching of nitric oxide (NO) by advanced glycosylation end-products (AGE). We studied the effects of AGE in juxtamedullary (JM) afferent arterioles (AA) from rats with 40-50 days diabetes mellitus (DM) induced via streptozotocin. JM AA were perfused in vitro with solutions containing fresh RBCs suspended in either 6% bovine albumin or 6% AGE-albumin in euglycaemic Krebs-Ringer. Autoregulatory responses were evident in the DM vessels: AA constricted 31 +/- 2% (n=9) when perfusion pressure (PP) was raised from 60 to 140 mmHg. ACh (10 microM) caused a 43 +/- 15% dilation and Ca2+-channel blockade elicited a 95 +/- 14% dilation at 100 mmHg PP, indicating substantial basal vascular tone in DM AA. L-NAME (0.1 mM) constricted DM AA by 21 +/- 2% (n=9) at 100 mmHg PP, indicating significant basal NO production in DM vessels. Segments of renal resistance arteries from DM rats perfused in vitro responded to muscarinic stimulation and elevated glucose levels with significant increments in NO production, as measured with an NO-sensitive electrode. This observation shows that the renal endothelial NO system is intact in DM. While AGE in the perfusate dilated control AA, they had no effect on DM AA at all PP levels, although they blunted ACh-induced dilation. Hence, although AGE do appear to have vasoactive properties in the absence of hyperglycaemia, the results of this study are inconsistent with substantial NO quenching by AGE.

Nitric oxide and preglomerular vascular lesions in lyon spontaneously hypertensive rats.

Accumulation of Sudan black-stainable (SB+) lipids is a hallmark of the focal inflammato-proliferative lesions that develop along preglomerular vessels in N G-nitro-L-arginine methyl ester (L-NAME) and angiotensin II hypertensive rats. We extended our findings to genetically hypertensive Lyon (LH) rats aged 14 and 30 weeks and to age-matched normotensive (LN) rats. Vessels were isolated by HCl maceration. Despite high systolic blood pressure (SBP), hypercholesterolaemia, albuminuria and increased interlobular and afferent arteriolar media thickness, SB+ lesions were rarely found in LH rats, regardless of age. To probe nitric oxide as a potential source of vascular protection, 14-week-old LN and LH rats received L-NAME for 10 days (20 mg kg-1 day-1, per os), which increased SBP to 174 +/- 5 and to >200 mmHg, respectively. It induced formation of focal SB+ lesions less frequently in LN than LH rats, in which they affected 39 +/- 7, 44 +/- 5 and 15 +/- 5% of arcuate arterial branches, interlobular arteries and afferent arterioles, respectively. Immunoreactive endothelin-1 was found to accumulate at the level of SB+ lesions. Co-administered with L-NAME, hydralazine (15 mg kg-1 day-1, per os) limited SBP rise to approximately 10 mmHg in both LN and LH rats. As a result, SB+ lesions were rare in LN rats, but were frequent in LH rats. In conclusion, preglomerular SB+ lesions are spontaneously lacking in LH rats. Endogenous nitric oxide production provides protection against vascular barotrauma. Endothelin-1 likely plays an autocrine/paracrine role in vascular lesion formation.

New method for imaging innervation of the renal preglomerular vasculature. Alterations in hypertensive rats.

OBJECTIVE: To develop a new method for viewing adrenergic innervation along renal preglomerular vessels; to assess nerve densities and vascular lesions along arcuate arteries (ArcA), arcuate arterial branches (ArcB), and interlobular arteries (ILA) in spontaneously hypertensive rats (SHR) and in angiotensin II (AngII) and in N(G)-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. METHODS: Preglomerular vasculatyres were isolated after HCl maceration and were immunostained against synaptophysin, a membrane protein of synaptic vesicles. Lesions were stained with Sudan black. Longitudinal nerve densities and relative frequencies of ArcA, ArcB, and ILA endowed with sudanophilic lesions were assessed separately. RESULTS: Synaptophysin immunostaining revealed the vascular neural plexus. Nerves were adrenergic, as the plexus was destroyed by treatment with 6-hydroxy dopamine. Vascular lesions were not seen in SHR, and increased nerve density was observed along ArcA and ILA. In L-NAME- and AngII-hypertensive rats, vascular lesions affected predominantly ArcB and ILA, and nerve density was reduced by 12% and 28% (ArcA), 37% and 31% (ArcB), and by 55% and 34% (ILA), respectively, versus normotensive controls. Endothelin-1 receptor blockade did not affect AngII-induced hypertension but prevented both lesion development and reduction of density of the vascular neural plexus. CONCLUSIONS: The method we have devised provides a direct en face view of the vascular adrenergic innervation of isolated preglomerular vasculature. Measurements in hypertensive rat models suggest a link between vascular lesions and reduction in nerve density in hypertension. Endothelin-1 likely plays a key role in mediation both vascular injury and altered vascular nerve density in hypertension.

Vascular endothelin-1 gene expression and synthesis and effect on renal type I collagen synthesis and nephroangiosclerosis during nitric oxide synthase inhibition in rats.

BACKGROUND: The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process. METHODS AND RESULTS: Treatment of rats for 4 weeks with the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) 50 mg. kg-1. d-1 increased systolic blood pressure to 159+/-12 mm Hg. In animals treated with L-NAME, histological evaluation of renal sections revealed an increased formation of extracellular matrix (Masson's trichrome), and specifically of collagens (Sirius red). A part of this fibrosis was attributed to abnormal collagen I presence, because mRNA expression of the collagen I alpha1 chain (reverse transcription-polymerase chain reaction) and procollagen I formation (radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the renal resistance vessels of hypertensive animals. In subsequent experiments, we examined whether ET-1 was involved in activation of collagen I formation. mRNA expression (RNase protection assay) of preproET-1 and ET-1 content (radioimmunoassay) were 10-fold and 3-fold increased, respectively, in renal microvessels of rats treated with L-NAME. Interestingly, in these vessels, ET-1 (immunostaining) was colocalized with sudanophilic lesions. Bosentan, an ET receptor antagonist (20 mg. kg-1. d-1), coadministered with L-NAME canceled the increased mRNA expression and synthesis of collagen I and attenuated the severity of renal vascular lesions without affecting L-NAME-induced high blood pressure. CONCLUSIONS: These data demonstrate that ET-1 synthesis is increased in renal microvessels when NO production is suppressed. In this model of hypertension, ET-1 is a major activator of collagen I formation in renal resistance vessels and participates in the development of renal fibrosis without affecting systolic blood pressure.

Candesartan and progression of preglomerular lesions in N(G)-nitro-L-arginine methyl ester hypertensive rats.

Chronic administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces systemic hypertension and progressive development of preglomerular sudanophilic (SB+) lesions. This study investigates whether progression of SB+ lesion formation froin 4 to 6 wk of L-NAME treatment (20 mg/kg per d, orally) would be affected by 2 wk administration of either the angiotensin II type 1 receptor antagonist candesartan cilexetil (3 and 10 mg/kg per d) or the vasodilator hydralazine (15 mg/kg per d). Frequencies of arcuate arterial branches (ArcB), interlobular arteries (ILA), and afferent arterioles (AA) endowed with SB+ lesions were assessed on preglomerular vasculatures isolated after HCl maceration. Systolic BP (SBP, tail-cuff manometry) increased from a baseline of 125+/-2 to 185+/-4, and to 193+/-4 mmHg after 4 and 6 wk of L-NAME treatment, respectively. During the fourth- to sixth-week period, albumin excretion increased significantly from 3.7+/-1.1 to 52.5+/-22.4 mg/24 h. At that time, SB+ lesions affected 62+/-8, 61+/-8, and 13+/-4% of ArcB, ILA, and AA, respectively. Candesartan cilexetil dose dependently reduced SBP, albumin excretion, and lesion development. At the highest dose, SB+ lesions only affected 12+/-6, 15+/-7, and 1+/-1% of ArcB, ILA, and AA, respectively. Hydralazine similarly reduced SBP and albumin excretion, although frequencies of SB+ lesions appeared less affected along ArcB and ILA. In conclusion, progression of preglomerular SB+ lesion formation during L-NAME hypertension can be prevented by angiotensin II type 1 receptor blockade, partly through pressure-lowering effects.

Insulin-like growth factor-I restores microvascular autoregulation in experimental chronic renal failure.

Impairment of autoregulation (AR) is associated with accelerated progression of chronic renal failure (CRF). As the bioavailability of insulin-like growth factor-I (IGF-I) is low in CRF, we investigated the effects of acute luminal application of 10 nM recombinant human IGF-I on AR in juxtamedullary (JM) afferent arterioles (AA) perfused in vitro with a blood solution [(approximately 30% hematocrit (HCT)]. Studies were conducted in AA from adult male rats three to four weeks after five-sixths nephrectomy (Nx) by either surgical excision (N = 7) or infarction (N = 5) of two thirds of the remnant kidney; controls (N = 6) had sham surgery. AA from both Nx groups exhibited marked hypertrophy and impaired AR responses (60 to 140 mm Hg perfusion pressure), features more pronounced in the infarction group. Responses to abluminal acetylcholine (10 microM) were similar in sham and excision groups but were significantly blunted in the infarction group. All groups vasodilated significantly after Ca-channel blockade (10 mM MnCl2). IGF-I restored AR in AA from both Nx groups (P < 0.05, analysis of variance) while it vasodilated AA from controls. These results suggest that IGF-I may protect the glomerulus from injury by maintaining autoregulatory control of renal blood flow, thereby slowing the progression of CRF.

Bosentan prevents preglomerular alterations during angiotensin II hypertension.

The present study was performed to characterize structurofunctional alterations of preglomerular vessels during chronic angiotensin II (Ang II)-induced hypertension (Ang II group: 400 ng x kg[-1] x min[-1], 10 days) and to assess the role of endothelin-1 in rats receiving Ang II and the mixed receptor antagonist bosentan (Ang II+B group: 30 mg x kg[-1] x d[-1], 10 days). Systolic blood pressure rose by 56+/-3 and 54+/-6 mm Hg in Ang II and Ang II+B rats, respectively. Albuminuria increased similarly in both Ang II-treated groups, reflecting glomerular barrier dysfunction. Preglomerular vessels were isolated after HCI maceration and comprised arcuate arteries and their branches, interlobular arteries (ILA), and afferent arterioles (AA). In the Ang II group, focal vascular lesions affected 36+/-6%, 20+/-5%, and 4+/-1% of arcuate arterial branches, ILA, and AA, respectively. They were characterized by 74% increased media thickness and accumulation of Sudan black-positive (SB+) lipid droplets, and media cell proliferation was documented through immunohistochemistry. The occurrence of SB+ lesions was strikingly reduced with bosentan. Autoregulatory responses (AR) were assessed along ILA and AA with the use of blood-perfused juxtamedullary nephron preparations. AR were elicited by raising blood perfusion pressure from 60 to 160 mm Hg and quantified through videomicroscopy as pressure-induced constrictions. AR were inhibited in Ang II-treated rats along ILA and AA; Ang II-induced AR changes were prevented by bosentan. Maximal relaxation induced by Mn2+ revealed equal basal tone in Ang II-treated, Ang II+B-treated, and control vessels. Chronic Ang II-induced hypertension is therefore associated with the development of SB+ lesions and selective impairment of AR in juxtamedullary nephrons. Endothelin-1 likely mediates the structurofunctional alterations of preglomerular vasculature during Ang II hypertension.

Branching patterns and autoregulatory responses of juxtamedullary afferent arterioles.

The spatial organization of autoregulatory responses (AR) was assessed in couples of afferent arterioles (AA), either grouped as anatomic pairs or branched sequentially along the same arcuate arterial branch (ArcB). With blood-perfused juxtamedullary nephron (JMN) preparations, AR were elicited by raising blood perfusion pressure from 60 to 120 mmHg and quantified by videomicroscopy as pressure-induced constrictions. Paired AA had unequal lengths (long-to-short ratio, 1.9 +/- 0.1; n = 36); however, no statistical difference in AR was found between long and short AA at juxtaglomerular or early AA (EAA) sites. Sequentially branched AA had the same length heterogeneity as paired AA (proximal-to-distal AA length ratio, 2.0 +/- 0.2; n = 30). However, AR exhibited a significant axial gradient, being higher in distal than in proximal AA or ArcB sites. In both AA branching patterns, EAA and nearby sites of the feed arteries had similar AR. Hence, our results are consistent with hemodynamic coupling in paired JMN. Around branching sites, AR are spatially organized in a way consistent with electrotonic vascular coupling.

Effects of endotoxin on tone and pressure-responsiveness of preglomerular juxtamedullary vessels.

Endotoxin might affect renal vasoreactivity, but in vivo this is difficult to assess (systemic influences). Therefore, we used the in vitro blood-perfused juxtamedullary nephron preparation to study early changes in preglomerular vascular reactivity induced by exposure to endotoxin. Pressure-evoked vasomotor responses were determined videometrically by measuring steady-state inside vessel diameters at a perfusion pressure of 60 or 120 mmHg. Intraluminal application of endotoxin (primary contact with endothelium) for 120 min elicited an early (within 30 min) and sustained approximately 25% vasoconstriction from arcuate artery to the distal portions of the afferent arterioles; autoregulatory responses, indicated by pressure-induced vasoconstriction, were unchanged. When topically applied, endotoxin (primary contact with smooth muscle cells) had no vasomotor effects. Significant constrictions, and increases in autoregulatory responses were obtained when the preparation was taken from kidneys from endotoxin-treated rats. Endotoxin had no effect on efferent arteriolar dimensions. Such preferential preglomerular early vasoconstriction is consistent with the early increase in renal resistance and parallel decrease in renal blood flow and glomerular filtration observed during endotoxin shock in vivo. Our results support the concept of local, endothelium-mediated effects of endotoxin on renal vessels.

Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin.

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.

Control of the renal microcirculation: cellular and integrative perspectives.

Recent studies targeting ionic signalling events have revealed that considerable segmental heterogeneity exists between pre- and post-glomerular vascular smooth muscle cells, and that even preglomerular vascular smooth muscle cells are not a homogeneous population. Preglomerular branch points enriched with calcium channels may be critical for initiating contractile responses, with subsequent propagation along the vascular wall, and may also facilitate nephron-nephron coupling events. These processes ultimately promote coordinated network behaviour and can underlie development of synergistic vasoactive responses, such as those necessary to provide efficient autoregulation of blood flow and glomerular filtration rate.

Chronic L-NAME hypertension in rats and autoregulation of juxtamedullary preglomerular vessels.

The impact of chronic NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (20 mg.kg-1.day-1 po, for 25 days) on pressure responsiveness was assessed in vessels ranging from arcuate arteries (ArcA) to juxtaglomerular afferent arterioles (JAA), using videomicroscopy and blood-perfused juxtamedullary nephron (JMN) preparations. Respective tail-cuff pressures of control and L-NAME rats were 127 +/- 2 (n = 8) and 173 +/- 4 mmHg (n = 5). Corresponding vessels of both groups had similar calibers at 60 mmHg. Increasing blood perfusion pressure to 200 mmHg constricted control ArcA and JAA by 26 +/- 4% (n = 20) and 43 +/- 5% (n = 15), respectively. Instead, a respective 3 +/- 4% (n = 15) and 21 +/- 9% (n = 6) pressure-induced dilation occurred in L-NAME vessels, and 86 +/- 2% of glomeruli expressed alpha-smooth muscle actin. Responses to acetylcholine (1 microM) but not to nitroprusside (1 mM) were impaired by L-NAME. Maximal relaxation induced by Mn2+ (10 mM) revealed equal basal tone and similar passive viscoelastic properties in control and L-NAME vessels. No vascular hypertrophy was found in L-NAME vessels. Chronic L-NAME hypertension is therefore associated with a selective loss of vascular autoregulation in JMNs, which may contribute to glomerular injury.

Interaction between cGMP-dependent dilators and autoregulation in rat preglomerular vasculature.

The influence of guanosine 3',5'-cyclic monophosphate (cGMP)-dependent dilators on autoregulatory responses (AR) of arcuate arteries (ArcA) and afferent arterioles at early sites and at juxtaglomerular sites (JAA) was assessed by videomicroscopy using in vitro blood-perfused juxtamedullary nephron preparations. AR were quantified as fractional changes in luminal diameter induced by doubling blood perfusion pressure (60-120 mmHg). Baseline AR ranged from 17 +/- 2% to 21 +/- 2% in ArcA and from 24 +/- 2% to 34 +/- 4% in JAA. Direct perivascular applications of increasing concentrations of 8-bromo-cGMP (8-BrcGMP, 10 microM to 1 mM), of the NO donors sodium nitroprusside (10 microM to 1 mM) and 3-morpholino-sydnonimine chlorhydrate (SIN1; 10 microM to 1 mM), and of rat atrial natriuretic factor (ANF, 0.1 nM to 10 nM) dose- and pressure-dependently dilated all vessels at 60 mmHg. Concomitantly, AR values were dose-dependently reduced or reversed to pressure-induced dilations. During application of 8-BrcGMP and NO donors, the segmental gradient of sensitivity of AR was ArcA > JAA; the opposite gradient was found with ANF (i.e., JAA > ArcA). The present results demonstrate that compounds known to utilize the cGMP-signaling pathway act as modulators of AR along the juxtamedullary preglomerular vasculature.

Anatomic pairing of afferent arterioles and renin cell distribution in rat kidneys.

Close afferent arteriolar (AA) connectivity is a prerequisite for hemodynamic interaction between superficial rat nephrons. Studies were conducted in rat, mouse, rabbit, and human renal vasculatures obtained by an HCl maceration-microdissection technique to document the extent of AA connectivity. In rat kidneys, we assessed the possibility for a slow component of internephron coupling, as reflected by arteriolar renin cell distribution after specific immunostaining for renin. In the four species examined, 51% (human) to 60% (mouse) of total AA populations were organized as vascular units consisting of mostly two AA sharing a common origin and a connecting arterial segment. In rat AA pairs, branch lengths were significantly correlated, suggesting coordinated arteriolar growth. The sum of AA branch lengths averaged 278 +/- 6 microns. Rat arteriolar renin status, ranging from no renin cells to renin-recruited midafferent arterioles, distributed in a significantly nonrandom fashion within AA pairs, and 52% of the pairs had equal renin status. Hence, AA pairing is a consistent anatomic characteristic of mammalian kidneys and may constitute an optimal vascular design for hemodynamic as well as endocrine interactions.

Ascending myogenic autoregulation: interactions between tubuloglomerular feedback and myogenic mechanisms.

A mathematical model of the renal vascular and tubular systems was used to examine the possibility that synergistic interactions might occur between the tubuloglomerular feedback (TGF) and myogenic autoregulatory mechanisms in the kidney. To simulate the myogenic mechanism, the renal vasculature was modelled with a resistance network where the total preglomerular resistance varies with intravascular pressure. In addition, a steady-state model of glomerular filtration, proximal and Henle's loop reabsorption, and TGF-modulation of afferent arteriolar resistance was derived. The results show that, if TGF acts on the distal portion of the preglomerular vasculature, then any TGF-induced vasoconstriction should raise upstream intravascular pressure and, thereby, trigger a myogenic (AMYO) response. The model further predicts that the magnitude of the AMYO response can be similar in magnitude to the TGF-induced increment in afferent resistance. Hence, the effects of TGF excitation on whole kidney hemodynamics may be much greater than predicted from measurements in single nephrons. Moreover, a significant fraction of the intrinsic myogenic autoregulatory response to increased renal perfusion pressure may result from a synergistic interaction between the TGF and myogenic mechanisms.