Systolic pressure and the myogenic response of the renal afferent arteriole.

The transmission of elevated blood pressure to the glomerulus and pressure-induced glomerular injury play central roles in the pathogenesis of kidney disease and its progression to end-stage renal failure. The renal afferent arteriole sets the pre-glomerular resistance and pressure-induced or 'myogenic' afferent arteriolar vasoconstriction is a primary mechanism protecting the glomerulus from the damaging effects of hypertension. The systolic pressure, being the highest level of pressure attained and most frequent pressure oscillation impacting on the renal vasculature, potentially represents the most damaging component of the blood pressure. Indeed, recent studies indicate that elevations in systolic blood pressure are more closely linked to kidney disease than are elevations in diastolic pressure. However, the current view, derived from dynamic studies of autoregulation, is that the renal vasculature responds passively to pressure signals presented at rates exceeding the myogenic operating frequency (0.2-0.3 Hz in the rat). Thus existing concepts do not explain the mechanisms that normally protect the kidney from elevations in the systolic pressure which are presented at the heart rate (6 Hz in the rat). A recent study from our laboratory addressed this issue. Using a modelling approach and direct measurements of myogenic responses, we found that the afferent arteriole is able to sense and appropriately adjust tone in response to changes in systolic pressure, presented at the heart rate. Key kinetic attributes allowing this vessel to respond in this manner appear to be a very short delay in activation, an unusually rapid rate of vasoconstriction and a longer delay in vasodilation. The present review summarizes this work and presents recent findings addressing the determinants of the myogenic vasoconstriction in the afferent arteriole.

Genetic susceptibility to renal injury in hypertension.

Substantial evidence indicates that hypertension plays a predominant role in the progression of most chronic renal diseases including diabetic nephropathy. Nevertheless, significant differences are observed in the susceptibility to develop hypertension-associated renal damage between individuals, racial groups and animal strains despite comparable hypertension. Recent studies employing a variety of genetic methods both in humans and in experimental models, have provided strong support for the potential importance of genetic factors and have suggested that genes influencing susceptibility to renal damage may be inherited separately from genes that influence blood pressure. However, due to the genetic complexity involved in a multifactorial trait such as the susceptibility to hypertensive renal damage, very limited progress has been achieved thus far in attempts to link such susceptibility to specific genetic mechanisms, chromosome regions and/or candidate genes. It is anticipated that the rapid recent advances in molecular genetic techniques and the simultaneous use of multiple complementary strategies, as is currently under way, will greatly facilitate this search and provide fundamental new insights into the pathogenesis of hypertensive renal damage.

Kidney-specific chromosome transfer in genetic hypertension: the Dahl hypothesis revisited.

BACKGROUND: A central dogma in the field of essential hypertension research is that the genetic transmission of increased blood pressure is determined solely by the genotype of the kidney. This concept is based in large part on studies in experimental rat models of spontaneous hypertension in which transplantation of a kidney from a hypertensive strain into a normotensive strain was reported to increase blood pressure, and transplantation of a kidney from a normotensive strain into a hypertensive strain was reported to decrease blood pressure. The enduring interpretation of these now classic experiments remains virtually unchanged from the view originally espoused a quarter century ago by Lewis Dahl, one of the founding fathers of the field of genetic hypertension research: "Blood pressure is determined by the genotype of the donor kidney and not the genotype of the recipient." METHODS: To test the Dahl hypothesis, we determined the blood pressure effects of selective intrarenal versus extrarenal exchange of single chromosome regions between the spontaneously hypertensive rat (SHR) and the normotensive Brown Norway (BN) rat. RESULTS: The replacement of a defined segment of chromosome 1 in the SHR with the corresponding chromosome region of the BN rat was sufficient to attenuate hypertension when selectively achieved either inside the kidney or outside the kidney. CONCLUSIONS: The current finding (1) demonstrates that naturally occurring genetic variants exist that can regulate blood pressure when selectively expressed outside the kidney as well as inside the kidney, and (2) compels reconsideration of the long-held view that in essential hypertension, the genetic transmission of increased blood pressure is determined solely by the genotype of the kidney.

Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model.

We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is approximately 10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141+/-3 mm Hg) and amlodipine (143+/-5 mm Hg) compared with untreated rats (188+/-5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (r=0.74 to 0.85, P<0.02). However, the slope of the relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7+/-0.2; P<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.

Differential salt-sensitivity in the pathogenesis of renal damage in SHR and stroke prone SHR.

The spontaneously hypertensive rat (SHR) and the stroke prone SHR (SHRsp) display contrasting susceptibilities to the development of the severe hypertensive lesions of malignant nephrosclerosis, both with aging and after the provision of a high salt intake on the background of a Japanese style "stroke prone" rodent diet. The SHR is relatively resistant, whereas the SHRsp is markedly susceptible. The responsible mechanisms remain controversial. Blood pressure (BP) radiotelemetry was used to investigate the interrelationship between salt intake, systolic BP, and renal damage in 8- to 12-week-old male SHR and SHRsp given a standard North American style diet for 6 weeks, a standard diet plus 1% NaCl as drinking water for 6 weeks, or an 8% NaCl diet plus tap water for 4 weeks. After 4 weeks, BP was significantly greater in the SHRsp compared to the SHR and was significantly more sensitive to supplemental salt in the SHRsp than in SHR. Average systolic pressures during week 5 (after 4 weeks on standard diet plus tap water, standard diet plus 1% NaCl, and 8% NaCl diet plus tap water) were 188.0 +/- 3.0 mm Hg, 207.3 +/- 5.6 mm Hg, and 226 +/- 9.4 mm Hg in SHRsp compared with 171.4 +/- 3.8 mm Hg, 180.6 +/- 3.8 mm Hg, and 190.3 +/- 5.0 mm Hg in SHR. In the absence of supplemental NaCl, both strains exhibited minimal evidence of hypertensive renal damage until about 16 weeks of age. A high salt intake resulted in the development of lesions of malignant nephrosclerosis (fibrinoid necrosis and thrombosis of small vessels and glomeruli) in the SHRsp but not in the SHR; semiquantitative histologic renal damage scores in SHRsp versus SHR being 10.4 +/- 2.0 versus 0.7 +/- 0.2 after 6 weeks of standard diet plus 1% NaCl, and 32.1 +/- 2.5 versus 0.7 +/- 0.4 after 4 weeks of 8% NaCl diet plus tap water; P < .001 for both comparisons. The development of more severe hypertension in salt-supplemented SHRsp could only partly account for the severity of renal damage in SHRsp, the increase in which was disproportionate to the increase in absolute BP. However, the rate of increase of BP was greater in the SHRsp and this might have contributed to the greater renal damage observed in the SHRsp. These data indicate that the contrasting genetic susceptibility to renal damage between SHR and SHRsp is mediated, at least in part, by a differential BP salt sensitivity.

Lack of evidence of blood pressure-independent protection by renin-angiotensin system blockade after renal ablation.

BACKGROUND: The superiority of renin-angiotensin system (RAS) blockade in providing renoprotection has been attributed to class-specific blood pressure "(BP)-independent" mechanisms. However, the conventional BP measurement methodology on which such conclusions are based is inherently limited for an accurate assessment of the fluctuating ambient BP profiles. The present studies were undertaken to rigorously examine the relationship of renoprotection to the antihypertensive effects of RAS blockade using chronic BP radiotelemetry in the 5/6 renal ablation model. METHODS: Rats with 5/6 renal ablation received either no treatment, the angiotensin-converting enzyme inhibitor benazepril at a dose of 25, 50, and 100 mg/L; or the angiotensin receptor antagonist losartan at a dose of 50, 120, and 180 mg/L of drinking H2O; and were followed for seven weeks. RESULTS: Glomerulosclerosis (GS) at sacrifice (approximately 7 weeks) demonstrated a close correlation with the average systolic BP in untreated (r = 0.76, N = 20), benazepril-treated (r = 0.80, N = 33), losartan-treated (r = 0.83, N = 32), or all animals combined (r = 0.81, N = 85, P < 0.0001 for all correlations). The slope of the relationship between GS and BP (percentage of increase in GS/mm Hg increase in BP) in untreated rats (0.7 +/- 0.14) was not significantly altered by either benazepril (0.96 +/- 0.13) or losartan (0.60 +/- 0.08), indicating that RAS blockade, by either agent, resulted in renoprotection that was proportionate to the achieved BP reductions. CONCLUSIONS: These data demonstrate that RAS blockade provides renoprotection in the rat remnant kidney model of progressive GS, primarily through "BP-dependent" and not "BP-independent" mechanisms.

Genetic isolation of a chromosome 1 region affecting susceptibility to hypertension-induced renal damage in the spontaneously hypertensive rat.

Linkage studies in the fawn-hooded hypertensive rat have suggested that genes influencing susceptibility to hypertension-associated renal failure may exist on rat chromosome 1q. To investigate this possibility in a widely used model of hypertension, the spontaneously hypertensive rat (SHR), we compared susceptibility to hypertension-induced renal damage between an SHR progenitor strain and an SHR congenic strain that is genetically identical except for a defined region of chromosome 1q. Backcross breeding with selection for the markers D1Mit3 and Igf2 on chromosome 1 was used to create the congenic strain (designated SHR.BN-D1Mit3/Igf2) that carries a 22 cM segment of chromosome 1 transferred from the normotensive Brown Norway rat onto the SHR background. Systolic blood pressure (by radiotelemetry) and urine protein excretion were measured in the SHR progenitor and congenic strains before and after the induction of accelerated hypertension by administration of DOCA-salt. At the same level of DOCA-salt hypertension, the SHR.BN-D1Mit3/Igf2 congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage have been trapped in the differential chromosome segment of the SHR.BN-D1Mit3/Igf2 congenic strain. This congenic strain represents an important new model for the fine mapping of gene(s) on chromosome 1 that affect susceptibility to hypertension-induced renal injury in the rat.

Class differences in the effects of calcium channel blockers in the rat remnant kidney model.

BACKGROUND: Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved. METHODS: Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three weeks after renal ablation. RESULTS: Although an excellent linear correlation was observed between the average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), significant protection was not achieved with any of the CCBs, but for different reasons. The antihypertensive effects of diltiazem were not sustained beyond the second week. Verapamil significantly reduced the average BP (144 +/- 4 mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5 vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on the relationship between BP and GS, the rank order of GS for any given BP elevation was as follows: felodipine > verapamil > diltiazem = untreated. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil on GS were attributable to the greater amplitude of BP fluctuations that was observed in the verapamil-treated rats such that for any given average BP, these rats were exposed to greater peak pressures as compared with the other groups. None of the CCBs had a significant effect on glomerular hypertrophy. CONCLUSIONS: These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.

Calcium-channel blockers and the progression of renal disease.

Effective blood pressure (BP) reduction is now generally recognized as a clinically proven strategy to retard the seemingly inexorable downhill progression of patients with diabetic and nondiabetic chronic renal disease. Although calcium-channel blockers (CCBs) are effective antihypertensive agents, the available experimental and clinical data are quite contradictory as to whether BP reduction achieved with CCBs provides the expected renoprotection. Blockade of the "L" type, voltage-gated Ca channels that mediate the BP reduction also concurrently impairs renal autoregulatory responses of the preglomerular vasculature. Because these renal autoregulatory resistance changes provide the primary protection against the transmission of systemic hypertension to the renal microvasculature, the adverse effects of CCBs on renal autoregulation counteract the beneficial effects on BP reduction. The degree of renoprotection achieved, therefore, depends on the balance between these two opposing effects. The data also indicate that there are probably important and clinically relevant differences between the classes of CCBs, with the dihydropyridine (DHP) CCBs most likely to have consistent deleterious effects on renal autoregulation. However, the available data also indicate that the adverse effects of DHP CCBs are not likely to be observed if BP is lowered well into the normotensive range, possibly through the use of combination therapies. Even when used as adjunctive therapy, close monitoring may be advisable to ensure BP normalization and the absence of any untoward effects on proteinuria and renal function.

Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury.

BACKGROUND: Angiotensin converting enzyme inhibitors have uniformly been shown to prevent the development both of proteinuria and of glomerulosclerosis in rats with a remnant kidney. Conversely, dihydropyridine calcium antagonists (DCA) have failed to demonstrate such a benefit in spite of causing an equivalent reduction in blood pressure. OBJECTIVE: To test the hypothesis that concomitant administration of an angiotensin converting enzyme inhibitor and a DCA would lead to a smaller increase both in proteinuria and in glomerulosclerosis relative to that caused by administration of a DCA alone at similar levels of blood pressure. METHODS: Experiments were carried out using Sprague-Dawley rats that had been subjected to five-sixths renal ablation. Animals were allocated randomly to one of four groups: control (no treatment), amlodipine (A rats), benazepril (B rats), or a combination of benazepril and amlodipine (B + A rats). We implanted intraperitoneal sensors for telemetric monitoring of the animal's blood pressure. Other parameters measured at baseline included proteinuria and inulin clearance. After approximately 7 weeks all of the parameters were remeasured and animals killed for morphologic assessment of the kidney. RESULTS: The B + A rats had lower levels of proteinuria than did the rats in group A (21 +/- 12 mg/day for B + A rats versus 59 +/- 24 mg/day for A rats, P < 0.05). The degree of glomerulosclerosis in the B + A rats was also reduced markedly compared with that in A rats (12 +/- 4% for B + A rats versus 43 +/- 12% for A rats, P < 0.05). Moreover, the results on proteinuria and glomerulosclerosis of B + A rats were similar to those for B rats. These differences could not be explained totally in terms of differences in blood pressure control (144 +/- 12 mmHg in A rats versus 132 +/- 13 mmHg in B + A rats, NS). CONCLUSION: The results were consistent with the observation that a combination of benzepril and amlodipine provides additional protection against renal injury compared with that provided by amlodipine alone. The mechanism for this benefit is not known.

Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer.

To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies (a) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and (b) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertension-induced renal injury in the rat.

Chronic alpha 1-adrenoreceptor stimulation increases DNA synthesis in rat arterial wall. Modulation of responsiveness after vascular injury.

Despite indirect evidence from studies using adrenergic antagonists or sympathectomy, catecholamines have never been shown directly to stimulate vascular smooth muscle cell (SMC) DNA replication in vivo. We studied whether a chronic infusion of catecholamine stimulates SMC replication in vivo in both uninjured arteries and arteries with a neointima formed after vascular injury. Animals were killed after 2 weeks of continuous infusion of bromodeoxyuridine (to label replicating DNA) and either phenylephrine, norepinephrine, or vehicle solution, starting early (third week) or late (ninth week) after balloon injury to the left common carotid artery. In catecholamine-infused animals, the uninjured carotid artery or thoracic aorta showed a marked increase in cross-sectional area (> 25%) and frequency of cells undergoing DNA synthesis among medial SMCs (4- to 10-fold) and endothelial cells (13-fold). With catecholamine infusion at 9 to 10 weeks after injury, the media or neointima of the injured carotid artery showed a smaller increase in SMC DNA replication (< or = 4-fold) than did the normal arterial media. In contrast, catecholamine infusion at 3 to 4 weeks did not cause significant SMC growth in the injured vessel. Catecholamine infusion caused labile elevations of systolic blood pressure. Taken together with our previous observation that alpha 1-blockers suppress arterial SMC replication without preventing severe hypertension in the rat, the present data strongly suggest that alpha 1-adrenoreceptors stimulate SMC DNA synthesis in vivo in arteries with or without intimal thickening, although not during the first weeks after balloon injury. The stimulation of DNA synthesis in vascular cells via the alpha 1-adrenoreceptor pathway may contribute to the vascular remodeling that occurs in hypertension and atherosclerosis.

Kallikrein excretion in Dahl salt-sensitive and salt-resistant rats with native and transplanted kidneys.

Urinary kallikrein excretion is decreased in Dahl salt-sensitive (S) vs. salt-resistant (R) rats, and several lines of reasoning suggest not only that decreased kallikrein excretion is a marker for salt-sensitive hypertension but also that kallikrein might play a pathogenic role. Because previous cross-transplantation studies have demonstrated that the kidney's genotype plays a role in determining the blood pressure of the recipient in Dahl S and R rats, the present experiments were designed to determine whether both blood pressure and urinary kallikrein excretion "traveled with the kidney" in transplantation. The Rapp strains of S and R were maintained on a low- NaCl (0.13%) diet until kidney transplantation (bilaterally nephrectomized recipients), at which time the diet was switched to high NaCl (7.8%). Sixteen days later, blood pressures (tail-cuff plethysmography) of the cross-transplant groups (R/S and S/R, indicating kidney genotype/recipient genotype) were nearly identical to each other and intermediate between the blood pressures of the control groups with transplanted kidneys (R/R and S/S). Renal function studies, performed on anesthetized rats 17 days after surgery, demonstrated that R kidneys had higher glomerular filtration rates, renal plasma flows, and urinary kallikrein excretion rates than S kidneys. These differences tended to be preserved in the cross-transplant groups, and therefore they must be genetically determined intrinsic differences between R and S kidneys. This was especially striking with respect to urinary kallikrein excretion. The rank order of urinary kallikrein excretion was R/R = R/S > S/R = S/S, which implies that it is completely determined by the genotype of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys.

Hypertensive mechanisms are postulated to play a major role in the progressive glomerulosclerosis (GS) after renal mass reduction. But, in contrast to converting enzyme inhibitors, BP reduction by calcium channel blockers, has not provided consistent protection. Radiotelemetric BP monitoring for 7 wk was used to compare nifedipine (N) and enalapril (E) in the rat approximately 5/6 renal ablation model. After the first week, rats received N, E, or no treatment (C). The overall averaged systolic BP in C (173 +/- 7 mmHg) was reduced by both E and N (P < 0.001), but E was more effective (113 +/- 2 vs. 134 +/- 3 mmHg, P < 0.01). GS was prevented by E (2 +/- 1 vs. 26 +/- 5% in C) but not by N (25 +/- 6%). GS correlated well with the overall averaged BP in individual animals of all groups, but the slope of the relationship was significantly steeper in N compared with C+E rats (P < 0.02), suggesting greater pressure transmission to the glomeruli and GS for any given BP. Since autoregulatory mechanisms provide the primary protection against pressure transmission, renal autoregulation was examined at 3 wk in additional rats. Autoregulation was impaired in C rats, was not additionally altered by E, but was completely abolished by N. These data demonstrate the importance of autoregulatory mechanisms in the pathogenesis of hypertensive injury and suggest that calcium channel blockers which adversely affect pressure transmission may not provide protection despite significant BP reduction.

The mesangium in the long-term remnant kidney model.

Hypertension, which develops during the course of the remnant kidney model (RK), plays a major role in the pathogenesis of glomerular injury. Morphologic studies have implicated mesangial injury and dysfunction in the pathogenesis of glomerular scarring in the hypertensive RK, but a separate role for mesangial injury has not been demonstrated in the absence of systemic hypertension. We studied glomerular injury and mesangial structure and function in a long-term (26 weeks) normotensive rat RK by using morphologic and morphometric studies and mesangial clearance of aggregated rate IgG (AggRaIgG). After right nephrectomy and infarction of two thirds of the left kidney (RK), the rats gained weight and developed mild but stable elevations of serum creatinine and urinary protein excretion as compared with the sham-operated controls (SHAM) over the course of the study. Systolic blood pressure was only mildly elevated (129 +/- 9 mm Hg versus 114 +/- 8 mm Hg, p < or = 0.05). Virtually all of the RK rats developed glomerular scarring, with segmental sclerosis in 8% +/- 8% and global sclerosis in 2% +/- 2% of the glomeruli, whereas the SHAM animals had no glomerular scarring, but we found limited morphologic evidence of mesangial cell injury in RK. The RK glomeruli were hypertrophied as compared with glomeruli in SHAM rats (glomerular diameter 199.3 +/- 15.2 microns versus 160.5 +/- 4.4 microns, p < or = 0.05), and the accompanying increase in capillary volume was caused by an increase in capillary length without a significant increase in diameter. Despite the glomerular hypertrophy and increased initial uptake in RK, the mesangial clearance of AggRaIgG was similar between RK and SHAM rats. We conclude that WKY rats with RK develop a progressive glomerulopathy characterized by segmental glomerulosclerosis, proteinuria, and mild hypertension. The normal mesangial clearance function and the absence of mesangial pathology in the hypertrophic remnant glomeruli mitigate against a role for mesangial injury in this form of experimental renal disease.

Radiotelemetric BP monitoring, antihypertensives and glomeruloprotection in remnant kidney model.

The mechanisms by which antihypertensives exert a glomeruloprotective effect in the remnant kidney model remain controversial. Based on periodic tail-cuff BP measurements, the variable glomeruloprotective efficacy of antihypertensive agents has been ascribed to mechanisms other than or in addition to their ability to lower BP. To more precisely define the relationship between BP control and glomeruloprotection, systolic BP was continuously monitored radiotelemetrically at 10-minute intervals for approximately 65 days in rats after approximately 5/6 renal ablation. Rats with remnant kidneys received either no therapy or one of three antihypertensive regimens in their drinking water after the first week: enalapril, a triple therapy regimen (reserpine, hydralazine, hydrochlorothiazide); or a high dose triple therapy regimen. Although all antihypertensive regimens significantly lowered BP, considerable interanimal variability was observed. Additionally, marked lability of BP was present in both untreated and treated rats. Glomerular injury in individual animals (N = 34) was very strongly correlated with their overall averaged systolic BP during the final eight weeks (r = 0.91) and with the frequency of systolic BP readings > 150 mm Hg (r = 0.89). These data do not provide evidence of a therapeutic advantage for any of the regimens independent of their antihypertensive effects but indicate that the glomeruloprotective efficacy of these antihypertensive regimens is directly proportional to their antihypertensive efficiency.

Renal ablation acutely transforms 'benign' hypertension to 'malignant' nephrosclerosis in hypertensive rats.

The present studies examine the consequences of the hemodynamic changes associated with approximately 5/6 renal ablation in the spontaneously hypertensive rat (SHR), a strain that normally does not exhibit evidence of vascular and/or glomerular injury until late in life despite significant hypertension. Control SHR with intact renal mass demonstrated normal renal autoregulation and an absence of vascular or glomerular injury. Renal mass reduction resulted in an initial expected decrease in renal blood flow to the remnant kidney at 5 days (2.8 +/- 0.3 mL/min) compared with control SHR (8.1 +/- 0.7 mL/min) at a mean arterial pressure of approximately 160 mm Hg (P < .01). By 10 to 14 days after renal ablation, marked renal vasodilation was observed (renal blood flow 8.3 +/- 0.8 mL/min at mean arterial pressure of approximately 160 mm Hg) along with severe impairment of autoregulatory ability. Striking and florid vascular injury to interlobular arteries and afferent arterioles had also developed by 10 to 14 days after approximately 5/6 renal ablation in a pattern similar to that observed in "malignant" hypertension, despite systolic blood pressures that were not significantly different from those in control SHR (168.2 +/- 6.4 versus 165.6 +/- 4.7 mm Hg). An additional group of SHR that were made normotensive with a triple-therapy antihypertensive regimen before and after approximately 5/6 renal ablation also exhibited hemodynamic changes similar to those in the untreated rats at 10 to 14 days but did not develop significant vascular or glomerular injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury.

The hypertension, proteinuria, and glomerulosclerosis that develop in the remnant kidney model (uninephrectomy plus infarction of approximately 2/3 of the other kidney) have been generally considered to represent the adverse consequences of a severe reduction in nephron number. To differentiate the blood pressure (BP) responses to infarction from those of reduced renal mass per se, BP was continuously monitored radiotelemetrically in rats whose total renal mass was reduced by 2/3 (infarction) and by 5/6 (infarction or surgical excision of both poles) and in sham-operated controls. Hypertension only developed in the two infarcted groups. Overall averages of systolic BP monitored every 10 min over 6 wk were 144 +/- 8 and 156 +/- 5 mm Hg in the 2/3 and 5/6 infarction groups (N = 10 each), respectively, as compared with 120 +/- 2 mm Hg (N = 12) in the approximately 5/6 surgical excision group (P < 0.01) and 117 +/- 5 mm Hg (N = 8) in controls. Changes in kidney weights, glomerular volumes, RBF, GFR, and renal autoregulatory ability after renal mass reduction by the two methods were qualitatively similar in additional animals from each group monitored for 2, 4, or 6 wk without radiotelemetry. Significant proteinuria and glomerulosclerosis only developed in the two infarction (hypertensive) groups. At 6 wk, 18 +/- 4 and 19 +/- 3% of the glomeruli exhibited injury in the 2/3 (N = 22) and the 5/6 infarction groups (N = 21), respectively, in contrast to 3 +/- 1% glomerular injury in the 5/6 surgical excision group (N = 24) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous telemetric blood pressure monitoring and glomerular injury in the rat remnant kidney model.

The pathogenesis of glomerular injury in the remnant kidney (RK) model remains controversial. Increased glomerular transmission of systemic hypertension has been postulated to be an important pathogenic mechanism, but the precise relationship between systemic pressures and glomerular injury has not been defined because of the limitations of the tail-cuff method. Systolic blood pressure (BP) was continuously recorded radiotelemetrically at 10-min intervals for 6 wk in rats after approximately 5/6 renal ablation (n = 16) or sham ablation (n = 7). Overall mean systolic BP in RK rats was significantly higher than sham (138 +/- 3.3 vs. 117 +/- 1.3 mmHg, P < 0.01). Additionally, marked lability of systolic BP was observed in RK rats as compared with sham rats. Glomerular injury was essentially confined to RK rats, but the percentage of injured glomeruli ranged between 1 and 55%. Glomerular injury in individual animals was strongly correlated (r = 0.88) with the mean systolic BP during the last approximately 4 wk and with the frequency of systolic BP readings of > 140 mmHg. These data strongly suggest that transmission of systemic hypertension to the renal microvasculature plays a predominant role in the pathogenesis of glomerular injury in the RK model and also support the potential usefulness of the radiotelemetric technique to investigate hypertensive target organ injury.