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Biomedical subjects

I Ichikawa

Publications and source records attributed to I Ichikawa.

At least 109 records · Page 6Linked to original sources
PubMed1990

A regulatory role for large vessels in organ circulation. Endothelial cells of the main renal artery modulate intrarenal hemodynamics in the rat.

After arterial denudation by external rubbing of the left main renal artery, we assessed renal plasma flow rate (RPF) and glomerular filtration rate (GFR) in left and right kidneys of Munich-Wistar rats before and after intravenous infusion of acetylcholine (ACH), atrial natriuretic peptide (ANP), or nitroprusside (NP). In the right kidney RPF and/or GFR increased in response to both endothelium-derived relaxing factor (EDRF)-dependent (i.e., ACH) and -independent vasodilators (i.e., ANP and NP); on average, RPF rose by 22 +/- 4% (P less than 0.005), 19 +/- 10% (P less than 0.005), and 37 +/- 12% (P greater than 0.05), respectively. By contrast, in the left kidney RPF failed to increase after ACH (falling by 23 +/- 10%, P less than 0.001) and rose only in response to ANP and NP. To further evaluate the main renal artery's contribution to renal vasodilation, ACH and another EDRF-dependent agent, histamine, were infused through a micropipette into either the proximal or distal portions of the endothelium-intact renal artery. Proximal infusion of ACH led to increases in RPF and GFR, on average by 8 +/- 2% (P less than 0.025) and 10 +/- 3% (P less than 0.01), while bypassing the arterial endothelium by distal infusion failed to increase RPF and GFR, which fell by 24 +/- 6% (P less than 0.025) and 22 +/- 6% (P less than 0.005), respectively. Similarly, proximal infusion of histamine increased RPF by 12 +/- 3% (P less than 0.05), while distal infusion was virtually without effects on plasma flow. Micropuncture study during intravenous ACH infusion revealed significantly higher afferent and efferent arteriolar resistances and lower ultrafiltration coefficients in denuded versus nondenuded kidneys. These data indicate that the main renal artery is a major regulator of renal blood flow and vascular resistances. Similar to other endothelium-derived substances, EDRF may be elaborated mainly by large vessels and may act on the downstream microcirculatory systems, which determine organ blood flow and transcapillary fluid transfer.

Acetylcholine↗
PubMed1990

Mechanism of the unique susceptibility of deep cortical glomeruli of maturing kidneys to severe focal glomerular sclerosis.

The alterations in single glomerular hemodynamics, glomerular size, and development of glomerular sclerosis after subtotal nephrectomy were assessed in approximately 32-d-old young and greater than 3-mo-old adult Munich-Wistar rats. In 6 wk, young rats developed more pronounced glomerular sclerosis and more marked elevation in blood urea nitrogen. The deep (versus superficial) cortical region of young rats was characterized by having a greater number of glomeruli with advanced sclerosis. Single nephron glomerular filtration rate of superficial glomeruli of the young increased to a much greater extent than whole kidney glomerular filtration rate, whereas there were comparable post-subtotal nephrectomy increases in whole kidney glomerular filtration rate in these two age groups, indicating that the deep glomeruli were exposed to a lesser hemodynamic load than were the superficial. Since the remnant nephrons of young and adult rats achieved equally high glomerular pressures and comparably large glomerular size shortly after subtotal nephrectomy, the unique susceptibility of young glomeruli to sclerosis is attributed to the intrinsic property of these glomeruli, rather than the abnormal hemodynamics or stimuli promoting hypertrophy and mesangial matrix accumulation imposed upon the glomeruli.

Age Factors↗
PubMed1989

Effects of antihypertensive drugs on glomerular morphology.

We quantitated the glomerular size and the degree of sclerosis simultaneously in individual glomeruli with the use of three-dimensional histological analysis on serial sections obtained from remnant kidneys with highly heterogeneous glomerular lesions after subtotal nephrectomy (sNPX). Four to six weeks after sNPX (Group I, N = 7), 90% of glomeruli had mild sclerosis (sclerosis index, SI; less than 1.5 on a 0 to 4 scale) with a strong positive correlation between the maximum planar area of glomerulus (PAmax) versus SI. Twelve weeks after sNPX (Group II, N = 6) more than 50% of glomeruli had advanced sclerosis (average SI:1.88), and a significant positive correlation was again found between PAmax and SI in glomeruli with mild to modest sclerosis (SI less than 1.5), whereas these two variables were correlated inversely in glomeruli with advanced sclerosis. Administration of enalapril (50 mg/liter drinking water) or hydralazine (200 mg/liter) + hydrochlorothiazide (50 mg/liter) for 12 weeks (Group III, N = 12) markedly attenuated the sclerosis to comparable degrees (average SI: 0.15 vs. 0.22). The former antihypertensive therapy decreased glomerular capillary hydraulic pressure (PGC) to normal range, whereas the latter triple drug therapy was largely without effect on PGC. Of note, the positive correlation between SI and PAmax remained unaffected by these anti-hypertensive drugs. SI of the glomeruli from both treated groups was expressed as a first-order function of PAmax. The correlation coefficient is identical to that found in non-treated Group II remnant glomeruli, so that the degree of sclerosis is mathematically uniquely correlated with the glomerular size, regardless of drug treatment. Thus, within a given remnant kidney, the magnitude of glomerular hypertrophy has a direct correlation with the degree of sclerosis, while the altered glomerular hemodynamic pattern has little modulatory role in determining the magnitude of this hypertrophy. Enalapril and triple drug therapy, at equi-depressor doses in regard to systemic blood pressure, had identical potency in sparing glomerular structure. The primary determinant for this antisclerotic potency appears to be related to the drugs' potency to inhibit glomerular growth rather than an effect on the abnormal hemodynamics which develop in the glomerulus.

Animals↗
PubMed1989

Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis.

In a variety of recent studies in animals with chronic renal diseases, investigators have found a tight correlation between the elevation in glomerular pressures and flows versus glomerular hypertrophy. To investigate a possible causal link between the glomerular hyperfunction and hypertrophy, we studied the functional and morphological sequelae of nephrectomy and those of unilateral ureteral diversion (UD) into the peritoneal cavity (that is, removal of renal clearance function while keeping the kidney tissue in situ). In all nine experimental groups of 54 Munich-Wistar rats, 2/3 of the renal mass was removed from the left kidney by ligation of two or three branches of the left renal artery. In addition, right nephrectomy (NPX) was performed in Groups 1B, 2B and 3B or UD in Groups 1C, 2C and 3C. The right kidney was left untouched in control groups, Groups 1A, 2A and 3A. Micropuncture measurements and histological studies were performed at four days (Groups 1A, 1B and 1C), two weeks (Groups 2A, 2B and 2C) or four weeks (Groups 3A, 3B and 3C). At both four days and two weeks, NPX and UD groups had marked and comparable degrees of glomerular hypertension, hyperperfusion and hyperfiltration compared to the control group in the left kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Role of endogenous atrial natriuretic peptide in congestive heart failure.

Effects of purified rabbit anti-rat 25-amino acid atrial natriuretic peptide (ANP) immunoglobulin G (IgG) on renal sodium excretion and glomerular filtration rate were studied in a rat model of congestive heart failure (CHF) having high circulating ANP levels. Bolus injection of anti-ANP into anesthetized rats with surgically induced myocardial infarction (MI) significantly and markedly depressed both absolute and fractional urinary excretion of sodium without affecting mean arterial pressure or glomerular filtration rate. By contrast, anti-ANP failed to affect these renal functions in normal or acutely water-deprived rats. Nonimmune IgG did not affect renal function in MI rats. These results indicate that high circulating ANP plays an important role in sodium homeostasis of congestive heart failure: by promoting sodium excretion, ANP opposes the tendency of sodium retention characteristic of CHF.

Animals↗
PubMed1989

Impaired preservation of GFR during hypotension in preexistent renal hypoperfusion.

Autoregulation of renal blood flow and filtration rate was studied using micropuncture technique in Munich-Wistar rats with acute water deprivation (AWD) or congestive heart failure (CHF). In the first set of experiments, reduction of renal perfusion pressure to approximately to 70% of its initial value resulted in uncoupling of glomerular plasma flow rate and single-nephron glomerular filtration rate (GFR) (i.e., disproportionally profound fall in the latter) in AWD and CHF rats, whereas both indices changed little in normal control (NC) rats. The profound decrease in single-nephron GFR in AWD and CHF rats was primarily due to a reduction in glomerular capillary pressure (change from base-line value was -29 +/- 2% in AWD, -27 +/- 1% in CHF, and -8 +/- 2% in NC). This profound fall in glomerular capillary pressure in AWD and CHF rats was associated with a reduction in efferent arteriolar resistance, which contrastingly increased in NC. To investigate the mechanism underlying this unique efferent arteriolar responsiveness in AWD and CHF, the response of renal arterioles to exogenous angiotensin II was examined in separate groups of AWD, CHF, and NC. There was a markedly attenuated efferent arteriolar vasoconstrictive response in AWD and CHF (the change of efferent arteriolar resistance in both groups was some 5% of that in NC). Thus impairment in the ability to preserve GFR in these two conditions is attributed, at least in part, to altered efferent arteriolar response in the face of reduced renal perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Glomerular dysfunction induced by polymorphonuclear leukocyte-derived reactive oxygen species.

The role of reactive oxygen species (ROS) derived from polymorphonuclear leukocytes (PMN) on glomerular microcirculation was evaluated in Munich-Wistar rats. To induce local activation of PMN, phorbol myristate acetate (PMA, 20 micrograms) was infused unilaterally into the renal artery in six rats and the micropuncture study was performed 18 h later. In these animals, there was a significant (P less than 0.005) glomerular PMN accumulation in the PMA-injected kidney (on average 2.2 +/- 0.2 per 3-microns glomerular section) compared with the contralateral kidneys of the same rats or the vehicle-treated kidneys from a separate group of seven rats (0.2 +/- 0.1 and 0.2 +/- 0.1 per 3-microns glomerular section, respectively). In the PMA-treated kidneys, whole kidney glomerular filtration rate (GFR) was significantly reduced compared with that of the contralateral kidney of the same rats or vehicle-treated kidneys of a separate group of rats (0.61 +/- 0.04, 1.18 +/- 0.05, and 1.02 +/- 0.04 ml/min, respectively, P less than 0.05). This PMA-induced reduction in GFR was largely prevented by pretreatment of rats with a scavenger of hydrogen peroxide, catalase (1,000 kU; n = 7), or by depletion of PMN with an intravenous nitrogen mustard administration (1.7 mg/kg; n = 7). The reduction of GFR in the PMA-treated kidneys therefore appeared to be mediated by the ROS derived from activated PMN. The micropuncture measurement of glomerular microcirculatory dynamics in PMA-treated kidneys without above pretreatment revealed that there was a profound fall in single-nephron GFR and ultrafiltration coefficient and an increase in renal arteriolar resistances (greater in efferent than afferent arteriole).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Glomerular actions of endothelin in vivo.

In Munich-Wistar rats, a micropipette was inserted into a first-order branch of the left main renal artery and continuously infused with human/porcine endothelin (0.4 ng/min). Micropuncture measurements revealed substantial differences within the cortical microcirculation of the same left kidney: SNGFR was some 35% lower in glomeruli exposed to endothelin compared with non-endothelin-perfused glomeruli (P less than 0.005). Similarly, glomerular plasma flow rate was some 38% lower in the endothelin-exposed glomeruli (P less than 0.001). The hypoperfusion and hypofiltration in the endothelin-exposed glomeruli reflected an increase in resistances in the afferent and efferent arterioles. There was no difference in the value of the glomerular capillary ultrafiltration coefficient between the two populations of glomeruli. We also studied kidneys that underwent 25 min of renal artery clamping 48 h before study. Antiendothelin antibody infused into one of the branches of the main renal artery ameliorated the vasoconstriction characteristic of postischemic nephrons: within the cortical microcirculation, the SNGFR in glomeruli exposed to antiendothelin antibody was 27.0 +/- 3.1 nl/min as compared with 17.4 +/- 1.7 measured in glomeruli not perfused with the antibody (P less than 0.001). Similarly, glomerular plasma flow rate was higher in the glomeruli exposed to antiendothelin antibody (128.7 +/- 14.4 nl/min vs. 66.6 +/- 5.6, P less than 0.005). Resistances in both the afferent and efferent arterioles were substantially lower in the antibody-exposed glomeruli. It is, therefore, suggested that endothelin, presumably released from damaged endothelium, may play an important intermediary role in the hypoperfusion and hypofiltration observed in postischemic kidneys.

Animals↗
PubMed1988

The progression of renal disease.

The diversity of its causes, the unpredictability of its clinical course, and our expanding knowledge of the conditions that may exacerbate or retard its progression suggest that glomerular sclerosis cannot be attributed to a single aberration in glomerular physiology. Nonetheless, the welter of clinical and experimental observations is beginning to yield a pattern. Agents or conditions injurious to glomerular epithelium tend to cause glomerular sclerosis. Agents or conditions that induce short-term or long-term activation of mesangial cells may lead to glomerular sclerosis. Indeed, one contribution of the healthy epithelium may be to serve as a tonic inhibitor of the intraglomerular processes arising from mesangial-cell activation. Long-term activation of the mesangium is associated with the proliferation and infiltration of cells and with the expansion of the mesangial matrix--the antecedents of sclerosis. We anticipate that different diseases associated with glomerular sclerosis will be found to depend to varying extents on these two potential mechanisms of sclerosis. Beyond a certain threshold of glomerular injury, glomerular diseases share an additional factor: the capacity of both intrinsic cells and infiltrating cells to alter the microenvironment of the glomerulus so that sclerosis progresses inexorably long after the disappearance of the initiating insult. Several potential risk factors may contribute to the progression of chronic renal disease. These factors include systemic hypertension, proteinuria, hyperlipidemia, high protein intake, and probably conditions that lead to glomerular hypertrophy. Interventions designed to minimize the potential contribution of these factors to the progression of renal insufficiency may halt or slow the loss of function of the kidney. Clinical trials designed to examine the effects of these factors on the progressive course of renal insufficiency will help to establish their role and relative importance in humans.

Humans↗
PubMed1988

Effect of heparin on the glomerular structure and function of remnant nephrons.

The development of glomerular structural abnormalities in remnant nephrons, after ablation of renal mass (subtotal nephrectomy), in rats is largely prevented by the daily injection of heparin. To investigate if this protective effect of heparin is due to attenuation of glomerular hyperperfusion, hypertension and hyperfiltration, which develop in remnant nephrons soon after subtotal nephrectomy, we measured various parameters of glomerular hemodynamics at two weeks (Group 1) and four weeks (Group 2) after removal of 1-3/4 of total kidney mass in heparin-treated (Groups 1A and 2A) and untreated (Groups 1B and 2B) Munich-Wistar rats. When compared to normal non-nephrectomized rats (Group 1C), the values for glomerular capillary hydraulic pressure (PGC), glomerular plasma flow rate (QA) and single nephron filtration rate (SNGFR) in remnant nephrons were found to be markedly and similarly elevated in both Groups 1A and 1B, averaging 71 +/- 4 and 73 +/- 4 mm Hg, 229 +/- 41 and 176 +/- 13 nl/min, 58.9 +/- 6.4 and 60.8 +/- 7.8 nl/min, respectively. Thus, glomerular hemodynamic parameters two weeks after subtotal nephrectomy did not differ between untreated and heparin-treated rats. Likewise, heparin treatment did not decrease the values of PGC and SNGFR assessed four weeks after subtotal nephrectomy, with the average values being 65 +/- 2 mm Hg and 83.8 +/- 7.1 nl/min in Group 2A versus 62 +/- 4 mm Hg and 63.7 +/- 6.5 nl/min in Group 2B.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of diet, age and sex on the renal response to immune injury in the rat.

We investigated the effect of three factors, namely dietary protein intake, age and sex, on the susceptibility of the renal glomerulus to the binding of antiglomerular basement membrane antibody (anti-GBM) in the early (heterologous) phase of anti-GBM nephritis, and the consequent reduction in glomerular filtration rate (GFR) as measured by inulin clearance (CIn). The effect of diet was examined in approximately equal to 8 week-old female Munich-Wistar rats fed a 40% high (HP) or a 6% low (LP) protein diet, and that of sex and age in male and female rats, 6 week or 10 month old. Following an intravenous dose (3 to 20 micrograms/g body wt) of radiolabeled nephritogenic anti-GBM, assessment of glomerular function was followed by quantitation of anti-GBM binding (values corrected for GBM surface area) in isolated glomeruli. At a given plasma level of antibody, the degree of binding of anti-GBM was slightly but significantly higher in HP than LP-fed rats; the decrease in GFR was significantly more pronounced in HP than LP-fed animals. The amount of anti-GBM binding was significantly greater in adult than young animals; however, the consequent decrease in GFR was more pronounced in the young than adult animals. Sex dependency was not discernible in anti-GBM binding or reduction in GFR. In all of the above experimental groups, the degree of anti-GBM binding was closely correlated with the plasma level of anti-GBM, but not with effective renal plasma flow rate, measured by PAH clearance. Separate groups of rats were subjected to experimental manipulation of single nephron GFR, glomerular capillary hydraulic pressure and glomerular plasma flow rate, by partial aortic constriction and saralasin administration. This set of experiments, using a tracer amount of non-nephritogenic anti-GBM, revealed that glomerular anti-GBM binding is independent of any of the above parameters. The studies indicate that dietary protein intake and age, but not sex, are among the factors determining the susceptibility of the glomerulus to acute immune injury. Since the binding of anti-GBM is determined by the affinity property of the glomerulus per se, and not by the prevailing hemodynamic pattern, the observed dependence of susceptibility to functional impairment on age and protein intake appears to also reflect a property of the glomerulus, which is influenced by age and the degree of dietary protein intake.

Aging↗
PubMed1988

Serial micropuncture analysis of single nephron function in subtotal renal ablation.

We developed a series of methodology to analyze function-structure relationship at single nephron level in animal models of chronic renal disease. Micropuncture measurements were repeated to measure single nephron GFR (SNGFR) and glomerular capillary hydraulic pressure (PGC) in the same nephrons, and subsequently examine the morphology of these glomeruli by serial section histological analysis. Using this approach, a potential causal link between early functional pattern and late structural abnormalities was examined in glomeruli of 10 Munich-Wistar rats up to six weeks after surgical removal of 5/6 total renal mass. After two weeks all SNGFR and PGC values increased uniformly but to varying degrees within each remnant kidney. Thereafter, values for SNGFR were highly variable, many declining while other increased in the same kidney. PGC showed an initial increase with subsequent decrease by four to six weeks. Serial section histological analysis of these same glomeruli revealed that the extent of glomerular sclerosis positively correlated with the functional deterioration, that is, the degree of reduction in SNGFR (P less than 0.01). However, the degree of sclerosis had no tendency to correlate with the levels of SNGFR or PGC recorded in early stage. These studies indicate that pathophysiologic mechanisms other than, or in addition to, early hyperfunction are involved in determining the extent of glomerular structural damage in this model of chronic renal failure.

Animals↗
PubMed1988

Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist.

Leukotriene D4, a potent biologically active lipoxygenase derivative of arachidonic acid in activated leukocytes, depresses the glomerular capillary ultrafiltration coefficient (Kf) and contracts mesangial cells in culture. We therefore investigated its potential role in mediating the reduction in nephron filtration rate seen after induction of experimental nephrotoxic serum (NTS)-induced glomerulonephritis in the rat. Micropuncture measurements were performed in euvolemic Munich-Wistar rats 2 h after i.v. administration of 0.8 ml of rabbit serum (group 1, n = 6), 0.8 ml of rabbit anti-rat glomerular basement membrane antibody in the absence (group 2, n = 8), or presence (group 3, n = 7) of the new highly specific LTD4 receptor antagonist SK&F 104353. Quantitation of antibody binding and neutrophil infiltration revealed no differences between groups 2 and 3. Antagonism of endogenous LTD4 actions, however, was associated with prevention of the NTS-induced fall in SNGFR because of the abrogation of the fall in Kf which characterizes this form of experimental glomerulonephritis. Antagonism of endogenous LTD4 had no effect on the NTS-induced increases in pre- and postglomerular arteriolar resistances, and did not affect nephron plasma flow rate or net transcapillary hydraulic pressure difference. The observed highly localized protective action of the LTD4 antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD4, likely originating from infiltrating leukocytes, in the pathophysiology of this form of glomerulonephritis.

Acute Disease↗
PubMed1988

Serial micropuncture analysis of glomerular function in two rat models of glomerular sclerosis.

We have recently developed a micropuncture technique to assess repeatedly function of the same nephrons in chronic renal disease and subsequently examine the morphology of their glomeruli by serial thin-section histological analysis. Using this approach, a potential causal linkage between early functional patterns and late structural abnormalities was examined in glomeruli of two established rat models of glomerular sclerosis. The models are (a) puromycin aminonucleoside (PAN) administration in unilaterally nephrectomized Munich-Wistar rats and (b) adriamycin (ADM) treatment in nonnephrectomized Munich-Wistar rats. Single nephron GFR (SNGFR) and glomerular capillary hydraulic pressure (PGC) were measured repeatedly for 8 (PAN rats) or 31 wk (ADM rats). In all animals studied, values for PGC remained at, or slightly below, levels measured before PAN or ADM administration. SNGFR values declined progressively in all glomeruli in PAN rats. Although some glomeruli in ADM rats had an increase in SNGFR above levels observed in nonnephrectomized control rats, these hyperfiltering glomeruli did not have abnormally high PGC nor did they exhibit glomerular sclerosis at the completion of the study. Histological analysis revealed the existence of a significant inverse correlation between the degree of sclerosis and SNGFR assessed at the time of sacrifice in both PAN and ADM groups. Chronic administration of captopril, an angiotensin I converting enzyme inhibitor, in PAN rats substantially attenuated development of glomerular sclerosis without affecting PGC in earlier stages. The observations in these models indicate that glomerular hyperfiltration and hypertension are not required for the development of glomerular sclerosis in renal diseases, and angiotensin I converting enzyme inhibitor can exert its protective effect independently of its effect on glomerular capillary pressure.

Animals↗