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Biomedical subjects

P Rohmeiss

Publications and source records attributed to P Rohmeiss.

At least 19 recordsLinked to original sources
PubMed2001

Treatment of chronic renal allograft rejection in rats with a low-molecular-weight heparin (reviparin).

BACKGROUND: Low-molecular-weight heparin (LMWH) has been shown to prolong survival of rat cardiac allografts independently from immunosuppressive treatment. Furthermore, long-term treatment reduces the development of chronic graft vascular disease after experimental heart transplantation. The aim of the present study was to determine whether treatment with the LMWH reviparin has a beneficial effect on chronic rejection in a rat renal allograft model. METHODS: Kidneys of Fisher (F344) rats were transplanted into unilaterally nephrectomized Lewis (LEW) recipients. LEW-->LEW isografts served as controls. Animals were treated with cyclosporine (5 mg/kg/d) for the first 10 days. Nephrectomy of the remaining kidney was performed after 10 days. Allografted animals were treated either with reviparin (2 mg/kg/d subcutaneously) for 24 weeks (Allo-24), from week 12 to 24 (Allo-12), or with vehicle for 24 weeks. Proteinuria was determined at regular intervals. Kidneys were harvested after 24 weeks for histomorphological and immunohistochemical evaluation. RESULTS: No major bleeding complications were observed in reviparin-treated animals. Proteinuria was significantly reduced in allografted animals both by early as well as by late-onset treatment with reviparin. Transplant glomerulopathy was diminished in Allo-24 and in Allo-12 groups compared to vehicle-treated animals, whereas tubulointerstitial inflammation was influenced only in animals immediately treated with reviparin. Immunohistochemical studies demonstrated a marked reduction of renal monocyte and T-cell infiltration as well as expression of MHC II by treatment with reviparin. CONCLUSIONS: Treatment with the LMWH reviparin significantly improved chronic renal allograft rejection in the F344-to-LEW rat model, both after early and late start of therapy. Although the exact mechanisms of this beneficial effect remain unclear, our data offer a potential new therapeutical approach for prevention of chronic allograft nephropathy.

Animals↗
PubMed2001

Therapeutic administration of an endothelin-A receptor antagonist after acute ischemic renal failure dose-dependently improves recovery of renal function.

Endothelin (ET) is known to reduce glomerular filtration rate and renal blood flow and is a possible mediator of acute renal failure (ARF). We recently demonstrated that the administration of a very high dose of the ET(A)-receptor antagonist LU 135252 (LU) accelerates recovery from postischemic acute renal failure by an improvement of renal perfusion in a rat model. The aim of this study was to investigate whether this effect of LU is dose dependent. ARF was induced in rats by clamping both renal arteries. Serum creatinine was measured and endogenous creatinine clearance and fractional sodium excretion were calculated up to 4 days after acute ischemia. Rats were treated either with the selective ET(A)-receptor antagonist LU or with vehicle only after reperfusion. LU in doses of 0.5, 1, or 5 mg/kg per day was infused via a femoral vein using an osmotic minipump. Serum creatinine was increased approximately eightfold after induction of ARF. Creatinine clearance decreased from 4.35 +/- 0.26 ml/min before acute renal failure to 0.15 +/- 0.02, 0.54 +/- 0.1, and 1.49 +/- 0.19 ml/min on days 1, 2, and 4 after ischemia (p < 0.05). Fractional sodium excretion increased from baseline 0.77 +/- 0.05% to 7.5 +/- 1.21 % on day 1 and 8.53 +/- 1.34% on day 2 (p < 0.05). Treatment with LU improved kidney function dose relatedly. There was no significant change in creatinine clearance, but compared with controls, with doses of 0.5 mg/kg per day and 1 mg/kg per day (0.28 +/- 0.1, 0.88 +/- 0.22, and 1.93 +/- 0.24 ml/min on days 1, 2, and 4), we noted a significant increase under 5 mg/kg per day (day 1: 0.62 +/- 0.17 ml/min; day 2: 1.38 +/- 0.26 ml/min; and day 4: 2.45 +/- 0.21 ml/min; p < 0.05). Fractional sodium excretion decreased dose-relatedly to a maximally 2.48 +/- 0.58% on day 1 and 2.25 +/- 0.71 % on day 2 after treatment with the highest dose when compared with untreated control rats (p < 0.05). Our data support the hypothesis that ET plays a major role in ARF. It can be concluded from these results that recovery from ischemic ARF is significantly and dose-dependently enhanced by treatment with a selective ET(A)-receptor antagonist.

Acute Kidney Injury↗
PubMed2000

Improvement of renal dysfunction in rats with chronic heart failure after myocardial infarction by treatment with the endothelin A receptor antagonist, LU 135252.

OBJECTIVE: To investigate the role of an activated endothelin system in the renal dysfunction observed in chronic heart failure after myocardial infarction. METHODS: In rats with heart failure after myocardial infarction and in sham-operated animals (Sham), we investigated the effect on renal function of long-term oral treatment with the selective endothelin A (ETA) receptor antagonist, LU 135252 (30 mg/kg per day; groups MI/LU and Sham/LU) or placebo (groups MI/P, Sham/P). Only animals with extensive myocardial infarction (at least 46% of the left ventricle) were included in the study. Infarct size was matched between groups MI/P and MI/LU. Endogenous creatinine clearance, fractional sodium excretion, and plasma and urinary concentrations of endothelin were determined 12 weeks after myocardial infarction. RESULTS: Endogenous creatinine clearance was significantly lower in group MI/P than in group Sham/P (MI/P: 0.64 +/- 0.05, Sham/P: 0.81 +/- 0.04 ml/min per 100 g body weight; P= 0.01 (means +/- SEM)). Treatment with LU 135252 completely prevented the decline in creatinine clearance in rats with chronic myocardial infarction (MI/LU: 0.98 +/- 0.21; Sham/LU: 0.83 +/- 0.10). Fractional sodium and protein excretion did not differ among the four groups. Group MI/P had a marked increase in plasma endothelin concentrations, which was not affected by treatment with LU 135252. Urinary endothelin excretion was significantly lower in group MI/P than in group Sham/P. In the treatment groups, no difference could be observed between animals that had suffered myocardial infarction and the sham-operated group, although LU 135252 markedly increased the urinary excretion of endothelin. CONCLUSION: Our data demonstrate a restoration of impaired renal function in chronic ischaemic heart failure by treatment with the selective ETA receptor antagonist, LU 135252. These results offer a promising therapeutic option for the treatment of renal insufficiency in patients with chronic heart failure.

Animals↗
PubMed2000

Treatment with a combined endothelin A/B-receptor antagonist does not prevent chronic renal allograft rejection in rats.

A markedly increased expression of endothelin (ET)-1 has been observed in renal allografts with chronic rejection, one of the most common causes of kidney graft loss. In this study we investigated the effect of treatment with a combined ET-A/B-receptor antagonist on the course of chronic renal allograft rejection. Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-to-Lewis isografts and uninephrectomized Lewis rats served as controls. Animals were treated with either the oral combined ET-A/B-receptor antagonist LU224332 (20 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light-microscopic evaluation and immunohistochemical assessment of cell-surface markers. Treatment with LU224332 did not improve survival after 24 weeks (0.47 vs. 0.38; p > 0.05 by log-rank test), nor did it have an influence on blood pressure, creatinine clearance, or proteinuria. Combined ET-A/B-receptor blockade was associated with a reduction of expression of cell-surface markers for macrophages (EDI), T-cells (R73), and major histocompatibility complex (MHC) II (F17-23-2), but did not lead to an improvement of histologic changes of chronic allograft rejection. Our data show that blocking both ET-A- and -B receptors, in opposition to a previously published beneficial effect of selective ET-A blockade, does not prevent the progression of chronic renal allograft rejection and does not prolong survival in this model. Functional integrity of the ET-B receptor therefore seems to play an important role in the nephroprotection provided by selective ET-A-receptor antagonists in chronic renal allograft nephropathy.

Animals↗
PubMed2000

The renoprotective potential of endothelin receptor antagonists.

The endothelin system has been identified as having a substantial role in renal failure, both acute and chronic. Beside its well characterised haemodynamic effects, its mitogenic and pro-fibrotic properties have gained increased interest in the pathophysiology of chronic renal failure. This review outlines the role of endothelin in the pathogenesis of various renal diseases with a special focus on the potential of blocking this system with endothelin receptor antagonists. So far, most data were derived from animal models, but they provide strong evidence that endothelin receptor antagonists may represent a powerful therapeutic strategy in ameliorating the course of acute and chronic renal failure.

Animals↗
PubMed1999

Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist.

BACKGROUND: Chronic rejection is the most common cause of graft loss in renal transplantation. The pathomechanisms underlying chronic rejection are poorly understood, and no treatment has yet successfully been established. We hypothesized that, in analogy to models of reduced renal mass, the administration of a selective endothelin (ET) A receptor antagonist could improve the course of chronic rejection in renal allografts. METHODS: Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-->Lewis isografts served as controls. Animals were treated with either the oral selective ET-A receptor antagonist LU135252 (50 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light microscopical evaluation, determination of ET mRNA expression and tissue protein concentration, and immunohistochemical assessment of cell surface markers. RESULTS: Rats with chronic rejection showed an increase in renal ET mRNA synthesis and ET protein content. Treatment with LU135252 resulted in a significant improvement in survival after 24 weeks (0.92 vs. 0.38, P<0.01 by log-rank test). Creatinine clearance was higher in animals treated with the selective ET-A receptor antagonist (P<0.05). LU135252 had no influence on blood pressure and proteinuria. Selective ET-A blockade was associated with significantly less morphological changes and a significant reduction of expression of cell surface markers for macrophages (ED1), T cells (R73), and MHC II (F17-23-2). CONCLUSION: The renal ET-A system plays an important role in the pathomechanisms underlying chronic renal allograft rejection, because the treatment with a selective ET-A receptor antagonist dramatically improves the course of chronic renal failure after allograft transplantation. These results offer a novel therapeutical option for treatment of chronic renal allograft rejection, for which so far no therapy is known.

Administration, Oral↗
PubMed1999

The endothelin antagonist bosentan does not improve survival in severe experimental pancreatitis in rats.

BACKGROUND: Severity of pancreatitis seems to be aggravated by impairment of vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent inflammatory response. Because vasoactive substances, including endothelin, seem to contribute to early mortality in acute pancreatitis, we tested the hypothesis that the inhibition of endothelin action could alter the outcome after severe experimental pancreatitis. METHODS: In two groups of rats, pancreatitis was induced by intraductal infusion into the pancreatic duct of 1 microL/g body weight (b.w.) of either a 4% or a 5% sodium taurocholate solution. The mixed endothelin A and endothelin B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected intravenously in 12-h intervals for 3 d starting 1 h after induction of bile acid pancreatitis. This dose of bosentan is known to completely inhibit the effect of exogenous endothelin. The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepared for histological and biochemical evaluation. RESULTS: Irrespective of the treatment protocol (bosentan versus saline), survival was not different in animals challenged with either 4% or 5% sodium taurocholate. The corresponding survival rates were 62% with bosentan and 77% without bosentan in the 4% sodium taurocholate group. In the 5% sodium taurocholate group, the survival rates were 20% with and 27% without bosentan. Morphological and biochemical alterations were identical in control as well as in endothelin-antagonist-treated rats. CONCLUSION: Therapy with the mixed endothelin A and endothelin B receptor antagonist bosentan does not influence the outcome after severe experimental pancreatitis. Therefore, blockade of endothelin A and B receptor subtypes may not be of major importance as a therapeutic principle in this model of experimental pancreatitis.

Animals↗
PubMed1998

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats.

BACKGROUND: Bezafibrate, a fibric acid analogue, has well-established lipid- and fibrinogen-lowering properties. Some data exist pointing towards a blood-pressure-lowering effect of bezafibrate. Thus the aim of this study was to examine the acute effect of bezafibrate on blood pressure and renal haemodynamics in hypertensive and normotensive rats. METHODS: 8 Wistar-Kyoto (WKY) and 12 spontaneously hypertensive rats (SHR) were treated with i.v. bolus injections of vehicle and 1-10 mg of bezafibrate in increasing doses every 15 min. Mean arterial pressure (MAP), renal blood flow (RBF), cortical blood flow (CBF), and medullary blood flow (MBF) were monitored continuously, together with plasma renin activity (PRA), urine volume and urinary Na+, K+, and protein concentration (15-min intervals). RESULTS: Bezafibrate reduced MAP in a dose-dependent manner (mean +/- SEM): in WKY, 1 mg bezafibrate, -1.13 +/- 0.61 mmHg and after 10 mg bezafibrate, -7.25 +/- 1.10 mmHg; in SHR, -0.60 +/- 0.43 and -5.83 +/- 0.90 mmHg respectively. In contrast to vehicle, bezafibrate induced a dose-dependent increase in RBF (WKY, 0.21 +/- 0.10 and 0.83 +/- 0.48 ml/min; SHR, 0.38 +/- 0.10 and 3.09 +/- 0.45 ml/min respectively) and a corresponding decrease in renal vascular resistance which was significantly greater in SHR than in WKY. The increase in RBF was paralleled by an increase in CBF. No effect of bezafibrate on MBF, PRA, urine flow, or urinary Na+, K+ or protein excretion was observed. The observed effects could not be attributed to one of the classic vasodilating mechanisms. CONCLUSIONS: We conclude that in rats bezafibrate is a potent hypotensive drug exhibiting additional effects on renal haemodynamics.

Animals↗
PubMed1998

The Endothelin system in polycystic kidneys of Han:SPRD rats.

Polycystic kidney disease (PKD) is characterized by structural alterations such as thickening of the tubule basement membrane, interstitial fibrosis, and formation of cysts. Han:SPRD rats are a well-known rat model of human PKD. Interestingly, interstitial fibrosis, glomerulosclerosis, and cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. We therefore analyzed the tissue concentrations of ET-1 and the expression of ET receptor subtypes in the kidneys of young homozygous (cy/cy), heterozygous (cy/+) 6 week-old male Han:SPRD, and corresponding control rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared to age-matched controls. Scatchard analysis, on the other hand, revealed markedly decreased ETA and ETB receptor density in all groups of affected rats. The binding affinity of both ET receptor subtypes was slightly decreased in Han:SPRD rats. These data show that the renal paracrine ET system is activated in PKD and might contribute to renal cyst formation and development of end-stage kidney disease.

Animals↗
PubMed1998

Pathophysiology in endothelin-1 transgenic mice.

Transgenic mice expressing the human endothelin-1 (ET-1) were generated. These mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. Consequently, a progressive decrease in renal blood flow and/or glomerular filtration rate was observed, demonstrated by altered creatinine clearance and by magnetic resonance imaging. These genetically altered transgenic mice provide an interesting animal model in which to elucidate the role of ET-1 in the modulation of renal hemodynamics and glomerular and tubule functions.

Animals↗
PubMed1998

Apoptosis in kidneys of endothelin-1 transgenic mice.

Endothelin-1 (ET-1) transgenic mice are characterized by age-dependent development of renal cysts and renal fibrosis (interstitial fibrosis and glomerulosclerosis), leading to a progressive decrease in glomerular filtration rate. The mechanism causing the loss of functionally and morphologically normal renal tissue is unknown. An imbalance between cell proliferation and apoptosis in the kidneys of ET-1 transgenic mice might contribute to this process. We identified apoptotic cells in kidney sections by in situ end-labeling and by the typical nuclear chromatin morphology after propidium iodide (PI) staining. Cell proliferation was measured by estimating the proliferating cell nuclear antigen (PCNA)-positive cells. The numbers of apoptotic cells were significantly increased (p < 0.001) in the kidneys of 14-month-old ET-1 transgenic mice, whereas cell proliferation was not enhanced. Apoptotic cells were detected in the glomeruli, tubular cells, and renal interstitial cells in ET-1 transgenic mice. In conclusion, apoptotic loss of functional renal tissue appears to be associated with the progression of cyst formation and renal fibrosis. Therefore, an imbalance between cell proliferation and apoptosis could be an important cellular mechanism in ET-1 transgenic mice leading to end-stage kidney disease.

Animals↗
PubMed1998

Influence of the renal endothelin A system on the autoregulation of renal hemodynamics in SHRs and WKY rats.

In this study, we investigated the influence of a short-term blockade of the renal endothelin A system on the autoregulation of total renal blood flow, cortical renal blood flow, and pressure-dependent plasma renin activity in spontaneously hypertensive rats (SHRs) and normotensive controls [Wistar-Kyoto (WKY) rats]. In anesthetized rats, renal blood flow was measured by a transit-time flow probe and cortical blood flow by a laser flow probe. Blood samples were taken for measurement of plasma renin activity. Renal perfusion pressure was reduced in 5-mm Hg steps by means of a servocontrolled electropneumatic device by an inflatable suprarenal cuff. During the experiments, the rats (n = 6, each group) received an intrarenal infusion of either the selective endothelin A-receptor antagonist BQ123 (3 mg/kg/h) or vehicle. We observed an improvement of total and cortical blood flow autoregulation as indicated by a shift of lower limits of autoregulation to lower threshold pressures [103 +/- 2 vs. 132 +/- 4 mm Hg compared with 98 +/- 3 vs. 120 +/- 4 mm Hg (mean +/- SEM); p < 0.01 resp. p < 0.05] in BQ123-treated SHRs, whereas BQ123 had no influence on breakpoints of autoregulation in WKY rats (p > 0.05). Pressure-dependent plasma renin activity in SHRs was not influenced by BQ123. Renal blood flow autoregulation is improved in SHRs after short-term blockade of the renal endothelin A system. This effect is independent of the renin-angiotensin system. The endothelin A system does not seem to play an important role in the autoregulation of renal blood flow in normotensive WKY rats.

Animals↗
PubMed1998

Improvement of postischemic acute renal failure with the novel orally active endothelin-A receptor antagonist LU 135252 in the rat.

The endothelin (ET) system may play an important role in the pathogenesis of acute renal failure (ARF). We hypothesize that the course of ARF in an ischemia-reperfusion model will be markedly attenuated by the orally active ET(A)-receptor antagonist LU 135252 (LU) because of an improvement of renal perfusion. ARF was induced in rats by clamping both renal arteries for 60 min. The study was divided into two parts. In part 1, Rats received LU orally (100 mg/kg/day) starting 1 h after induction of ARF for 14 days. Cr(s), Cl(cr) and FE(na) were measured on days 1, 6, 9, and 14 after ARF. Cr(s) was lower in the treatment group on days 1 [1.3 +/- 0.31 mg/dl (n = 9) vs. 2.7 +/- 0.46 mg/dl (n = 10); p < 0.05] and 6 [0.5 +/- 0.1 mg/dl (n = 9) vs. 1.0 +/- 0.2 mg/dl (n = 9); p < 0.05], and Cl(cr) was higher on day 1 [0.9 +/- 0.17 ml/min (n = 9) vs. 0.2 +/- 0.1 ml/min (n = 8); p < 0.05] and 6 [1.8 +/- 0.29 ml/min (n = 9) vs. 1.0 +/- 0.21 ml/min (n = 9); p < 0.05] compared with vehicle. Additionally, FE(na) was lower in treated rats on day 1 [1 +/- 0.4% (n = 9) vs. 8 +/- 3% (n = 8); p < 0.051 compared with vehicle. In part 2, ARF was induced as described. Treated animals received 10 mg/kg LU on days 0, 1, 3, 6, 9, and 14 after ARF as an i.v. bolus injection. RBF, cortex blood flow (CBF), and medulla blood flow (MBF) were measured after application of LU on the same days: LU induced an increase in RBF (day 1: 14 +/- 5.3%, n = 6, p = 0.04; day 3: 15 +/- 2.8%, n = 8; p = 0.0008; day 6: 21 +/- 5.8%, n = 6, p = 0.02; day 9: 13 +/- 4%, n = 6; p = 0.03) and CBF (day 1: 8 +/- 2.2%, n = 7, p = 0.03; day 3: 7 +/- 2.5%, n = 7; p = 0.05; day 6: 18 +/- 4.8%, n = 6, p = 0.04; day 9: 10 +/- 2.5%, n = 6; p = 0.008) up to the first 9 days. MBF did increase on days 1 (9 +/- 3.1%, n = 6; p = 0.04) and 6 (13 +/- 3.6%, n = 6; p = 0.03). Our data confirm the hypothesis that ET plays a major role in the genesis of ARF associated with ischemia-reperfusion.

Acute Kidney Injury↗
PubMed1998

Renal endothelin system in polycystic kidney disease.

Polycystic kidney disease (PKD) is characterized by interstitial fibrosis and formation of renal cysts. Interestingly, interstitial fibrosis and renal cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. This study, therefore, analyzes the tissue distribution of ET-1, the tissue concentrations of ET-1, as well as the expression of ET receptor subtypes in the kidneys of a rat model of PKD: Han:SPRD rats. Six-week-old heterozygous (cy/+) and homozygous (cy/cy), as well as 6-mo-old heterozygous (cy/+) Han:SPRD rats and the corresponding age-matched Sprague Dawley littermates (SD) (+/+) were analyzed. Furthermore, the acute effects of the mixed (A/B) endothelin receptor antagonist bosentan on hemodynamic and renal function were investigated in 6-mo-old, conscious, chronically instrumented (cy/+) rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared with age-matched controls (3.5 +/- 0.3-fold in young cy/cy rats, P < 0.01; 1.4 +/- 0.2-fold in young cy/+ rats, P < 0.01; 6.2 +/- 0.4-fold in old cy/+ rats, P < 0.001) due to a highly increased ET-1 synthesis within the epithelial cells of the cysts. Analyzing tissue sections from patients with typical autosomal dominant PKD demonstrated a high ET-1 expression within the epithelial cells of the cysts as well. Scatchard analysis revealed a markedly decreased ETA and ETB receptor density in all groups of affected rats. The acute blockade of both endothelin receptor subtypes using bosentan in 6-mo-old heterozygous PKD rats led to a significant decrease in mean arterial BP (MAP) (-19.7 +/- 2.1 mmHg, P < 0.05) and GFR (-41 +/- 5%, P < 0.005). Renal blood flow (RBF) was significantly increased (+2.1 +/- 0.5 ml/min, P < 0.05) after bosentan, whereas bosentan had no effect on MAP, GFR, and RBF in age-matched controls. These data show that the paracrine renal endothelin system is activated in PKD and participates in the regulation of MAP, GFR, RBF, and possibly contributes to renal cyst formation and fibrosis.

Analysis of Variance↗
PubMed1997

Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

Animals↗
PubMed1997

Effects of bradykinin and icatibant on renal hemodynamics in conscious spontaneously hypertensive and normotensive rats.

We investigated the effects of bradykinin (BK) and icatibant (HOE 140), a highly selective bradykinin-B2-receptor antagonist, on mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), and renal vascular resistance (RVR) in conscious Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Experiments were performed in conscious male WKY rats and SHRs instrumented over the long term with arterial and venous catheters and a transit-time flow probe for measurement of RBF. In WKY rats (n = 16), intraaortic (i.a.) bolus injections of BK (0.1, 1.0, and 10 microg) produced dose-dependent decreases in MAP and RBF with reciprocal increases in RVR. Intrarenal (i.r.) injections of BK (10 microg; n = 6) induced the same hemodynamic response pattern, although the increase in RVR was higher compared with i.a. injections (p < 0.05). Neither vasopressin V1-receptor nor alpha1-adrenoceptor blockade had an effect on the renal vasoconstrictor responses on i.a. BK. The i.a. injections of icatibant (0.1, 1.0, 5.0, and 10 microg; n = 6-10 for each dose) led to a dose-dependent blockade of the hemodynamic responses to BK (10 microg, i.a.). Icatibant (10 microg, i.a) had no effect on resting MAP and HR but induced a biphasic response in RBF and RVR with significant changes compared with basal values (p < 0.05). In SHRs (n = 9), after injection of increasing i.a. doses of BK (0.1, 1.0, and 10 microg), dose-dependent decreases in MAP were proportionately greater compared with those in WKY rats. In contrast to WKY rats, RBF and RVR exhibited a biphasic response pattern on BK in SHRs. Neither vasopressin V1-receptor nor alpha1-adrenoceptor blockade had an effect on the renal vasoconstrictor responses on i.a. BK. The i.a. injections of icatibant (10 microg) almost completely blocked the hemodynamic responses on BK in SHRs (n = 13). Icatibant (10 microg, i.a.) itself induced an increase in resting MAP and HR (p < 0.05) and a biphasic response in RBF and RVR with significant changes of basal values (p < 0.05). Our results provide evidence that BK exhibits renal vasoconstrictor and vasodilator properties in vivo, both mediated by B2-receptors. Furthermore, we demonstrated that SHRs display an increased B2-receptor-mediated vasodilatory responsiveness to BK. Finally we showed that blockade of B2 receptors leads to an increase of MAP in SHRs in contrast to WKY rats, suggesting an important role of the kallikrein/kinin system in the regulation of high blood pressure in SHRs.

Adrenergic alpha-1 Receptor Antagonists↗