Endothelial dysfunction in gestational hypertension induced by catechol-O-methyltransferase inhibition.

The present study evaluated whether catechol-O-methyltransferase inhibition in pregnant rats results in increased blood pressure and vascular endothelial dysfunction as a consequence of decreased nitric oxide bioavailability. Pregnant Sprague-Dawley rats were given entacapone (a catechol-O-methyltransferase inhibitor) by gavage from the 10th to the 20th day of pregnancy. Blood pressure was measured by plethysmography in the tail artery. Vascular endothelial function and NO release were assessed both in the absence and in the presence of tempol. Systolic blood pressure increased significantly in pregnant rats treated with entacapone compared with untreated pregnant rats on days 14 (143 ± 4 versus 122 ± 3 mmHg) and 19 of gestation (129 ± 4 versus 115 ± 5 mmHg). Both conductance (aortic rings) and resistance vessels (mesenteric small arterial vessels) from entacapone-treated pregnant rats showed diminished relaxation in response to acetylcholine compared with vessels from vehicle-treated pregnant and virgin rats. In mesenteric arterioles, this endothelial dysfunction was abolished in the presence of l-NAME, indicating that it was caused by reduced NO availability, and it also improved in the presence of tempol, suggesting increased oxidative stress in hypertensive pregnant rats. Endothelial release of nitric oxide induced by calcium ionophore (A23187) was significantly greater in aortas from vehicle-treated pregnant rats than in aortas from pregnant rats given entacapone. This endothelial dysfunction seen in hypertensive rats was prevented by addition of tempol. The present study provides evidence that catechol-O-methyltransferase inhibition in pregnant rats produces arterial hypertension and endothelial dysfunction due to reduced nitric oxide bioavailability.

2-Methoxyestradiol attenuates hypertension and coronary vascular remodeling in spontaneously hypertensive rats.

OBJECTIVES: Accumulating data provide evidence that some metabolites of 17beta-estradiol are biologically active and mediate multiple effects on the cardiovascular and renal systems. We investigated the effect of 2-methoxyestradiol (an active metabolite of estradiol with non-feminizing activity) on the development of hypertension and myocardial vascular remodeling in male and female ovarectomized SHR. METHODS: Rats were divided into five groups: intact females, ovarectomized (OVX), OVX+ 2-methoxyestradiol (2ME), control males, and male+2ME. Systolic blood pressure was determined from 10 to 18 weeks. Structural changes in coronary vessels were quantified by an image analyzer. Immunoblotting of phosphorylated ERK1/2 and NADPH oxidase activity were performed on mesenteric arteries. RESULTS: Treatment with 2ME reduced the increase in systolic blood pressure in male and ovarectomized rats to values not different from those obtained in intact females. Myocardial arterioles and small arteries showed significant increases in wall-to-lumen ratio and perivascular fibrosis in male and ovarectomized rats when compared with intact females. NADPH oxidase activity was increased in mesenteric arteries from males and ovarectomized females as compared with intact females. Finally, the expression of phosphorilated ERK1/2 were significantly higher in mesenteric arteries from male and ovariectomized animals than in those from intact females. Those effects of ovarectomy and gender differences were totally or partially prevented by treatment with 2-methoxyestradiol. CONCLUSIONS: These data demonstrate that 2-methoxyestradiol protects the vasculature from hypertension-induced myocardial arterial remodeling in male and ovarectomized SHR, and that might be in part related to decreased superoxide generation and ERK1/2 activation.

Mesangial cell immune injury. Hemodynamic role of leukocyte- and platelet-derived eicosanoids.

The role of leukocytes and platelets and of leukocyte- and platelet-derived eicosanoids in mediating acute changes in renal and glomerular hemodynamics was assessed in a model of antibody-induced mesangial cell injury in the rat. After a single intravenous injection (6 mg/kg) of the monoclonal antibody (ER4) against the mesangial cell membrane antigen Thy 1, significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) were observed at 1 h, and were associated with increments in glomerular LC (+) leukocyte counts and in the synthesis of thromboxane (Tx)B2, leukotriene (LT)B4, and 12-hydroxyeicosatetraenoic acid (HETE). In rats with immune leukopenia, the rise in glomerular LC (+) leukocytes and in eicosanoid synthesis were abolished and the fall in GFR and RBF after administration of ER4 were completely ameliorated. Likewise, pretreatment of rats with both a thromboxane synthase and a 5-lipoxygenase inhibitor also blocked the fall in GFR and RBF and the rise in glomerular synthesis of TxB2 and LTB4 produced by ER4 without changing glomerular LC (+) leukocyte counts. Selective inhibition of thromboxane or 5-lipoxygenase alone only partially ameliorated the decrements in GFR and RBF produced by ER4. In animals with immune thrombocytopenia, the elevated glomerular synthesis of 12-HETE and fall in RBF but not GFR was ameliorated after administration of ER4. The ER4 antibody-induced fall in GFR was mainly caused by a marked decrement in the ultrafiltration coefficient, Kf, which was dependent on TxA2 and 5-lipoxygenase products, since pretreatment of animals with a thromboxane receptor antagonist or with a 5-lipoxygenase inhibitor partially ameliorated this decrement. Structural changes such as infiltration of glomerular capillaries by leukocytes and endothelial cell damage may also have accounted for the fall in Kf. These observations indicate that in antibody-mediated mesangial cell injury, infiltrating leukocytes and platelets mediate the changes in renal hemodynamics via synthesis of thromboxane and arachidonate 5-lipoxygenation products.

Enhanced vascular tone in the renal vasculature of spontaneously hypertensive rats.

The renal microvascular responses of Wistar-Kyoto and spontaneously hypertensive rats to changes in perfusion pressure were compared using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. In the spontaneously hypertensive rats, the internal diameters of arcuate and interlobular arteries and the proximal and distal afferent arterioles averaged 307 +/- 26, 52 +/- 2, 24 +/- 0.9, and 22 +/- 1.2 microns, respectively, at 80 mm Hg. They were 18-35% smaller (p less than 0.05) than the corresponding vessels measured in Wistar-Kyoto rats. In low calcium media, the arcuate and interlobular arteries and the proximal and distal afferent arterioles of spontaneously hypertensive rats exhibited a greater dilation than the vessels of Wistar-Kyoto rats. These observations suggest that the diameters of the preglomerular vasculature of the spontaneously hypertensive rats are reduced because of an elevated vascular tone rather than structural changes narrowing the lumen of these vessels. These results suggest that enhanced vascular tone in the preglomerular vasculature of juxtamedullary nephrons may contribute to the elevated renal medullary vascular resistance and resetting of the pressure-natriuretic relation previously observed in spontaneously hypertensive rats.

Normalization of pressure-natriuresis by nisoldipine in spontaneously hypertensive rats.

This study examined whether the calcium antagonist nisoldipine can shift the relations between sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure toward lower pressures in spontaneously hypertensive rats. Mean arterial pressure decreased similarly by 9% and 12% in Wistar-Kyoto and spontaneously hypertensive rats after nisoldipine (0.5 microgram/kg bolus + 0.017 microgram/kg/min). Urine flow and sodium excretion increased by 35% and 24% in Wistar-Kyoto rats after nisoldipine. In contrast, urine flow and sodium excretion rose by 121% and 132% in spontaneously hypertensive rats, and fractional sodium excretion rose from 1.9 +/- 0.3 to 4.2 +/- 0.4%. Control sodium excretion, papillary blood flow, and renal interstitial pressure were significantly lower in spontaneously hypertensive rats than in Wistar-Kyoto rats when compared at similar renal perfusion pressures. Sodium excretion, papillary blood flow, and renal interstitial pressure all increased in spontaneously hypertensive rats after nisoldipine, whereas it had no effect on papillary blood flow or renal interstitial pressure in Wistar-Kyoto rats. The relations among sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure were shifted toward lower pressures in spontaneously hypertensive rats given nisoldipine and became similar to those seen in Wistar-Kyoto rats. These results indicate that nisoldipine normalizes the relations among sodium excretion, renal interstitial pressure, papillary blood flow, and renal perfusion pressure in spontaneously hypertensive rats perhaps by correcting the defect in renal medullary perfusion associated with resetting of pressure natriuresis in this model of hypertension.

Effect of an angiotensin II and a kinin receptor antagonist on the renal hemodynamic response to captopril.

The role of angiotensin II and kinins on the renal cortical and papillary hemodynamic and on the sodium and water excretory responses to converting enzyme inhibition with captopril was examined in euvolemic Munich-Wistar rats. Cortical and papillary blood flows were measured using a laser Doppler flowmeter. Cortical blood flow increased 28% after blockade of angiotensin II receptors with DuP 753 (2 mg/kg i.v., n = 6). Captopril (2 mg/kg i.v., n = 6) had no effect on cortical blood flow in rats pretreated with the angiotensin II antagonist. DuP 753 had no effect on papillary blood flow, nor did it prevent the rise in papillary blood flow produced by captopril (2 mg/kg, n = 6). Infusion of a kinin receptor antagonist, D-Arg, [Hyp3,Thi5,8,D-Phe7]-bradykinin (2.5 micrograms/min i.v.), reduced basal papillary blood flow by 15% and blocked the rise in papillary blood flow produced by captopril. Renal blood flow rose by 11% after DuP 753 (2 mg/kg, n = 6), and subsequent administration of captopril and the kinin antagonist had no effect on renal blood flow. Urine flow and sodium excretion increased after DuP 753, but captopril produced additional increases in urine flow and sodium excretion of 68% and 46% respectively. Fractional sodium excretion rose from 0.85 +/- 0.15% to 1.56 +/- 0.14% after captopril. Infusion of the kinin antagonist returned sodium and water excretion to control levels, but fractional sodium excretion was not significantly altered. Glomerular filtration rate was not altered by DuP 753 or captopril; however, it fell from 1.6 +/- 0.1 to 1.2 +/- 0.1 ml/min/g kidney wt during infusion of the kinin antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of nitric oxide on papillary blood flow and pressure natriuresis.

This study examined whether nitric oxide synthesis blockade or potentiation (with N omega-nitro-L-arginine methyl ester [L-NAME] or N-acetylcysteine, respectively) can shift the relations between sodium excretion, papillary blood flow, and renal perfusion pressure. Papillary blood flow was measured by laser Doppler flowmetry. A low dose of L-NAME (3.7 nmol/kg per minute) reduced papillary blood flow only at high arterial pressure (140 mm Hg), but it had no effect on pressure natriuresis. Infusion of 37 nmol/kg per minute L-NAME reduced cortical blood flow by 9% at all perfusion pressures studied, lowered papillary blood flow by 8% and 19% at 120 and 140 mm Hg, respectively, and blunted the pressure-natriuresis response. The administration of 185 nmol/kg per minute L-NAME reduced cortical blood flow by 30% and decreased papillary blood flow by 25% in the range of 100 to 140 mm Hg of arterial pressure. Blockade of nitric oxide synthesis with L-NAME at all doses studied reduced papillary blood flow only at high renal perfusion pressures, but papillary blood flow remained essentially unchanged at low perfusion pressures, thus restoring papillary blood flow autoregulation. N-Acetyl-cysteine (1.8 mmol/kg) increased papillary blood flow by 9% and shifted the relations between papillary blood flow, sodium excretion, and renal perfusion pressure toward lower pressures. This effect of N-acetylcysteine on papillary blood flow was blocked by subsequent L-NAME administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between nitric oxide and angiotensin II on renal cortical and papillary blood flow.

This study examined the role of angiotensin II (Ang II) on the effects of nitric oxide (NO) synthesis blockade on renal cortical and papillary blood flow in innervated and denervated kidneys of volume-expanded Munich-Wistar rats with hormonal influences on the kidney that were held constant by intravenous infusion. Cortical (CBF) and papillary (PBF) blood flow were measured by laser-Doppler flowmetry. A low dose of N omega-nitro-L-arginine methyl ester (L-NAME, 3.7 nmol x kg[-1] x min[-1]) reduced CBF only in innervated kidneys, and this effect was abolished by subsequent administration of valsartan (an AT1 antagonist). L-NAME 3.7 nmol x kg(-1) x min(-1) improved PBF autoregulation by lowering PBF to the range of 100 to 140 mm Hg of perfusion pressure, and this effect was attenuated or abolished by valsartan in innervated and denervated kidneys, respectively. These results indicate that the cortical and medullary vasoconstriction induced by a low dose of L-NAME are caused by potentiation of the vasoconstrictor influence of renal sympathetic nerves and Ang II. A higher dose of L-NAME (37 nmol x kg[-1] x min[-1]) lowered CBF and PBF in both innervated and denervated kidneys. This effect of L-NAME on the cortical circulation was abolished by valsartan, but this AT1 antagonist had no effect on the medullary vasoconstriction produced by NO synthesis blockade. Therefore, a higher dose of L-NAME induces a renal cortical vasoconstriction through potentiation of the renin-angiotensin system, whereas the fall of PBF seen after L-NAME 37 nmol x kg(-1) x min(-1) seems to be caused primarily by NO suppression. This Ang II potentiation produced by L-NAME in the renal cortex seems to be mediated by AT1 receptors, because it was unaffected by PD123319 (an AT2 antagonist). The results of the present study indicate that NO is an important modulator of the vasoconstrictor influence of Ang II in the renal cortical circulation of the rat. However, although there are some interactions between NO and renal nerves and Ang II on the medullary circulation, the renal medullary vasoconstriction produced by L-NAME appears to be caused primarily by NO suppression, with little influence of the renal vasoconstrictor systems.

Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion.

BACKGROUND: Renal ischemia is produced during orthotopic liver transplantation when the inferior vena cava is clamped above the renal veins (inferior vena cava occlusion [IVCO]), and it often leads to postoperative renal failure. Although free radicals and nitric oxide (NO) have been implicated in the pathogenesis of ischemic renal failure, the effect of free radical scavengers in this model is unknown. METHODS: The effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, on the acute renal failure that follows IVCO were evaluated in pentobarbital-anesthetized dogs. The effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester (NAME) was also studied. Renal vascular endothelial function was tested by infusing acetylcholine (Ach) into the renal artery before the ischemia and during reperfusion. RESULTS: Renal failure developed during IVCO and persisted during reperfusion in all groups. However, in NAC-pretreated dogs, the glomerular filtration rate recovered progressively, reaching 31% of basal preischemic values 150 min after reperfusion. During reperfusion, fractional excretion of sodium increased above preischemic values only in the control group, which indicates a beneficial effect of NAC and NAME on the tubular dysfunction observed during reperfusion. The renal response to Ach was abolished in control dogs and in animals given NAME during reperfusion, which indicates endothelial dysfunction. However, in NAC-pretreated dogs, the renal response to Ach was preserved during reperfusion. CONCLUSIONS: These results demonstrate that NAC ameliorates the renal failure and renal endothelial dysfunction induced by IVCO. This protective effect was abolished by NAME, which suggests that NO is involved in the beneficial effects of NAC. These data also suggest that the use of NAC could be beneficial in ameliorating the acute renal failure observed after orthotopic liver transplantation.

Effects of N omega-nitro-L-arginine and N-acetyl-L-cysteine on the reversal of one-kidney, one-clip hypertension.

The present study evaluated whether nitric oxide (NO) synthesis blockade or potentiation (with N omega-nitro-L-arginine or N-acetyl-L-cysteine, respectively) modulates the systemic and renal responses to unclipping in anesthetized one-kidney, one-clip hypertensive rats (1K-1C). Cardiac output was measured by thermodilution. In time-control rats, mean arterial pressure (MAP) decreased from 197 +/- 8 mm Hg to 139 +/- 4 mm Hg 3 h after unclipping, and cardiac index (CI) decreased by 35%, with a transient rise in sodium and water excretion and no changes in total peripheral resistance (TPR), glomerular filtration rate (GFR), or renal plasma flow (RPF). Administration of N omega-nitro-L-arginine methyl ester (NAME, 10 micrograms/kg/ min) blunted the hypotensive (from 190 +/- 6 mm Hg to 157 +/- 3 mm Hg), diuretic and natriuretic responses and potentiated the decrease in CI (40%) observed after unclipping, whereas TPR increased by 103%. Also, in rats given NAME, GFR and RPF decreased by 20% and 45%, respectively, at the end of the experiment. The effect of N-acetyl-L-cysteine (NAC, 300 mg/kg), a sulfhydryl group donor that may protect NO from free radical destruction by forming an S-nitrosothiol compound, was also evaluated. NAC potentiated the depressor response to unclipping (from 180 +/- 5 mm Hg to 97 +/- 3 mm Hg), and GFR and RPF increased by 80% and 35%, respectively. These effects of NAC appear to be NO dependent, as they were blocked by simultaneous administration of NAME. However, no significant differences were observed among groups in cumulative excretion of sodium and water, demonstrating that the hemodynamic effects of NAME and NAC after unclipping are due to mechanisms other than renal excretory changes. The results of the present study indicate that the cardiovascular depressor effects of unclipping are modulated by endothelium-derived nitric oxide.

Effects of DuP 753 on renal function of normotensive and spontaneously hypertensive rats.

This study examined the effects of a new, orally-active, nonpeptide angiotensin II (AII) receptor antagonist, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4- yl)methyl] imidazole, DuP 753, on renal function of anesthetized, volume-expanded Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), and in a group of euvolemic Munich-Wistar (MW) rats. Plasma renin activities were similar and averaged 4.4 +/- 0.7 and 4.3 +/- 1.4 ng AI/mL.h, respectively, in the SHR and WKY rats. In WKY rats (n = 15), DuP 753 (2 or 10 mg/kg, intravenously) had no effect on urine flow, sodium excretion, renal blood flow (RBF), or glomerular filtration rate (GFR). Fractional excretion of lithium (FELi) rose from 32 +/- 5 to 40 +/- 4% of the filtered load and arterial pressure decreased slightly from 129 +/- 2 to 122 +/- 2 mm Hg. In SHR (n = 9), urine flow fell 24%, and FELi and RBF increased by 27% and 30%, respectively, after 2 mg/kg DuP 753, but sodium excretion, GFR, and arterial pressure were not significantly altered. A higher dose of DuP 753 (10 mg/kg; n = 8) reduced arterial pressure, urine flow, and sodium excretion in the SHR. RBF increased 34%, while GFR and FELi were not significantly altered. Similar effects were seen in SHR (n = 11), given an equivalent antihypertensive dose of captopril (20 mg/kg). In euvolemic MW rats in which plasma renin activity was elevated to 18.8 +/- 3.3 ng AI/mL.h, DuP 753 (2 mg/kg, n = 7) increased RBF, urine flow, and sodium excretion, while mean arterial pressure and GFR were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of renal medullary circulation on arterial pressure.

PRESSURE-NATRIURESIS EFFECTS IN HYPERTENSION: Considerable advances have been made in our understanding of pressure-natriuresis and the effects of this mechanism in hypertension. We have shown that in the absence of changes in neural and endocrine factors, sodium and water excretion doubled when arterial pressure was increased by only 10 mmHg. These responses were greatly blunted or obscured by elevations in renal sympathetic tone, infusion of the vasoconstrictors angiotensin and vasopressin or by inhibition of paracrine factors such as eicosanoids and nitric oxide. EFFECT OF CHANGES ON MEDULLARY BLOOD FLOW: The pressure-natriuresis response is closely associated with changes in papillary blood flow as determined by laser-Doppler flowmetry. In volume-expanded rats, papillary blood flow is not well autoregulated, which results in elevations of vasa recta capillary pressure and renal interstitial fluid pressure. The increased interstitial fluid pressure is transmitted from the medulla to the cortex in the encapsulated organ and is associated with inhibition of sodium transport in the proximal tubule and/or the thin descending loop of Henle of deep nephrons. Selective reductions in medullary blood flow by infusion of the nitric oxide inhibitor N6-nitro-L-arginine methylester (L-NAME) into the renal medullary interstitial space resulted in decreased interstitial fluid pressure and reduced sodium excretion. The mechanisms by which small elevations in renal interstitial fluid pressure alter tubular sodium reabsorption remain to be determined. PRESSURE-NATRIURESIS EFFECTS IN HYPERTENSIVE RATS: Our studies have also shown that the pressure-natriuresis response is blunted in spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. This abnormality is associated with shifts in the relationships among papillary flow, renal interstitial pressure and renal perfusion pressure towards higher pressures. The calcium antagonist nisoldipine corrected the defect in vasa recta hemodynamics in SHR and normalized relationships among sodium excretion, renal interstitial pressure and renal perfusion pressure. CONCLUSIONS: These studies indicate that sodium and water excretion is very sensitive to small changes in renal perfusion pressure due to associated changes in papillary blood flow, and that alterations in medullary hemodynamics can have an important effect on the relationship between arterial pressure and sodium and water excretion.

Effect of tempol on myocardial vascular remodeling in female spontaneously hypertensive rats.

OBJECTIVE: The present study evaluated whether the treatment with the superoxide anion dismutase mimetic tempol prevents the worsening in hypertension and in myocardial vascular remodeling induced by ovariectomy in female spontaneously hypertensive rats (SHR). METHODS: Experiments were performed in ten week old female SHRs randomly assigned to the groups: intact (INT: given vehicle; INT+T: treated with tempol, 90 mg/kg/day), ovariectomized (OVX: vehicle and OVX+T: tempol, respectively) and ovariectomized treated with 17ß-estradiol (OVX+E2 and OVX+E2+T). Evolution of systolic blood pressure (SBP) was determined every other week in lightly restrained awake rats using a noninvasive computerized tail-cuff plethysmography system. At 18 weeks of age the heart was excised and structural changes in histopathological sections of coronary vessels were quantified on a computerized imaging system analyzer. RESULTS: SBP was significantly lower in female SHRs treated with tempol compared to the values measured in untreated animals. In the vascular remodeling of myocardial arterioles, OVX+T rats had a lower media cross sectional area and media-to-lumen ratio than those observed in the OVX SHR. Interestingly, treatment with tempol in the presence of estradiol (in female INT and OVX+E2 SHR ) increased media cross sectional area and wall-to-lumen ratio of myocardial arterioles, despite the fact that it lowered arterial pressure in those groups. CONCLUSIONS: These results indicate that tempol prevents arterial hypertension and blunts myocardial vascular remodeling in ovariectomized SHR. Paradoxically, when tempol is given in presence of estradiol it has a detrimental effect on myocardial arteriolar remodeling.

Effect of volume expansion on papillary blood flow and sodium excretion.

The present study examined whether changes in plasma oncotic pressure or hematocrit play a role in the redistribution of renal blood flow and the natriuretic response to extracellular fluid volume (ECFV) expansion with saline. Intravenous infusion of saline produced a 46% increase in the flow of red blood cells (RBCs) in the papilla of Inactin-anesthetized euvolemic Munich-Wistar rats (n = 6). This was primarily due to an increase in the number of functional capillaries perfused with moving RBCs, as indicated both by laser-Doppler flowmetry and videomicroscopy. The velocity of RBCs in ascending or descending vasa recta was not significantly altered by the infusion of saline. Plasma volume expansion with a 6% solution of albumin (n = 6) did not increase papillary RBC flow, whereas volume expansion with whole blood produced a 17% increase in the flow of RBCs in the papilla. Sodium excretion after ECFV expansion with saline (n = 6) was greater than that seen after plasma volume expansion with a 6% solution of albumin (n = 5). The results indicate that the rise in papillary RBC flow after ECFV expansion with saline is due to an increase in the number of perfused vasa recta capillaries. The failure of plasma volume expansion to alter papillary RBC flow suggests that changes in plasma oncotic pressure and/or renal interstitial pressure may signal the rise in papillary RBC flow after intravenous infusion of saline. The present study also indicates that laser-Doppler flowmetry is a useful technique to monitor changes in the flow, velocity, and concentration of moving RBCs in tissue.

Effect of kinin receptor antagonists on renal hemodynamic and natriuretic responses to volume expansion.

The role of kinins in the natriuretic and papillary blood flow (PBF) responses to intravenous administration of 0.9% sodium chloride solution equal to 5% of body weight over 30 min was evaluated using a B1-kinin receptor antagonist (des-Arg9, [Leu8]bradykinin, 2.5 micrograms/min i.v.) and a B2-kinin receptor antagonist (D-Arg, [Hyp3,Thi5,8,D-Phe7]bradykinin, 2.5 micrograms/min i.v.). In control rats, PBF increased 43 +/- 5% after the volume expansion with saline. Administration of the B1-kinin receptor antagonist had no significant effect on basal PBF or the rise in PBF produced by volume expansion. In contrast, administration of the B2-kinin receptor antagonist decreased basal PBF by 18 +/- 3% and prevented the rise in PBF during volume expansion. Urine osmolality was lower in the rats treated with the B1-antagonist and higher in rats infused with the B2-kinin antagonist than in control animals after volume expansion (587 +/- 47 and 1,082 +/- 83 vs. 907 +/- 124 mosmol/kgH2O, respectively). The initial natriuretic response during the first 30 min after volume expansion was similar in rats given vehicle or the kinin antagonists. However, cumulative sodium excretion over the 2-h course of the experiment was significantly lower in the rats given the B2-receptor antagonist than in control rats (92 +/- 7 vs. 101 +/- 9% of the administered load). The B1-kinin receptor antagonist had no effect on cumulative sodium excretion; however, glomerular filtration rate was 30% lower in rats receiving the B1-antagonist than in control rats after volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of converting enzyme inhibition with captopril on baroreflex sensitivity.

Clinical and experimental data suggest that both Captopril and angiotensin II (AII) reduce baroreflex responsiveness, and the main action of this converting enzyme inhibitor (CEI) seems clear to suppress AII synthesis. The aim of this work is to investigate this striking similarity of effects. We have verified that CEI (4 mg/kg) originates tachycardia significantly lower (P less than 0.001) than that produced in response to a similar hypotension elicited by an unspecific vasodilator: sodium nitroprusside (10-45 micrograms/kg min). CEI SQ 20881 has been reported to increase plasma vasopressin concentrations (AVP); this peptide is also known to modify baroreflex responses and has a small direct negative chronotropic effect. However, our determinations of AVP do not show any difference between the control group and the group treated with Captopril (4.78 +/- 0.87 and 5.26 +/- 0.19 pg/ml respectively). On the other hand, although CEI did not modify the rapid responses of heart rate (HR) to changes of mean arterial pressure (MAP), the decrease of MAP induced by nitroprusside was higher in the group treated with Captopril than in control group; it could mean a baroreflex ability decrease to buffer the hypotension. However, AII elicited a strong impairment of both rapid responses of HR and the buffering of hypotension produced by NP, these actions being suggested as centrally mediated. These results could indicate that the suppression of peripheral AII synthesis and therefore, the lack of pre- and postjunctional sympathetic potentiation owing to this hormone, is responsible for the absence of tachycardia under Captopril treatment.

Adrenal and vascular renin-like activity in chronic 'two-kidney, one-clip' hypertensive rats.

In order to study the vascular and adrenal renin angiotensin system in the chronic phase (4 months after clipping) of 'two-kidney, one-clip' hypertension in rats, systolic blood pressure, plasma renin activity, and tissue renin-like activity in both aorta and adrenal have been measured. Renin activity in adrenal gland was studied in both the zona glomerulosa (GLO) and the remainder of the gland. Results showed an increase in vascular renin activity in chronic hypertensive rats. Moreover it was found that GLO of hypertensive rats presented a significant increase in renin-like activity compared with controls (349.43 +/- 43.86 versus 167 +/- 34.25 ng AI/g/20 h, p less than 0.01) and the fasciculata-reticular-medullar (FRM) portion also showed greater renin activity (345.16 +/- 64.36 versus 57.90 +/- 4.83 ng AI/g/20 h, p less than 0.01). The higher levels of vascular and FRM renin-like activity in chronic renal hypertension are probably a consequence of plasma renin increase. This hypothesis is supported by the fact that bilateral nephrectomy in normal rats induces a significant decrease in plasma renin activity and both aortic and FRM renin-like activity. On the other hand the GLO renin-like activity could depend on both plasma renin and local synthesis since bilateral nephrectomy induces an increase in the renin-like activity in this tissue. These data support the idea that aortic and FRM renin are, at least in part, due to plasma renin uptake and GLO renin is an autonomic system.

Difference between intracarotid and intravenous infusions of angiotensin II on baroreflex sensitivity and vasopressin release in conscious rats.

A carotid infusion of angiotensin (AII) (10 ng/kg/min) has been found to increase significantly higher mean arterial pressure (MAP) and produces significantly lower bradycardia than AII intravenous infusions at the same dose and rate. Besides, i.v. administration of AII elicits greater impairment on baroreflex sensitivity than carotid infusion of AII does. On the other hand, vasopressin vascular receptor blockade did not modify the baroreflex sensitivity either in the carotid or in the i.v. infusions of AII, and plasma AVP measurements did not change significantly in any group. It clearly indicates that neither AVP nor baroreflex impairment plays any role on the pressor action of AII intracarotid infusions at a low dose. The present results further suggest that baroreflex impairment in rats may unlikely be located in the region irrigated by the carotid artery.

Hemodynamic effects of chronic infusion of rANP in renal hypertensive rats.

The purpose of this study was to evaluate the hemodynamic effects induced by an infusion of synthetic rat atrial natriuretic peptide (rANP, 0.5 micrograms/h iv) during 5 consecutive days in conscious normotensive and two-kidney, one-clip hypertensive (2K,1C) rats. Changes in plasma ANP (pANP) levels and plasma renin activity (PRA) were also determined. The administration of ANP in 2K,1C rats induced a significant decrease in mean arterial pressure (MAP) from 169 +/- 3 to 138 +/- 3, and 149 +/- 3 mmHg by 2 and 5 days of infusion, respectively. This hypotension was accompanied by a significant fall in cardiac index (CI) from 400 +/- 16 to 348 +/- 14 ml.min-1.kg-1 after 2 days of ANP treatment. However, CI returned to the basal levels at the third day, and a significant decrease in total peripheral resistance (TPR) was observed by 3 and 5 days of ANP infusion. The administration of the same dose of ANP in normotensive rats did not induce changes in MAP, but CI decreased (P less than 0.001) transitorily during the first 2 days and returned to control values thereafter. Basal pANP levels were significantly elevated in the hypertensive animals (176 +/- 40 pg/ml) when compared with the normotensive rats (82 +/- 10 pg/ml). The ANP infusion resulted in lower (P less than 0.05) pANP levels in hypertensive (1,017 +/- 234 pg/ml) than in normotensive rats (3,466 +/- 975 pg/ml). PRA did not change in any group during the administration of ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of converting-enzyme inhibitor on hemodynamic actions of ANP in renal hypertensive rats.

In the present study, we have evaluated whether the hemodynamic effects of atrial natriuretic peptide (ANP) infusion in two-kidney, one-clip (2K, 1C) hypertensive rats are mediated by inhibition of the renin-angiotensin system (RAS). Hemodynamic determinations were performed by thermodilution in conscious, chronically instrumented animals. ANP (1.5 micrograms.kg-1.min-1) and converting-enzyme (CE) inhibitor captopril (1 mg/kg plus 1 mg.kg-1.h-1), produced a similar fall of blood pressure through different hemodynamic mechanisms. ANP induced hypotension by decreasing cardiac index (CI; from 337.3 +/- 24.9 to 255.1 +/- 21.3 ml.min-1.kg-1, P less than 0.001), whereas a fall in total peripheral resistance (TPR) was observed during CE inhibition (from 0.568 +/- 0.02 to 0.488 +/- 0.02 mmHg.min.ml-1.kg, P less than 0.05). In addition, the ANP-induced decrease in CI was not significantly modified by previous CE inhibition. Furthermore, the decrease in TPR induced by CE inhibition did not change when CE inhibitor was administered during ANP treatment. The results of the present study indicate that the acute hemodynamic responses to ANP in 2K, 1C hypertensive rats are not mediated through antagonism of the vasoconstrictor actions of the RAS.