Role of extrarenal and intrarenal converting enzyme inhibition in renal vasodilator response to intravenous captopril

Participation of intrarenal converting enzyme (ICE) in mediation of the renal vasodilator response to captopril (C) was studied in 7 anesthetized dogs. Blood pressure (BP), renal blood flow (RBF) and femoral blood flow (FBF) were measured and vasoconstrictor responses were elicited by i.a. injections of angiotensin (A) I to the renal and femoral vascular beds. The latter responses served as indices of intrarenal and skeletal muscle converting enzyme activity, respectively. Successive infusions of C were given i.a. to the kidney at 0.4, 0.8 and 1.6 μg/kg/min for 30 min each. RBF and renal vascular resistance (RVR) were unaffected by any of these doses of C. The % changes in RBF caused by A-I were reduced from 45 to 23, 20 and 17% by these successive doses of C, respectively; however, the decrements were not significantly different from each other. When C was administered i.v., 0.5 mg/kg, after the highest i.a. dose had been given, there was no further decrease in the response to A-I, suggesting maximal blockade of ICE obtainable by C. BP, RBF and RVR were further affected by the i.v. administration of C. BP decreased from 146 to 136 mm Hg (P<0.05), RBF increased from 240 to 290 ml/min (P<0.01) and RVR decreased from 32 to 24 mm Hg/ml/min/g (P<0.01). These results suggest that ICE plays a minor role in the renal vasodilator response to C, and implicate an influence of circulating peptides on the kidney.     

Prevention of systemic and regional haemodynamic alterations, hypercreatininemia, hyperuremia and hyperphosphatemia by losartan in hypertension with acute renal failure

Patients with pre-existing hypertension are at a particular risk of fatal outcome due to acute renal failure (ARF). We investigate the effects of angiotensin II type-1 receptor blocker (ARB) losartan, on haemodynamics and biochemical parameters in adult male spontaneously hypertensive rats (SHR) with ischemia/reperfusion ARF. SHR were randomly selected in three experimental groups: sham-operated group (SHAM), ARF group, and ARF+LOS group (losartan, 10 mg/kg/b.w. given by infusion during the period of three hours after reperfusion). Beside the improvement of systemic haemodynamics 24 h after reperfusion, losartan significantly increased renal blood flow (RBF: 19.33±3.29 ml/min/kg vs. 8.03±1.04 ml/min/kg, p<0.05) and decreased renal vascular resistance (RVR) compared to ARF (8.85±1.21 mmHg × min × kg/ml vs. 19.90±2.35 mmHg × min × kg/ml, p<0.001). Plasma creatinine (Pcr), urea (Pu) and phosphates (Pphos) were significantly reduced in ARF+LOS group compared to ARF group (Pcr: 99.11±14.56 μmol/l vs. 242.71±20.25 μmol/l, p<0.001; Pu: 33.72±4.69 mmol/l vs. 61.90±3.93 mmol/l, p<0.001; 2.7±0.42 mmol/l vs. 5.57±0.61 mmol/l, p<0.01). Our results demonstrate that losartan improves systemic and regional haemodynamic and biochemical parameters in hypertension with ARF.     

Adrenal-renal portal circulation contributes to decrease in renal blood flow after renal artery stenosis in rats.

The aim of the present study was to investigate a role of adrenal-renal portal circulation (ARPC) in a decrease in renal blood flow due to acute stenosis of the renal artery in rats. Animals were divided into three groups. In the control group (I), in order to eliminate the ARPC tissue between the adrenal gland and the ipsilateral kidney was cut. In the second and the third group (II) (III), left renal artery was stenosed by a silver clip (ID 0.40 mm). Then, in the group II, ARPC was surgically eliminated. In the group II, prior to the elimination of ARPC, alpha-adrenergic receptors blockade was produced by phentolamine administration. In the control group, ARPC elimination did not influence either renal blood flow (RBF) or renal vascular resistance (RVR). In the group II, elimination of ARPC caused increase in RBF and decrease in RVR In the group III elimination of ARPC influenced neither RBF nor renal vascular resistance (RVR). Results of the present study provide the functional evidence that catecholamines reaching the kidney through ARPC, contribute to the decrease in RBF and increase in RVR during acute renal artery stenosis in the rat.     

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 micron radioactive microspheres during normocapnia (PaCO2 congruent to 30 mmHg) and hypercapnia (PaCO2 congruent to 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n = 6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438 +/- 61 and 326 +/- 69 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 +/- 59 ml/min per 100 g during normocapnia and 295 +/- 60 ml/min per 100 g during hypercapnia (P less than 0.05). In the vehicle group, RBF was 409 +/- 74 and 226 +/- 45 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371 +/- 46 ml/min per 100 g during normocapnia and 219 +/- 50 (P less than 0.05) ml/min per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.     

Prostanoids and hypothermic renal preservation injury

The effect of 48 hours of hypothermic renal ischemia utilizing Euro-Collins flush and short term reperfusion on renal prostaglandin synthesis was studied in dogs. Hypothermic ischemia followed by 60 minutes of reperfusion in-vivo resulted in significant elevations in renal Thromboxane B2 (TXB2) production in the outer cortex, inner cortex, and medulla, relative to non-ischemic kidneys. Prostaglandin E2 (PGE2) and 6-keto Prostaglandin F1 alpha (6-K PGF1 alpha) production were not significantly affected by ischemia and reperfusion. Enhanced TXB2 production was not seen with ischemia alone (without reperfusion) or with reperfusion with O2 saturated buffer, indicating a blood born source or stimuli. Early postreperfusion renal blood flow after hypothermic ischemia followed a biphasic pattern; blood flow increased for the first 10 minutes of reperfusion to achieve normal values, and then steadily declined over the next 20 minutes. This pattern was not altered by the cyclooxygenase inhibitors Idomethacin (5 mg/kg, P.O.) or Mefenamic acid (10 mg/kg, I.V.). Administration of the TXA2 synthesis inhibitor CGS-12970 (3 mg/kg, I.V.) or the TXA2/endoperoxide receptor antagonist SQ-29548 (80 micrograms/min, I.A.) significantly increased renal blood flow during reperfusion but neither agent altered the basic time dependent pattern observed in the control group. These data indicate that 48 hours of hypothermic renal ischemia results in dramatic changes in intrarenal TXA2 synthesis at the time of reperfusion. Enhanced TXA2 production is not dependent on reoxygenation per se, but rather requires reperfusion with blood suggesting a circulatory source.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.     

Role of EP(2) and EP(3) PGE(2) receptors in control of murine renal hemodynamics

The kidney plays a central role in long-term regulation of arterial blood pressure and salt and water homeostasis. This is achieved in part by the local actions of paracrine and autacoid mediators such as the arachidonic acid-prostanoid system. The present study tested the role of specific PGE(2) E-prostanoid (EP) receptors in the regulation of renal hemodynamics and vascular reactivity to PGE(2). Specifically, we determined the extent to which the EP(2) and EP(3) receptor subtypes mediate the actions of PGE(2) on renal vascular tone. Renal blood flow (RBF) was measured by ultrasonic flowmetry, whereas vasoactive agents were injected directly into the renal artery of male mice. Studies were performed on two independent mouse lines lacking either EP(2) or EP(3) (-/-) receptors and the results were compared with wild-type controls (+/+). Our results do not support a unique role of the EP(2) receptor in regulating overall renal hemodynamics. Baseline renal hemodynamics in EP(2)-/- mice [RBF EP(2)-/-: 5.3 +/- 0.8 ml. min(-1). 100 g kidney wt(-1); renal vascular resistance (RVR) 19.7 +/- 3.6 mmHg. ml(-1). min. g kidney wt] did not differ statistically from control mice (RBF +/+: 4.0 +/- 0.5 ml. min(-1). 100 g kidney wt(-1); RVR +/+: 25.4 +/- 4.9 mmHg. ml(-1). min. 100 g kidney wt(-1)). This was also the case for the peak RBF increase after local PGE(2) (500 ng) injection into the renal artery (EP(2)-/-: 116 +/- 4 vs. +/+: 112 +/- 2% baseline RBF). In contrast, we found that the absence of EP(3) receptors in EP(3)-/- mice caused a significant increase (43%) in basal RBF (7.9 +/- 0.8 ml. min(-1). g kidney wt(-1), P < 0.05 vs. +/+) and a significant decrease (41%) in resting RVR (11.6 +/- 1.4 mmHg. ml(-1). min. g kidney wt(-1), P < 0.05 vs. +/+). Local administration of 500 ng of PGE(2) into the renal artery caused more pronounced renal vasodilation in EP(3)-/- mice (128 +/- 2% of basal RBF, P < 0.05 vs. +/+). We conclude that EP(3 )receptors mediate vasoconstriction in the kidney of male mice and its actions are tonically active in the basal state. Furthermore, EP(3) receptors are capable of buffering PGE(2)-mediated renal vasodilation.     

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 μm radioactive microspheres during normocapnia (PaCO₂ 30 mmHg) and hypercapnia (PaCO₂ 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n=6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438±61 and 326 ± 69 (P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 ± 59 ml/min per 100 g during normocapnia and 295 ± 60 ml/min per 100 g during hypercapnia (P<0.05). In the vehicle group, RBF was 409±74 and 226±45(P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371±46 ml/min per 100 g during normocapnia and 219 ± 50 (P<0.05) per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.     

Androgens augment renal vascular responses to ANG II in New Zealand genetically hypertensive rats

Males develop higher blood pressure than do females. This study tested the hypothesis that androgens enhance responsiveness to ANG II during the development of hypertension in New Zealand genetically hypertensive (NZGH) rats. Male NZGH rats were obtained at 5 wk of age and subjected to sham operation (Sham) or castration (Cas) then studied at three age groups: 6-7, 11-12, and 16-17 wk. Mean arterial blood pressure (MAP), heart rate (HR), and renal blood flow (RBF) measurements were recorded under Inactin anesthesia. These variables were measured after enalapril (1 mg/kg) treatment and during intravenous ANG II infusion (20, 40, and 80 ng/kg/min). Plasma testosterone was measured by ELISA. Angiotensin type 1 (AT1) receptor expression was assessed by Western blot analysis and RT-PCR. ANG II-induced MAP responses were significantly attenuated in Cas NZGH rats. At the highest ANG II dose, MAP increased by 40+/-4% in Sham vs. 22+/-1% in Cas NZGH rats of 16-17 wk of age. Similarly, renal vascular resistance (RVR) responses to ANG II were reduced by castration (209+/-20% in Sham vs. 168+/-10% in Cas NZGH rats at 16-17 wk of age). Castration also reduced MAP recorded in conscious NZGH rats of this age group. Testosterone replacement restored baseline MAP and the pressor and RVR responses to ANG II. Castration reduced testosterone concentrations markedly. Testosterone treatment restored these concentrations. Neither castration nor castration+testosterone treatment affected AT1 receptor mRNA or protein expression. Collectively, these data suggest that androgens modulate renal and systemic vascular responsiveness to ANG II, which may contribute to androgen-induced facilitation of NZGH rat hypertension.     

N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure

This study evaluated the effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, on the changes in renal function, intrarenal blood flow distribution (laser-Doppler flowmetry), and plasma peroxynitrite levels during the acute renal failure (ARF) produced by inferior vena cava occlusion (IVCO; 45 min) in anesthetized rats. Renal blood flow fell on reperfusion (whole kidney by -45.7%; cortex -58.7%, outer medulla -62.8%, and papilla -47.7%); glomerular filtration rate (GRF) also decreased (-68.6%), whereas fractional sodium excretion (FE(Na%)) and peroxynitrite and NO/NO plasma levels increased (189.5, 46.5, and 390%, respectively) after ischemia. Pretreatment with L-NAME (10 microg. kg(-1). min(-1)) aggravated the fall in renal blood flow seen during reperfusion (-60%). Pretreatment with NAC (150 mg/kg bolus + 715 microg. kg(-1). min(-1) iv) partially prevented those changes in renal function (GFR only fell by -29.2%, and FE(Na%) increased 119.4%) and laser-Doppler blood flow, especially in the outer medulla, where blood flow recovered to near control levels during reperfusion. These beneficial effects seen in rats given NAC seem to be dependent on the presence of NO, because they were abolished in rats pretreated with L-NAME. Also, the antioxidant effects of NAC prevented the increase in plasma peroxynitrite after ischemia. In conclusion, NAC ameliorates the renal failure and the outer medullary vasoconstriction induced by ICVO, effects that seem to be dependent on the presence of NO and the scavenging of peroxynitrite.     

AT1 receptors in the paraventricular nucleus mediate the hyperthermia-induced reflex reduction of renal blood flow in rats

Increasing body core temperature reflexly decreases renal blood flow (RBF), and the hypothalamic paraventricular nucleus (PVN) plays an essential role in this response. ANG II in the brain is involved in the cardiovascular responses to hyperthermia, and ANG II receptors are highly concentrated in the PVN. The present study investigated whether ANG II in the PVN contributes to the cardiovascular responses elicited by hyperthermia. Rats anesthetized with urethane (1-1.4 g/kg iv) were microinjected bilaterally into the PVN (100 nl/side) with saline (n = 5) or losartan (1 nmol/100 nl) (n = 7), an AT1 receptor antagonist. Body core temperature was then elevated from 37°C to 41°C and blood pressure (BP), heart rate (HR), RBF, and renal vascular conductance (RVC) were monitored. In separate groups losartan (n = 4) or saline (n = 4) was microinjected into the PVN, but body core temperature was not elevated. Increasing body core temperature in control rats elicited significant decreases in RBF (-48 ± 5% from a resting level of 14.3 ± 1.4 ml/min) and MVC (-40 ± 4% from a resting level of 0.128 ± 0.013 ml/min·mmHg), and these effects were entirely prevented by pretreatment with losartan. In rats in which body core temperature was not altered, losartan microinjected into the PVN had no significant effects on these variables. The results suggest that endogenous ANG II acts on AT1 receptors in the PVN to mediate the reduction in RBF induced by hyperthermia.     

Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids

This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 2 mg/kg plus 1.5 mg.kg(-1).h(-1)), on renal hemodynamic responses to infusions of [Phe(2),Ile(3),Orn(8)]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe(2),Ile(3),Orn(8)]vasopressin (30 ng.kg(-1).min(-1)) reduced MLDF by 62 +/- 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 +/- 8 and 59 +/- 13%, respectively, when [Phe(2),Ile(3),Orn(8)]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe(2),Ile(3),Orn(8)]vasopressin (43 +/- 9% reduction). ANG II (20 ng.kg(-1).min(-1)) reduced RBF by 45 +/- 10% and CLDF by 41 +/- 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe(2),Ile(3),Orn(8)]vasopressin (0.2-20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V(1)-receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of cortical blood flow to V(1)-receptor activation [corrected].     

Effects of Bay K 8644 on renal function and renin secretion in anesthetized rats

Our previous study on kidney cortical slices showed that Bay K 8644, a dihydropyridine calcium channel agonist, produced a dose-dependent inhibitory action on the release of renin. The present study was performed to examine the effect of Bay K 8644 on renal function and renin secretion in vivo. When Bay K 8644 was directly infused into the renal artery of anesthetized rats, 2 micrograms/kg/min had no effect on renal blood flow (RBF) and glomerular filtration rate (GFR), but decreased urine flow (UF), urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) by about 30%, 55% and 35%, respectively, thereby suggesting that Bay K 8644 enhanced the tubular reabsorption of water and sodium. When 10 micrograms/kg/min were infused, RBF, GFR, UF, UNaV and FENa decreased to about 95%, 70%, 35%, 35% and 30% of each control value. The administration of Bay K 8644 at 10 micrograms/kg/min did not influence the basal levels of plasma renin activity (PRA) and renin secretion rate (RSR), but did inhibit significantly isoproterenol-induced increasing effects on PRA and RSR. These results indicate that the activation of voltage-dependent calcium channels with Bay K 8644 influences the control of renal function and renin secretion in vivo.     

Effect of cardiac receptor stimulation on renal vascular resistance in the pregnant rat

Stimulation of cardiac receptors (CR) evokes blunted reflex reductions in mean arterial pressure (MAP) in pregnant compared with virgin rats. Because CR-mediated sympathoinhibition has preferential effects on the kidney, we tested whether, during pregnancy, renal vascular resistance (RVR) changes less in response to CR stimulation and investigated possible mechanisms. MAP, right atrial pressure, renal sympathetic nerve activity (RSNA), renal blood flow (RBF), and RVR were measured in anesthetized animals in response to CR stimulation by graded atrial injections of saline. Baseline MAP and RVR and reflex changes in these variables during CR stimulation were reduced in late-pregnant vs. virgin rats (P<0.05). Reflex changes in RSNA were attenuated in pregnant rats, but changes in RBF as a function of RSNA were similar in both groups. ANG II AT(1)-receptor blockade increased basal RBF more in virgin rats (P<0.05), but between-group differences in reflex changes in MAP, RSNA, and RVR were maintained after AT(1) blockade. Thus during CR simulation, reflex changes in RVR were reduced in pregnant versus virgin rats. This difference does not appear to involve differential effects of ANG II.     

Polyuria and impaired renal blood flow after asphyxia in preterm fetal sheep

Renal impairment is common in preterm infants, often after exposure to hypoxia/asphyxia or other circulatory disturbances. We examined the hypothesis that this association is mediated by reduced renal blood flow (RBF), using a model of asphyxia induced by complete umbilical cord occlusion for 25 min (n = 13) or sham occlusion (n = 6) in chronically instrumented preterm fetal sheep (104 days, term is 147 days). During asphyxia there was a significant fall in RBF and urine output (UO). After asphyxia, RBF transiently recovered, followed within 30 min by a secondary period of hypoperfusion (P < 0.05). This was mediated by increased renal vascular resistance (RVR, P < 0.05); arterial blood pressure was mildly increased in the first 24 h (P < 0.05). RBF relatively normalized between 3 and 24 h, but hypoperfusion developed again from 24 to 60 h (P < 0.05, analysis of covariance). UO significantly increased to a peak of 249% of baseline between 3 and 12 h (P < 0.05), with increased fractional excretion of sodium, peak 10.5 +/- 1.4 vs. 2.6 +/- 0.6% (P < 0.001). Creatinine clearance returned to normal after 2 h; there was a transient reduction at 48 h to 0.32 +/- 0.02 ml.min(-1).g(-1) (vs. 0.45 +/- 0.04, P < 0.05) corresponding with the time of maximal depression of RBF. No renal injury was seen on histological examination at 72 h. In conclusion, severe asphyxia in the preterm fetus was associated with evolving renal tubular dysfunction, as shown by transient polyuria and natriuresis. Despite a prolonged increase in RVR, there was only a modest effect on glomerular function.     

Roles of adrenomedullin 2 in regulating the cardiovascular and sympathetic nervous systems in conscious rats

Recently, a new member of the calcitonin gene-related peptide (CGRP) family, adrenomedullin 2 (AM2) or intermedin (IMD), was identified. AM2/IMD has been shown to have a vasodilator effect in mice and rats and an effect on urine formation in rats. In the present study, we investigated the effects of intravenously infused rat AM2 (rAM2) on blood pressure (BP), heart rate (HR), renal sympathetic nerve activity (RSNA), and renal blood flow (RBF) in conscious unrestrained rats relative to the effects of rat adrenomedullin (rAM) and proadrenomedullin NH2-terminal 20 peptide (rPAMP). Intravenous infusion of rAM2 (5 nmol/kg) significantly decreased BP and increased HR, RSNA, and RBF. These hypotensive and sympathoexcitatory effects diminished after 20 min, and HR returned to control levels 30 min after cessation of the infusion. In contrast, a significant increase in RBF was still evident 60 min after cessation of the peptide infusion. The duration of BP, HR, and RSNA responses was longer with rAM (5 nmol/kg) than with rAM2 infusion, whereas the increases in RBF induced by rAM2 and rAM were similar in their amplitude and duration. Infusion of rPAMP (200 nmol/kg) increased HR and RSNA but had no effect on RBF. Baroreceptor denervation suppressed, but did not diminish, the increases in HR and RSNA to rAM2. These findings indicate that the physiological roles of rAM2 and rAM are similar and that rAM2 also has a long-lasting vasodilator action on the renal vascular bed.     

The effect of lidocain on the renal function

The evidence supporting a role for direct neurogenic control of renal function was investigated in twenty anaesthetized dogs. Unilateral renal sympathectomy was induced by 0.5 mg/kg/min of lidocain infusion into the left renal artery and the kidney function changes were compared to those observed in the right non infused kidney. The renal parameters were similar in the kidneys during the control periods. 0.5 mg/kg/min of lidocain infusion into the left renal artery resulted in significant reductions of the RBF, GFR, urine and sodium excretion in the left kidney. The intrarenal lidocain infusion induced a small decrease of the arterial blood pressure but this can not explain the changes observed in the left kidney. The modifications of the right kidney function during lidocain infusion were significantly less than those observed in the left kidney. Comparing the measured RBF and the renal blood flow calculated by the CPAH in the left kidney during the lidocain infusion, we have found a marked difference, when the decrease of the calculated RBF was greater. We believe that effects of pharmacological denervation can be best explained by the intrarenal hemodinamically mediated changes. The sympathectomy produces a considerable vasoconstriction in the renal cortical vascular bed, subsequently it decreases the RBF, GFR renal sodium and water excretion. But the lidocain blocks the sympathetic nerves influencing the renal medullary vessels and the renal medullary blood flow increases. These observations are not consistent with the notion that renal nerves are at least partially responsible for the natriuresis accompanying salt loading.     

Acute effects of angiotensin II on renal haemodynamics and excretion in conscious dogs

The effects of a 60-min intravenous infusion of angiotensin II (A II; 4 or 20 ng A II/min/kg body weight) on renal blood flow (RBF; electromagnetic flow transducer, control value 19-25 ml/min/kg), glomerular filtration rate (GFR; control value 4.2-5.0 ml/min/kg), mean arterial blood pressure, sodium excretion, water excretion, and plasma A II and plasma aldosterone concentrations were examined in 6 chronically instrumented female conscious beagle dogs kept on three different dietary sodium intakes (SI): SI 0.5 or SI 2.5 mmol Na/kg/day or SI 4.5 mmol Na/kg/day plus an oral saline load prior to the experiment SI 4.5(+) dogs. Four nanograms A II decreased RBF and GFR in SI 4.5(+) dogs without changing the filtration fraction (FF%); in SI 0.5 dogs the RBF decreased, and the FF% increased. Twenty nanograms A II decreased RBF and increased FF% in all dietary protocols, less in SI 4.5(+) dogs. The mean arterial blood pressure increased in all dietary protocols by 10-15 mm Hg (4 ng A II) and 32-37 mm Hg (20 ng A II). Sodium and water excretions decreased by 32 and 46%, respectively, in SI 4.5(+) dogs at both doses of A II. The plasma aldosterone concentration increased in all but one protocol: 4 ng A II, SI 4.5(+) dogs. It is concluded that when A II plasma concentrations are most likely borderline to pathophysiological conditions (up to an average of 370 pg/ml), the GFR is less decreased than the RBF. This phenomenon also can be observed at lower plasma A II concentrations (average 200 pg/ml), when the renin-angiotensin system had been previously moderately activated.     

Effects of calcitonin gene-related peptide on renal blood flow in the rat

The effects of alpha-rat calcitonin gene-related peptide (alpha-rCGRP) on systemic and renal hemodynamics and on renal electrolyte excretion were examined in normal anesthetized rats. In one group of rats (n = 7), infusions of alpha-rCGRP at doses of 10, 50, 100, and 500 ng/kg/min for 15 min each produced dose-related and significant decreases in mean arterial pressure from a control of 130 +/- 3 mm Hg to a maximal depressor response of 91 +/- 2 mm Hg. During the first three doses of alpha-rCGRP, renal blood flow progressively and significantly increased from a control of 5.0 +/- 0.3 ml/min to a peak level of 6.3 +/- 0.3 ml/min achieved during the 100 ng/kg/min infusion. With the highest infusion rate of 500 ng/kg/min, renal blood flow fell below the control level to 4.5 +/- 0.2 ml/min (P less than 0.05). The responses in renal blood flow and mean arterial pressure were associated with reductions in renal vascular resistance. After cessation of alpha-rCGRP infusions, arterial pressure, renal blood flow, and renal vascular resistance gradually returned toward the baseline values. In another group of rats (n = 9), infusion of alpha-rCGRP for 30 min at 100 ng/kg/min produced a significant reduction in urinary sodium excretion from 0.28 +/- 0.06 to 0.14 +/- 0.5 muEq/min (P less than 0.05). Urine flow and urinary potassium excretion also appeared to decrease, but the changes were not significantly different (P greater than 0.05) from their respective baselines. These results demonstrate that alpha-rCGRP is a potent and reversible hypotensive and renal vasodilatory agent in the anesthetized rat. The data also suggest that alpha-rCGRP may have significant effects on the excretory function of the kidney.     

20-HETE-mediated vasoconstriction by hemoglobin-O2 carrier in Sprague-Dawley but not Wistar rats.

Hypothetically either decreased nitric oxide (NO) or increased O(2) could initiate 20-HETE-mediated vasoconstriction associated with hemoglobin-based blood substitutes (HBOC). To test this hypothesis, we infused Tm-Hb, an HBOC with low O(2) affinity, into isoflurane-anesthetized Wistar (W) and Sprague-Dawley (SD) rats after exchanging 20% of their blood with Ringer lactate. For comparison we infused an equal amount of BSA or BSA with N(G)-nitro-L-arginine methyl ester (BSA + NAME). Tm-Hb increased blood pressure (BP) and renal vascular resistance (RVR) equally in W and SD rats. Renal blood flow (RBF; Doppler ultrasound) decreased. BSA decreased RVR and raised glomerular filtration rate. BSA + NAME raised BP, RVR, and GFR. HET0016, an inhibitor of 20-HETE production, blunted BP and RVR responses to Tm-Hb and BSA+NAME in SD but not W rats. Arterial O(2) content with BSA was lower than with Tm-Hb but O(2) delivery was 60% higher with BSA because of higher RBF. BSA raised Po(2) (Oxylite) in cortex and medulla and reduced RVR. Tm-Hb decreased Po(2) and increased RVR. Switching rats from breathing air to 100% O(2) raised intrarenal Po(2) two- to threefold and increased BP and RVR. HET0016 did not alter hyperoxic responses. In conclusion, 20-HETE contributes to vasoconstriction by Tm-Hb in SD but not in W rats, and increased 20-HETE activity results primarily from decreased NO.