Reduction In Renal Vascular Resistance Research Articles

Randomized, Placebo-Controlled Trial on the Renal and Systemic Hemodynamic Effects of Empagliflozin

IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcomes in type 2 diabetes (DM2) and chronic kidney disease (CKD). A decrease in renal blood flow (RBF) with attenuation of glomerular hyperfiltration may contribute. We examined renal and systemic hemodynamic effects of SGLT2i in relevant patient categories. MethodsUsing a double-blind placebo controlled cross-over design we randomized patients with DM2 and estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m2 (n=16), patients with DM2 and eGFR 20-60 ml/min/1.73m2 (n=17) and patients with non-diabetic CKD and eGFR 20-60 ml/min/1.73m2 (n=16) to empagliflozin 10 mg daily or placebo for four weeks and crossed over to the opposite treatment after two-week washout. RBF was measured with 82Rubidium-positron emission-tomography/computed-tomography, GFR with 99mTechnetium-diethylene-triamine-pentaacetate-clearance. 24-hour blood pressure (BP) and total vascular resistance (TVR) were recorded using a Mobil-O-graph. ResultsCompared to placebo empagliflozin reduced RBF by 6% in the DM2-CKD group (p<0.001) with non-significant decreases of 4% in the DM2 group and 1% in the CKD group (p=0.29 and 0.72). Empagliflozin reduced GFR, BP and TVR in all groups, while renal vascular resistance (RVR) remained unchanged ConclusionEmpagliflozin reduced RBF in patients with DM2 and CKD, whereas GFR, BP and TVR were reduced in all groups. This pattern, together with a lack of reduction in RVR, suggests SGLT2i protect the glomerulus through combined pre-glomerular and post-glomerular effects.

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib-Induced Hypertension.

BackgroundThe tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib‐induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib‐treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib‐induced hypertension.Methods and ResultsArterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib‐treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib‐treated rats. Nitrate supplementation did not mitigate sunitinib‐induced hypertension. Endothelium‐dependent reductions in renal vascular resistance were similar in control and sunitinib‐treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib‐treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1‐subunit protein abundance were less in sunitinib‐treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15‐20 mm Hg in sunitinib‐treated rats.ConclusionsRenal cortical sGC is downregulated in the presence of intact endothelium‐dependent renal vascular resistance regulation in developing sunitinib‐induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib‐induced hypertension.

The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and beta 2-adrenoceptors in the dog.

The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 X 10(-9)-10(-7) mol kg-1 min-1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the beta 2-adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1-receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1- and DA2-receptor and beta 2-adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac beta 2-adrenoceptors. Thus the beta 2-adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.

Gender difference in response to thromboxane A2/prostaglandin H2 receptor antagonism in spontaneously hypertensive rats

Blood pressure (BP) is typically higher in men than in women. As in humans, BP is higher in male spontaneously hypertensive rats (SHRs) than in female SHRs. The mechanism(s) responsible for the higher BP in men and male rats has not been elucidated. The present study tested the hypothesis that thromboxane and/or the thromboxane A(2)/prostaglandin H(2) receptor (TxR) plays a role in the gender difference in BP in SHRs. Male and female SHRs were treated with the TxR antagonist SQ29548 (2 microg/kg/min into the jugular vein) via minipump for 2 weeks; mean arterial pressure (MAP) and renal hemodynamic function were measured. To determine whether thromboxane played a role in the higher MAP in SHRs, male and female rats were treated with the thromboxane synthase inhibitor (TxI) furegrelate, 30 mug/kg/min, via minipump, for 2 weeks. MAP was reduced with TxR antagonism in male but not in female SHRs. In addition, TxR antagonism in males caused renal vasodilation with increases in glomerular filtration rate and renal plasma flow, and reductions in renal vascular resistance. In contrast, MAP was not affected by the TxI in either males or females. These data support a role for TxR, but not thromboxane, in mediating the gender difference in BP in SHRs.

L-arginine-induced vasodilation of the renal vasculature is preserved in uremic type 1 diabetic patients after kidney and pancreas but not after kidney-alone transplantation.

In uremic type 1 diabetic patients, kidney and pancreas transplantation (KP) and kidney-alone transplantation (KD) provide full restoration of normal renal function; however, only KP, i.e., curing diabetes, is expected to prevent endothelial damages. Our aim was to study L-arginine-induced vasodilation of the renal vasculature in uremic type 1 diabetic patients after KP or KD using magnetic resonance (MR). MR quantitative flow measurements were performed in 15 KP patients (mean age 39.0 +/- 1.7 years, 10 men and 5 women), in 11 KD patients (mean age 47.3 +/- 1.9 years, 7 men and 4 women), and in 8 nondiabetic kidney transplant patients (mean age 44.0 +/- 4.8 years, 7 men and 1 woman), who were used as control subjects, to measure renal blood flow and velocity and renal vascular resistance before and immediately after infusion of L-arginine. Renal blood flow and velocity were not different at baseline in KP, KD, and control subjects. In contrast, during L-arginine administration renal blood flow increased significantly in KP subjects (basal 8.4 +/- 0.6 vs. post 9.6 +/- 0.8 ml/s, Delta 14.3 +/- 4.4%, P < 0.05) and in control subjects (basal 9.3 +/- 0.8 vs. post 9.1 +/- 0.8 ml/s, Delta 17.3 +/- 6.2%, P < 0.01), while it remained unchanged in KD subjects (basal 10.0 +/- 0.8 vs. post 11.6 +/- 0.9 ml/s, Delta -1.36 +/- 6.9%, NS). Parallel results have been achieved for renal blood velocity (KP subjects: 20.1 +/- 4.9%, P < 0.01; control subjects: 23.0 +/- 7.99%, P < 0.01; and KD subjects: -0.3 +/- 6.5%; NS). A reduction in renal vascular resistance in response to L-arginine was evident in KP and control subjects but not in KD patients. L-Arginine vasodilatory response was successfully assessed with MR quantitative flow measurements. KP patients and control subjects, but not those with KD, showed a preserved L-arginine-induced vasodilation of the renal vasculature.

Usefulness and limits of distal echo-Doppler velocimetric indices for assessing renal hemodynamics in stenotic and non-stenotic kidneys.

Distal echo-Doppler velocimetric indices are widely used for revealing the presence of a renal artery stenosis but there is scarce information as to whether they reflect the renal hemodynamics in stenotic and nonstenotic kidneys. We evaluated the pulsatility and resistive indices (PI and RI), acceleration (A) and acceleration time (At) and correlated their values with those of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), renal vascular resistance (RVR) and filtration fraction (FF) estimated by single kidney scintigraphy in 24 kidneys with 70-95% renal artery stenosis (atherosclerotic n = 17, fibromuscular n = 7) and in 27 non-stenotic kidneys (11 contralateral to renal artery stenosis and 16 of patients with essential hypertension). In patients with stenotic kidneys, these measurements were repeated within 7 days after a successful percutaneous transluminal renal angioplasty (PTRA) (in 11 arteries performed in combination with stent implantation). Prior to dilation we found that the stenotic kidneys had significantly lower values of ERPF, GFR and higher RVR than the non-stenotic kidneys and that these hemodynamic alterations were associated with those, also statistically significant, of the four velocimetric indices. In non-stenotic kidneys, there were highly significant relationships between PI and ERPF, and RVR (r = -0.68 and 0.81 respectively P < 0.01); similar relationships were found for RI (r = -0.67 and 0.78 P < 0.01) whereas no such correlations were found between these two velocimetric indices and GFR and FF; also no correlations were found between A and Atand ERPF, GFR, RVR and FF. In stenotic kidneys no significant correlations were found between any of the velocimetric and the hemodynamic indices. Renal artery dilation induced clear cut increments in ERPF, GFR and reduction in RVR in post-stenotic kidneys, which were associated with normalization of all four velocimetric indices. No relationships were observed between the renal hemodynamic and the velocimetric changes induced by dilation; however in post-stenotic kidneys the relationships between PI and RI, ERPF and RVR were restored as in nonstenotic kidneys. These data indicate that PI and RI can be used to assess ERPF and RVR both in non-stenotic and post-stenotic kidneys; however, none of the velocimetric indices examined in this study can provide valid informations on the renal hemodynamics of stenotic kidneys and on their changes induced by PTRA.

Intraoperative transesophageal ultrasonography can measure renal blood flow

Objective: To determine the feasibility of acquiring Doppler-derived indices of renal blood flow by transesophageal ultrasonography in the perioperative period. Design: Prospective, sequential, institutional review board—approved study. Setting: University teaching hospital. Participants: Nine patients with normal renal function, scheduled for elective primary coronary artery bypass graft surgery. Interventions: Two-dimensional images of renal parenchyma and Doppler measurement of intrarenal arterial blood flow during internal mammary dissection were acquired. To effect renal blood flow changes, the renal vasodilator dopamine, 2 μg/kg/min, was infused for 20 minutes after baseline measurements were made. Renal Doppler measurements were repeated to determine whether transesophageal ultrasonography can follow these changes. Measurements and Main Results: Hemodynamic measurements (heart rate, mean arterial blood pressure, cardiac output, and cardiac index) and Doppler velocity measurements of intrarenal arterial blood flow (peak systolic, end-diastolic, and mean velocity) were made at time 1 (T1 = baseline) and at time 2 (T2 = after 20 minutes of dopamine infusion). The derived Doppler indices, pulsatility index and resistive index, were calculated according to standard formulae. Measurements were compared by paired Student's t-test (two-tailed, p < 0.05, significant). There were no statistical differences between cardiac index (2.10 ± 0.93 L/min/m2v 2.21 ± 0.92 L/min/m2, p = 0.254) and mean arterial pressure (82.3 ± 11.2 mmHg v 83.3 ± 14.5 mmHg, p = 0.872) between T1 and T2. Systolic renal velocity increased from 44.7 ± 13.0 cm/s to 63.0 ± 20.4 cm/s (p = 0.005), diastolic velocity increased from 12.7 ± 4.0 cm/s to 22.4 ± 7.8 cm/s (p = 0.0003), and mean velocity increased from 22.5 ± 6.6 cm/s to 34.1 ± 11.7 cm/s (p = 0.003) after infusion of dopamine. These results indicate an increase in renal blood flow from baseline values. The pulsatility index decreased from 1.44 ± 0.29 to 1.21 ± 0.24 (p = 0.0005), whereas the resistive index decreased from 0.71 ± 0.06 to 0.64 ± 0.06 (p = 0.0004) after dopamine. Reductions in pulsatility and resistive indices indicate a reduction in renal vascular resistance. Conclusion: This study demonstrates the ability to acquire two-dimensional images of kidney and renal arterial Doppler velocities using transesophageal ultrasonography during cardiac surgery. Transesophageal renal arterial Doppler waveform analysis can follow changes in renal blood flow patterns secondary to interventional therapy. Copyright © 2001 by W.B. Saunders Company

Long-Term Oral Intake of Low-Dose Cadmium Exacerbates Age-Related Impairment of Renal Functional Reserve in Rats

Our study was designed to clarify whether renal functional reserve (RFR) was impaired in rats chronically treated with oral low-dose cadmium (Cd). Rats (n = 15) were treated with 1 ppm of cadmium chloride added to drinking water. We measured RFR (representing the ability to increase glomerular filtration rate [GFR] and renal plasma flow [RPF] in response to infusion of glycine) at 2 and 10 months after initiation of exposure to Cd. Urinary excretion of Cd was significantly higher in 10-month Cd-treated rats than in age-matched control rats (provided with distilled water only). Weight gain was noted in Cd-treated rats, which was identical to that in age-matched control rats. Urinary volume and urinary excretions of sodium, protein, and glucose were similar in the two groups. There were no differences in the basal mean arterial pressure (MAP) and renal hemodynamics between 2-month Cd-treated and age-matched control rats. Infusion of glycine resulted in significant increases in GFR and RPF and a significant reduction in renal vascular resistance (RVR) in both 2-month Cd-treated and age-matched control rats (control, GFR: 133 ± 10%, RPF: 148 ± 8%; 2-month Cd-treated rats, GFR: 152 ± 12% and RPF: 154 ± 7%). The basal MAP and renal hemodynamics in 10-month Cd-treated rats were also identical to those in age-matched control rats. Infusion of glycine significantly increased GFR in 10-month control rats (132 ± 15%), but not in 10-month Cd-treated rats (98 ± 11%), but did not change MAP, RPF, and RVR in both groups. In addition to age-related pathological changes, mild renal interstitial edema and degenerative mitochondria with diminished matrix density and loss of the cristae in the proximal tubular cells were more frequent in 10-month Cd-treated rats. Our results suggest that long-term oral intake of low-dose Cd in rats exacerbate age-related impairment of renal functional reserve and degeneration of the proximal tubular epithelial cells.

Candesartan cilexetil and renal hemodynamics in hypertensive patients

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT 1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min −1 (95% CI, 0.01;0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, −0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks’ treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.

Influence of hemodilution on the renal blood flow autoregulation during acute expansion in rats.

Autoregulation of renal blood flow (RBF) was studied in rats that underwent equivalent blood volume expansion with saline (Sal; 5% body wt), 7% BSA solution (1.4% body wt), and reconstituted whole blood from donor rats (WBL; 1.4% body wt). Renal perfusion pressure (RPP) and renal neural reflexes were prevented by clamping RPP and sectioning the vagus, baro/chemoreceptor, and renal nerves. Sal and BSA expansion increased RBF by approximately 60%, whereas no effect was observed with WBL. RBF autoregulation was markedly attenuated after expansion with cell-free solutions, but no change occurred in WBL-expanded rats. Correction of the fall in hematocrit in Sal- and BSA-expanded rats restored RBF and its autoregulation to control levels. Expansion with Sal or BSA after inhibition of renal vascular tone with intrarenal infusion of papaverine still increased RBF and further changed the RBF-RPP relationship. These findings suggest that the hemodilution plays a central role in the reduction of renal vascular resistance and in the attenuation of the autoregulatory efficiency of renal circulation that accompany expansion with cell-free solutions.

Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.

Bradykinin B 2-receptors mediate the pressor and renal hemodynamic effects of intravenous bradykinin in conscious rats

Bradykinin (BK) is a peptide which evokes remarkably different changes in cardiovascular function. Systemic bolus injection of BK results in a rapid drop in blood pressure via an endothelium-dependent mechanism. On the other hand, local administration of BK can activate a powerful pressor reflex by stimulating afferent nerves located in the abdominal viscera, the heart, and the kidney. In the present study, the cardiovascular and renal hemodynamic effects during sustained (intravenous infusion) and transient (intravenous bolus injection) elevations in circulating BK were characterized and the receptor mechanism eliciting these effects was investigated. Mean arterial pressure (MAP), heart rate (HR), and renal blood flow (RBF) were recorded from conscious unrestrained rats while five-point cumulative dose-response curves were constructed during infusion or bolus injection of BK (5–80 μg kg −1). Infusion of BK produced dose-dependent increases in MAP (maximum response=27±3 mm Hg) accompanied by a significant tachycardia (maximum response=159±20 bpm), a 28±6% increase in RBF, and no changes in renal vascular resistance (RVR). The BK-induced increases in MAP, HR, and RBF were abolished after treatment with a ganglion blocker (maximum responses: MAP=2±3 mm Hg, HR=13±4 bpm, RBF=4±2%) or with an agent which blocks B 2-receptors (maximum responses: MAP=1±1 mm Hg, HR=6±5 bpm, RBF=6±2%). In marked contrast, bolus administration of BK resulted in hypotensive responses (maximum decline in MAP=−37±4 mm Hg), reflex tachycardia (maximum increase in HR=45±9 bpm), increases in RBF (maximum response=13±4%), and significant reductions in RVR (maximum response=38±5%). These responses were also prevented when B 2-receptors were blocked (maximum responses: MAP=3±2 mm Hg, HR=17±6 bpm, RBF=3±3%, RVR=9±4%). In summary, BK infusions activated a cardiopressor reflex while BK injections caused hypotension. These opposite effects were both mediated via B 2-receptors. These findings suggest that BK can have complex effects on the cardiovascular system that may be dependent on the sites, magnitude, and duration of elevated BK concentrations.

Dietary calcium decreases blood pressure without decreasing renal vascular resistance or altering the response to NO blockade

Many vasoactive elements are involved in the elevation of blood pressure in spontaneously hypertensive rats (SHR). Elevated dietary calcium has been observed to reduce blood pressure in SHR. This study investigates interactions among dietary calcium, renal vascular resistance (RVR), elevation of blood pressure and effects of norepinephrine and nitric oxide synthesis. We completed a series of experiments on two groups each (fed low, 0.1% and high, 2.0% dietary calcium, respectively) of 9-week-old Wistar Kyoto (WKY), 9-week-old and 6-week-old SHR. Although 9-week-old SHR had elevated baseline blood pressure compared to 9-week-old WKY and also compared to 6 week-old SHR, there was no corresponding elevation in baseline RVR. All SHR fed high calcium diets had lower blood pressure compared to low calcium diets, and there was no corresponding reduction in RVR. WKY controls' blood pressure and RVR were unaffected by dietary calcium levels. In all hypertensive rats the blood pressure and renal vascular resistance were elevated by N G-nitro- l-arginine methylester ( l-NAME), but the dietary differences were sustained. Blood pressure of WKY was unaffected by the low dose of l-NAME. The increase in RVR to l-NAME was greater in SHR than in controls. The renal vascular response to norepinephrine was related to diet in older SHR, but smaller and unrelated to diet in younger SHR. Following l-NAME, WKY had greater responses to norepinephrine than 9-week-old SHR. We conclude that noradrenergic vasoconstriction is enhanced in the adult SHR, especially in the absence of high calcium diet. Alterations in NO synthesis may effect the norepinephrine response.

Developmental changes in renal artery blood flow velocity during the first three weeks of life in preterm neonates

Changes in color Doppler imaging measurements of renal artery blood flow velocity have been reported previously during fetal life and during the first week postnatally in term and preterm infants. This study reports longitudinal, developmental changes in renal artery and aortic blood flow velocities occurring postnatally, from birth to day 1 of life, at 1 week, and at 2 to 3 weeks of age in 14 premature babies (mean gestation, 30 ± 4 [SD] weeks; birth weight, 1.45 ± 0.57 kg), and identified by means of color Doppler imaging and pulsed Doppler spectral analysis. Results indicate that a significant increase in renal artery systolic blood flow velocity occurs within the first week of life (from 40 ± 3 [SEM] cm/sec at birth or on day 1, to 53 ± 3 cm/sec on day 7, to 51 ± 4 cm/sec on day 14 to 21; repeated-measures analysis of variance, p = 0.004), concurrently with a significant increase in abdominal aortic blood flow velocities, both systolic (from 40 ± 4 at birth or on day 1, to 70 ± 8 on day 7, to 76 ± 8 cm/sec on day 14 to 21; p <0.001) and diastolic (from 4 ± 2 at birth or on day 1, to 11 ± 2 on day 7, to 11 ± 2 cm/sec on day 14 to 21; p = 0.001). Systemic blood pressure did not increase concomitantly during the same period. Neither the presence of respiratory distress syndrome or patent ductus arteriosus nor treatment with indomethacin altered developmental increases in observed renal artery blood flow velocities. The presence of an umbilical artery catheter in the high thoracic position in five infants, however, created turbulence at the level of the renal arteries, significantly increasing renal artery systolic flow velocity from 32 ± 4 to 44 ± 5 cm/sec ( p = 0.009) and increasing renal resistive index from 0.90 ± 0.03 to 0.96 ± 0.04 ( p = 0.046). These results suggest that renal artery blood flow velocity increases during the first postnatal week in preterm infants and is likely related to increases in aortic blood flow velocity and reduction in renal vascular resistance. (J P EDIATR 1996;129:251-7)

Renal vasodilatory effect of endothelial stimulation in patients with chronic congestive heart failure

Objectives. This study sought to examine the vasodilatory response of the renal circulation to endothelial stimulation in patients with chronic heart failure.Background. Renal blood flow is often reduced in patients with chronic congestive heart failure and may lead to deterioration of renal function. Stimulation of renal endothelium has been shown to cause renal vasodilation in animals and in isolated human renal artery. The vasoregulatory role of the renal endothelium in patients with heart failure has not been evaluated.Methods. Renal vasodilatory effect of endothelial stimulation with acetylcholine was assessed and compared with that of endothelial-independent vasodilation with nitroglycerin. Both drugs were infused into the main renal artery. Renal artery cross-sectional area was measured with intravascular ultrasound and renal blood flow velocity with the aid of an intravascular Doppler technique.Results. Both drugs caused a significant and comparable increase in renal artery cross-sectional area (maximal increase [mean ± SE] 14 ± 5% with acetylcholine, 15 ± 5% with nitroglycerin; both changes <0.05 vs. baseline). Acetylcholine also caused a significant reduction in renal vascular resistance (maximal reduction 55 ± 6%) and increase in renal blood flow (maximal increase 136 ± 54%). In contrast, nitroglycerin administration showed no significant effect on renal vascular resistance and blood flow.Conclusions. Stimulation of endothelium-derived nitric oxide with acetylcholine results in a significant vasodilatory effect on both conductance and resistance renal blood vessels and leads to a marked reduction in renal vascular resistance and enhancement of renal blood flow. Nitroglycerin, an exogenous nitric oxide donor, caused a selective vasodilatory effect on renal conductance but not on resistance blood vessels and failed to increase renal blood flow. These data suggest the possibility that stimulation of endogenous nitric oxide production in the kidney could be used as a therapeutic target for enhancement of renal flow in patients with heart failure.

Section Review; Cardiovascular &amp; Renal: Calcium channel blockers for the treatment of renal disease

Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease, diabetic renal disease, and in renal transplant recipients with or without cyclosporin therapy. In general, studies in both animal models and humans have demonstrated maintenance or reduction in renal vascular resistance, and preservation or enhancement of renal blood flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well-suited for the treatment of patients with hypertensive disease even in the presence of renal impairment.

Effect of verapamil on renal haemodynamics in a portal hypertensive rat model

In order to investigate the effects of verapamil on renal haemodynamics in rats with portal hypertension, verapamil was given at either a low (0.2 mg/kg) or high (2 mg/kg) dose to rats after portal vein ligation. An approximate 12% decrease in mean arterial pressure followed administration of low dose verapamil, with a significant decrease in cardiac output and renal blood flow, as well as reduced portal pressure, observed; these signs were all indicative of a rise in renal vascular resistance. In contrast, the marked fall in both mean arterial pressure and cardiac output with high dose verapamil, accompanied by a significant decrease in portal pressure and no change in renal blood flow, suggests a reduction in renal vascular resistance. This study shows that the acute effects of verapamil on renal haemodynamics may vary with the dose used. Also, acute verapamil administration tends to decrease renal blood flow to alter the autoregulation of the kidney; thus, caution should be taken in the clinical use of verapamil in the treatment of cirrhosis with portal hypertension.

Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats

Six weeks after the onset of insulin-treated streptozotocin diabetes (STZ) in Munich-Wistar rats, the effect of a low-sodium (LNa) and a low-salt (LNaCl) diet on renal function and on plasma and kidney tissue angiotensin II (AIIp, AIIk) was tested. Clearance experiments were performed in anesthetized rats 7 days after starting on LNa or LNaCl. On a control diet, STZ exhibited an increase in GFR, RBF, and kidney weight (KW) and a reduction in renal vascular resistance (RVR) and AIIk, but no change in AIIp, compared with nondiabetic normal rats (CON). Although sodium restriction reduced and salt restriction increased AIIk in CON, both diets increased AIIp without affecting renal hemodynamics or KW. In diabetic rats, both salt and sodium restriction further increased GFR and RBF by reducing RVR, increased KW, and changed AIIk and AIIp in a similar pattern, but at significantly lower values compared with CON. Daily treatment of STZ-LNa with the AII-receptor blocker losartan (20 mg/L, in drinking water) did not affect the reduction in RVR and the increase in KW but slightly reduced RBF because of a decrease in mean arterial blood pressure and further increased GFR. It was concluded that (1) AIIk but not AIIp is affected differently by LNa compared with LNaCl in both CON and STZ; (2) LNaCl and LNa change AIIp and AIIk in a similar pattern but at significant lower values in STZ compared with CON; and (3) with regard to renal hemodynamics and KW, the response to LNa and LNaCl is different in CON compared with rats 6 wk after the onset of diabetes mellitus, the latter exhibiting a further increase in renal hyperfiltration and KW by a mechanism that is not directly AII receptor dependent.

Renal and Limb Vasodilatation during Acute Beta‐Adrenoceptor Blockade with Indenolol

Indenolol is a noncardioselective beta-adrenoceptor blocking drug with partial agonist activity. The mechanism of its acute antihypertensive activity has been evaluated in a double-blind, inpatient, crossover, randomized study versus placebo in 12 patients (eight men, four women, mean age 53 +/- 13 yr) with I and II WHO grade essential hypertension. Patients discontinued all antihypertensive and diuretic drugs at least 4 weeks before entry into the study. The effects of indenolol (120 mg) and placebo (2 weeks apart) were measured, in the same patient, 2 hours after a single oral administration. Variations of cardiac function were assessed by radionuclide angiocardiography, renal blood flow by sequential scintigraphy, and leg blood flow by strain-gauge plethysmography. Compared with placebo, indenolol reduced systolic blood pressure by 27.9 mm Hg and diastolic blood pressure by 17.1 mm Hg. Heart rate was also significantly decreased. The hemodynamic profile of indenolol activity was characterized by a decrease of cardiac index, without significant changes in systemic vascular resistance. Both renal and leg blood flow were increased by indenolol, and vascular resistance in these districts was considerably reduced. The percent reduction of renal vascular resistance was correlated significantly with the percent reduction of mean blood pressure. In conclusion, acute administration of indenolol exerts a considerable antihypertensive activity associated with a marked vasodilation in vascular districts involved in the progression of hypertensive disease such as the renal and muscular vasculature.

779-5 The Effect of Endothelial Stimulation on the Renal Circulation in Patients with Chronic Heart Failure

Impairment of renal blood flow (RBF) is common in pts with chronic heart failure (CHF) and may lead to renal dysfunction. Although abnormal RBF may be due to depressed cardiac output, individual correlations are weak and suggest for local vasoregulatory mechanisms. We assessed the role of endothelium (END) derived nitric oxide (NO) on the renal circulation in 12 pts with CHF. Acetylcholine (ACh) (END-dependent vasodilator) and nitroglycerin (NTG) (END-independent vasodilator) were infused in a randomized, crossover design into the renal artery (RA). Effects on renal arterial (RAP) and renal venous IRVP) pressures, RA cross sectional area (CSA), RBF and renal vascular resistance (RVR) were studied. CSA was measured by intravascular ultrasound and RA flow velocity by a Doppler flow wire. The results were as follows:Empty CellRAP mmHgRVP mmHgCSA mm2RBF ml/minRVR dynes.cm-5BLl91 ± 410 ± 1.03.7 ± 0.3610 ± 4611171 ± 1295ACh 10-8M88 ± 410 ± 0.93.8 ± 0.4*1015 ± 118*6685 ± 723* 10-7M87 ± 410 ± 0.83.9 ± 0.3*l360 ± 154*5188 ± 805* 10-6M90 ± 411 ± 0.94.0 ± 0.3*1499 ± 181*4868 ± 660*BL291 ± 310 ± 1.03.5 ± 0.3635 ± 3010275 ± 931NTG 10-7M91 ± 410 ± 1.037 ± 0.3†782 ± 808842 ± 1060 10-6M95 ± 410 ± 1.03.9 ± 0.3†753 ± 789972 ± 1415 10-5M89 ± 310 ± 1.13.9 ± 0,3†755 ± 588595 ± 809*p &lt; 0.05 vs Baseline 1 (BL1)†p &lt; 0.05 vs Baseline 2 (BL2) p &lt; 0.05 vs Baseline 1 (BL1) p &lt; 0.05 vs Baseline 2 (BL2) 1) Exogenous NO (NTG) causes a vasodilatory effect on renal conductance but not on resistance vessels; 2) In contrast, stimulation of endothelium-derived NO results in a significant vasodilation of both conductance and resistance vessels. This effect leads to reduction in RVR and increase in RBF and may be an important regulatory mechanism of renal circulation in pts with CHF.