Effects of angiotensin-converting enzyme inhibition on altered renal hemodynamics induced by low protein diet in the rat.

We assessed the role of angiotensin II in mediating the alterations in renal hemodynamics known to result from low protein feeding to normal rats by examining the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril. 2 wk of low protein (6% casein) diet resulted in decreased glomerular filtration rate (normal protein [NP], 1.82 +/- 0.17 vs. low protein [LP], 0.76 +/- 0.01 ml/min; P less than 0.05) and renal plasma flow (NP, 6.7 +/- 0.2 vs. LP, 3.3 +/- 0.3 ml/min; P less than 0.05); renal vascular resistance rose (NP, 8.7 +/- 0.4 vs. LP, 19.8 +/- 1.4 dyn . s per cm5; P less than 0.05). These changes were accompanied by a significant decrease in plasma renin activity (NP, 7.0 +/- 0.7 vs. LP, 4.4 +/- 0.8 ng A I/ml per h; P less than 0.05), plasma aldosterone concentration (NP, 7.0 +/- 0.6 vs. LP, 4.1 +/- 0.7 ng/dl; P less than 0.05), and urinary PGE2 excretion (NP, 3,120 +/- 511 vs. LP, 648 +/- 95 pg/mgCr; P less than 0.05); by contrast renal renin content was significantly increased (NP, 2,587 +/- 273 vs. LP, 7,032 +/- 654 ng A I/mg protein; P less than 0.05). Treatment with captopril (30 mg/kg per d) raised glomerular filtration rate (GFR; LP + capt, 1.6 +/- 0.2 ml/min) and renal plasma flow (RPF; LP + capt, 6.7 +/- 0.7 ml/min), and reduced renal vascular resistance (LP + capt, 9.2 +/- 0.5 dyn/s per cm5) in low protein-fed animals. These values were not different from those measured in untreated and captopril-treated rats fed a normal (23%) protein diet. There were no changes in systemic mean arterial pressure in any group of rats. These data provide evidence that intrarenal angiotensin II mediates the changes in intrarenal hemodynamics induced by protein deprivation. The effects of low protein feeding may be partly potentiated by the reduction in PGE2 synthesis. However, the normalization of GFR and RPF in view of only modest increases in PGE2 excretion after captopril (LP, 648 +/- 95 vs. LP + capt, 1,131 +/- 82 pg/mgCr; P less than 0.05) suggests that if PGE2 is involved in these changes, it plays a permissive but not essential role in the increased renovascular resistance.     

Thromboxane mediates the renal hemodynamic effects of platelet activating factor

The mechanism by which platelet-activating factor affects renal hemodynamics is controversial. In the present study we examined the hypothesis that thromboxane mediates the renal hemodynamic response to platelet activating factor (PAF) by determining the effects of pretreatment with a selective thromboxane receptor antagonist. Infusion of platelet-activating factor into the left renal artery of normal rats in a dose that failed to alter mean arterial pressure or blood hematocrit values reduced urinary flow rate from 25.9 +/- 6.3 to 12.6 +/- 1.5 microliters/min (P less than .01), reduced effective renal plasma flow rate from 14.01 +/- 2.09 to 5.42 +/- 2.38 ml/min/kg body weight (P less than .01), reduced glomerular filtration rate from 4.81 +/- 1.00 to 1.68 +/- 0.34 ml/min/kg (P less than .03), and increased the fractional excretion of protein from 0.021 +/- 0.008 to 0.094 +/- 0.005 percent (P less than .05). Pretreatment with the selective thromboxane receptor antagonist SKF 96148 (10 mg/kg) not only prevented PAF-induced reductions in effective renal plasma flow rate and glomerular filtration rate but increased these values (effective renal plasma flow rate: 14.09 +/- 2.76 vs. 16.84 +/- 2.08 ml/min/kg, P less than .05; glomerular filtration rate: 4.42 +/- 0.43 vs. 5.50 +/- 0.59 ml/min/kg, P less than .03) and aborted proteinuria. Pretreatment with indomethacin (2 mg/kg) ameliorated PAF-induced alterations in renal hemodynamics and glomerular permselectivity in the final collection period. Infusion of lyso-PAF, a biologically inactive precursor of PAF, or of indomethacin alone or SKF 96148 alone had no significant effect on measured parameters. These observations suggest that thromboxane mediates the renal hemodynamic and permselective effects of PAF.     

Vasoactive intestinal peptide: a direct renal natriuretic substance

To establish whether or not vasoactive intestinal peptide (VIP) acts directly on the kidney and also to define the renal responses to it, we compared the natriuretic and haemodynamic responses to VIP (10(-4)-100 pmol min-1 kg-1) infused intravenously with those obtained by direct infusion into the renal artery in seven conscious male rabbits. VIP had significant effects on the renal circulation without changing systemic arterial pressure or pulse rate. There was a significant fall from control in effective renal plasma flow (P less than 0.05 renal infusion, P less than 0.01 intravenous infusion) and glomerular filtration rate (P less than 0.01 renal, P less than 0.05 intravenous). The derived renal vascular resistance rose significantly from control (P less than 0.01 renal, P less than 0.01 intravenous). Despite the significant decline in filtered sodium load (P less than 0.01 renal, P less than 0.001 intravenous), there was a significant log dose-related increase in fractional sodium excretion (P less than 0.005) with intrarenal infusion of VIP. We conclude that the actions of VIP on intrarenal blood vessels and renal tubules are direct, leading to increases in renal vascular resistance and fractional sodium excretion.     

Split intrarenal hemodynamics in renovascular hypertension.

Split intrarenal hemodynamics in stenotic and contralateral kidneys of unilateral renovascular hypertension (RVH) were estimated by Gomez's formulae. Ten patients with RVH were studied. Split para-amino hippurate and inulin clearances were measured by ureteral catheterization as indexes for renal plasma flow and glomerular filtration rates, allowing the estimation of intrarenal hemodynamics such as preglomerular arteriolar resistance, postglomerular arteriolar resistance and glomerular hydrostatic pressure in each kidney. Renal plasma flow and glomerular filtration rates were lower in the stenotic kidney (83 +/- 12, 19 +/- 2 ml/min/m2) than in the contralateral kidney (170 +/- 19, 43 +/- 4). Preglomerular arteriolar resistance was elevated due to the stenotic lesion in the stenotic kidney (30,900 +/- 4,500 dyns.sec.cm-5) while the elevation in the contralateral kidney (11,300 +/- 1,000) was less. Postglomerular arteriolar resistance was high in both kidneys. Glomerular pressure was lowered in the stenotic kidney (54 +/- 1 mmHg), while elevated in the contralateral kidney (71 +/- 3). Although the stenotic kidney of RVH was protected from systemic hypertension (138 +/- 6 mmHg) by stenosis of the renal artery, the increase in preglomerular arteriolar resistance in the contralateral kidney was not sufficient, making glomerular pressure elevated. Thus, glomerular hypertension and hyperfiltration were demonstrated in the contralateral kidney of RVH.     

米力农改善心脏手术后心力衰竭所致低心排血量综合征患者的肾功能

目的评价正性肌力药米力农在治疗体外循环(CPB)心脏手术后心力衰竭所致低心排血量综合征时对患者肾脏的影响。方法选取2018年1月至2020年6月间在我院心胸外科治疗的CPB心脏手术患者,在患者心脏停跳后30 min(基线期)和60 min(治疗后)进行肾脏和全身血流动力学检测。CPB术后30 min发生低心排血量综合征患者接受米力农治疗,根据患者CPB心脏手术后是否应用米力农,将患者分为米力农组(n=59)和对照组(n=82)。比较两组患者血流动力学指标和肾血流动力学指标基线期值、治疗后值、治疗后较基线期变化值。比较治疗后两组患者预后指标及并发症发生率。结果治疗后米力农组患者心脏指数变化值[(0.55±0.26) L/(min·m²) vs.(-0.35±0.28) L/(min·m²),t=19.394,P <0.001]、心搏容量指数变化值(t=8.776,P <0.001)、氧释放系数变化值(t=8.143,P <0.001)、混合静脉血氧饱和度变化值(t=9.935,P <0.001)与对照组比较显著提高,周身血管阻力指数变化值(t=10.574,P <0.001)、肺血管阻力指数变化值(t=10.654,P <0.001)与对照组比较显著降低。治疗后米力农组患者肾血流量变化值[(117.30±153.82) m L/min vs.(-63.73±157.64) m L/min,t=6.795,P <0.001]、肾脏供氧量变化值(t=4.248,P <0.001)与对照组比较显著提高,肾小球滤过分数变化值(t=6.382,P <0.001)、肾血管阻力变化值[(-0.06±0.05) mm Hg/(m L·min) vs.(0.03±0.06) mm Hg/(m L·min),t=9.407,P <0.001]和肾氧摄取率变化值(t=7.625,P <0.001)与对照组比较显著降低。结论米力农在心脏手术后早期用于治疗急性心力衰竭所致低心排血量综合征,可以增加患者心输出量和肾血流量,扩张肾血管。米力农可以改善患者易感肾脏的氧合作用,但不会引起肾小球滤过率的显著变化。     

Multiple oral doses of nicardipine, a calcium-entry blocker: effects on renal function, plasma renin activity, and aldosterone concentration in mild-to-moderate essential hypertension

We studied the effects of nicardipine administered in a 4-week fixed oral maintenance dosage (20 or 40 mg t.i.d.) on renal function, plasma renin activity (PRA), and plasma aldosterone concentration in seven patients with mild-to-moderate essential hypertension. Glomerular filtration rate and renal blood flow were measured by means of sodium thiosulfate and para-aminohippurate, respectively. Nicardipine increased renal blood flow by 11.5% +/- 4.3% (mean +/- SE; P less than 0.05) and glomerular filtration rate by 16.3% +/- 6.4% (P less than 0.05) and decreased total renal vascular resistance by 30.0% +/- 2.7% (P less than 0.05), with a significant (P less than 0.05) reduction in systolic and diastolic blood pressure as compared with placebo values. Nicardipine increased PRA significantly (P less than 0.05), whereas plasma aldosterone concentration remained unchanged. Our results indicate that nicardipine given in a multiple oral dosage has some favorable renal effects with a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. Nicardipine appears to blunt the secretion of aldosterone responding to an increased PRA possibly through its calcium-antagonizing action.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Renal hemodynamics increase dramatically during pregnancy, and pressor responsiveness to exogenous administration of vasoconstrictors is attenuated. We investigated whether or not vasodilatory prostaglandins mediate these phenomena. Trained, chronically instrumented, conscious pregnant rats were used. Control values of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated at midgestation (P less than 0.01 and P = 0.05 from prepregnant means, respectively), and effective renal vascular resistance was decreased (P = 0.05). Indomethacin (4.5-6.5 mg/kg body weight [BW]) failed to decrease renal hemodynamics at this stage of pregnancy; in fact, it raised GFR somewhat further (P less than 0.05). Systemic pressor responsiveness to bolus administration of norepinephrine and angiotensin II (AII) was significantly attenuated by at least gestational day 20. Neither indomethacin (7 mg/kg BW) or meclofenamate (6 mg/kg BW) affected the refractory response. The renal vasculature was also relatively unresponsive to an intravenous infusion of AII (5 ng X kg-1 X min-1) during late gestation (day 19); in particular, the fall in ERPF in response to AII (16 +/- 3%) was markedly less than that observed in the prepregnant condition (34 +/- 3%; P less than 0.05). Indomethacin (6 mg/kg BW) failed to restore this blunted response, and further attenuation was evident, despite the presence of the inhibitor (gestational day 21). We conclude that vasodilatory prostaglandins do not appear to mediate the rise in renal hemodynamics, and the attenuation of the systemic and renal pressor responsiveness observed during pregnancy, insofar as these phenomena were unaffected by acute cyclooxygenase inhibition in unstressed, conscious rats.     

Glomerular dynamics and morphologic changes in the generalized Shwartzman reaction in postpartum rats.

The roles of glomerular functional and morphologic changes were examined in the acute renal failure associated with generalized Shwartzman reaction in postpartum Munich Wistar rats. The susceptibility of postpartum rats to acute deterioration in renal function after a 2-h endotoxin infusion was found to be greater than in virgin litter mates: glomerular filtration rate fell by 93% in the former vs. 24% in the latter group (P less than 0.001). In postpartum rats there were marked changes in platelet count and fibrinogen level (P less than 0.025) compatible with consumption coagulopathy. Renal blood flow and glomerular filtration rate fell from 5.5 +/- 0.9 and 0.74 +/- 0.12 to 2.0 +/- 0.7 and 0.12 +/- 0.01 ml/min, respectively (both P less than 0.001). Blood pressure did not change. Results of glomerular dynamics studies showed decreases in single nephron filtration rate from 28 +/- 7 to 6 +/- 4 nl/min and in glomerular plasma flow rate from 77 +/- 26 to 23 +/- 12 nl/min (both P less than 0.001). Afferent net ultrafiltration pressure fell from 20 +/- 3 to 5 +/- 4 mm Hg due to a fall in glomerular capillary hydraulic pressure from 47 +/- 1 to 29 +/- 5 mm Hg (P less than 0.001). There were four- and twofold increases in afferent and efferent arteriolar resistances, respectively. Less than 20% of glomeruli had evidence of fibrin deposition after 2 h of endotoxin infusion, a time when glomerular filtration rate was reduced by greater than 90%. [1-Sar, 5-Ile, 8-Gly] angiotensin II infusion before endotoxin significantly protected glomerular filtration rate, 62 vs. 7% of control in rats with no preinfusion (P less than 0.01) despite consumption coagulopathy and glomerular fibrin deposition similar to rats without pretreatment. These data suggest that the early deterioration in renal function in the generalized Shwartzman reaction in the postpartum rat is due to major changes in glomerular dynamics induced by neurohumoral agents and that glomerular fibrin deposition plays a lesser pathogenetic role at this time in this disorder. The study does not address the pathogenesis of renal failure in pregnancy nor peripartum renal failure in another species.     

HEMODYNAMIC, RENAL, AND ENDOCRINE EFFECTS OF 4- H INFUSIONS OF HUMAN ATRIAL NATRIURETIC PEPTIDE IN NORMAL VOLUNTEERS

A synthetic human atrial natriuretic peptide of 26 aminoacids [human (3-28)ANP or hANP] was infused into normal male volunteers. Six subjects were infused for 4 h at 1-wk intervals with either hANP at the rate of 0.5 or 1.0 microgram/min or its vehicle in a single-blind randomized order. Human (3-28)ANP at the dose of 0.5 microgram/min raised immunoreactive plasma ANP levels from 104 +/- 17 to 221 +/- 24 pg/ml (mean +/- SEM), but it induced no significant change in blood pressure, heart rate, effective renal plasma flow, glomerular filtration rate, or renal electrolyte excretion. At the rate of 1.0 microgram/min, human (3-28)ANP increased immunoreactive plasma ANP levels from 89 +/- 12 to 454 +/- 30 pg/ml. It reduced effective renal plasma flow from 523 +/- 40 to 453 +/- 38 ml/min (P less than 0.05 vs. vehicle), but left glomerular filtration rate unchanged. Natriuresis rose from 207 +/- 52 to 501 +/- 69 mumol/min (P less than 0.05 vs. vehicle) and urinary magnesium excretion from 3.6 +/- 0.5 to 5.6 +/- 0.5 mumol/min (P less than 0.01 vs. vehicle). The excretion rate of the other electrolytes, blood pressure, and heart rate were not significantly modified. At both doses, human (3-28)ANP tended to suppress the activity of the renin-angiotensin-aldosterone system. In 3 additional volunteers, the skin blood flow response to human (3-28)ANP, infused for 4 h at the rate of 1.0 microgram/min, was studied by means of a laser-doppler flowmeter. The skin blood flow rose during the first 2 h of peptide administration, then fell progressively to values below baseline. After the infusion was discontinued, it remained depressed for more than 2 h. Thus, in normal volunteers, human (3-28)ANP at the dose of 1.0 microgram/min produced results similar to those obtained previously with rat (3-28)ANP. It enhanced natriuresis without changing the glomerular filtration rate while effective renal plasma flow fell. It also induced a transient vasodilation of the skin vascular bed.     

Influence of nifedipine on cyclosporin A nephrotoxicity after unilateral nephrectomy in the spontaneously hypertensive rat.

1. Nifedipine ameliorates cyclosporin A-induced renal impairment in surgically intact (two-kidney) rats. This study investigates the effect of nifedipine on cyclosporin A nephrotoxicity in spontaneously hypertensive rats after either uninephrectomy or uninephrectomy with contralateral renal denervation. 2. Fourteen days after uninephrectomy pair-fed rats were injected for 14 days with cyclosporin A (25 mg/kg body weight) via the subcutaneous route and with nifedipine (0.1 mg/kg body weight) via the intraperitoneal route. Renal and systemic haemodynamics were measured in conscious unrestrained rats. 3. Whole-blood levels of cyclosporin A did not differ between groups (overall 352 +/- 22 ng/ml, means +/- SEM). After uninephrectomy, cyclosporin A decreased the glomerular filtration rate (olive oil versus cyclosporin A: 0.96 +/- 0.04 versus 0.70 +/- 0.06 ml min-1 100 g body weight, P less than 0.02) and effective renal plasma flow (1.94 +/- 0.10 versus 1.38 +/- 0.13, P less than 0.01), and increased renal vascular resistance [(20.2 +/- 1.8) x 10(4) versus (31.6 +/- 3.3) x 10(4) kPa l-1 s [(20.2 +/- 1.8) x 10(3) versus (31.6 +/- 3.3) x 10(3) dyn s cm-5], P less than 0.02] and mean arterial pressure (146.7 +/- 6.7 versus 167.3 +/- 2.9 mmHg, P less than 0.05). Neither renal denervation nor nifedipine prevented the reduction in glomerular filtration rate or effective renal plasma flow induced by cyclosporin A. 4. This study infers that the sympathetic nervous system does not play an active role in cyclosporin A nephrotoxicity and demonstrates that the concomitant administration of nifedipine to rats with reduced renal mass does not ameliorate cyclosporin A-induced renal impairment.     

Increased renal secretion of norepinephrine and prostaglandin E2 during sodium depletion in the dog.

To determine whether vasoactive renal hormones modulate renal blood flow during alterations of sodium balance, simultaneous measurements of arterial and renal venous concentrations of norepinephrine and prostaglandin E2 (PGE2) and of plasma renin activity, as well as renal blood flow and systemic hemodynamics were carried out in 24 sodium-depleted and 28 sodium-replete anesthetized dogs. The mean arterial blood pressure of the sodium depleted dogs was not significantly different from that of the animals fed a normal sodium diet, but cardiac output was significantly lower (3.07 +/- 0.18 vs. 3.77 +/- 0.17 liters/min, mean +/- SEM; P < 0.01). Despite the higher total peripheral vascular resistance in the sodium-depleted dogs (46.1 +/- 2.9 vs. 37.0 +/- 2.1 arbitrary resistance U; P < 0.02), the renal blood flow and renal vascular resistance were not significantly different in the two groups. The arterial plasma renin activity and concentration of norepinephrine were higher in the sodium-depleted animals than in the controls; the arterial concentration of PGE2 was equal in both groups. The renal venous plasma renin activity was higher in the sodium-depleted dogs. Similarly, the renal venous norepinephrine concentration was higher in the sodium-depleted dogs than in the controls (457 +/- 44 vs. 196 +/- 25 pg/ml; P < 0.01); renal venous PGE2 concentration was also higher in the sodium depleted dogs (92 +/- 22 vs. 48 +/- 11 pg/ml; P < 0.01). Administration of indomethacin to five sodium-replete dogs had no effect on renal blood flow. In five sodium-depleted dogs indomethacin lowered renal blood flow from 243 +/- 19 to 189 +/- 30 ml/min (P < 0.05) and PGE2 in renal venous blood from 71 +/- 14 to 15 +/- 2 pg/ml (P < 0.02). The results indicate that moderate chronic sodium depletion, in addition to enhancing the activity of the renin-angiotensin system, also increases the activity of the renal adrenergic nervous system and increases renal PGE2 synthesis. In sodium-depleted dogs, inhibition of prostaglandin synthesis was associated with a significant decrease in renal blood flow. The results suggest that the renal blood flow is maintained during moderate sodium depletion by an effect of the prostaglandins to oppose the vasoconstrictor effects of angiotensin II and the renal sympathetic nervous system.     

Acute effects of nitric oxide synthase inhibition on systemic, hepatic, and renal hemodynamics in patients with cirrhosis and ascites.

BACKGROUND: Nitric oxide synthase (NOS) inhibition has been demonstrated to correct systemic vasodilation and renal hypoperfusion in studies of patients with cirrhosis. In patients with decompensated cirrhosis, NOS blockade increases arterial pressure, but the acute effects on hepatic and renal hemodynamics are not known. METHODS: We examined the acute systemic, hepatic, and renal hemodynamic effects of N(G)-monomethyl-L-arginine (L-NMMA) in 10 patients with decompensated cirrhosis. After baseline measurements, 3 mg/kg L-NMMA was administered as an IV bolus. At 20 minutes, if mean arterial pressure did not increase by at least 10 mm Hg above the baseline value, a second injection of 6 mg/kg was administered. RESULTS: In 5 of 10 patients, the second injection of L-NMMA 6mg/kg was necessary to achieve at least a 10 mm Hg increase in mean arterial pressure. Acute NOS inhibition increased systemic vascular resistance and decreased cardiac output, without causing changes in the hepatic venous pressure gradient. Hepatic blood flow decreased, but the indocyanine green intrinsic clearance and extraction remained unchanged. Plasma renin activity (from 9.5 +/- 2.9 to 6.7 +/- 1.6 ng/ml/h) and urinary prostaglandin E2 (from 299 +/- 40 to 112 +/- 36 pg/ml) significantly decreased. No significant changes in glomerular filtration rate, renal plasma flow, and natriuresis occurred, however. CONCLUSIONS: Acute L-NMMA infusion in patients with decompensated cirrhosis reduced hepatic blood flow and decreased plasma renin activity and urinary prostaglandin E2, without causing significant changes in renal hemodynamics.     

Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.     

Mechanism of preservation of glomerular perfusion and filtration during acute extracellular fluid volume depletion. Importance of intrarenal vasopressin-prostaglandin interaction for protecting kidneys from constrictor action of vasopressin.

Glomerular circulatory dynamics were assessed in 60 adult anesthetized rats, which were either deprived or not deprived of water for 24-48 h. Water-deprived rats (n = 21) were characterized by a depressed level of single nephron glomerular filtration rate (SNGFR) when compared with nonwater-deprived controls (n = 8) (23.2 +/- 1.3 vs. 44.8 +/- 4.1 nl/min). This was primarily due to decreased glomerular plasma flow rate (71 +/- 5 vs. 169 +/- 23 nl/min) and glomerular capillary ultrafiltration coefficient (0.028 +/- 0.003 vs. 0.087 +/- 0.011 nl/[s . mmHg]). Infusion of saralasin to these water-deprived rats resulted in significant increases in plasma flow rate and ultrafiltration coefficient, and decline in arteriolar resistances. Consequently, SNGFR increased by approximately 50% from pre-saralasin levels. When water-deprived saralasin-treated rats were given a specific antagonist to the vascular action of arginine vasopressin (AVP), d(CH2)5Tyr(Me)AVP, a fall in systemic blood pressure occurred, on average from 102 +/- 5 to 80 +/- 5 mmHg, unaccompanied by dilation of renal arterioles, so that both plasma flow rate (129 +/- 8 vs. 85 +/- 13 nl/min) and SNGFR (31.0 +/- 2.9 vs. 18.2 +/- 4.4 nl/min) decreased. This more selective extrarenal constrictor action of AVP was further documented in additional studies in which cardiac output and whole kidney blood flow rate were simultaneously measured. In water-diuretic rats, administration of a moderately pressor dose of AVP (4 mU/kg per min) resulted in a significant rise in kidney blood flow rate (from 8.8 +/- 1.2 to 9.6 +/- 1.3 ml/min). The higher kidney blood flow rate occurred despite a fall in cardiac output (from 111 +/- 7 to 98 +/- 9 ml/min), and was associated with a significant increase in the ratio of systemic vascular to renal vascular resistance (on average from 0.083 +/- 0.014 to 0.106 +/- 0.019). Furthermore, infusion of d(CH2)5Tyr(Me)AVP to water-deprived animals (n = 6) to antagonize endogenous AVP resulted in systemic but not renal vasodilation, so that kidney blood flow rate fell (by approximately 30%), as did systemic-to-renal resistance ratio (by approximately 30%). When the above two experiments were repeated in indomethacin-treated animals, exogenous AVP administration in water-diuretic rats (n = 6) and antagonism of endogenous AVP in water-deprived rats (n = 7) caused, respectively, parallel constriction and dilation in systemic and renal vasculatures. The net effect was unaltered systemic to renal vascular resistance ratio in both cases. These results indicate that (1) unlike angiotensin II, AVP maintains glomerular perfusion and filtration in acute extracellular fluid volume depletion by a more selective constriction of the extrarenal vasculature. (2) The relative renal insensitivity to the vasoconstrictor action of AVP appears to be due to an AVP-induced release of a potent renal vasodilator, sensitive to indomethacin, presumably prostaglandins.     

Hemodynamic and renal effects of atrial natriuretic factor in portal hypertensive rats. Potentiation by Phe-Ile-Orn-vasopressin

The effects of atrial natriuretic factor (ANF) on splanchnic hemodynamics and renal function in portal hypertensive models are described incompletely. Furthermore, ANF-induced vasodilatation and hypotension may limit the assessment of its own renal physiological effects. We infused ANF (human ANF 102-126) to anesthetized portal vein-ligated rats, a model with prehepatic portal hypertension. Arterial pressure was reduced by 17%, but portal pressure was unaffected. Diuresis and natriuresis were explained in part by an increase in glomerular filtration rate; in addition, renal vascular resistance was significantly decreased. The natriuretic response to ANF was slightly, but significantly, decreased in portal hypertensive rats as compared to controls (fractional excretion of sodium, 1.8 +/- 0.4 vs. 2.9 +/- 0.3; P less than .05). The addition of Phe-Ile-Orn-vasopressin, a V1 receptor agonist, normalized arterial pressure but induced a significant decrease in portal pressure (15 +/- 0.9 mm Hg base line vs. 12.8 +/- 0.7 combination group; P less than .01). Furthermore, the combination of both drugs markedly potentiated the natriuretic effects (0.4 +/- 0.1 microEq/min of control vs. 10.0 +/- 2.3 ANF vs. 32.2 +/- 3.3 combination group; P less than .001). The natriuretic potentiation resulted from increments in glomerular filtration rate and renal blood flow. Normalization of arterial pressure may enhance the renal physiological effects of ANF, in this portal hypertensive model.     

Mechanisms of amphotericin B-induced reduction of the glomerular filtration rate: a micropuncture study

Amphotericin B infusions cause acute reductions in renal plasma flow and glomerular filtration rate. The exact mechanism by which these changes occur has not been identified fully, nor have the effects of the drug on the renal microcirculation been studied adequately. In this study, we examined the effect of intrarenal amphotericin B infusions (0.05 mg/kg/min) on glomerular hemodynamics in the anesthetized rat. Amphotericin B did not affect systemic blood pressure and slightly increased hematocrit (5%), but significantly decreased renal blood flow and glomerular filtration rate by 40 and 35%, respectively. Glomerular micropuncture revealed decreases in single nephron plasma flow and glomerular filtration rate (from 142 +/- 12 to 89 +/- 14 and from 35.3 +/- 2.2 to 22.8 +/- 2.8 nl/min, respectively). These changes were due to significant increases in pre- and postglomerular resistances (from 1.91 +/- 0.17 to 3.95 +/- 0.38 and from 1.30 +/- 0.10 to 2.08 +/- 0.12 10(10) dyn.sec.cm-5, respectively), and to a significant decrease in the glomerular capillary ultrafiltration coefficient which fell from 0.043 +/- 0.008 to 0.032 +/- 0.009 nl/(sec.mm Hg). These results provide further insight into the mechanisms of the acute renal effects of amphotericin B, and suggest possible mediators that may be involved in these effects.     

Effects of cyclosporin A on glomerular barrier function in the nephrotic syndrome.

1. To elucidate the mechanisms by which cyclosporin A diminishes proteinuria, we studied 20 patients with severe nephrotic syndrome. Biopsy-established pathologies included minimal change disease (n = 5), membranous glomerulopathy (n = 6), membranoproliferative glomerulonephritis (n = 5) and focal segmental glomerulosclerosis (n = 4). Before, at the end of a 90 day course of cyclosporin A, and finally 1 month after stopping cyclosporin A we determined 24 h protein excretion. Measurements of glomerular filtration rate, effective renal plasma flow, fractional clearance rates of albumin and immunoglobulins with different charges and the transglomerular sieving of uncharged dextrans of broad size distribution were used to study the effects of cyclosporin A on renal perfusion and the glomerular filtration barrier. The findings were analysed with a theoretical model of solute transport. 2. Among the different forms of glomerulopathy the response to low-dose cyclosporin A (trough levels 32.0-36.9 ng/ml) varied markedly. In minimal change disease, proteinuria decreased from 9.5 +/- 3.1 to 1.3 +/- 0.2 g/24 h (mean +/- SEM, P less than 0.01). This response was due to restoration of the charge selectivity of the glomerular barrier. The depressed value of the glomerular permeability coefficient also returned to normal. Glomerular filtration rate, effective renal plasma flow and renal vascular resistance did not change. Proteinuria returned after stopping cyclosporin A, although it did not reach pretreatment levels. In membranous glomerulopathy, proteinuria fell from 9.9 +/- 1.5 to 1.8 +/- 0.3 g/24 h (P less than 0.01). Changes in protein excretion and dextran sieving were compatible with an increase in glomerular permselectivity and a decrease in filtrate flow through the 'shunt' pathway. Glomerular filtration rate was maintained, although effective renal plasma flow fell significantly. Proteinuria relapsed after stopping cyclosporin A. In membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis proteinuria did not respond to cyclosporin A, although cyclosporin A exerted important haemodynamic effects. 3. In minimal change disease and membranous glomerulopathy cyclosporin A exerts its beneficial effects on proteinuria through changes in the properties of the glomerular barrier, resulting in increased charge and size selectivity, respectively.     

Role of prostaglandins and thromboxane in the control of renal hemodynamics in experimental liver cirrhosis

Although there is considerable evidence that vasodilator prostaglandins such as prostaglandin E2 (PGE2) modulate renal hemodynamics in liver cirrhosis, the role of the vasoconstrictor thromboxane A2 (TXA2) is controversial. We measured renal hemodynamics and glomerular eicosanoid production in cirrhotic and control rats. Renal plasma flow, as estimated by para-aminohippurate clearance (CPAH) and glomerular filtration rate, as determined by inulin clearance (CIN), were comparable between groups; glomerular production of PGE2 and TXA2 (estimated by the metabolite thromboxane B2 [TXB2]) was slightly but not significantly higher in cirrhotic than in control rats (PGE2: 1060 +/- 142 pg/mg glomerular protein vs 854 +/- 288 pg/mg glomerular protein; TXB2: 782 +/- 103 pg/mg glomerular protein vs 468 +/- 104 pg/mg glomerular protein). Addition of serum from cirrhotic rats to the incubation media failed to increase eicosanoid production in glomeruli obtained from either cirrhotic or control rats. Cyclooxygenase inhibition with 5 mg/kg indomethacin, a dose sufficient to result in a 68% inhibition of glomerular PGE2 synthesis, decreased both CPAH (from 6.59 +/- 0.69 ml/min to 4.52 +/- 0.67 ml/min, p less than 0.05) and CIN (from 1.34 +/- 0.16 ml/min to 0.68 +/- 0.07 ml/min, p less than 0.01) in cirrhotic rats. Thromboxane synthesis inhibition with 1 mg/kg UK-38485, which resulted in an 84% decrease in glomerular TXB2, did not significantly affect either CPAH or CIN; however, there was a strong trend toward improvement in CIN (from 1.23 +/- 0.11 ml/min to 1.43 +/- 0.15 ml/min (0.05 less than p less than 0.1). Neither drug affected renal hemodynamics in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal hemodynamic and tubular transport effects of nitrendipine

Nitrendipine, a 1,4-dihydropyridine derivative, is a new calcium entry blocker with marked antihypertensive effects. Because relatively few data are available regarding its renal effects, we studied the drug's action on renal hemodynamics and electrolyte excretion in normal male volunteers. During sustained water diuresis, 5 to 10 mg nitrendipine given orally caused an increase in urine flow rate and a modest but consistent increase in sodium excretion (from 1.0% to 2.2% of filtered load, P less than 0.01). Furthermore, both solute-free water clearance and percentage of free water excreted rose (from 10.1 +/- 0.6 ml/min to 12.0 +/- 0.8 ml/min and from 8.7% +/- 0.5% to 10.5% +/- 1.1%, respectively, P less than 0.05 in each case). In addition, during the peak effect of the drug on sodium and free water excretion, there was no consistent change in either glomerular filtration rate or effective renal plasma flow. Nitrendipine was also phosphaturic and calciuric but did not alter acid excretion. When administered to subjects with hydropenia receiving hypertonic saline infusion, the drug had no effect on solute-free water reabsorption. We interpret these results to indicate that nitrendipine has direct tubular effects on renal electrolyte transport and that the locus of these effects is probably the proximal tubule. Thus, nitrendipine appears to differ from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.