Decrease In Renal Perfusion Pressure Research Articles

Abstract P397: Preservation Of Renal Microvascular Function In Ischemia-reperfusion Induced Kidney Injury In Rats

Proper renal blood flow and glomerular filtration rate are critical for maintaining normal kidney function by precisely adjusting preglomerular microvascular resistance. Renal ischemia-reperfusion (IR) insult markedly increased mRNA expression of the inflammatory chemokine (C-C motif) Ligand 2 (CCL2) in rat kidney tissues. We hypothesized that depletion of macrophages prevented IR-induced renal autoregulatory impairment via reduction of CCL2 in preglomerular microvessels (PGMV). IR was induced in male rats by 60-minute bilateral renal artery occlusion followed by reperfusion. Some IR rats were treated with the selective macrophage inhibitor, Liposome-encapsulated clodronate (LC) following reperfusion and repeated 72 hours post-IR. Afferent arteriolar autoregulatory reactivity was assessed using the in vitro blood-perfused juxtamedullary nephron preparation in sham, IR, and IR+LC rats on day 7. Afferent arterioles from sham-operated rats exhibited pressure-dependent vasoresponsiveness. The baseline arteriolar diameter averaged 13.4 ± 0.5 μm at renal perfusion pressure (RPP) of 100 mmHg. Diameter increased to 117 ± 4% of baseline at RPP of 65 mmHg and decreased to 69 ± 2% at 170 mmHg, respectively. In contrast, afferent arterioles from IR rats only increased to 104 ± 2% and decreased to 91 ± 5% of baseline at 65 and 170 mmHg, respectively (P < 0.05 vs sham), indicating the impaired autoregulatory capacity in IR rats. LC-treated IR rats, however, markedly improved the pressure-dependent vasoresponsiveness. A decrease in RPP to 65 mmHg resulted in a 124 ± 17% increase in the baseline diameter, whereas increasing RPP to 170 mmHg led to a 74 ± 7% decrease in diameter. Additionally, IR markedly increased CCL2 mRNA expression in isolated PGMV by 10-fold 7 days post-IR. IR also elevated NADPH oxidase subunits (gp91 phox , P67 phox , and P47 phox ). Significantly, LC treatment suppressed mRNA expression of CCL2, gp91 phox , P67 phox , and P47 phox in IR-PGMV. In conclusion, depletion of macrophages preserves afferent arteriolar autoregulatory capacity and reduces PGMV CCL2 mRNA expression in IR rats, suggesting a critical role of macrophages in mediating renal microvascular autoregulatory impairment in IR-induced kidney injury via the increase of CCL2 in PGMV.

Defining Hemodynamic Significance of Renal Artery Stenosis: Insights From a Porcine Model of Graded Renal Artery Stenosis

To investigate the renal pressure-flow relationship and its relation to renin release, because the renal perfusion pressure below which renal flow starts to decline and renin secretion isupregulatedis unclear. A porcine model of graded unilateral renal artery stenosis was created. The severity of the stenosis was expressed as the ratio between distal renal pressure (Pd) and aortic pressure (Pa). Pd and renal flow velocity were continuously measured using a combined pressure-flow wire (Combowire®). Hemodynamic measurements and blood sampling for renin, angiotensin and aldosterone were performed in baseline conditions and during progressive balloon inflation in the renal artery leading to Pd decrease per 5% increment. Resistive index (RI)was computed as (1-(End Diastolic V/Peak Systolic V))*100. For a 5% decrease in renal perfusion pressure (95% of aortic pressure or 5% decrease compared to Pa), peak systolic velocity started to decrease. A significant decrease in average peak flow velocitywas observed when distal renal perfusion pressure decreased by 25% and was associated with activation of ipsilateral renin secretion. The RI decreased already for minimal changes in Pd/Pa ratio. In an animal model of unilateral graded renal artery stenosis, a 25% decrease in perfusion pressure results in a significant decrease in distal renal flow, causing upregulation of renin secretion.

Comprehensive Management of Blood Pressure in Patients with Septic AKI.

Acute kidney injury (AKI) is one of the serious complications of sepsis in clinical practice, and is an important cause of prolonged hospitalization, death, increased medical costs, and a huge medical burden to society. The pathogenesis of AKI associated with sepsis is relatively complex and includes hemodynamic abnormalities due to inflammatory response, oxidative stress, and shock, which subsequently cause a decrease in renal perfusion pressure and eventually lead to ischemia and hypoxia in renal tissue. Active clinical correction of hypotension can effectively improve renal microcirculatory disorders and promote the recovery of renal function. Furthermore, it has been found that in patients with a previous history of hypertension, small changes in blood pressure may be even more deleterious for kidney function. Therefore, the management of blood pressure in patients with sepsis-related AKI will directly affect the short-term and long-term renal function prognosis. This review summarizes the pathophysiological mechanisms of microcirculatory disorders affecting renal function, fluid management, vasopressor, the clinical blood pressure target, and kidney replacement therapy to provide a reference for the clinical management of sepsis-related AKI, thereby promoting the recovery of renal function for the purpose of improving patient prognosis.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites

The safety of non-selective β-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs.-2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p<0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r>0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. β-blockade should be used cautiously or even avoided in patients with RA. We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

Acute kidney injury in patients with acute pancreatitis

Summary Introduction: Acute kidney injury is a common diagnosis in clinical practice, occurring in virtually all fields of medicine. Critically ill patients on intensive care units are especially prone to the development of acute kidney injury. Methods: Early diagnostic approach of pancreatitis severity, diagnosis of acute kidney injury and adequate preventive/therapeutic measures might help in prevention of disease progression to multiple organ dysfunction syndrome. Results: The pathophysiology of acute kidney injury in patients suffered from acute pancreatitis is a result of many including factors and mechanisms. Release of pancreatic amylase from the injured pancreas with resulting impairment of renal microcirculation, hypoxemia, decrease in renal perfusion pressure due to abdominal compartment syndrome, intraabdominal hypertension and hypovolemia. Systemic inflammation also play an important role in the pathophysiology of acute pancreatitis and acute kidney injury. Discussion: In therapeutic approach of acute kidney injury in patient with acute pancreatitis is necessary to take into account both pathological situations with support of renal function with or without use of renal replacement therapy or blood purification techniques. Conclusion: Early and adequate preventive and therapeutic measures can prolong patient survival, improve outcome and lead to recovery of kidney function.

CHANGES IN RENAL PERFUSION PRESSURE DURING HEMODYNAMICALLY GUIDED THERAPY IS ASSOCIATED WITH WORSENING RENAL FUNCTION

Background: Patients in acute decompensated heart failure (ADHF) undergoing diuretic therapy are vulnerable to worsening renal function (WRF). We hypothesized that decreases in renal perfusion pressure (RPP), the difference between mean arterial pressure and central venous pressure, would provide a

Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.

The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, KCa channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys. BLSL and AR were moderately hypertensive without kidney disease while ARSL developed severe hypertension and renal failure. In the four groups, methacholine induced biphasic endothelium-dependent responses, a transient decrease in RPP followed by a cyclooxygenase-dependent increase in RPP. In the presence or not of indomethacin, the vasodilatations were poorly sensitive to NO synthase inhibition. However, in the presence of cyclooxygenase and NO synthase inhibitors, apamin, and/or TRAM-34, blockers of KCa2.3 and KCa3.1, respectively, abolished the decrease in RPP in response to either methacholine or the two activators of KCa2.3/KCa3.1, NS309, and SKA-31. Thus, KCa2/3 channels play a major role in the regulation of murine kidney perfusion and this mechanism is maintained in hypertension, even when severe and associated with kidney damage.

Acute kidney injury following acute pancreatitis: A review

BACKROUND. Acute kidney injury (AKI) is a common serious complication of severe acute pancreatitis (SAP) and an important marker of morbidity and mortality in critically ill septic patients. AKI due to severe acute pancreatitis can be the result of hypoxemia, release of pancreatic amylase from the injured pancreas with impairment of renal microcirculation, decrease in renal perfusion pressure due to abdominal compartment syndrome, intraabdominal hypertension or hypovolemia. Endotoxins and reactive oxygen species (ROS) also play an important role in the pathophysiology of SAP and AKI. Knowledge of the pathophysiology and diagnosis of AKI following SAP might improve the therapeutic outcome of critically ill patients. An overview of the pathophysiology, diagnosis and potential treatment options based on a literature search of clinical human and experimental studies from 1987 to 2013. Early recognition of AKI and SAP in order to prevent severe complication like septic shock, intraabdominal hypertension or abdominal compartment syndrome leading to multiple organ dysfunction syndrome is a crucial tool of therapeutic measures in intensive care.

Proteinase-Activated Receptors 1 and 2 Exert Opposite Effects on Renal Renin Release

Proteinase-activated receptors (PARs) 1 to 4 are highly expressed in the kidney and are involved in the regulation of renal hemodynamics and tubular function. Since intravascular infusion of the proteinase thrombin, which activates PARs, has been shown to decrease plasma renin activity in rats, we investigated the effects of the respective PAR subtypes on renin release using the isolated perfused mouse kidney model. Thrombin dose-dependently reduced perfusate flow and inhibited renin secretion rates (RSRs) that had been prestimulated by the β-adrenoreceptor agonist isoproterenol. The suppression of RSRs was prevented by the selective PAR1 inhibitor SCH79797, and direct activation of PAR1 by TFLLR mimicked the effects of thrombin on RSRs and vascular tone. Moreover, TFLLR suppressed the stimulations of RSRs in response to the loop diuretic bumetanide, to prostaglandin E(2), or to a decrease in renal perfusion pressure but not in response to a reduction in extracellular calcium. The PAR2-activating peptide SLIGRL concentration dependently increased RSR and perfusate flow. The stimulation of RSRs by SLIGRL was markedly attenuated by N(G)-nitro-L-arginine methyl ester, suggesting an NO-dependent mechanism. Activation of PAR4 by AYPGKF did not modulate RSRs or perfusate flow. PAR1 and PAR2 immunoreactivity were detected in the juxtaglomerular region and were colocalized with renin immunoreactivity. Our data provide evidence that PAR1 activation inhibits renal renin secretion and induces renal vasoconstriction, whereas PAR2 activation stimulates renin release and induces vasodilation mainly via the release of NO.

Decreased renal perfusion rapidly increases plasma membrane Na-K-ATPase in rat cortex by an angiotensin II-dependent mechanism

To understand how rapid changes in blood pressure can regulate Na-K-ATPase in the kidney cortex, we tested the hypothesis that a short-term (5 min) decrease in renal perfusion pressure will increase the amount of Na-K-ATPase in the plasma membranes by an angiotensin II-dependent mechanism. The abdominal aorta of anesthetized Sprague-Dawley rats was constricted with a ligature between the renal arteries, and pressure was monitored on either side during acute constriction. Left renal perfusion pressure was reduced to 70 +/- 1 mmHg (n = 6), whereas right renal perfusion pressure was 112 +/- 4 mmHg. In control (nonconstricted) rats (n = 5), pressure to both kidneys was similar at 119 +/- 6 mmHg. After 5 min of reduced perfusion, femoral venous samples were taken for plasma renin activity (PRA) and the kidneys excised. The cortex was dissected, minced, sieved, and biotinylated. Lower perfusion left kidneys showed a 41% increase (P < 0.003) in the amount of Na-K-ATPase in the plasma membrane compared with right kidneys. In controls, there was no difference in cell surface Na-K-ATPase between left and right kidneys (P = 0.47). PRA was 57% higher in experimental animals compared with controls. To test the role of angiotensin II in mediating the increase in Na-K-ATPase, we repeated the experiments (n = 6) in rats treated with ramiprilat. When angiotensin-converting enzyme was inhibited, the cell surface Na-K-ATPase of the two kidneys was equal (P =0.46). These results confirm our hypothesis: rapid changes in blood pressure regulate trafficking of Na-K-ATPase in the kidney cortex.

Na,K‐ATPase in the Plasma Membrane of the Rat Proximal Tubule is Increased by An Acute Reduction in Renal Perfusion Pressure

Increases in blood pressure inhibit sodium reabsorption in proximal tubule (Zhang, Y. et al., Am. J. Physiol. 274:C1090, 1998). Conversely, an acute decrease in renal perfusion pressure should stimulate sodium reabsorption. To test this hypothesis we placed a constricting ligature around the aorta between the renal arteries, and monitored perfusion pressure to kidneys above and below the constriction in anesthetized male Sprague-Dawley rats. Perfusion pressure to the left kidney was reduced to 69 ± 1mm Hg by tightening the ligature. Right renal perfusion pressure was 107 ± 4 mm Hg. Pressures were maintained constant for 10 min, after which the kidneys were flushed, excised, and the cortex dissected, minced, and sieved. The cell mixture was centrifuged and the proteins in the pellet biotinylated at pH 9.0. Membrane proteins were extracted, and biotinylated plasma membrane proteins isolated with immobilized streptavidin. Based on western blotting and densitometry, there was a 75% ± 35% (P< 0.03) increase in arbitrary units in the immunoblot signal from the alpha-subunit of Na, K-ATPase from kidneys subjected to the lower perfusion pressure compared to normal pressure. There was no difference observed in sham constricted controls (n=4). Since increased amounts of Na,K-ATPase in the plasma membrane should promote sodium reabsorption, our data suggest that acutely reduced renal perfusion results in increased proximal sodium reabsorption mediated by enhanced incorporation of Na,K-ATPase into the proximal plasma membrane. Supported by DK60752-01A1.

Putting the Brakes on Renin Release

Modulation of renin release from juxtaglomerular cells is critical for appropriate adjustments of the cardiovascular and renal systems to internal and external stresses, and dysregulation of renin release participates in the pathophysiology of hypertension, vascular disease, heart failure, and chronic renal disease. This justifies investments in research to elucidate the fundamental mechanisms regulating renin release. These investments have yielded, and continue to yield, high returns, as exemplified by Schweda et al1 in this issue of Hypertension , showing that A1 receptors mediate high perfusion pressure–induced inhibition of renin release, whereas prostaglandins (PGs) participate in low perfusion pressure–mediated stimulation of renin release. The purpose of this commentary is to discuss how Schweda et al’s findings confirm and challenge present-day models of renin release. As comprehensively reviewed by Davis and Freeman2 and Keeton and Campbell,3 investigators recognized early on that three systems, namely the sympathetic nervous system, the macula densa apparatus, and the intrarenal baroreceptor, are the primary physiological mechanisms regulating renin release from juxtaglomerular cells. A key development was the recognition that the two most important biochemical accelerators of renin release are catecholamines (mediating sympathetically induced renin release) and PGI2 (mediating macula densa–induced and intrarenal baroreceptor–stimulated renin release).4 Subsequently, a third autocoid, adenosine (acting via A1 receptors), was proposed to serve as a molecular brake on renin release and thereby to moderate the effects of catecholamines and PGI2 on renin secretion.5 Because cAMP is a critical second messenger mediating the exocytosis of renin from juxtaglomerular cells, adenylyl cyclase unifies these concepts because β-adrenoceptors and PGI2 receptors accelerate, whereas A1 receptors brake the rate of cAMP production. The results reported by Schweda et al corroborate the accelerator/brake model of renin release because they report that PGs mediate stimulation of renin release …

Effects of intravenous nesiritide on renal hemodynamics in patients with congestive heart failure

Objectives: To evaluate the renal circulatory effects of intravenous nesiritide in patients with congestive heart failure (CHF). Background: Nesiritide, recombinant human B-type natriuretic peptide, has been shown to be efficacious in the treatment of decompensated heart failure and to improve renal function. The exact mechanism of nesiritide effect on the kidney and renal circulation in patients with CHF has not been fully investigated. Methods: Thirteen patients with CHF underwent cardiac catheterization and measurements of renal blood flow using quantitative renal artery angiography and intra renal arterial Doppler flow velocity at baseline, after nesiritide bolus injection (2μ/kg) and 15 minutes after initiation of continuous nesiritide infusion (0.01μ/kg/min). Results: Fifteen minutes of continuous nesiritide infusion resulted in 13% reduction in mean right atrial pressure (p=0.16), 15% in mean pulmonary artery pressure (p<0.005) and 30% in mean pulmonary capillary wedge pressure (p<0.005). Changes in renal hemodynamics were as follows: (please see table). Conclusions: Nesiritide exerts a renal vasodilatory effect predominantly on the large conductance vessels. Renal blood flow is increased after bolus nesiritide administration and is maintained during nesiritide continous infusion in spite of a significant decrease in renal perfusion pressure.∗Changes in renal hemodynamics post nesiritide bolus and during a 15 minutes nesiritide infusion compared to baselineMean Renal Artery Pressure (mmHg)Renal Artery Diameter (mm)Average Renal Peak Velocity (m/s)Renal Blood Flow (ml/min)Baseline99±176.24±0.729±16269±164Bolus93±156.36±0.832±18316±213∗Infusion89±12∗6.73±0.8∗∗24±16∗262±189†∗p<0.05 vs baseline∗∗p<0.0005 vs baseline†p=0.02 vs bolus

Intrarenal expression and distribution of cyclooxygenase isoforms in rats with experimental heart failure.

The generation of PGs from arachidonic acid is mediated by cyclooxygenase (COX), which consists of a constitutive (COX-1) and an inducible (COX-2) isoform. The present study evaluated the relative expression and immunoreactive levels of COX-1 and COX-2, by means of RT-PCR, Western blot analysis, and immunohistochemistry, in the renal cortex and medulla of rats with congestive heart failure (CHF), induced by the placement of an aortocaval fistula. In addition, we examined the effects of a COX-1 inhibitor (piroxicam), COX-2 inhibitor (nimesulide), and nonselective COX inhibitor (indomethacin) at a dose of 5 mg/kg, on intrarenal blood flow by laser Doppler flowmetry. COX-1 and COX-2 mRNAs were abundantly expressed in the renal medulla of control and CHF rats and only minimally in the cortex. Moreover, both RT-PCR (32-36 cycles) and Western blot techniques revealed upregulation of medullary COX-2, but not of COX-1, in rats with advanced heart failure. In line with these findings, all three tested COX inhibitors provoked significant and sustained decreases (Delta approximately -20%) in medullary blood flow (MBF), which were similar in magnitude and duration in control animals. However, in CHF rats, indomethacin produced a greater reduction in MBF than that obtained with either piroxicam or nimesulide. Taken together, these results indicate that 1) both COX-1 and COX-2 are predominantly expressed in the renal medulla and 2) experimental CHF is associated with selective overexpression of COX-2. The latter may represent a mechanism aimed at defending MBF in the face of a decrease in renal perfusion pressure during the development of CHF.

Role of the renal nerves and angiotensin II in the renal function curve.

The relationship between renal perfusion pressure and urinary sodium is involved in arterial pressure regulation. The aim of this study was to investigate the role of renal nerves and angiotensin II in the pressure-natriuresis relationship. Experiments were performed in anaesthetised cats in which one kidney was surgically denervated. Renal perfusion pressure (RPP), renal blood flow (RBF) glomerular filtration rate (GFR, creatinine clearance), urinary volume (V) and sodium excretion (Una + V) were separately measured from both kidneys. RPP was progressively reduced in two consecutive steps by a suprarenal aortic snare. Two groups of animals were studied: the first without any pharmacological treatment (Untreated), the second during treatment with an angiotensin converting enzyme inhibitor (Captopril, 0.4 mg/Kg intravenously followed by an infusion of 0.4 mg/Kg/h). In the Untreated group RPP was reduced from 152.4 +/- 7.3 to 113.6 +/- 5.8 and 83.0 +/- 4.4 mmHg during the first and second step respectively. RBF and GFR were only slightly reduced during the second step of reduced RPP. In control conditions V and UNa + V were greater in the denervated compared to the innervated kidney. The graded decrease in RPP reduced both V and UNa + V in the innervated as well as in the denervated kidney. In the Captopril group V and UNa + V were larger than in the Untreated group in both the innervated and the denervated kidney. A decrease of RPP similar to that observed in the Untreated group, produced similar haemodynamic changes. Also in the Captopril group the graded decrease in RPP reduced both V and UNa + V in the innervated as well as in the denervated kidney. Matching UNa + V against RPP values significant correlations were found in the innervated and denervated kidneys of both groups. Both renal denervation and ACE inhibition were accompanied by an increased gain of the pressure-natriuresis curve, but only renal denervation shifted the crossing of the pressure axis to the left. In the ACE inhibited animals renal denervation only shifted the curve to the left. In conclusion our data suggest that i) at each level of RPP renal nerves and angiotensin II decrease renal sodium excretion, ii) renal nerves and angiotensin II increase the slope of the renal function curve, iii) renal nerves shift to the right the renal function curve.

Quantitative changes in rat renin secretory granules after acute and chronic stimulation of the renin system.

In order to study the cellular mode of renin secretion, stereological methods were used to estimate number and volume of rat renin secretory granules during stimulation of the renin system. An acute decrease in renal perfusion pressure to 40 mmHg for 5 min increased plasma renin concentration (PRC) twofold, but did not significantly change the number of renin granules per arteriole or the renin-containing volume of the arteriole. Chronic stimulation was achieved by a combination of low-salt diet and inhibition of angiotensin-converting enzyme (ACE) for 14 days, and resulted in a 36-fold increase in PRC, a 20-fold increase in the number of granules per arteriole, and a 17-fold increase in the arteriolar volume that contained renin. An acute decrease in renal perfusion pressure to 40 mmHg for 5 min in the chronically stimulated rats increased PRC further (1.6-fold), and significantly reduced the number of granules per arteriole by 4000 (45% reduction), but did not change the renin-containing arteriolar volume significantly. The average renin granule size was 0.35 microm3 with no significant differences among the groups. We conclude that recruited granular cells contribute significantly to renin release, and that all granular cells along the arteriole participate in secretory responses. The reduced number of renin granules after acute stimulation is compatible with exocytosis as the dominating mechanism of renin release.

BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS

1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemodynamics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.

Perfusion pressure dependency of in vivo renal tubular dynamics.

To examine whether changes in renal perfusion pressure (RPP) within the range of autoregulation induce detectable changes in tubular dynamics in an entire nephron population of the intact kidney, we measured, using electron beam computed tomography (EBCT), transit times (TT, s) and intratubular concentration (%) of filterable contrast media in various nephron segments simultaneously with renal regional perfusion. In seven dogs (group A) this was performed at the upper and lower limits of autoregulation (RPP = 130 and 95 mmHg, respectively) while group B (n = 5) served as control. In group A alone, a decrease in RPP led to an increase in TT by 40%, 68%, and 32% in the proximal tubules, ascending limb of Henle's loop, and distal tubules, respectively, in association with an increase in intratubular concentration (+ 50%, 80%, and 42%, respectively). Papillary perfusion decreased, whereas perfusion of the adjacent, outlying inner medulla increased. The decrease in papillary perfusion correlated positively with the concurrent change in sodium excretion (R = 0.81). This study demonstrates that changes in RPP within the autoregulatory range elicit changes of tubular sodium reabsorption mainly in proximal, distal, and ascending tubules, in which most of the nephrons participate. These tubular changes are associated with an alteration of perfusion circumscribed to two areas of the inner renal medulla.

Abnormal renal vascular reactivity to acetylcholine and nitroprusside in aging rats

1. 1. The actions of acetylcholine (ACh), CaCl 2 and nitroprusside (NP) were studied in aortic strips and in the perfused kidneys from adult (4–6 months old) and aging (23–24 months old) rats. 2. 2. ACh and CaCl 2 produced a dose-related relaxation in aortic strips from adult and old rats; maximal responses to both vasodilators were significantly reduced (ACh: adult=66.4±6.1%, Old=27.1±5.7%, P<0.001; CaCl2: adult=75.6±3.9%, Old=54.1±4.1%, P<0.01) in aortas from old rats. NP-evoked relaxation was not significantly different between the two groups. 3. 3. In kidneys from adult rats, ACh produced dose-related decreases in renal perfusion pressure (RPP), whereas, in kidneys from old rats, ACh produced a dose-related decrease at low doses, and biphasic responses (vasodilatation followed by vasoconstriction) at medium to high doses, with a reduced vasodilator component. Vasodilator response to ACh to the highest dose; ACh; adult=78.7±2.8%, Old=40.6±2.6%, P<0.001). In kidneys from adult rats, NP produced a dose-related decrease in RPP. However, in kidneys from old rats, NP produced vasoconstriction at low doses, biphasic responses at medium doses (vasoconstriction followed by vasodilation), and vasodilation at the highest dose. 4. 4. The results of the present study demonstrated that: (a) The isolated perfused kidney from aging rats had a dual response (with an important vasoconstrictor component) to ACh and NP, which may be due to the release of a nonprostanoid vasoconstrictor or to abnormalities in the renal vascular smooth muscle. In contrast, in aortic strips from old and adult rats, these agents only caused relaxation; (b) aging is accompanied by reduced endothelium-dependent relaxation both in large arteries and in resistance vessels; and (c) large arteries from aging rats require a higher concentration of extracellular calcium to stabilize the membrane of smooth muscle cells.

Atrial and arterial baroreceptor influences on the circulatory response to acute changes in renal perfusion.

We have recently reported a neurally mediated reflex increase in hindlimb vascular resistance associated with an acute decrease in renal perfusion pressure in the chloralose-urethane-anesthetized rabbit. The present study was designed to investigate the influence of this reflex in the body's integrated response to circulatory disturbances by investigating the influence of carotid baroreceptor and left atrial receptors on this reflex and assessing the effect of acute changes in renal perfusion on the heart. Interaction of the renal-generated reflex with carotid baroreceptors was investigated by independent perfusion of the carotid sinus region. Responses in hindlimb perfusion pressure, at constant flow, to changes in renal perfusion were greatest with the carotid sinus perfusion pressure (CSP) low (27 +/- 4 mmHg (1 mmHg = 133.3 Pa) increase in hindlimb pressure at low CSP vs. 19 +/- 3 mmHg increase at normal CSP) and were inhibited with maximum carotid stimulation. Partial mitral obstruction, resulting in left atrial distension and atrial receptor stimulation, attenuated the hindlimb vascular response. The increase in hindlimb pressure under control conditions was 34 +/- 10 mmHg compared with 20 +/- 5 mmHg during atrial receptor stimulation. However, acute reduction of renal perfusion pressure did not result in any changes in heart rate, cardiac output, or inotropic state. It appears that both atrial and arterial baroreflexes modify the reflex change in hindlimb vascular resistance associated with acute alterations of renal perfusion.