Left ventricular volume measurement in mice by conductance catheter: evaluation and optimization of calibration

The conductance catheter (CC) allows thorough evaluation of cardiac function because it simultaneously provides measurements of pressure and volume. Calibration of the volume signal remains challenging. With different calibration techniques, in vivo left ventricular volumes (V(CC)) were measured in mice (n = 52) with a Millar CC (SPR-839) and compared with MRI-derived volumes (V(MRI)). Significant correlations between V(CC) and V(MRI) [end-diastolic volume (EDV): R(2) = 0.85, P < 0.01; end-systolic volume (ESV): R(2) = 0.88, P < 0.01] were found when injection of hypertonic saline in the pulmonary artery was used to calibrate for parallel conductance and volume conversion was done by individual cylinder calibration. However, a significant underestimation was observed [EDV = -17.3 microl (-22.7 to -11.9 microl); ESV = -8.8 microl (-12.5 to -5.1 microl)]. Intravenous injection of the hypertonic saline bolus was inferior to injection into the pulmonary artery as a calibration method. Calibration with an independent measurement of stroke volume decreased the agreement with V(MRI). Correction for an increase in blood conductivity during the in vivo experiments improved estimation of EDV. The dual-frequency method for estimation of parallel conductance failed to produce V(CC) that correlated with V(MRI). We conclude that selection of the calibration procedure for the CC has significant implications for the accuracy and precision of volume estimation and pressure-volume loop-derived variables like myocardial contractility. Although V(CC) may be underestimated compared with MRI, optimized calibration techniques enable reliable volume estimation with the CC in mice.     

Validation of a mouse conductance system to determine LV volume: comparison to echocardiography and crystals

The application of left ventricular pressure-volume analysis to transgenic mice to characterize the cardiac phenotype has been problematic due to the small size of the mouse heart and the rapid heartbeat. Conductance technology has been miniaturized for the mouse and can solve this problem. However, there has been no validation of this technique. Accordingly, we performed echocardiography followed by simultaneous ultrasonic crystals, flow probe, and conductance studies in 18 CD-1 mice. Raw conductance volumes were corrected for an inhomogenous electrical field (alpha) and parallel conductance (G(pi)) yielding a stroke volume of 14.1 +/- 3.7 microliter/beat, end-diastolic volume of 20.8 +/- 6.5 microliter, and end-systolic volume of 9.0 +/- 5.8 microliter. The mean conductance volumes were no different from those derived by flow probe and echocardiography but did differ from ultrasonic crystals. G(pi) was determined to be 14.9 +/- 8.7 microliter. However, hypertonic saline altered dimension and pressure in the mouse left ventricle. Although G(pi) can be determined by the hypertonic saline method, saline altered hemodynamics, questioning its validity in the mouse. Although mean measures of absolute volume may be similar among different techniques, individual values did not correlate.     

Estimating left ventricular offset volume using dual-frequency conductance catheters

The measurement of left ventricular volume by the conductance-catheter technique has many advantages, but it is difficult to determine absolute volumes with this method. Current procedure requires that a bolus of concentrated hypertonic saline be injected to measure absolute volume. It also demands that the subject be in a steady state and that measurements only be made at discrete intervals. The saline bolus may affect the cardiovascular state of the subject. This paper describes a new technique for estimating absolute volume utilizing the conductance catheter that relies on the different frequency responses of blood and muscle. Good correlation between the salt-injection method and the dual-frequency method was found in nine closed-chest pigs anesthetized with pentobarbital sodium (r = 0.922). Further refinements may extend the utility of the dual-frequency approach.     

Increased heat-escape/cold-seeking behavior following hypertonic saline injection in rats

We examined the effect of hypertonic saline injection on heat-escape/cold-seeking behavior in desalivated rats. Rats were exposed to 40 degrees C heat after normal (154 mM NaCl, control) or hypertonic saline (2,500 mM NaCl) injection (1 ml/100 g body wt). The rats received a 0 degrees C air for 30 s when they entered a specific area in an experimental box. Core temperature (T(c)) surpassed 40 degrees C in both conditions when 0 degrees C air was not available. Hypertonic saline injection produced a lower baseline T(c) than control [36.9 +/- 0.2 and 37.9 +/- 0.2 degrees C (means +/- SE), P < 0.05] and a greater number of 0 degrees C air rewards during the 2-h heat with lower T(c) at the end (48 +/- 1 and 34 +/- 2, 37.6 +/- 0.1, and 37.3 +/- 0.1 degrees C in the control and hypertonic saline injection trial, respectively, P < 0.05, n = 6). However, T(c) was similar (37.7 +/- 0.2 and 37.6 +/- 0.4 degrees C in the control and hypertonic saline injection trial, n = 5) when 0 degrees C air was automatically and intermittently (35 times) given during the heat. Rats augment heat-defense mechanisms in response to osmotic stress by lowering the baseline T(c) and increasing heat-escape/cold-seeking behavior.     

Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the alpha-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 +/- 3 vs. MMP 51 +/- 12 microl; P = 0.003] and systolic (C 7 +/- 2 vs. MMP 28 +/- 14 microl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 +/- 4 vs. MMP 23 +/- 3 microl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 +/- 7% vs. MMP 48 +/- 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 +/- 84 vs. MMP 78 +/- 49 mW/microl(2); P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 +/- 1.5 vs. MMP 4.7 +/- 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.     

Conductance catheter-based assessment of arterial input impedance, arterial function, and ventricular-vascular interaction in mice

Global assessment of both cardiac and arterial function is important for a meaningful interpretation of pathophysiological changes in animal models of cardiovascular disease. We simultaneously acquired left ventricular (LV) and aortic pressure and LV volume (V(LV)) in 17 open-chest anesthetized mice (26.7 +/- 3.2g) during steady-state (BL) and caval vein occlusion (VCO) using a 1.4-Fr dual-pressure conductance catheter and in a subgroup of eight animals during aortic occlusion (AOO). Aortic flow was obtained from numerical differentiation of V(LV). AOO increased input impedance (Z(in)) for the first two harmonics, increased characteristic impedance (0.025 +/- 0.007 to 0.040 +/- 0.011 mmHg x microl(-1) x s, P < 0.05), and shifted the minimum in Z(in) from the third to the sixth harmonic. For all conditions, the Z(in) could be well represented by a four-element windkessel model. The augmentation index increased from 116.7 +/- 7.8% to 145.9 +/- 19.5% (P < 0.01) as well as estimated pulse-wave velocity (3.50 +/- 0.94 to 5.95 +/- 1.62 m/s, P < 0.05) and arterial elastance (E(a), 4.46 +/- 1.62 to 6.02 +/- 1.43 mmHg/microl, P < 0.01). AOO altered the maximal slope (E(max), 3.23 +/- 1.02 to 5.53 +/- 1.53 mmHg/microl, P < 0.05) and intercept (-19.9 +/- 8.6 to 1.62 +/- 13.51 microl, P < 0.01) of the end-systolic pressure-volume relation but not E(a)/E(max) (1.44 +/- 0.43 to 1.21 +/- 0.37, not significant). We conclude that simultaneous acquisition of Z(in) and arterial function parameters in the mouse, based solely on conductance catheter measurements, is feasible. We obtained an anticipated response of Z(in) and arterial function parameters following VCO and AOO, demonstrating the sensitivity of the measuring technique to induced physiological alterations in murine hemodynamics.     

MitoK(ATP) opener,diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 microl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 +/- 0.7, n = 13) compared with sham treatment (9.5 +/- 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 +/- 3.6% (n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 +/- 4.8% (n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 microl saline), a selective blocker of mitoK(ATP) channels (n = 6). These results indicate that selective opening of the mitoK(ATP) channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.     

Deficiency of iNOS does not attenuate severe congestive heart failure in mice

Inducible nitric oxide synthase (iNOS) has been implicated in the pathophysiology of congestive heart failure (CHF). Given the extensive evidence supporting this concept, we hypothesized that iNOS deficiency (iNOS(-/-)) would attenuate the severity of CHF in mice. Mice were subjected to permanent occlusion [myocardial infarction (MI)] of the proximal left anterior descending coronary artery to produce CHF. Cardiac function was assessed in vivo using echocardiography and ultraminiature ventricular pressure catheters. Sham wild-type (n = 17), sham iNOS(-/-) (n = 8), MI wild-type (n = 56), and MI iNOS(-/-) (n = 48) mice were subjected to MI (or sham MI) and followed for 1 mo. Deficiency of iNOS did not alter survival during CHF compared with wild type (35% vs. 32%, P = not significant). Furthermore, fractional shortening and cardiac output were not significantly different between wild-type (9.6 +/- 2.0% and 441 +/- 20 microl.min(-1).g(-1)) and iNOS(-/-) (9.8 +/- 1.3% and 471 +/- 26 microl.min(-1).g(-1)) mice. The extent of cardiac hypertrophy and pulmonary edema was also similar between wild-type and iNOS(-/-) mice. None of the indexes demonstrated any significant differences between iNOS(-/-) and wild-type mice subjected to MI. These findings indicate that deficiency of iNOS does not significantly affect severe CHF in mice after MI.     

Central angiotensin AT1-receptor blockade affects thermoregulation and running performance in rats

The effect of central angiotensin AT1-receptor blockade on thermoregulation in rats during exercise on a treadmill (18 m/min, 5% inclination) was investigated. Core (Tb) and skin tail temperatures were measured in rats while they were exercising until fatigue after injection of 2 microl of losartan (Los; 20 nmol, n = 4; 30 nmol, n = 4; 60 nmol, n = 7), an angiotensin II AT1-receptor antagonist, or 2 microl of 0.15 mol/l NaCl (Sal; n = 15) into the right lateral cerebral ventricle. Body heat rate (BHR), heat storage rate, threshold Tb for tail vasodilation (TTbV), time to fatigue, and workload were calculated. During exercise, the BHR and heat storage rate of Los-treated animals were, respectively, 40 and 53% higher (P < 0.01) than in Sal-treated animals. Additionally, rats injected with Los showed an increased TTbV (38.59 +/- 0.19 degrees C for Los vs. 38.12 +/- 0.1 degrees C for Sal, P < 0.02), a higher Tb at fatigue point (39.07 +/- 0.14 degrees C Los vs. 38.66 +/- 0.07 degrees C Sal, P < 0.01), and a reduced running performance (27.29 +/- 4.48 min Los vs. 52.47 +/- 6.67 min Sal, P < 0.01), which was closely related to the increased BHR. Our data suggest that AT1-receptor blockade attenuates heat dissipation during exercise due to the higher TTbV, leading to a faster exercise-induced increase in Tb, thus decreasing running performance.     

A self-calibrating telemetry system for measurement of ventricular pressure-volume relations in conscious, freely moving rats

Using Bluetooth wireless technology, we developed an implantable telemetry system for measurement of the left ventricular pressure-volume relation in conscious, freely moving rats. The telemetry system consisted of a pressure-conductance catheter (1.8-Fr) connected to a small (14-g) fully implantable signal transmitter. To make the system fully telemetric, calibrations such as blood resistivity and parallel conductance were also conducted telemetrically. To estimate blood resistivity, we used four electrodes arranged 0.2 mm apart on the pressure-conductance catheter. To estimate parallel conductance, we used a dual-frequency method. We examined the accuracy of calibrations, stroke volume (SV) measurements, and the reproducibility of the telemetry. The blood resistivity estimated telemetrically agreed with that measured using an ex vivo cuvette method (y=1.09x - 11.9, r2= 0.88, n=10). Parallel conductance estimated by the dual-frequency (2 and 20 kHz) method correlated well with that measured by a conventional saline injection method (y=1.59x - 1.77, r2= 0.87, n=13). The telemetric SV closely correlated with the flowmetric SV during inferior vena cava occlusions (y=0.96x + 7.5, r2=0.96, n=4). In six conscious rats, differences between the repeated telemetries on different days (3 days apart on average) were reasonably small: 13% for end-diastolic volume, 20% for end-systolic volume, 28% for end-diastolic pressure, and 6% for end-systolic pressure. We conclude that the developed telemetry system enables us to estimate the pressure-volume relation with reasonable accuracy and reproducibility in conscious, untethered rats.     

Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition

Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the post-MI remodeling process has not been completely established. The goal of this project was to define the effects of altering endogenous MMP inhibitory control through combined genetic and pharmacological approaches on post-MI remodeling in mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 mg.kg(-1).day(-1)) on LV geometry and function (conductance volumetry) after MI in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into four groups: WT-MI/MMPi (n = 10), TIMP1-KO-MI/MMPi (n = 10), WT-MI (n = 22), and TIMP1-KO-MI (n = 23). LV end-diastolic volume (EDV) and ejection fraction were determined 14 days after MI. Age-matched WT (n = 20) and TIMP1-KO (n = 28) mice served as reference controls. LVEDV was similar under control conditions in WT and TIMP1-KO mice (36 +/- 2 and 40 +/- 2 microl, respectively) but was greater in TIMP1-KO-MI than in WT-MI mice (48 +/- 2 vs. 61 +/- 5 microl, P < 0.05). LVEDV was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 +/- 2 and 36 +/- 2 microl, respectively, P < 0.05) but was reduced to the greatest degree in TIMP1-KO mice (P < 0.05). LV ejection fraction was reduced in both groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. These unique results demonstrated that myocardial TIMP-1 plays a regulatory role in post-MI remodeling and that the accelerated myocardial remodeling induced by TIMP-1 gene deletion can be pharmacologically "rescued" by MMP inhibition. These results define the importance of local endogenous control of MMP activity with respect to regulating LV structure and function after MI.     

Effects of cardiac hormones on arterial pressure and sodium excretion in NPRA knockout mice

These studies were designed to determine if the atria contains natriuretic substances that act through a non-natriuretic peptide type A (NPRA) receptor mechanism. C57BL/6 mice, either wild-type NPRA++ (WT) or NPRA-- knockout (KO), were anesthetized with pentobarbital. Catheters were placed in the trachea, carotid artery, jugular vein, and bladder. Urine was collected for six 30-min periods. Both groups received an iv injection of 100 ng of rat atrial natriuretic peptide (rANP) in 200 microl of saline after the first period (30 mins) and 200 microl of rat atrial extract after the fourth period (120 mins). ANP injection increased urine flow (UF) to 2.7 +/- 0.5 microl/min in the WT versus 1.9 +/- 0.2 in KO. Extract increased UF to 7.9 +/- 1.5 microl/min in WT versus 2.7 +/- 0.4 in KO (P < 0.01). ANP increased sodium excretion (ENa) to 0.47 +/- 0.10 micromoles/min in WT versus 0.27 +/- 0.04 in KO (P < 0.05). Extract increased ENa to 1.44 +/- 0.47 micromoles/min in WT versus 0.26 +/- 0.06 in KO (P < 0.05). Extract decreased mean arterial pressure (MAP) to 62 +/- 3 mm Hg in the WT versus 81 +/- 5 in KO (P < 0.01). ENa and MAP responses to extract in KO were not different from responses to 200 microl of saline. A constant 150-min infusion of rat atrial extract increased urine flow by 3-fold and ENa by 5-fold (both P < 0.05) in the WT mice but had no significant effect in the KO mice. Thus, acute renal and MAP responses to atrial extracts require the NPRA receptor.     

Cardiovascular and renal characteristics, and responses to acute volume expansion of a rat model of diabetic pregnancy

The objective of this study was to characterize the cardiovascular and renal alterations that occur during diabetic pregnancy, and to evaluate the effect of insulin treatment in 12-14 days pregnant diabetic rats. Four groups of female Sprague Dawley rats were studied: virgin control group (NP), pregnant control group (CP), diabetic pregnant group (DP), and diabetic pregnant group with insulin treatment (DPI). Systolic arterial pressure (SAP) was increased on day 12, whereas heart rate (HR) decreased starting with day 3 in DP group of rats. DP rats exhibited marked renal hypertrophy with greater kidney weight (wt) and kidney wt/body wt ratio. Insulin treatment normalized blood glucose (BG) concentration, SAP and HR, and prevented the increase in kidney wt/body wt ratio in DPI rats. At the time of the terminal acute experiment, acute saline volume expansion (VE, 5% body wt/30 min) significantly increased renal interstitial hydrostatic pressure (RIHP), urinary sodium excretion (U(Na)V) and urine flow rate (V) in all groups, but the increases (Delta) were significantly attenuated in both CP (1.7 +/- 0.2mmHg, 12.0 +/- 1.5 microEq.min(-1).g kidney wt(-1) and 76.2 +/- 10.9 microl.min(-1).g kidney wt(-1) for DeltaRIHP, DeltaU(Na)V and DeltaV respectively) and DP (1.3 +/- 0.1 mmHg, 6.8 +/- 1.8 microEq.min(-1).g kidney wt(-1) and 32.3 +/- 9.3 microl.min(-1).g kidney wt(-1) for DeltaRIHP, DeltaU(Na)V and DeltaV respectively) group of rats as compared to NP (4.0 +/- 0.6 mmHg, 21.6 +/- 1.4 microEq.min(-1).g kidney wt(-1)and 136.8 +/- 10.5 microl.min(-1).g kidney wt(-1) for DeltaRIHP, DeltaU(Na)V and DeltaV respectively) group of rats. Although RIHP response to VE was similar in DP and CP group of rats, the natriuretic and diuretic responses to VE were significantly lower in DP as compared to CP group of rats. Insulin treatment had no effect on RIHP response (DeltaRIHP = 1.5 +/- 0.3 mmHg), but restored most of the natriuretic (DeltaU(Na)V = 15.7 +/- 2.9 microEq.min(-1).g kidney wt(-1)) and diuretic (DeltaV = 100.2 +/- 19.3 microl.min(-1).g kidney wt(-1)) responses to VE in DPI as compared with CP group of rats. These data suggest that with VE, the restoration of the increase in U(Na)V and V with insulin treatment in diabetic pregnant rats is not mediated by changes in RIHP.     

脑室内注射高张盐水抑制近曲小管对水和钠的重吸收

实验在麻醉大鼠上进行。用锂清除率为指标观察脑室内注射高张盐水对近曲小管重吸收水和钠的影响。在切断单侧肾神经的动物中,脑室内注射高张盐水后的锂清除率与肾小球滤过率比值在去神经侧肾脏从0.37±0.04增加至0.51±0.05(P<0.01);神经完好侧肾脏则从0.26±0.03增加至0.31±0.04(P<0.05);双侧肾脏的肾小球滤过率、尿量、尿钠和尿钾量均增加,且去肾神经肾脏的增加幅度高于肾神经完好肾脏。在肾小管微穿刺实验中,脑室内注射高张盐水后,近曲小管末段小管液流量从24.42±1.84nl/min增加至31.86±3.09nl/min(P<0.01),小管液的渗透压无显著变化。以上实验结果表明,脑室内注射高张盐水引起的利尿、尿钠增多反应与肾小球滤过率增加和近曲小管对水、钠重吸收减少有关,体液因素在该反应中可能起主要作用。     

Brain region-dependent effects of dexamethasone on counterregulatory responses to hypoglycemia in conscious rats

The aim of this study was to determine whether activation of central type II glucocorticoid receptors can blunt autonomic nervous system counterregulatory responses to subsequent hypoglycemia. Sixty conscious unrestrained Sprague-Dawley rats were studied during 2-day experiments. Day 1 consisted of either two episodes of clamped 2-h hyperinsulinemic (30 pmol x kg(-1) x min(-1)) hypoglycemia (2.8 +/- 0.1 mM; n = 12), hyperinsulinemic euglycemia (6.2 +/- 0.1 mM; n = 12), hyperinsulinemic euglycemia plus simultaneous lateral cerebroventricular infusion of saline (24 microl/h; n = 8), or hyperinsulinemic euglycemia plus either lateral cerebral ventricular infusion (n = 8; LV-DEX group), fourth cerebral ventricular (n = 10; 4V-DEX group), or peripheral (n = 10; P-DEX group) infusion of dexamethasone (5 microg/h), a specific type II glucocorticoid receptor analog. For all groups, day 2 consisted of a 2-h hyperinsulinemic (30 pmol x kg(-1) x min(-1)) or hypoglycemic (2.9 +/- 0.2 mM) clamp. The hypoglycemic group had blunted epinephrine, glucagon, and endogenous glucose production in response to subsequent hypoglycemia. Consequently, the glucose infusion rate to maintain the glucose levels was significantly greater in this group vs. all other groups. The LV-DEX group did not have blunted counterregulatory responses to subsequent hypoglycemia, but the P-DEX and 4V-DEX groups had significantly lower epinephrine and norepinephrine responses to hypoglycemia compared with all other groups. In summary, peripheral and fourth cerebral ventricular but not lateral cerebral ventricular infusion of dexamethasone led to significant blunting of autonomic counterregulatory responses to subsequent hypoglycemia. These data suggest that prior activation of type II glucocorticoid receptors within the hindbrain plays a major role in blunting autonomic nervous system counterregulatory responses to subsequent hypoglycemia in the conscious rat.     

Intracerebroventricular infusion of hypertonic NaCl increases urinary CGMP in healthy and cirrhotic rats

Implication of serum atrial natriuretic peptide (ANP) and endothelin-1 (ET1) in the central nervous system (CNS)-induced natriuresis and hypertension respectively, was investigated in healthy and cirrhotic rats. Both healthy and nonascitic CCl(4)-induced cirrhotic rats under pentobarbital anesthesia received either normotonic (140 mmol/L) or hypertonic (320 mmol/L) NaCl artificial cerebrospinal fluid into the CNS lateral ventricle at a rate of 8.3 microl/min for 120 min. A sham operated group, but not centrally infused, served as matched control. Hypertonic NaCl solution significantly increased mean arterial pressure (MAP) similarly in both healthy (n = 5) ((MAP: 16 mm Hg, 13%) and cirrhotic rats (n = 6) ((MAP: 20 mm Hg, 15%) (ANOVA, p <.001) although the latter showed a slower increment. Under hypertonic NaCl infusion, natriuresis was also significantly increased in a similar manner in both healthy (U (Na) V: baseline: 0.38 +/- 0.22 micromol/min x 100 g; experiment: 2.36 +/- 0.90 micromol/min x 100 g; mean +/- SD) and cirrhotic rats (0.69 +/- 0.48 vs. 3.16 +/- 0.87; p <.001). By contrast, central hypertonic NaCl solutions did not show a significant modification of serum ANP in neither healthy (62 +/- 18 fmol/ml vs. 51 +/- 17 fmol/ml) nor cirrhotic rats (126 +/- 61 vs. 115 +/- 30). Likewise, ET-1 was not significantly modified under central hypertonic NaCl infusion in neither healthy (352 +/- 46 pg/ml vs. 344 +/- 39 pg/ml) nor cirrhotic rats (287 +/- 58 vs. 277 +/- 61). Despite no modification in serum ANP, there was a significant increment in urinary excretion of cGMP under central hypertonic NaCl infusions in bo th healthy (6.8 +/- 4.1 pmol/min x 100 g vs. 13.0 +/- 6.5 pmol/min x 100 g; p <.05) and cirrhotic rats (8.6 +/- 1.7 vs. 11.1 +/- 1.3; p <.05). Our data indicate the preservation of the mechanisms of central natriuresis in a model of non-ascitic CCl(4 )-induced cirrhosis in rats. An increment in urinary cGMP could potentially be implicated in the natriuretic response obtained by intracerebroventricular hypertonic NaCl stimulus in both healthy and cirrhotic rats. The lack of modification of serum ANP and ET-1 does not appear to support a systemic implication of these peptides in the natriuretic and hypertensive responses respectively induced by this manoeuvre.