The cardiovascular pharmacology of prostacyclin (PGI2) in the rat.

Physiological roles have been suggested for prostacyclin in the cardiovascular system. Prostacyclin was administered by intravenous infusion to unanesthetized rats. Over a 24 hr period, 0.32 mg/kg/day caused only flushing of the ears. Larger doses (0.56 and 1 mg/kg/day) caused hypothermia, behavioral depression, and swelling of the paws. Cumulative dose-response curves for its depressor action were determined in both unanesthetized and anesthetized, vagotomized, ganglion-blocked rats. In unanesthetized rats, the threshold dose was about 0.1 ug/kg/min. Respiratory depression precluded doses larger than 1 ug/kg/min. In anesthetized rats, the threshold dose was about 0.001 ug/kg/min, and the maximally effective dose was about 0.1 micrograms/kg/min. At 0.032 ug/kg/min, blood pressure first fell and then rose slightly. This compensatory rise did not occur in nephrectomized rats, suggesting renin release as the mechanism. Intravenous infusion of 0.1 but not 0.01 ug/kg/min in unanesthetized rats doubled plasma renin activity. In saline-loaded unanesthetized rats, urine volume and urinary sodium excretion were decreased by 0.1 ug/kg/min of prostacyclin.     

The cardiovascular pharmacology of prostacyclin (PGI2) in the rat

Physiological roles have been suggested for prostacyclin in the cardiovascular system. Prostacyclin was administered by intravenous infusion to unanesthetized rats. Over a 24 hr period, 0.32 mg/kg/day caused only flushing of the ears. Larger doses (0.56 and 1 mg/kg/day) caused hypothermia, behavioral depression, and swelling of the paws. Cumulative dose-response curves for its depressor action were determined in both unanesthetized and anesthetized, vagotimized, ganglion-blocked rats. In unanesthetized rats, the threshold dose was about 0.1 μg/kg/min. Respiratory depression precluded doses larger than 1 μg/kg/min. In anesthetized rats, the threshold dose was about 0.001 μg/kg/min, and the maximally effective dose was about 0.1 μg/kg/min. At 0.032 μg/kg/min, blood pressure first fell and then rose slightly. This compensatory rise did not occur in nephrectomized rats, suggesting renin release as the mechanism. Intravenous infusion of 0.1 but not 0.01 μg/kg/min in unanesthetized rats doubled plasma renin activity. In saline-loaded unanesthetized rats, urine volume and urinary sodium excretion were decreased by 0.1 μg/kg/min of prostacyclin.     

Natriuretic response to saline load in one-kidney/one-clip hypertensive rats.

Parameters of renal function were studied in conscious and anesthetized one-kidney (1K) and one-kidney/one-clip (1K-1C) rats. Effective renal blood flow (ERBF) was significantly lower in anesthetized 1K-1C rats than in conscious ones (12.1 +/- 1.6 vs. 16.4 +/- 1.2 ml/min). Renal function was evaluated in two-kidney (2K), 1K and 1K-1C unanesthetized rats. ERBF was lower in 1K and 1K-1C animals than in 2K rats. Glomerular filtration rate (GFR) and urinary sodium excretion (UNa.V) were not affected by uninephrectomy with or without clipping the renal artery. In 1K-1C rats, mean arterial pressure (MAP) increased from 100 +/- 2 to 140 +/- 1 mm Hg. Subsequently, the renal ability of unanesthetized rats to handle Na was studied by a sustained extracellular fluid volume expansion (EFVE) in all groups. During EFVE, MAP remained unchanged in the 2K and 1K groups and decreased significantly in the 1K-1C group, ERBF did not change and GFR increased to the same extent in all groups. The increase in UNa.V was 40% higher in 2K than in 1K or 1K-1C rats. These findings indicate that the relatively smaller natriuretic response to a saline load of 1K rats with or without a clip in the renal artery, as compared with 2K rats, could be ascribed to renal mass reduction. Finally, the study shows the advantage of performing studies of renal function in hypertension in conscious rather than anesthetized rats.     

Effect of nephrectomy and of adrenergic receptor blockers on the cardiorenal actions of endothelin

The cardiorenal actions of endothelin-1 (ET-1) were evaluated in rats following nephrectomy, in rats during alpha-adrenergic blockade with phentolamine, and in rats during beta-adrenergic blockade with propranolol. Female rats were anesthetized with pentobarbital and, following surgery, were allowed 60 min to stabilize before 3 x 20 min-control clearances were collected. ET-1 was then infused at a rate of 100 ng kg-1 min-1 for 30 min, the infusion was stopped, and three additional clearances were collected. Four groups of rats were studied: in Group 1 (n = 10), ET-1 was infused; in Group 2 (n = 5), a bilateral nephrectomy was performed 120 min before infusing ET-1; in Group 3 (n = 5), ET-1 was infused into rats treated with phentolamine (0.015 mg kg-1 min-1); and in Group 4 (n = 5), ET-1 was infused into rats treated with propranolol (0.015 mg kg-1 min-1). At 30 min during infusion of ET-1 into Group 1 rats, mean arterial blood pressure had increased (P less than 0.01) by 27 +/- 2% (SE) and the glomerular filtration rate had decreased (P less than 0.01) by 71 +/- 6% of baseline values. Nephrectomy potentiated and prolonged the ET-1-induced systemic vasoconstriction. Phentolamine had no effect on the cardiorenal actions of ET-1 whereas propranolol enhanced ET-1-induced changes in mean arterial blood pressure; mean arterial blood pressure increased 38 +/- 2% at 30 min during ET-1 + propranolol infusion (P less than 0.01 versus value with ET-1 alone). These data indicate that the kidney affects ET-1-induced systemic vasoconstriction and that beta-adrenergic (but not alpha-adrenergic) receptors are activated during infusion of ET-1 with a resultant attenuation of ET-1-induced changes in systemic blood pressure.     

Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex

Cellular GABA levels are determined by the dynamic balance between synthesis and catabolism and are regulated at the level of glutamate decarboxylase, precursor availability (e.g., glutamate and glutamine), and possibly GABA degradation. GABA levels rise and stabilize within hours in human cortex following orally administered vigabatrin, an irreversible inhibitor of GABA-T, suggesting potential product inhibition of GABA synthesis or enhanced GABA degradation through the non-inhibited GABA-T fraction. In this study time courses of the rise in cortical GABA were measured in anesthetized rats in vivo after vigabatrin treatment using localized (1)H magnetic resonance spectroscopy and the times to reach steady-state for a given dose were determined. Rates of GABA synthesis were estimated for the period of constant GABA level from the accumulation of [2-(13)C]GABA following a short intravenous infusion (20 min) of either [1,6-(13)C(2)]glucose or [2-(13)C]acetate. No evidence of product inhibition of glutamate decarboxylase by the increased GABA concentration or reduced synthesis from [1,6-(13)C(2)]glucose (control, 0.031+/-0.010; vigabatrin-treated, 0.037+/-0.004 micromol/g/min, P=0.30) or [2-(13)C]acetate (control, 0.078+/-0.010; vigabatrin-treated, 0.084+/-0.006 micromol/g/min, P=0.42) was found. Fractional changes in steady-state GABA levels and GABA-T activities 5-6 h after vigabatrin treatment were approximately equal. The lack of change in GABA synthesis (and GABA catabolic flux for constant GABA levels) suggests that GABA-T has a near-zero flux control coefficient in vivo-capable of greatly altering the steady-state GABA concentration but exerting little or no control on GABA synthesis or GABA/glutamine cycling flux. The findings are consistent with a Michaelis-Menten kinetic model whereby cellular GABA levels increase until flux through the remaining (uninhibited) transaminase equals the rate of GABA synthesis. The findings suggest that astroglia may be the site of continuing GABA catabolism after acute vigabatrin treatment.     

Angiotensin restores atrial natriuretic factor-induced decrease of baroreceptor sensitivity in normotensive rats, but not in spontaneously hypertensive rats

The effect of atrial natriuretic factor (ANF) on baroreflex sensitivity was determined in unanesthetized normotensive (Wistar-Kyoto, WKY) or spontaneously hypertensive rats (SHR) during acute hypertensive stimuli (phenylephrine) or hypotensive stimuli (sodium nitroprusside). The i.v. dose of rat ANF [( Ser99,Tyr126]ANF) was 50 ng/min per rat, sufficient to decrease mean arterial blood pressure (ABP) by about 6 mmHg (1 mmHg = 133.3 Pa) in WKY. SHR showed no change in ABP with this ANF dose. During a control infusion of physiological saline, the mean heart rate (HR) response to increases in ABP was -1.30 +/- 0.27 beats/min (bpm)/mmHg in WKY and -0.37 +/- 0.22 in SHR (p less than 0.05). These values were not affected significantly by ANF. However, ANF blunted chronotropic responses to ABP decreases. The control values of the delta HR/delta ABP slope in WKY and SHR were -2.34 +/- 0.57 and -2.01 +/- 0.37 bpm/mmHg, respectively. In the presence of ANF, the slope changed to -0.36 +/- 0.43 (i.e., bradycardia in response to hypotension) in WKY and to +0.20 +/- 0.21 in SHR (p less than 0.005 for the difference from control for both). This ANF-induced loss of baroreflex sensitivity was reversed in WKY by the addition of angiotensin I (sufficient to increase ABP by 5 mmHg in control rats). Angiotensin did not restore baroreflex sensitivity in ANF-infused SHR, and ANF had no effect on the ABP increase caused by angiotensin in either group. The data suggest that ANF does not act on baroreceptor structures directly, but inhibits mechanisms involved in efferent sympathetic activation. Parasympathetic responses do not appear to be compromised.     

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

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

Effect of glucose infusion on muscle malonyl-CoA during exercise

Previous work in this laboratory has shown that muscle malonyl-CoA, the inhibitor of carnitine palmitoyltransferase I (CPT I), decreased during exercise. Hepatic malonyl-CoA content decreases when glucose availability decreases such as during fasting or when the glucagon-to-insulin ratio increases such as during prolonged exercise or in response to insulin deficiency. To investigate the effect of glucose infusion on muscle malonyl-CoA during exercise, male rats were anesthetized (pentobarbital via venous catheters) at rest or after running (21 m/min, 15% grade) for 30 or 60 min. During exercise rats were infused with either glucose (0.625 g/ml) or saline at a rate of 1.5 ml/h. Gastrocnemius muscles and liver samples were frozen at liquid nitrogen temperature. Muscle malonyl-CoA decreased from 1.24 +/- 0.06 to 0.69 +/- 0.05 nmol/g with glucose infusion and to 0.43 +/- 0.04 nmol/g with saline infusion during 60 min of exercise. In the liver, glucose infusion prevented the drop in malonyl-CoA. This indicates that glucose infusion attenuates the progressive decline in muscle malonyl-CoA and prevents the decline in liver malonyl-CoA during prolonged exercise.     

Baroreflex depression persists in the early phase after hypertension reversal

The baroreflex control of heart rate (HR) was evaluated in conscious chronic renal hypertensive rats (RHR; 1K-1C, 2 mo) under control conditions and after reversal of hypertension by unclipping the renal artery or sodium nitroprusside infusion. Unclipping and nitroprusside infusion were both followed by significant decreases in the mean arterial pressure (unclipping: from 199 +/- 4 to 153 +/- 8 mmHg; nitroprusside infusion: from 197 +/- 9 to 166 +/- 6 mmHg) as well as slight and significant increases, respectively, in the baroreflex bradycardic response index (unclipping: from 0.2 +/- 0.04 to 0.6 +/- 0.1 beats x min(-1) x mmHg(-1); nitroprusside infusion: from 0.1 +/- 0.04 to 0.5 +/- 0.1 beats x min(-1) x mmHg(-1)). However, this index was still depressed compared with that for normotensive control rats (2.1 +/- 0.2 beats x min(-1) x mmHg(-1)). The index for the baroreflex tachycardic response was also depressed under control conditions and remained unchanged after hypertension reversal. RHR possessed markedly attenuated vagal tone as demonstrated by pharmacological blockade of parasympathetic and sympathetic control of HR with methylatropine and propranolol, respectively. A reduced bradycardic response was also observed in anesthetized RHR during electrical stimulation of the vagus nerve or methacholine chloride injection, indicating impairment of efferent vagal influence over the HR. Together, these data indicate that 2 h after hypertension reversal in RHR, the previously described normalization of baroreceptor gain occurs independent of the minimal or lack of recovery of baroreflex control over HR.     

Peripheral vascular responses to hyperthermia in the rat

To investigate the sequence and nature of the peripheral vascular responses during the prodromal period of heat stroke, rats were implanted with Doppler flow probes on the superior mesenteric (SMA), left iliac (LIA) or left renal (LRA), and external caudal (ECA) arteries. Studies were performed in unanesthetized rats (n = 6) exposed to 46 degrees C and in chloralose-anesthetized animals (n = 11) at 40 degrees C. Core (Tc) and tail-skin temperatures, heart rate, and mean arterial blood pressure (MAP) were also monitored. In both groups, prolonged (70-150 min) exposure progressively elevated Tc from 37.0 to 44.0 degrees C. MAP rose to a plateau then fell precipitously as Tc exceeded 41.5 degrees C. SMA resistance increased throughout the early stages of heating, with a sharp decline from this elevated level 10-15 min before the precipitous fall in MAP. ECA resistance fell initially but increased in the terminal stage of heating. In unanesthetized animals, LIA resistance progressively declined. In chloralose-anesthetized animals LRA resistance rose progressively, then increased markedly as Tc exceeded 41.5 degrees C. These data support the hypothesis that a selective loss of compensatory splanchnic vasoconstriction may trigger the cascade of events that characterize heat stroke. This differential vascular response was similar in both unanesthetized and anesthetized animals.     

大鼠下丘脑外侧区内微量注射胃动素对胃窦运动和迷走背核复合体神经元电活动的影响

采用清醒大鼠胃运动记录和玻璃微电极记录神经元活动的实验方法 ,研究下丘脑外侧区 (lateralhy pothalamicarea,LHA)微量注射胃动素 (motilin) ,对清醒大鼠胃窦运动和对麻醉大鼠迷走背核复合体 (dorsalvagalcomplex ,DVC)中胃扩张敏感神经元电活动的调节作用。LHA内微量注射胃动素 (0 37nmol/ 0 5 μl)可使胃窦运动增强 76 2 9± 4 0 9% (P <0 0 1)。DVC中 6 0个胃扩张 (gastricdistention ,GD)敏感神经元中 ,39(6 5 % )个GD刺激引起电活动增强 ,2 1(35 % )个电活动减弱 ,分别称之为GD兴奋型神经元和GD抑制型神经元。双侧LHA微量注射胃动素 0 37nmol/ 0 5 μl,14个GD抑制型神经元中有 12个单位放电频率增加 4 4 35± 7 89% (P <0 0 1) ;2 4个GD兴奋型神经元中有 15个单位放电频率减少 7 17± 7 89% (P <0 0 5 )。结果提示 ,中枢胃动素可能通过LHA-DVC-迷走神经实现对胃窦运动的调控     

Tetraethylammonium and p-aminohippurate as clearance markers for renal plasma flow in the rat during saline and glucose infusion.

Renal plasma clearances (C) of 14C-tetraethylammonium (TEA) and p-aminohippurate (PAH) as estimates of arterial renal plasma flow (ARPF) were evaluated in anesthetized rats during control conditions and during intravenous glucose infusion. Venous renal blood flow was measured directly by means of a servo-controlled pump, keeping the renal venous pressure constant. Arteriovenous extraction fractions (E = 1 - P(renal venous)/P(renal arterial)) for PAH averaged 88.3 +/- (SE) 0.8% in control rats and 82.0 +/- 0.9% in glucose-infused rats (p less than 0.001); E(TEA) averaged 92.0 +/- 0.6 and 90.1 +/- 0.6%, respectively (p less than 0.05). Under both experimental conditions, (C/E)PAH did not differ significantly from ARPF, while (C/E)TEA underestimated ARPF; the rate of extraction of TEA exceeded the rate of excretion by 15-20%, probably due to accumulation of TEA in renal tissue. It is concluded that, when corrected for E, C(PAH) is in general a more accurate estimate for ARPF than C(TEA). However, under conditions involving changes in plasma glucose levels C(TEA) may provide a better estimate of the effective renal plasma flow than C(PAH).     

Changes of deep cervical lymph flow following the infusion of isotonic, hypotonic, and hypertonic NaCl in rabbit.

Isotonic, hypotonic, or hypertonic saline was infused in anesthetized rabbits in order to test the effects of osmolality in cerebral vessels on lymph flow. The jugular lymph trunk was cannulated by PE tubing in a headward direction. Either a hypo-(100 mosmol), iso-(310 mosmol), or hypertonic (605 mosmol) NaCl solution was infused into the internal carotid artery (ICA) or the right lateral ventricle (RIV). Lymph was continuously collected at slight negative pressure, and measured over a 90 min preinfusion period, as well as during saline infusion and intermittent recovery periods. Mean peak flow rates for the first 30 min infusion of hypertonic saline via ICA and RLV were 5.1 +/- 1.2 and 6.7 +/- 1.6 microliters/min, respectively, or a significant increase of 38% and 40% over those of isotonic saline (3.7 +/- 0.9 microliters/min via ICA; 4.8 +/- 1.0 microliters/min via RLV). Conversely, for hypotonic saline, lymph flow rates were significantly reduced by 19% (2.9 +/- 0.6 microliters/min) and 23% (3.7 +/- 0.7 microliters/min) for the first 30 min infusion via ICA and RLV, respectively. Increases in arterial and intracranial pressures, as well as an enhancement of respiratory movements following hypertonic saline infusion, augmented lymph formation. The results suggest that the observed changes in jugular lymph flow following saline infusion can be correlated to the resulting increase in intracranial pressure and respiratory movements, and changes in the osmolality and blood pressure of cerebral vessels.     

Effects of liver blood flow on hepatic uptake kinetics of galactose in anesthetized cats: parallel tube model

Hepatic galactose uptake in cats anesthetized with pentobarbital was determined during (i) steady-state infusions at several doses, (ii) rapidly increasing infusion rates at different blood flows, and (iii) prolonged infusion of a single dose at different blood flows. The hepatic venous long-circuit technique was used to allow frequent sampling of arterial, portal, and hepatic venous blood without depletion of the animal's blood volume and to allow measurement and alteration of total hepatic blood flow. Uptake was shown to follow Michaelis-Menten kinetics and was consistent with the "parallel tube model." The kinetic parameters Vmax and Km could be determined under steady-state and nonsteady-state conditions and were independent of hepatic blood flow over the range 60-150% of control flow. Mean Vmax was 80 mumol/(min X 100 g liver) and mean Km was 215 microM. Vmax declined by 50% when flow was reduced to half normal. It is concluded that the parallel tube model can be used to describe and predict hepatic galactose kinetics in anesthetized cats, although other models may fit the data equally well.     

Diuretic activity of the infusion of flowers from Lavandula officinalis

The diuretic activity of an infusion of Lavandula officinalis was studied in the Wistar rat. Thus, the kinetics of hydroelectrolytic elimination in response to the oral administration of an infusion of pharmaceutical lavender flowers were measured in the rats. Experiments were completed under similar conditions using a synthetic pharmacological diuretic, Diamox. The aqueous extract of this aromatic plant accelerated the elimination of the water overload. At the peak of the diuretic response, urinary osmolarity was significantly less than that of controls (111+/-14 vs. 195+/-11 mosmol x kg(-1)). Sodium excretion was moderate following administration of the infusion when compared to the synthetic diuretic. The stability of the aldosterone concentrations in the plasma and the absence of correlation with plasma sodium concentrations, coupled with the observed clearance of the free water (0.055+/-0.007 vs. 0.045+/-0.012 mL x min(-1)) show that the increase in diuresis and the moderate increase in sodium excretion are of tubular origin. The result of the phytochemical analysis of hexane extracts in the infusion and in urine indicated that four or five chemical factors may be involved in the diuretic effect of lavender.     

Effect of adrenaline on insulin secretion in rats treated chronically with adrenaline.

To determine whether rats could adapt to a chronic exogenous supply of adrenaline by a decrease in the well-known inhibitory effect of adrenaline on insulin secretion, plasma glucose and insulin levels were measured in unanesthetized control and adrenaline-treated rats (300 mug/kg twice a day for 28 days) during an adrenaline infusion (0.75 mug kg-1 min-1), after an acute glucose load (0.5 g/kg), and during the simultaneous administration of both agents. Chronic treatment with adrenaline did not modify the initial glucose levels but it greatly diminished the basal insulin values (21.57+/-2.48 vs. 44.69+/-3.3muU/ml, p less than 0.01). In the control rats, despite the elevated glucose concentrations, a significant drop in plasma insulin levels was observed within the first 15 min of adrenaline infusion, followed by a period of recovery. In the adrenaline-treated group, in which plasma glucose levels were lower than in control animals, plasma insulin levels did not drop as in control rats, but a significant increase was found after 30 min of infusion. During the intravenous glucose tolerance test, the plasma glucose and insulin responses showed similar patterns; however, during the concomitant adrenaline infusion, the treated rats showed a better glucose tolerance than their controls. These results indicate that rats chronically treated with adrenaline adapt to the diabetogenic effect of an infusion of adrenaline by have a lower inhibition of insulin release, although the lower basal insulin levels may indicate a greater sensitivity to endogenous insulin.     

The Lumped Constant in the Deoxyglucose Procedure Declines with Age in Fischer-344 Rats

Concentrations of [14C]2-deoxy-D-glucose ([14C]DG) and of glucose were measured in plasma of arterial and sagittal sinus venous blood from awake Fischer-344 rats at 3, 12, and 24 months of age, during continuous intravenous infusion of [14C]DG and after a steady-state arterial plasma concentration of [14C]DG was reached. Brain extraction, i.e., the difference between arterial and venous plasma concentrations divided by the arterial plasma concentration, was calculated for both [14C]DG and glucose. Because exchange of both substances between rat plasma and erythrocytes is slow, the ratio of the brain extraction of [14C]DG to that of glucose is identical to the lumped constant in the deoxyglucose procedure of Sokoloff et al. [J. Neurochem. 28, 897-916. (1977)]. This ratio equaled 0.502 +/- 0.015 (SEM) at 3 months, 0.456 +/- 0.007 at 12 months, and 0.418 +/- 0.006 at 24 months of age (n = 15); the means differed significantly from each other (p less than 0.05). The results indicate that the lumped constant declines between 3 and 24 months of age in awake rats, and suggest that many reported age reductions in regional cerebral glucose utilization, of 15-25%, are artifactual.     

Cardiovascular changes in unanesthetized and ketamine-anesthetized Sprague-Dawley rats exposed to 2.8-GHz radiofrequency radiation.

Sprague-Dawley rats were exposed to 2.8-GHz radiofrequency radiation, first while unanesthetized and then while anesthetized with ketamine (150 mg/kg.I.M.). Irradiation at a power density of 60 mW/cm2 (whole-body average specific absorption rate of approximately 14 W/kg) was conducted for sufficient duration to increase colonic temperature from 38.5 to 39.5 degrees C. The time required for the temperature increase was significantly longer in the anesthetized state. During irradiation, heart rate increased significantly both with and without anesthesia, while mean arterial blood pressure increased only when the rats were unanesthetized. The heart rate increase in the anesthetized state contrasts with a lack of change in a previous study of Fischer rats. This difference between anesthetized Sprague-Dawley and Fischer rats should be considered when comparing cardiovascular data obtained from these two strains of rats.     

Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation

The kinetics of acetoacetate (A) and beta-hydroxybutyrate (B) have been studied following the injection as a pulse or continued infusion of [3-14C]acetoacetate (A*) or [14C]beta-hydroxybutyrate (B*) into six newly diagnosed, untreated, ketotic diabetic patients, ten obese subjects in the postabsorptive state, and the ten obese subjects after 1-2 weeks starvation (50 cal per day). Employing a compartmental model of acetoacetate and beta-hydroxybutyrate kinetics developed using CONSAM for normal subjects, the rate coefficients (Lij), rates of release of newly synthesized acetoacetate and beta-hydroxybutyrate into the blood (UA, UB), and fractional removal of each compound (FCRA and FCRB) were calculated. Ketone body release into blood (UA + UB) in diabetic subjects was threefold higher than normal (mean +/- SD, 208 +/- 118 versus 81 +/- 66 mumol min-1 m-2) and in obese subjects the rate increased on starvation from 171 +/- 70 to 569 +/- 286 mumol min-1 m-2. In each case most of the increase was in beta-hydroxybutyrate. The major change in diabetes and on starvation of the obese subjects was in the rate coefficient for removal of ketone bodies. Normally 0.168 +/- 0.109 min-1, it was 0.055 +/- 0.040 min-1 in the diabetic patients and fell from 0.066 +/- 0.040 to 0.027 +/- 0.019 min-1 in the obese subjects on starvation. In normal subjects, FCRA was similar to FCRB (0.226 +/- 0.142 versus 0.188 +/- 0.124 min-1). However, in diabetics, FCRA was 0.074 +/- 0.044 and FCRB was 0.050 +/- 0.034 min-1 and both were lower than normal. On starvation of obese subjects, FCRA fell from 0.199 +/- 0.047 to 0.089 +/- 0.035 min-1, whereas FCRB fell from 0.141 +/- 0.040 to 0.033 +/- 0.012 min-1. Therefore, the removal of beta-hydroxybutyrate was impaired more than that of acetoacetate in all patients. Our results confirm previous observations that ketosis is associated with high rates of ketogenesis and a decrease in fractional clearance. In addition, we found that in diabetes, obesity, and in obese subjects following starvation, most of the increased synthesis was in beta-hydroxybutyrate and that the clearance of beta-hydroxybutyrate decreased more than that of acetoacetate.     

Effects of atrial appendectomy on circulating atrial natriuretic factor during volume expansion in the rat

This study examined the changes in the circulating level of endogenous atrial natriuretic factor during diuresis and natriuresis produced by acute volume expansion in anesthetized rats with either bilateral atrial appendectomy (n = 9) or sham operation (n = 9). Following control measurements in the sham-operated rats, 1% body weight volume expansion with isotonic saline produced an increment in urinary sodium excretion of over 4 mueq/min (P less than 0.05) while urine volume increased by more than 20 microliter/min (P less than 0.05). These responses were associated with a significant increase in immunoreactive plasma atrial natriuretic factor from a baseline value of 82 +/- 10 pg/ml to a level of 120 +/- 14 pg/ml (P less than 0.05). In contrast, in the group of rats with bilateral atrial appendectomy an identical degree of volume expansion increased urinary sodium excretion and urine volume by only 0.61 mueq/min (P less than 0.05) and 3.07 microliter/min (P less than 0.05), respectively. In this group, immunoreactive plasma atrial natriuretic factor remained statistically unchanged from a control value of 70 +/- 12 pg/ml to a level of 82 +/- 16 pg/ml (P greater than 0.05). Comparison of the two groups indicates that the natriuresis, diuresis, and plasma atrial natriuretic factor levels during volume expansion were significantly reduced in the rats with bilateral atrial appendectomy. No differences in mean arterial pressure and heart rate were observed between the two groups. These data demonstrate that removal of both atrial appendages in the rat attenuated the release of atrial natriuretic factor during volume expansion; and this effect, in turn, was associated with a reduction in the natriuretic and diuretic responses.