Influence of angiotensin on the early progression of heart failure.

The purpose of this study was to elucidate the role of circulating ANG II in mediating changes in systemic and renal hemodynamics, salt and water balance, and neurohormonal activation during the early progression of heart failure. This objective was achieved by subjecting six dogs to 14 days of rapid ventricular pacing (240 beats/min) while fixing plasma ANG II concentration (by infusion of captopril + ANG II) either at approximately normal (days 1-8, 13-14) or at high physiological (days 9-12) levels. Salt and water retention occurred during the initial days of pacing before sodium and fluid balance was achieved by day 8. At this time, cardiac output and mean arterial pressure were reduced to approximately 55 and 75% of control, respectively; compared with cardiac output, reductions in renal blood flow were less pronounced. Although plasma ANG II concentration was maintained at approximately normal levels, there were sustained elevations in total peripheral resistance (to approximately 135% of control), filtration fraction (to approximately 118% of control), and plasma norepinephrine concentration (to 2-3 times control). During the subsequent high rate of ANG II infusion on days 9-12, there were no additional sustained long-term changes in either systemic or renal hemodynamics other than a further rise in right atrial pressure. However, high plasma levels of ANG II induced sustained antinatriuretic, sympathoexcitatory, and dipsogenic responses. Because these same long-term changes occur in association with activation of the renin-angiotensin system during the natural evolution of this disease, these results suggest that increased plasma levels of ANG II play a critical role in the spontaneous transition from compensated to decompensated heart failure.

Diastolic compliance is reduced in obese rabbits.

Obesity often leads to symptoms of cardiopulmonary congestion associated with normal systolic but abnormal diastolic function. This study analyzed alterations in passive diastolic compliance in obesity using the rabbit model. New Zealand White rabbits were fed a normal (n=8) or 10% added fat diet (n=8). After 12 weeks, rabbits fed the high fat diet developed obesity (5.34+/-0.11 versus 3.68+/-0. 04 kg, P

Renal size and composition in hypertensive, obese rabbits.

OBJECTIVE: To determine whether the renal growth associated with obesity is due to hypertrophy or hyperplasia. DESIGN: New Zealand white female rabbits were fed either standard rabbit chow (n=17) or chow fortified with 10% corn oil plus 5% lard (n=18) for 12-16 weeks. MEASUREMENTS: All rabbits were weighed, and intra-arterial blood pressures were successfully measured at the end of the study in 16 lean and 18 obese rabbits; percent water of entire kidneys (8 lean, 8 obese rabbits) and of defined regions of kidneys (8 lean, 10 obese rabbits) were obtained gravimetrically. Renal hemoglobin, protein and DNA was measured chemically (8 lean, 8 obese rabbits). RESULTS: Kidneys grew in size as the rabbits gained fat. In a series of 8 lean and 8 age-matched obese rabbits, weighing 3.7+/-0.1 kg and 5.4+/-0.4kg (P<0.05), the kidneys were 20% larger in the obese rabbits: 15.0+/-0.9 g vs 18.0+/-2.5 g (P<0.05). Kidney protein was also 20% greater in the obese rabbit: 1.38+/-0.06 g/kidney vs 1.66+/-0.06 g/kidney (P<0.05). While total renal DNA was 16% greater in the obese: 18.2+/-0.5 microg/kidney vs 21.1+/-0.61 g/kidney (P<0.05), no significant difference existed when the DNA was expressed as microg/mg protein. Fractional water content of the intact kidney declined with obesity: 78.7+/-1.1% vs 76.0+/-1.2% (P<0.05). Conversely, the hemoglobin content of the kidney at autopsy, an estimate of the unstressed vascular volume, increased with obesity: 55+/-19 mg/kidney vs 82+/-25 mg/kidney (P<0.05). By contrast, water content of renal parenchyma was constant: 80.8+/-1.0% vs 80.9+/-1.2% (cortex); 84.0+/-0.8% vs 83.6%+/-2.0% (outer medulla); and 85.7+/-0.8% vs 86.0+/-2.1% (inner medulla). CONCLUSION: The renal growth associated with obesity was predominantly hyperplastic and was associated with a partial exclusion of fluid from the renal sinus.

Renal denervation supersensitivity revisited.

To determine whether the chronically denervated kidney is supersensitive to either physiological or pathophysiological plasma levels of norepinephrine (NE), studies were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated and innervated kidneys. Plasma NE concentration was increased by chronic infusion of NE (4-5 days) at rates of 25, 100, and 200 ng . kg-1 . min-1. Twenty-four-hour control values for mean arterial pressure (MAP), plasma NE concentration, and ratios for urinary sodium and potassium excretion from denervated and innervated kidneys (Den/Inn) were 94 +/- 4 mmHg, 145 +/- 24 pg/ml, 1.05 +/- 0.05, and 0.97 +/- 0.07, respectively. With infusions of NE producing plasma levels of NE of up to approximately 3,000 pg/ml or plasma concentrations of NE at least threefold greater than present under most pathophysiological conditions and during acute activation of the sympathetic nervous system, there were no significant long-term changes in MAP or relative excretion rates of sodium and potassium from denervated and innervated kidneys. In marked contrast, pharmacological plasma levels of NE ( approximately 7,000 pg/ml) produced chronic increases in MAP (to 116 +/- 2% of control) and sustained reductions in Den/Inn for urinary sodium and potassium excretion to 57 +/- 4 and 68 +/- 5% of control, respectively, indicating a lower excretion rate of these electrolytes from denervated vs. innervated kidneys. We conclude that the chronically denervated kidney does not exhibit an exaggerated antinatriuretic response to either physiological or pathophysiological levels of circulating NE. It is therefore unlikely that renal denervation supersensitivity is a confounding issue in studies employing chronic renal denervation to elucidate the role of the renal nerves in the regulation of sodium excretion.

Reduced cardiac contractile responsiveness to isoproterenol in obese rabbits.

Although obesity is characterized by increased sympathetic nervous system activity, there is often a paradoxical reduction in cardiovascular end-organ response to sympathetic stimulation. Mechanisms involved in reduced sympathetic responsiveness in obesity have not been well characterized. Therefore, we determined cardiac contractile responsiveness to beta-stimulation in the obese rabbit model using both isolated heart (IH) and isolated papillary muscle (IPM) preparations. Female New Zealand White rabbits were fed control (IH: n=9; IPM: n=6) or 10% fat diets (IH: n=9; IPM: n=7) for 12 weeks. Contractile responsiveness in the IH was determined using a modified Langendorff preparation to evaluate the dose-response relationship between isoproterenol and 1) peak developed pressure/g of left ventricular wet weight and 2) maximal rate of pressure development (+dP/dt/P). Contractile responsiveness in the IPM was determined using right ventricular papillary muscles to evaluate the dose-response relationship between isoproterenol and (1) peak developed tension (T)/mm2 cross-sectional area (CSA) and (2) maximal rate of tension development (dT/dt/CSA). In the IH, baseline and maximum developed pressure/g were reduced in obese rabbits by 37% and 31%, respectively (P< or =.05). In the IPM, baseline and maximum T/CSA responses were reduced in obese rabbits by 59% and 33%, respectively (P< or =.05). Potency of isoproterenol as reflected by the EC50 did not differ between lean and obese animals in either preparation. These results demonstrate that left ventricular contractility in obesity is reduced at baseline and in response to stimulation with isoproterenol and suggest that decreased responsiveness to beta-stimulation may be a factor in the obesity-related systolic dysfunction.

Cholesterol feeding does not alter renal hemodynamic response to acetylcholine and angiotensin II in rabbits.

Aortic ring studies have demonstrated a decrease in endothelium-dependent relaxation or an enhanced response to vasoconstrictors in rabbits fed a high-cholesterol diet. Whether such abnormalities exist in the renal circulation is unclear. The purpose of this study was to determine functional renal responses to acetylcholine (ACh) or angiotensin II (ANG II) infusion in anesthetized rabbits after 8-10 wk of either a control diet (ACh, n = 6; ANG II, n = 6) or a 1% cholesterol diet (ACh, n = 7; ANG II, n = 7). Mean arterial pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) were measured. Renal vascular resistance (RVR) was calculated as MAP/RBF. For ANG II experiments, captopril (15 microg x kg(-1) x min(-1)) was infused to suppress endogenous ANG II production. After two control clearance periods, either ACh (1 microg x kg(-1) x min(-1)) or ANG II (0.5 ng x kg(-1) x min(-1)) was infused into the renal artery; RBF was allowed to stabilize before experimental clearances. RBF increased with ACh (control: 25 +/- 2 to 39 +/- 2 ml/min; cholesterol: 26 +/- 2 to 40 +/- 3 ml/min) and decreased with ANG II infusions (control: 40 +/- 4 to 25 +/- 3 ml/min; cholesterol: 36 +/- 3 to 24 +/- 2 ml/min). Nitrate/nitrite excretion also increased with ACh infusion (control: 2.3 +/- 1.0 to 5.2 +/- 1.8 nmol x kg(-1) x min(-1); cholesterol: 2.3 +/- 0.3 to 6.0 +/- 1.3 nmol x kg(-1) x min(-1)). However, there were no significant differences between control and cholesterol groups in either response. GFR was unaltered during ACh and ANG II infusions. MAP, RVR, and urinary sodium and potassium excretion did not differ between groups in response to either drug. These results suggest that, despite significant hypercholesterolemia and large-vessel atherosclerosis, both nitric oxideinduced vasodilation and endothelium-dependent modulation of ANG II vasoconstriction in the renal circulation are unaffected by cholesterol feeding.

Obese hypertensive rabbits develop concentric and eccentric hypertrophy and diastolic filling abnormalities.

We have developed a new small animal model of obesity in which rabbits fed a high diet develop abnormalities in common with obese humans, including left ventricular (LV) hypertrophy. Using M-mode and two dimensional Doppler echocardiography we examined the characteristics of LV hypertrophy and diastolic function in obese and lean rabbits. Obese rabbits had greater interventricular septum and LV posterior wall thickness and greater LV internal end-diastolic and end-systolic diameters. Functionally, obese rabbits had higher A/E ratios. Similarly to obese humans, obese hypertensive rabbits developed combined concentric and eccentric LV hypertrophy and diastolic filling abnormalities. Therefore, this model may be valuable in the study of the development and pathology of obesity-related LV hypertrophy.

Temporal influence of the renal nerves on renal excretory function during chronic inhibition of nitric oxide synthesis.

To determine whether the sympathetic nervous system contributes to the hypertension induced by long-term suppression of nitric oxide synthesis, we determined the neurally induced changes in renal excretory function during chronic administration of NG-nitro-L-arginine methyl ester (L-NAME). Studies were carried out in six conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into two hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. Animals were studied during acute (100 minutes) and chronic (5 days) intravenous infusion of L-NAME at 37.1 nmol/kg per minute (10 micrograms/kg per minute). During the first 100 minutes of L-NAME, there were no significant changes in mean arterial pressure (control: 96 +/- 3 mm Hg), but heart rate fell from 66 +/- 6 to 55 +/- 7 beats per minute. Changes in glomerular filtration rate were not significant, but renal plasma flow and urinary sodium excretion decreased to approximately 75% and 50% of control values, respectively; however, these changes were comparable in both kidneys. In association with these responses, plasma concentrations of norepinephrine (control: 887 +/- 130 pmol/L or 150 +/- 22 pg/mL) and epinephrine (control: 691 +/- 192 pmol/L or 108 +/- 30 pg/mL) tended to decrease. In contrast to the acute responses, mean arterial pressure increased from 92 +/- 3 to 106 +/- 3 mm Hg and heart rate decreased from 72 +/- 4 to 57 +/- 5 beats per minute by day 5 of L-NAME infusion, while renal plasma flow and glomerular filtration rate were not significantly different from control values. Most importantly, there were no significant differences in urinary sodium excretion between innervated (control: 31 +/- 2 mmol/d) and denervated (control 33 +/- 2 mmol/d) kidneys during chronic L-NAME infusion or during the recovery period. These results indicate that the renal sympathetic nerves do not play an important role in promoting sodium retention during either acute or chronic inhibition of nitric oxide synthesis in conscious dogs. Thus, increased renal sympathetic nerve activity does not contribute significantly to L-NAME-induced hypertension.

Atrial natriuretic peptide and sodium homeostasis in compensated heart failure.

The purpose of this study was to determine whether high plasma levels of atrial natriuretic peptide (ANP) in compensated heart failure are important in the maintenance of sodium balance. This was achieved by subjecting eight dogs to bilateral atrial appendectomy (APX) to blunt the ANP response to pacing-induced heart failure. Five intact dogs served as controls. In controls, 14 days of left ventricular pacing at 240 beats/min produced a sustained fall in cardiac output and mean arterial pressure of approximately 40 and 20%, respectively; compared with cardiac output, reductions in renal blood flow (up to approximately 25%) were less pronounced and even smaller decrements in GFR occurred (up to 9%). Despite these changes and a threefold elevation in plasma norepinephrine concentration, plasma renin activity (PRA) did not increase and sodium balance was achieved during the second week of pacing in association with a six- to eightfold rise in plasma levels of ANP. Similar responses occurred in four dogs in which APX was relatively ineffective in blunting the ANP response to pacing. In marked contrast, there were substantial increments in PRA and in plasma norepinephrine concentration, and marked sodium and water retention during the last week of pacing in four dogs with APX and severely deficient ANP. These results indicate that ANP plays a critical role in promoting sodium excretion in the early stages of cardiac dysfunction.

Hypertension, cardiac hypertrophy, and neurohumoral activity in a new animal model of obesity.

Although obesity is a major risk factor for morbidity and mortality, the mechanisms mediating cardiovascular abnormalities in response to weight gain are unclear. One reason for the paucity of information in this area is the lack of appropriate animal models for the study of human obesity. Therefore, the goal of the present study was to develop a small animal model of dietary-induced obesity that mimics many of the characteristics of human obesity. We studied female New Zealand White rabbits fed either a normal (n = 17) or high-fat diet (n = 15) and examined the cardiovascular consequences of obesity, including changes in blood pressure, humoral activation, and end-organ effects such as cardiac hypertrophy. After 12 wk, rabbits on the high-fat diet were 46% heavier than their lean counterparts (5.49 +/- 0.09 vs. 3.77 +/- 0.06 kg, respectively; P = 0.0001). Obese rabbits had higher resting heart rates than lean rabbits (220 +/- 7 vs. 177 +/- 6 beats/min; P = 0.0001) and developed hypertension (96 +/- 2 vs. 85 +/- 1 mmHg; P = 0.0001), hyperinsulinemia (32.5 +/- 3.4 vs. 15.5 +/- 1.0 microU/ml; P = 0.0001), hyperglycemia (162.4 +/- 2.9 vs. 141.9 +/- 2.7 mg/dl; P = 0.0001), and elevated triglycerides (102.3 +/- 9.1 vs. 48.5 +/- 4.0 mg/dl; P = 0.0001). Obese rabbits also developed cardiac hypertrophy, as evidenced by left ventricular (LV) dry weights that were 52% greater in obese than in lean rabbits (P = 0.0003). In addition, LV total protein was increased in proportion to the increase in LV weight. The results of this study suggest that rabbits fed a high-fat diet for a period of 12 wk develop many of the characteristics of human obesity. The obese rabbit should provide a small and relatively inexpensive animal model to investigate mechanisms of obesity-related cardiovascular abnormalities.

Renal sinus lipomatosis and body composition in hypertensive, obese rabbits.

OBJECTIVE: To test whether renal lipomatosis, an accretion of fat in the renal sinus associated with chronic renal infections, abscesses and calculi, can also be caused by rapid weight gain. DESIGN: New Zealand white rabbits were fed either standard rabbit chow (n = 24) or chow fortified with 10% corn oil plus 5% lard (n = 25) for 8-12 weeks. MEASUREMENTS: The rabbits and constituent tissues were weighed initially, after drying and after organic extractions. Renal tissue cholesterol and triglycerides were measured chemically. RESULTS: Rabbits made obese by increased fat intake were 1.8 kg heavier than controls (5.5 +/- 0.3 kg vs 3.7 +/- 0.2; n = 24,25), had 1.54 kg more body fat (1.90 +/- 0.25 vs 0.36 +/- 0.11 kg/rabbit; n = 10,9), and had a mean arterial blood pressure that was 9.2 mm Hg greater than controls (95.1 +/- 8.5 vs 85.9 +/- 5.6 mm Hg; n = 23,24). Individual organs grew in mass (lung, 15%; gastrocnemius, 17%; liver, 27%; kidney, 30%) and their parenchyma gained extractable lipids (lung, 5.5 mg/g tissue; gastrocnemius, 9.6 mg/g tissue; liver, 17.9 mg/g tissue). Total renal triglycerides were increased 2.1 fold, from 103 +/- 36 to 219 +/- 59 mg/kidney (n = 8,8), compared to the 5.3 fold increase in whole body fat. Renal cholesterol was increased 1.7 fold, from 7.5 +/- 1.1 to 12.7 +/- 2.9 mg/kidney, (n = 8,8). Within experimental error, the sum of the total renal triglycerides plus the total renal cholesterol equaled the net fat extracted from the renal sinus alone: 95 +/- 29 mg/kidney in lean rabbits and 253 +/- 71 mg/kidney in obese (n = 17,17). CONCLUSION: Obesity alone can cause renal lipomatosis. This increased volume of anatomically localized fat may be sufficient to externally compress renal veins and lymphatics, thus altering renal hemodynamic behavior.

Hemodynamic alterations in hypertensive obese rabbits.

There is little information on changes in overall and regional hemodynamics in obesity-associated hypertension. Therefore, the purpose of this study was to determine alterations in overall and regional blood flows and resistances in adipose and nonadipose tissues in a new model of obesity-associated hypertension in rabbits. Sixteen female New Zealand White rabbits were fed either a maintenance or high-fat diet; after 8 to 12 weeks cardiac output and regional blood flows were measured with the use of radioactive microspheres. Obese rabbits (5.22 +/- 0.14 versus 3.66 +/- 0.04 kg) had higher blood pressure (113 +/- 3 versus 95 +/- 1 mm Hg), cardiac output (812 +/- 59 versus 593 +/- 47 mL/min), and heart rate (269 +/- 12 versus 219 +/- 9 beats per minute) and lower overall peripheral resistance (0.14 +/- 0.01 versus 0.17 +/- 0.01 mm Hg/[mL/min]) than lean rabbits. Compared with lean controls, obese rabbits had higher weights of the ventricles, kidneys, liver, ovaries, adrenals, diaphragm, and spleen. Absolute blood flows were greater in the ventricles, kidneys, lungs, and ovaries, but differences were minimized when flows were normalized for organ weight. Adipose tissue flow per gram weight was significantly lower and resistance higher in obese rabbits. However, calculated total adipose tissue flow was higher in obese rabbits (86 versus 45 mL/min). Absolute resistances were lower in the left ventricle, kidneys, and large intestine, but when resistances were indexed for organ weight, kidney resistance tended to be higher in obese rabbits. These results indicate that even short periods of obesity-associated hypertension result in marked overall and regional hemodynamic changes.

Influence of the renal nerves on sodium excretion during progressive reductions in cardiac output.

The purpose of this study was to elucidate the role of the renal nerves in promoting sodium retention during chronic reductions in cardiac output. In five dogs, the left kidney was denervated and the urinary bladder was surgically divided to allow separate 24-h urine collection from the innervated and denervated kidneys. Additionally, progressive reductions in cardiac output were achieved by employing an externally adjustable occluder around the pulmonary artery and by servo-controlling right atrial pressure (control = 0.9 +/- 0.2 mmHg) at 4.7 +/- 0.1, 7.5 +/- 0.1, and 9.8 +/- 0.2 mmHg for 3 days at each level. At the highest level of right atrial pressure, the 24-h values for mean arterial pressure (control = 97 +/- 3 mmHg) and cardiac output (control = 2,434 +/- 177 ml/min) were reduced approximately 25 and 55%, respectively; glomerular filtration rate fell by approximately 35% and renal plasma flow by approximately 65%. However, despite the sodium retention induced by these hemodynamic changes, there were no significant differences in renal hemodynamics or sodium excretion between the two kidneys during pulmonary artery constriction. In contrast, after release of the pulmonary artery occluder on day 9, sodium excretion increased more (approximately 28% during the initial 24 h) in innervated than in denervated kidneys. These results suggest that the renal nerves are relatively unimportant in promoting sodium retention in this model of low cardiac output but contribute significantly to the short-term elimination of sodium after partial restoration of cardiac output and mean arterial pressure.

Reduced parasympathetic control of heart rate in obese dogs.

We investigated why resting heart rate is elevated in dogs fed a high saturated fat diet for 12.7 +/- 1.8 wk. Obese dogs exhibited elevated body weight (59%), blood pressure (14%), and heart rate (25%). Differences in resting heart rate (control, 58 +/- 5 beats/min; obese, 83 +/- 7 beats/min) were abolished after hexamethonium, indicating an autonomic mechanism. Hexamethonium also reduced blood pressure in obese (20 +/- 4 mmHg) but not control (9 +/- 6 mmHg) animals. Propranolol did not affect heart rate in either group, excluding a beta-adrenergic mechanism. Subsequent administration of atropine increased heart rate more in control than in obese dogs (110 +/- 9 vs. 57 +/- 11 beats/min). The sensitivity of the cardiac limb of the baroreflex (Oxford method) was reduced by 46% in the obese group, confirming impairment of the parasympathetic control of heart rate. The standard deviation of blood pressure measurements was normal when expressed as a percentage of the mean arterial blood pressure (control, 11.2 +/- 0.4%; obese, 11.2 +/- 0.5%). Our results indicate that the development of obesity in dogs fed a high saturated fat diet is accompanied by an attenuated resting and reflex parasympathetic control of heart rate.

Advantages of continuous measurement of cardiac output 24 h a day.

To test the hypothesis that continuous measurement of cardiac output 24 h a day would provide a better day-by-day reproducibility of the daily average cardiac output than acute measurements, we developed a computer-assisted method to monitor cardiac output continuously using an electromagnetic flow transducer. Because the diastolic aortic flow, which is used as a zero-flow reference, can drift significantly with electromagnetic flow probes, automatic tracking of the diastolic flow baseline was considered essential for long-term measurements. To accomplish this, the analog pulsatile flow signal was digitally converted and processed by an IBM PC to correct for signal drift on a beat-per-beat basis. Using this computerized system in 19 chronically instrumented dogs, we compared the values of cardiac output during 5 consecutive control days, measured either for 20 h each day (allowed 4 h for special care) or for 30 min in the morning when the trained dogs were required to lie quietly in their cages. The results show that the coefficient of variation of the five daily averages in cardiac output for each individual dog was three times smaller when cardiac output was measured 20 h each day (2.9 +/- 0.3 vs. 9.7 +/- 1.0%). Whole-day coefficients of variation were also smaller for mean arterial pressure, heart rate, stroke volume, and total peripheral resistance. Because of this greater day-by-day reproducibility, continuous monitoring of cardiac output is likely to be more sensitive to small changes in cardiac output induced by experimental protocols.

Hemodynamic and renal responses to chronic hyperinsulinemia in obese, insulin-resistant dogs.

We previously reported that chronic hyperinsulinemia does not cause hypertension in normal insulin-sensitive dogs. However, resistance to the metabolic and vasodilator effects of insulin may be a prerequisite for hyperinsulinemia to elevate blood pressure. The present study tested this hypothesis by comparing the control of systemic hemodynamics and renal function during chronic hyperinsulinemia in instrumented normal conscious dogs (n = 6) and in dogs made obese and insulin resistant by feeding them a high-fat diet for 6 weeks (n = 6). After 6 weeks of the high-fat diet, body weight increased from 24.0 +/- 1.2 to 40.9 +/- 1.2 kg, arterial pressure rose from 83 +/- 5 to 106 +/- 4 mm Hg, and cardiac output rose from 2.98 +/- 0.29 to 5.27 +/- 0.54 L/min. Insulin sensitivity, assessed by fasting hyperinsulinemia and by the hyperinsulinemic euglycemic clamp technique, was markedly reduced in obese dogs. Insulin infusion (1.0 mU/kg per minute for 7 days) in obese dogs elevated plasma insulin from 42 +/- 12 microU/mL to 95 to 219 microU/mL but failed to increase arterial pressure, which averaged 106 +/- 4 mm Hg during control and 102 +/- 4 mm Hg during 7 days of insulin infusion. Hyperinsulinemia for 7 days in obese dogs elevated heart rate from 116 +/- 8 to 135 +/- 7 beats per minute but caused no significant changes in cardiac output, in contrast to normal dogs (n = 6), in which marked increases in cardiac output (31 +/- 5% after 7 days) and decreases in total peripheral resistance occurred during chronic insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin.

Although recent studies have reported endogenous plasma endothelin levels to be elevated two- to fivefold in chronic pathophysiological states, whether such an increase in circulating endothelin levels alone can lead to significant long-term alterations in cardiovascular and renal function is not known. The purpose of this study was to examine the long-term systemic hemodynamic and renal effects of a pathophysiological increase in plasma endothelin concentration in chronically instrumented, conscious dogs (n = 7). Infusion of endothelin-1 (2.5 ng.kg-1.min-1) for 8 days increased plasma concentration of immunoreactive endothelin approximately two- to threefold from 6.7 +/- 0.4 to 16.0 +/- 2.2 pg/ml. Mean arterial pressure increased 21% from a control value of 86.7 +/- 2.1 to 105.0 +/- 2.5 mmHg during the endothelin infusion period. Cardiac output averaged 2,200 +/- 205 ml/min during control and fell by 33% on day 4 of endothelin infusion (1,484 +/- 146 ml/min) and was still 14% below control after day 8 of endothelin infusion (1,885 +/- 154 ml/min). Endothelin increased total peripheral resistance from 42.0 +/- 3.1 to 80.3 +/- 9.1 mmHg.l-1.min. Increasing plasma endothelin two- to threefold was associated with an increase in renal vascular resistance and decreases in glomerular filtration rate and renal plasma flow. Endothelin-1 had no long-term effect on plasma renin activity or aldosterone concentration. These data indicate the importance of pathophysiological levels of endothelin in controlling renal and cardiovascular function in chronic conditions. Furthermore, the results indicate that endothelin may play a role as a mediator of chronic hypertension in pathophysiological states associated with endothelial dysfunction.

Chronic endothelin-induced pressor and renal actions in conscious dogs do not require altered ANG II formation.

Plasma endothelin levels are elevated approximately two- to threefold in a number of chronic pathophysiological conditions associated with hypertension. Results from recent studies indicate an important interaction between endothelin and the renin-angiotensin system (RAS). The role of the RAS in mediating the increases in arterial pressure produced by long-term pathophysiological elevations in circulating levels of endothelin is unknown. Therefore, the purpose of this study was to chronically increase circulating levels of endothelin within the pathophysiological range and determine the long-term cardiovascular and renal actions of endothelin in control dogs (n = 6) and in dogs pretreated with a converting-enzyme inhibitor (CEI) (n = 6) or CEI + angiotensin II (ANG II) replacement (n = 6). Infusion of endothelin-1 for 8 days at a rate of 2.5 ng.kg-1.min-1 increased plasma endothelin from 7.1 +/- 0.9 to 19.8 +/- 3.3 pg/ml. In control dogs, endothelin increased mean arterial pressure (MAP) by 19% (90 +/- 2 to 107 +/- 3 mmHg) while decreasing renal blood flow (RBF) by 30% and glomerular filtration rate (GFR) by 15-20%. Long-term elevation of circulating endothelin produced similar elevations in MAP in dogs pretreated with CEI (+16%) or CEI + ANG II (+17%). Similar decreases in RBF and GFR also occurred in response to endothelin in all three groups. These results indicate that although long-term increases in circulating endothelin within the pathophysiological range produce significant increases in arterial pressure, this effect does not appear to be mediated by the RAS.

Role of atrial natriuretic peptide in long-term volume homeostasis.

1. Long-term volume homeostasis is linked very closely to long-term arterial pressure control through the renal-body fluid feedback mechanism. A key feature of this control system is the ability of the kidneys to respond to changes in arterial pressure by altering renal excretion of salt and water, often referred to as renal-pressure natriuresis. 2. Quantitative studies indicate that ANP secretion is relatively sensitive to changes in atrial pressure and that the rate of hormonal secretion does not adapt to continuous long-term stimulation. 3. Under normal conditions, the renal-body fluid feedback mechanism for arterial pressure control is very efficient in minimizing changes in body fluid volumes during alterations in sodium intake. Therefore, only small changes in atrial pressure and ANP secretion occur. Alterations in plasma ANP concentration within physiological levels have little effect on renal-pressure natriuresis and, therefore, have little impact on volume homeostasis. 4. When the renal-body fluid feedback mechanism for arterial pressure control is impaired and body fluid volumes are elevated, such as in heart failure, large increases in atrial pressure and ANP secretion occur. The resultant pathophysiological plasma levels of ANP exert sustained natriuretic effects and chronically shift renal-pressure natriuresis to lower arterial pressures. In the absence of this chronic effect of ANP on renal-pressure natriuresis, reduced arterial pressure in compensated heart failure would result in protracted retention of salt and water and additional increments in body fluid volumes.

Blunted natriuretic response to a high-sodium meal in obese dogs. Role of renal nerves.

Although the relation between body weight and arterial pressure is well established, the mechanisms involved in the pathogenesis of obesity-related hypertension are unclear. However, recent studies suggest that abnormalities in renal function may be involved. The purpose of this study was to test the hypothesis that obese animals have a reduced ability to excrete a sodium load as a result of abnormal renal nerve function. To quantify the role of renal nerves, we examined changes in renal hemodynamics and sodium excretion in response to a high-sodium meal (200 mmol Na) in separate innervated and denervated kidneys simultaneously within the same conscious dog. Two surgically designed hemibladders with indwelling catheters were used to collect urine from innervated and denervated kidneys of the same dog. Body weight averaged 19.9 +/- 1.0 kg in the control lean dogs and 25.1 +/- 1.1 kg in the obese dogs. Arterial pressure averaged 101 +/- 4 mm Hg in the obese dogs and 90 +/- 4 mm Hg in the lean dogs. In response to the high-sodium meal in lean dogs, urinary sodium excretion increased from 20.8 +/- 4.2 to 189.7 +/- 21.2 mumol/min in the innervated kidneys and from 25.3 +/- 5.9 to 194.8 +/- 26.9 mumol/min in the denervated kidneys. In contrast, urinary sodium excretion in obese dogs increased from 9.6 +/- 1.4 to 129.9 +/- 34.3 mumol/min in the innervated kidneys and from 18.4 +/- 3.7 to 125.2 +/- 30.5 mumol/min in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)