In all forms of chronic hypertension, the renal-pressure natriuresis mechanism is abnormal because sodium excretion is the same as in normotension despite the increased blood pressure. However, the importance of this resetting of pressure natriuresis as a cause of hypertension is controversial. Theoretically, a resetting of pressure natriuresis could necessitate increased blood pressure to maintain sodium balance or it could occur secondarily to hypertension. Recent studies indicate that, in several models of experimental hypertension (including angiotensin II, aldosterone, adrenocorticotrophic hormone, and norepinephrine hypertension), a primary shift of renal-pressure natriuresis necessitates increased arterial pressure to maintain sodium and water balance. In genetic animal models of hypertension, there also appears to be a resetting of pressure natriuresis before the development of hypertension. Likewise, essential hypertensive patients exhibit abnormal pressure natriuresis, although the precise cause of this defect is not clear. It is likely that multiple renal defects contribute to resetting of pressure natriuresis in essential hypertensive patients. With long-standing hypertension, pathological changes that occur secondary to hypertension must also be considered. By analyzing the characteristics of pressure natriuresis in hypertensive patients and by comparing these curves to those observed in various forms of experimental hypertension of known origin, it is possible to gain insight into the etiology of this disease. (Hypertension 1990;15:547-559)

A large body of correlational evidence relating plasma insulin levels and arterial pressure in obese hypertensives suggests that hyperinsulinemia may play a causal role in the development of hypertension in these subjects. However, experimental evidence supporting the ability of increased plasma insulin per se to increase blood pressure is lacking. The goal of this study was to determine the effect of hyperinsulinemia on mean arterial pressure and renal electrolyte excretion in eight conscious rats. Arterial pressure was determined by sampling the signal from an abdominal aortic catheter once per minute, 19 h/day by computer. A 5-day intravenous insulin and glucose infusion that increased plasma insulin concentration 43% significantly increased mean arterial pressure from 93 +/- 1 mmHg to an average of 101 +/- 2 mmHg for the 5-day experimental period. Heart rate increased from 369 +/- 8 to 406 +/- 3 beats/min. Urinary sodium excretion transiently decreased on day 1 of insulin, but no significant sodium retention was measured after 5 days of insulin infusion, suggesting that the blood pressure increase was not volume mediated. There were no changes in any of these variables in eight vehicle-infused rats. These results suggest that hyperinsulinemia can increase mean arterial pressure in conscious rats, but the underlying mechanism remains to be elucidated.

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.

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.

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 foriti®ed 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 de®ned 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 AE 0.1 kg and 5.4 AE 0.4 kg (P`0.05), the kidneys were 20% larger in the obese rabbits: 15.0 AE 0.9 g vs 18.0 AE 2.5 g (P`0.05). Kidney protein was also 20% greater in the obese rabbit: 1.38 AE 0.06 gakidney vs 1.66 AE 0.06 gakidney (P`0.05). While total renal DNA was 16% greater in the obese: 18.2 AE 0.5 mgakidney vs 21.1 AE 0.6 mgakidney (P`0.05), no signi®cant difference existed when the DNA was expressed as mgamg protein.Fractional water content of the intact kidney declined with obesity: 78.7 AE 1.1% vs 76.0 AE 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 AE 19 mgakidney vs 82 AE 25 mgakidney (P`0.05). By contrast, water content of renal parenchyma was constant: 80.8 AE 1.0% vs 80.9 AE 1.2% (cortex); 84.0 AE 0.8% vs 83.6% AE 2.0% (outer medulla); and 85.7 AE 0.8% vs 86.0 AE 2.1% (inner medulla). CONCLUSION: The renal growth associated with obesity was predominantly hyperplastic and was associated with a partial exclusion of¯uid from the renal sinus.

The purpose of this study was to test the hypothesis that hyperglycemia, comparable with that found in uncontrolled diabetes mellitus, increases renal blood flow (RBF) and glomerular filtration rate (GFR) through a tubuloglomerular feedback (TGF) mechanism. We infused glucose intrarenally (0.1-0.3 g/min) into anesthetized dogs with normal kidneys (NK), with nonfiltering kidneys (NFK) in which changes in TGF were blocked, and with normal kidneys in which renal perfusion pressure (RAP) was lowered to the limits of renal autoregulation (LPK). Calculated intrarenal plasma glucose levels rose to 250-400 mg/dl. In NK (n = 6) RBF and GFR increased by 18 +/- 3 and 19 +/- 5%, respectively, and renal vascular resistance fell by 17 +/- 2% after 90 min. The renal hemodynamic responses to glucose were abolished in NFK (n = 8); RBF averaged 96 +/- 4% of control after 60 min of hyperglycemia. RBF and GFR did not change during hyperglycemia in LPK (n = 5), averaging 96 +/- 1 and 100 +/- 8% of control, respectively, after 60 min. Autoregulation of RBF and GFR during reductions in RAP was impaired during hyperglycemia in NK; RBF and GFR were effectively autoregulated between RAP of 126 and 70-85 mmHg during the control period, whereas during glucose infusion RBF and GFR fell by 31 +/- 9 and 47 +/- 10%, respectively, when RAP was reduced in steps to 70 mmHg. These data suggest that hyperglycemia impairs renal autoregulation and may increase renal blood flow and GFR through a tubuloglomerular feedback mechanism.

The aims of this study were to determine whether chronic hyperinsulinemia, comparable to that found in obese hypertensives, elevates mean arterial pressure (MAP) or potentiates the hypertensive effects of angiotensin II (ANG II). Studies were conducted in conscious dogs with kidney mass reduced by 70% in order to increase their susceptibility to hypertensive stimuli. Insulin infusion (0.5 or 1.0 mU.kg-1.min-1 iv) for 7 days with plasma glucose held constant raised plasma insulin more than fivefold but did not increase MAP in four dogs on 138 meq/day Na intake. In seven dogs maintained on a high Na intake (319 meq/day), insulin infusion (1.0 mU.kg-1.min-1) for 28 days raised fasting insulin from 9.8 +/- 1.5 to 56-78 microU/ml but did not increase MAP, which averaged 106 +/- 2 mmHg during control and 102 +/- 2 mmHg during 28 days of insulin infusion. Insulin caused transient sodium and potassium retention followed by renal "escape" that was associated with increased glomerular filtration rate (12-27%). Plasma renin activity and plasma aldosterone were not altered by insulin. In five dogs infused with ANG II (2.0 ng.kg-1.min-1) to cause mild hypertension, insulin infusion (1.0 mU.kg-1.min-1) for 6-28 days did not increase MAP further. Thus chronic hyperinsulinemia did not elevate MAP, even when kidney mass was reduced, and did not potentiate the hypertensive effects of ANG II. These findings suggest that additional factors besides hyperinsulinemia per se are responsible for obesity-associated hypertension.

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.