To study the relationship between body weight and blood pressure, we have developed an animal model of obestiy-induced hypertension. Nine adult mongrel dogs were chronically instrumented with aortic and vena caval catheters. After a 2-week control period, all dogs were made to gain weight by adding 2 Ib/day of beef fat to their diet for 5 weeks. Blood pressure, heart rate, and body weight were measured daily before the addition of dietary fat, during the 5 weeks of the high fat diet, and for 6 weeks after the fat supplement was stopped. Plasma volume and cardiac output were measured prior to and after 5 weeks of the fat diet. During the 5-week high fat diet, the dogs' body weight increased from 22.2 ± 2.1 to 27.4 ± 3 kg (p<0.001); mean blood pressure increased from 90 ± 5 to 112 ± 6 mm Hg (p<0.01); and heart rate increased from 70 ± 7 to 85 ± 5 beats/min (p<0.05). Blood pressure, heart rate, and body weight returned to near control values after the fat diet was stopped. Over the 5-week fat diet, the dogs' plasma volume increased from 920 ± 130 to 1059 ± 195 ml (p<0.05); cardiac output increased from 2.5 ± 0.4 to 3.1 ± 0.3 L/min (p<0.05); and systemic vascular resistance increased from 35.3 ± 8 to 38.9 ± 9 mm Hg/L/min (p<0.1). Weight gain in the dogs was also associated with hyperinsulinemia and insulin resistance. Our findings have demonstrated that weight gain in the dog is associated with an increase in heart rate, blood pressure, cardiac output, plasma volume, and fasting insulin concentration, and we think that our animal model should be ideal for studying the pathogenesis of obesity-induced hypertension. (Hypertension 9 [Suppl III]: III-64-III-68, 1987) KEY WORDS • obesity • hypertension • hyperinsulinemia

We have previously shown that weight gain in the dog results in an increase in blood pressure. To study the pathogenesis of the rise in blood pressure associated with weight gain, we compared the serial changes in blood pressure, body weight, sodium balance, plasma volume, and three hormones known to affect sodium balance (norepinephrine, insulin, and aldosterone) in seven dogs fed a high fat diet for 6 weeks and seven dogs fed a control diet. The sodium content of both diets was equal. During a 2-week control period, no differences were noted between the two groups. Weight gain was associated with a progressive increase in blood pressure (mean pressure increased by 18.5±2.1 mm Hg in the high fat group) and plasma volume (plasma volume increased from 1,426±202 to 2,053±250 ml in the high fat group). Sodium retention occurred after 1 week of the high fat diet and persisted. Over the 6-week period, the dogs on the high fat diet increased their cumulative sodium balance by 2,024±462 meq versus an increase of only 289±97 meq for the dogs on the control diet. In the high fat diet group of dogs, there was a significant relation between change in cumulative sodium balance and the change in blood pressure and plasma volume. After 1 week of the high fat diet, norepinephrine was the only hormone that significantly increased from baseline. Over the next 5 weeks norepinephrine increased no further, whereas fasting insulin and aldosterone progressively increased. Over the entire study period, fasting insulin was the hormone that best correlated with the change in blood pressure observed in the high fat diet dogs. Thus, the change in blood pressure associated with weight gain in the dog is directly related to sodium retention. The observed change in sodium balance also appears to relate initially to a change in plasma norepinephrine concentration and later to a change in fasting insulin and aldosterone concentrations. (Hypertension 1989;13:922-928)

To determine whether hyperinsulinemia alters angiotensin II-medlated aldosterone secretion, the increase in plasma aldosterone after intravenous angiotensin II (5, 10, and 20 ng/kg/min for 15 minutes each) was measured before and after euglycemic hyperinsulinemia in seven chronically instrumented dogs. In a random sequence on 4 successive days, dogs received either 0, 2, 4, or 8 milllunits/kg/min insulin. Euglycemic hyperinsulinemia, at all insulin doses, resulted in a significantly greater (p<0.01) change in the angiotensin U-stimulated increments of plasma aldosterone than was observed when angiotensin II was administered alone. However, there was no dose-dependence of insulin's effect on angiotensin H-stimulated aldosterone. The effect of weight gain on the angiotensin II response was also evaluated in five dogs. After weight gain, euglycemic hyperinsulinemia augmented angiotensin H-stimulated aldosterone to the same magnitude that was observed before weight gain. Possible mechanisms whereby insulin could increase angiotensin II-stimulated aldosterone production include: increased intracellular potassium, reduced plasma free fatty acids, and a direct action of insulin to induce increased adrenal steroidogenesis. In addition to altering the angiotensin II-aldosterone dose-response curve, hyperinsulinemia also increased the pressor action of angiotensin II. In contrast to the angiotensin II-aldosterone response, progressive hyperinsulinemia resulted in a progressive increase in the pressor response to angiotensin II. The increased pressor response is probably due to an increased activation of the sympathetic nervous system by insulin. (Hypertension 1990;15:861-866)

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin-induced hair cell death and hearing loss. Here, a combination of nutrients previously shown to reduce oxidative stress in the hair cells and attenuate hearing loss after other insults was evaluated for potential protection against gentamicin-induced ototoxicity. Guinea pigs were maintained on a nutritionally complete standard laboratory animal diet or a diet supplemented with β-carotene, vitamins C and E, and magnesium. Three diets with iterative increases in nutrient levels were screened; the final diet selected for study use was one that produced statistically reliable increases in plasma levels of vitamins C and E and magnesium. In two separate studies, significant decreases in gentamicin-induced hearing loss at frequencies including 12 kHz and below were observed, with less benefit at the higher frequencies. Consistent with the functional protection, robust protection of both the inner and outer hair cell populations was observed, with protection largely in the upper half of the cochlea. Protection was independently assessed in two different laboratories, using two different strains of guinea pigs. Additional in vitro tests did not reveal any decrease in antimicrobial activity with nutrient additives. Currently, there are no FDA-approved treatments for the prevention of gentamicin-induced ototoxicity. The current data provide a rationale for continued investigations regarding translation to human patients.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.