Nongenetic Models Of Hypertension

In addition to the common genetic models of hypertension discussed earlier, there are also nongenetic models in which the hypertension is caused by infusion of a drug or by dietary manipulations or by placing a clip on the renal artery. The following is a list of such models.

DOCA and salt model in aging animals This model of hypertension is a model of mineralo-corticoid hypertension developed by implanting the rats with deoxycorticosterone acetate (DOCA) pellets (typically 100 mg) and treating them with salt water (1%). This is another model of salt-sensitive hypertension. The hypertension develops rapidly, usually within a week of the DOCA being implanted. The systems that mediate the hypertension include oxidative stress since antioxidants reduce the blood pressure (Elhaimeur et al., 2002). Agonists of serotonin receptor 5HT1A and antagonists of serotonin receptor 5HT2B reduce the blood pressure in DOCA-salt treated rats, implicating serotonin in the hypertension (Shingala and Balaraman 2005). In addition, blockade of the endothelin ETA receptor also protects against the increase in blood pressure (Callera et al., 2003). Blockade of the renin-angiotensin system (RAS), however, does not reduce blood pressure, as might be expected due to the reduction in renin release with the high-salt diet.

Infusion of low-dose Ang II in aging animals The infusion of a low dose (i.e., subpressor doses) of angiotensin II leads to hypertension that develops over approximately three to four days. The hypertension then is maintained at a stable level until approximately two weeks later, when another increase in blood pressure develops that plateaus within a few days (Hennington et al., 1998). The exact mechanism by which the second increase in blood pressure occurs is not clear.

In normotensive rats, angiotensin II induced hypertension can be produced by infusing Ang II at as little as 5 ng/kg/min when the endogenous RAS is blocked with converting enzyme inhibitors. If the endogenous system is not blocked, a higher dose of Ang II (50-80 ng/kg/min) is required. However, as the endogenous system is blocked by negative feedback caused by the Ang II infusion, the amount of Ang II necessary to maintain the hypertension progressively falls to that required to cause hypertension in endogenously blocked RAS rats. Similar findings have been made in mice, although mice require significantly more Ang II to cause a sustained increase in their blood pressure (600-1000 ng/kg/min).

The mechanisms responsible for the increase in blood pressure with low-dose Ang II are oxidative stress and endothelin activation (Reckelhoff and Romero, 2003). Treatment of animals with antioxidants attenuates the hypertensive response to Ang II. In addition, nonspecific blockade or specific blockade of the endothelin ETA receptor attenuates the hypertensive response to Ang II. It is likely that endothelin may stimulate oxidative stress since Ortiz and colleagues reported that treatment of Ang II infused rats with the superoxide scavenger, tempol, reduced blood pressure and oxidative stress, but failed to reduce plasma endothelin (Reckelhoff and Romero, 2003).

Studies in humans and animals have shown that aging may be associated with increased sensitivity of the cardiovascular and renal systems to Ang II. Acute infusion of Ang II is a common maneuver in aging humans, but chronic infusion of Ang II is performed only in animals.

Dietary-induced hypertension

Fat-fed rats—Obesity-induced hypertension. There is an epidemic in obesity that is occurring throughout the developed countries of the world. The mechanisms responsible for metabolic syndrome and the target organ injury associated with the complications of metabolic syndrome, such as type II diabetes, sleep apnea, end stage renal disease, and heart failure, are a major research focus today. Not all models of obesity are associated with elevated blood pressure. Why this is the case is also not clear at the present time.

The model of obesity-induced hypertension has been produced in dogs for years by feeding them a high-fat diet. However, only recently has a model of obesity and hypertension due to a high-fat diet been obtained in rats. Dobrian and colleagues have succeeded in producing a model of obesity in Sprague Dawley rats by feeding them 32% Kcal fat and 0.8% NaCl for 10 weeks (Dobrian et al., 2001). After 10 weeks, half the rats develop obesity (the so-called obese prone (OP) rats) whereas the other half do not (the so-called obese resistant (OR) rats). Typically, the OP rats weigh approximately 660 g compared to 540 g in OR rats. Control Sprague Dawley rats untreated with high-fat diets of similar ages exhibit similar weight as the OR rats. The OP rats develop mild hypertension and increased leptin levels. They also have increased plasma renin activity, an index of stimulated RAS. In addition, the rats have increased F2-isoprostanes, an index of oxidative stress, and renal injury. There have been no aging studies published with this model.

Fructose-fed rat—Model of insulin resistance and hypertension without obesity. The fructose-fed rat develops insulin resistance, increased triglycerides and glucose, and hypertension when approximately 60% of their diets contain fructose (Girard et al., 2005). Rats typically are treated for six to nine weeks before developing hypertension. The rats develop end organ damage of various types, and there is a sex difference in the development of hypertension, with only males becoming hypertensive despite the females becoming insulin resistant. This is a model that could lend itself to aging studies since aging normotensive rats could be given fructose with the expectation that they would become mildly hypertensive and insulin resistant within a few weeks.

Renovascular hypertension (2 kidney, 1 clip, or Goldblatt model)

The typical method for producing renovascular hypertension is by placing a silver clip on the renal artery of one kidney in rats and as they grow, the clip will cause a renal stenosis (Pipinos et al., 1998). The contralateral kidney becomes hypertrophied. The pressure in the clipped kidney is low due to the clip, whereas the pressure in the contralateral kidney is high due to the hypertension that develops. In the early phases, the blood pressure increases due to the release of renin from the clipped kidney. Oxidative stress also plays a role in the hypertension. Endothelin has been shown to be involved in the cardiac damage associated with renovascular hypertension, but not in the renal injury.

The Goldblatt model of hypertension is difficult to use since the hypertension is inconsistently produced. Even with rats of the same weight, the same size clip will cause moderate hypertension in some rats, but malignant hypertension in others (personal communication, Dr. William Beierwaltes). Whether this model could be reproduced in aging rats is not clear since the clips usually are placed in young animals, and as they grow, the renal vasoconstriction is produced. It is also not clear what the survival time would be for rats with 2-kidney, 1-clip maneuver that developed hypertension and were allowed to age.

The model of reduced renal mass (5/6 ablation model)

The model of renal ablation typically is produced by the removal of the right kidney and either the ligation of two of the three renal arteries on the left in the rat or the removal of the poles of the left kidney. Within days to a few weeks, this model develops hypertension and severe glomerulosclerosis. The renin-angiotensin system has been shown to play a role, but oxidative stress is likely to be involved as well (Sandberg and Ji, 2000). The endothelin system and reductions in NO are also involved. In addition, there is a component of the immune system involved in the hypertension in rats in the renal artery ligation model, but not in the model in which the renal tissue is removed. The model of renal ablation is one that could be reproduced in aging rats. There is only one aging study to our knowledge using this model, and the rats were studied 28 weeks after ablation was performed at approximately 34 to 36 weeks of age.

Diabetes 2

Diabetes 2

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