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Animals have been used by humans for centuries to understand their own biology. In cardiovascular research, animal models have allowed the study of cardiovascular disease in the early stages, as well as the investigation of the mechanisms of the pathogenesis of cardiovascular disease and the effects of drug intervention. The aim of these studies is to provide clear concepts for selected investigations in humans. An ideal animal model for any cardiovascular disease in humans should have five characteristics: (i) mimic the human disease, (ii) allow studies in chronic, stable disease, (iii) produce symptoms which are predictable and controllable, (iv) satisfy economical, technical and animal welfare considerations, and (v) allow measurement of relevant cardiac, biochemical and haemodynamic parameters.

The use of rats as animal models is rational from the economic viewpoint and many techniques have been developed to measure relevant functional parameters. However, there is often insufficient consideration as to whether the other criteria, especially the mimicry of human disease, are satisfied with the choice of rat models of cardiovascular disease. Three examples illustrate the problems. Firstly, cardiovascular diseases such as hypertension and heart failure in humans are usually slowly developing with wide-ranging neurohumoral adaptations in contrast to the acute onset of symptoms in many surgical or drug-induced rat models of these important diseases. Secondly, cardiovascular disease is uncommon in young humans but markedly increases with age [1]yet most models of hypertension and heart failure only use young adult rats. Animal models of ageing have been recently reviewed [2]. Thirdly, the development of atherosclerosis is very unusual in most strains of rats, even in the presence of sustained high blood lipid levels, in contrast to humans where atherosclerosis is common and an important risk factor in hypertension and heart failure.

Although this review … 

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Rat models of hypertension, cardiac hypertrophy and failure.

The accelerated formation of advanced glycation end products (AGEs) and the overexpression of transforming growth factor beta (TGF-beta) have both been implicated in the pathogenesis of diabetic microvascular and macrovascular complications. Previous studies in our laboratory have demonstrated that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment. Animals were studied at 7 d, 3 wk, and 8 mo after induction of diabetes. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight and an increase in media wall/lumen area. By Northern analysis, TGF-beta1 gene expression was increased 100-150% (P < 0.01) and alpha1 (IV) collagen gene expression was similarly elevated to 30-110% compared to controls (P < 0.05). AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with aminoguanidine resulted in significant amelioration of the described pathological changes including overexpression of TGF-beta1 and alpha1 (IV) collagen. These data implicate the formation of AGEs in TGF-beta overexpression and tissue changes which accompany the diabetic state.

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Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products.

Mechanisms for the clinical benefits of angiotensin II receptor blockers.

Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease.

Treatment with calcium channel blocker (CCB)s, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment.

Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension.

Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade.

The role of angiotensin-converting enzyme (ACE) inhibition with ramipril on mesenteric vascular hypertrophy and urinary albumin excretion was explored in a normotensive model of experimental diabetes. Serial measurements of albuminuria were performed in Sprague-Dawley control, diabetic rats, and diabetic rats treated with ramipril. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Ramipril prevented the increase in albuminuria over the whole study period. After 6 months, animals were perfused with glutaraldehyde and sacrificed for measurement of mesenteric vessel wall/lumen ratio and kidney weight. Diabetes was associated with increased mesenteric wall/lumen ratio and kidney weight. ACE inhibition, despite no effect on glycemic control, attenuated mesenteric vascular hypertrophy but did not decrease kidney weight. In addition to the well-described renoprotective effects of ACE inhibition in diabetes, this class of agents may have a favorable effect on diabetic vascular disease.

U. Lennart Hulthen

Papers

Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade.

Diabetic vascular hypertrophy and albuminuria: Effect of angiotensin converting enzyme inhibition