Hypertension In Experimental Animals Research Articles

Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension

Chronic hyperleptinemia induces arterial hypertension in experimental animals and may contribute to the development of hypertension in obese humans; however, the mechanism of hypertensive effect of leptin is not completely elucidated. We investigated the effect of leptin on whole-body oxidative stress, nitric oxide production, and renal sodium handling. The study was performed on male Wistar rats divided into 3 groups: 1) control, fed standard chow ad libitum, 2) leptin-treated group, receiving leptin injections (0.25 mg/kg twice daily s.c. for 7 days), 3) pair-fed group, in which food intake was adjusted to the leptin group. Leptin caused 30.5% increase in systolic blood pressure. Plasma concentration and urinary excretion of 8-isoprostanes in animals receiving leptin was 46.4% and 49.2% higher, respectively. The level of lipid peroxidation products, malonyldialdehyde + 4-hydroxyalkenals, increased by 52.5% in the renal cortex and by 48.4% in the renal medulla following leptin treatment, whereas aconitase activity decreased in these regions of the kidney by 45.3% and 39.2%, respectively. Urinary excretion of nitric oxide metabolites (NO x) was 55.0% lower, and fractional excretion of NO x was 55.8% lower in the leptin-treated group. Urinary excretion of cGMP decreased in leptin-treated rats by 26.3%. Following leptin treatment, absolute and fractional sodium excretion decreased by 35.0% and 41.2%, respectively. These results indicate that hyperleptinemia induces systemic and intrarenal oxidative stress, decreases the amount of bioactive NO possibly due to its degradation by reactive oxygen species, and causes renal sodium retention by stimulating tubular sodium reabsorption. NO deficiency and abnormal renal Na + handling may contribute to leptin-induced hypertension.

Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants.

Abnormalities of resistance arteries may play a role in the pathogenesis and pathophysiology of hypertension in experimental animals and humans. Vessels that, when relaxed, measure <400 microm in lumen diameter act as the major site of vascular resistance and include a network of small arteries (lumen approximately 100 to 400 microm) and arterioles (<100 microm). Because increased peripheral resistance is generated by a narrowed lumen diameter, significant effort has been focused on determining the mechanisms that reduce lumen size. Three important vascular components are clearly involved, including alterations of vascular structure, mechanics (stiffness), and function. Structural abnormalities comprise a reduced lumen diameter and thickening of the vascular media, resulting in an increased media-lumen ratio. Changes in the mechanical properties of an artery, particularly increased stiffness, may also result in a reduced lumen diameter. These vascular abnormalities may be caused or influenced by the expression and/or topographic localization of extracellular matrix components, such as collagen and elastin, and by changes in cell-extracellular fibrillar attachment sites, such as adhesion molecules like integrins. This article discusses the abnormalities of resistance arteries in hypertension and reviews the evidence suggesting an important role for adhesive and extracellular matrix determinants.

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women.

Genes that can be implicated in hypertension in experimental animals are plausible candidates in the pathogenesis of human hypertension. A recent genome-wide search for quantitative-trait loci (QTL) in hypertensive rats revealed a strong correlation between the interleukin-6 (IL-6) locus on rat chromosome 4 and systolic, diastolic, and mean arterial pressure in this mammalian species. To investigate a possible association between genetic variations of the IL-6 gene and hypertension in humans, we identified two novel single-nucleotide sequence variations, a C/G substitution at -634 in the promoter region and a G/A substitution at 4391 in a 3' non-coding portion of exon 5, and a previous reported sequence variant, an A/T variation in the composition of the AnTn tract around -447 in the promoter region (Fishman D et al. J Clin Invest 1998; 102: 1369-1376), within a test population of 96 Japanese subjects. Allelic associations involving these variations were analyzed in 150 hypertensive and 143 normotensive Japanese women. The distribution of alleles of the three polymorphisms, as well as a dinucleotide repeat present at the IL-6 locus, was similar in the two groups. Therefore, the IL-6 gene appears to play a minimal role in the genetic etiology of essential hypertension in Japanese women.

Hemoglobin-nitric oxide interaction and its implications.

T HE DIATOMIC molecule, nitric oxide (NO) has stimulated a tremendous amount of interest since it was proposed to be an important intercellular and intracellular messenger? It was even the of the year in 1993. The reason for this interest is that NO fulfills a role that was predicted many years ago. The numerous biological signaling activities of NO, including an important function as the endothelium-derived relaxing factor (EDRF), occurs through its chemical reaction with guanylate cyclase (GC), a heine protein that catalyzes the conversion of guanosine monophosphate to cyclic guanosine monophosphate (cGMP). NO binding stimulates the activity of this protein by 100 to 200-fold? The discovery of Furchgott and Zawadzki 3 that vascular relaxation induced by acetylcholine was dependent on the presence of the endothelium provided the first evidence that the modulation of vascular tone was mediated by a labile humoral factor, later known as EDRE Based on the similarities in the pharmacological behavior of EDRF, nitrovasodilators, such as glyceryl nitrate, and nitrous oxide generated from acidified nitrite solutions, it was suggested that EDRF is NO or a closely related molecule, a,5 The identification of the chemical properties of EDRF and the characterization of its biochemical pathway led to a better understanding of the role of vascular endothelium as a mediator of fundamental physiological and pharmacological activities. To influence vascular tone, NO must diffuse from its site of synthesis to reach GC, either intraor intercellularly. The accessibility of GC as a target can be limited by reactions of NO with other molecules, including 02, thiols, free radicals, or other intracellular or extracellular heine proteins, in the diffusion path. Thus, the ability of NO to stimulate GC activity depends on its reactivity with these molecules. It is now well established that inactivation of NO and the consequent depletion of NO from the vascular endothelium promote coronary vasoconstriction and produce hypertension in experimental animals and humans. 6 Because of its short-lived properties, the detection of NO in biological environments has been challenging, and scavengers of this molecule have been used, Hemoglobin, which avidly binds NO with an affinity much higher than that for either O2 or carbon monoxide (CO), is probably the most important NO scavenger, and its interaction with NO has been known for a long time. 7 The clinical implications of this reaction assumed a major significance in the last decades with the advent of chemically modified acellular hemoglobins, preparations that are currently investigated as potential red cell substitutes. 8 The research for blood substitutes represents a novel alternative to red cell transfusion, but to date no solutions that can be infused safely in humans have been approved for general clinical use. The major impediments to progress in the devel-

The endothelium of resistance arteries: physiology and role in hypertension

The endothelium plays a very important role in the regulation of vascular function by way of its barrier role, by interaction with circulating cells such as platelets, which may release vasoactive or growth regulating agents, and through production of substances which modulate vascular tone and smooth muscle cell growth, and which may also exert antithrombotic effects. The endothelium of resistance arteries, vessels critically involved in generating resistance to flow and which play an important role in hypertension, has been studied mainly from the point of view of generation of agents which regulate vascular tone and growth. Endothelium-derived relaxing factors such as nitric oxide, prostacyclin, hyperpolarizing factors (EDHF) and possibly C-type natriuretic peptide (CNP), are counteracted by endothelium-derived contracting factors, which include endothelins and contracting factors (EDCF) which are less well characterized and appear to be cyclooxygenase products. In experimental hypertension in animals, and in human essential hypertension, these mechanisms may be altered. There may be a reduced generation of endothelium-derived nitric oxide and enhanced production of EDCF. Some of the mechanisms involved in the role these agents play in the physiology of resistance arteries and pathologically in hypertension will be reviewed.

Effect of interleukin-2 on experimental emotional hypertension

The effect of human recombinant interleukin-2, one of the potent mediators of the immune system, on the course of emotional hypertension in non-linear white rats has been investigated. A significant and prolonged hypotensive action of a single injection of interleukin-2 in hypertensive rats has been revealed. The data obtained can be a new evidence of participation of immune system in the development of hypertension in experimental animals.

The borderline hypertensive rat (BHR) as a model for environmentally-induced hypertension: A review and update

In recent years, the burgeoning disciplines of health psychology and behavioral medicine have renewed interest in the important role that environmental factors can play in the disease process. Nowhere is this concern more well-founded than in the area of cardiovascular disorders, particularly hypertension. Epidemiologists and clinicians have long suspected that stressful life events can be a sufficient trigger for the expression of hypertension in some individuals. To understand better the ways in which these variables interact in the disease process, researchers have tried, with limited success, to produce experimental hypertension in animals by exposing them to stressful environmental paradigms. Additionally, recent investigations using the borderline hypertensive rat (BHR) have demonstrated the important role genetic factors can play in mediating both the behavioral and cardiovascular responses to environmental stressors. The current paper will review these attempts and discuss recent data from experiments using a relatively new animal model that appears to be especially appropriate for the study of environmental-genetic factors in the elaboration of essential hypertension. We will also discuss potential mechanisms by which environmental stress influences arterial pressure and suggest avenues for further inquiry into the stress-disease relationship.

The pathogenesis of DOCA-salt hypertension

Deoxycorticosterone acetate (DOCA) is an agent commonly used to induce hypertension in experimental animals. This form of hypertension is dependent on altered regulation of central pressor mechanisms including the brain renin-angiotensin system. Additionally, there are characteristic changes involving the cardiovascular system and baroreflex responses. This review will discuss aspects of the pathogenesis of DOCA hypertension and the effect of various antihypertensive agents on the development of this form of hypertension.

Sympathetic neural control of the kidney in hypertension.

Efferent renal sympathetic nerve activity is elevated in human essential hypertension as well as in several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow, the glomerular filtration rate, renal tubular sodium and water reabsorption, and the renin secretion rate, which are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of efferent renal sympathetic nerve activity, two environmental factors, a high dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in efferent renal sympathetic nerve activity and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

Pulmonary Capillary Density in Rats Given Monocrotaline: A Cast Corrosion Study

A mechanism for monocrotaline-induced pulmonary hypertension in experimental animals may be the loss of small blood vessels, but when pulmonary arteries have been studied, the results have been controversial. In this report, the density of the entire lung microvasculature as measured by gray-scale analysis of scanning electron microscopic images of corrosion casts is reported. In the first experiment, monocrotaline, 60 mg/kg, was injected intraperitoneally into Sprague-Dawley rats. After 16 days, the pulmonary vascular tree was cast with methylmethacrylate. The vascular density index of the casts at a magnification x 100 on the alveolar surface was 0.40 for the monocrotaline-treated animals and 0.48 for the saline-treated control animals (p less than 0.01). On the pleural surface, it was 0.51 for the monocrotaline animals and 0.67 for the saline animals (p less than 0.001). A second experiment found no significant difference in vascular density index between different doses of monocrotaline. Light and scanning electron microscopy suggest that capillary and small vessel thrombosis may account for the decrease in the density of vessels in pulmonary microvascular casts that occurs in response to monocrotaline.

Sympathetic nervous system influences on the kidney. Role in hypertension.

Efferent renal sympathetic nerve activity (ERSNA) is elevated in human essential hypertension as well as several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow and glomerular filtration rate, renal tubular sodium and water reabsorption, and renin secretion rate that are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of ERSNA, two environmental factors, dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in ERSNA and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

The opioid peptides. A role in hypertension?

This review is an attempt to highlight evidence that may implicate the endogenous opioid system in the pathogenesis of hypertension in humans. The evidence raised includes biochemical, physiological, pharmacological, and behavioral studies conducted in in vitro and in vivo systems, experimental models of hypertension, and humans with essential hypertension. While the compelling biochemical and pharmacological evidence in experimental animals clearly shows the presence of opioid peptides and their receptors in strategic sites of cardiovascular control and potent cardiovascular response to opioid peptides, opioid antagonists show no consistent blockade or reversal of hypertension in experimental animals or humans. One possible explanation for this phenomenon could be the vast redundancy in systems regulating blood pressure (i.e., the blockade of one system still leaves many other systems fully able to rapidly offset the eliminated system). Regarding the opioid system, the situation is much more complex, since some opioid receptors (mu-type) mediate pressor responses, while other receptors (kappa-type) mediate depressor responses. Therefore, nonselective opioid receptor antagonists (e.g., naloxone), which block both types of receptors, can be devoid of any cardiovascular activity, while a selective mu-receptor antagonist or a selective and potent kappa-receptor agonist may produce the desired antihypertensive effect. A combination of both actions (i.e., a drug that is both a mu-antagonist and a kappa-agonist) might be even more advantageous. Until such compounds are developed, this hypothesis will be hard to prove.

"How do adrenocortical steroid hormones produce hypertension?".

ACTH dependent and independent adrenocortical steroid hypertension in experimental animals is thought to be due to the 'mineralocorticoid' and/or 'glucocorticoid' activity of the steroid/s. Studies in sheep examining ACTH and adrenocortical steroid hypertension have provided evidence for a 'hypertensinogenic' class of steroid activity. A hypothesis is proposed to explain how the 'hypertensinogenic' actions of a steroid may produce hypertension. It is suggested that effects mediated via 'mineralocorticoid' and 'glucocorticoid' receptors may modulate or amplify the 'hypertensinogenic' activity. Individual steroids may express any, all or none of these three types of steroid hormone activity.

Central cardiovascular regulation and the role of vasopressin: a review.

This paper will review the current state of knowledge concerning interactions between vasopressin and central neural mechanisms of cardiovascular regulation. The development of information concerning systemic cardiovascular effects of vasopressin and interactions between vasopressin and the peripheral autonomic system is outlined to provide an introduction to the topic. Major themes discussed in the rest of the paper include a survey of information suggesting direct central effects of vasopressin on autonomic control of blood pressure and heart rate and the possible localization of the central site of effect. Evidence that circulating vasopressin may act on central cardiovascular control, especially baroreflex function, is reviewed, as is the possibility of vasopressin effects on baroreflex control independent of circulating vasopressin. A survey of central pathways containing vasopressin which may be relevant to central cardiovascular actions of vasopressin is presented along with a discussion of possible regulation of activity in these pathways. Some evidence of an association between alterations in brain vasopressin levels and hypertension in experimental animals is also introduced.

Renal nerves in the pathogenesis of hypertension in experimental animals and humans.

Efferent renal innervation is composed of postganglionic sympathetic fibers to the renal arterioles, juxtaglomerular apparatus, and renal tubules. Increased efferent renal sympathetic nerve activity results in increased renal vascular resistance, renin release, and sodium retention. These responses from enhanced renal sympathetic activity contribute to normal cardiovascular homeostasis but could also facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the DOCA-salt-treated rat, suggesting that these responses are due, at least in part, to loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in man. Recent studies indicate that the kidney is a sensory organ with mechano-receptive and chemoreceptive afferent renal nerves involved in renorenal and cardiovascular regulation. Renal denervation in established one-kidney one-clip and two-kidney one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not due to change in renin activity or sodium excretion but is associated with decreased activity of the sympathetic nervous system. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. The role of the afferent renal nerves in renovascular hypertension in humans warrants further study.

Antihypertensive effect of a calcium antagonistic drug: Regression of hypertensive cardiac hypertrophy by nifedipine

AbstractThe cardiac hypertrophy which develops in models of sustained hypertension in experimental animals cannot be prevented or reversed by all antihypertensive drugs. Clearly, blood pressure is only one of numerous factors which contribute to the development of hypertensive cardiomegaly. The ability of drugs to reduce cardiac hypertrophy depends primarily on their mode of action, rather than on the degree of blood pressure decrease. Vasodilators effectively control high blood pressure but enhance cardiac hypertrophy in rats. In currect experiments, minoxidil lowered blood pressure, but caused increases in heart weight and plasma‐renin activity (PRA) in spontaneously hypertensive rats (SHR). In contrast, the calcium antagonist, nifedipine, reduced blood pressure or prevented its increase in SHR concurrently reducing heart wight and decreasing PRA. Moreever, nifedipine prevented salt‐induced hypertension and heart hypertrophy in SD (sensitive)‐Dahl rats. It is suggested that in contrast to the vasodilator minoxidil, nifedipine reduces the high renovascular resistance in hypertensives thus enhancing sodium and water elimination. Thus, the action of the calcium antagonist, nifedipine, involve both renal vasodilation and reduction of renin‐angiotensin mediated renal vasoconstriction. In this way, the decreased volume load together with the decreased arterial afterload will contribute to the prevention or regression of hypertensive cardiac hypertrophy.

Hypertension in the Young and the Old

This book brings together current data relating to the epidemiology and characteristics of hypertension in children and in the elderly. The concept that an individual has a genetically determined mean blood pressure is strengthened by the studies presented in the book. The environmental factors of stress and a high sodium intake are shown to result in exaggerated pressor responses in the person who is genetically predisposed to hypertension. The development of vascular structure change in the hypertensive person and the resultant establishment of sustained hypertension is discussed. The portion of the book that deals with experimental hypertension in animals does not fit into the general theme and detracts from the overall impact of the important message that this book delivers. The synthesis in the book of epidemiology and the natural history of hypertension from infancy to old age is a valuable contribution.

Effects of stress on blood pressure and cardiac pathology in rats with borderline hypertension.

Repeated attempts to produce hypertension (HT) through psychological stress have failed to elevate blood pressure (BP) to levels seen in chronic, untreated essential HT in humans. In general, these studies have two characteristics in common: they utilize the normotensive animal, with no genetic history of HT, and they involve stressors to which animals readily adapt. The present study utilized offspring with one HT parent. The male F1, offspring of SHR x WKY had borderline HT (-/x +/- SEM = 152.4 +/- 1.34 mm Hg). With a conflict paradigm used as the stressor, experimental animals eventually developed severe HT (188.3 +/- 2.70 mm Hg) compared to two non-stressed control groups (158.4 +/- 2.31 mm Hg and 151.9 +/- 2.25 mm Hg). After 15 weeks of stress for 2 hours daily, termination of conflict for 10 weeks did not reduce the HT in experimental animals. Subsequent analyses revealed that stressed animals, when compared to nonstressed controls, exhibited elevated heart-weight-to-body-weight ratios and significant cardiac pathology in the form of myofibrillar degeneration, accumulation of inflammatory cells, and fibrosis. The implications of using this model for the analysis of cardiovascular concomitants of stress-induced HT are discussed.

Experimental portal hypertension in the rat

Previous attempts to produce sustained portal hypertension in experimental animals by portal venous obstruction have not been successful. Experiments were designed to study the effects of gradual portal venous occlusion plus hepatic lymphatic ligation in the rat. Adult male Lewis rats were divided into three groups: (A) nonoperated or sham-operated; (B) operated, with hepatic lymphatic ligation only; and (C) operated, with placement of a portal vein ameroid constrictor and hepatic lymphatic ligation. There were no differences noted in portal venous pressures (control 9.6 +/- 0.4 cm H2O) and portovenograms between groups A and B throughout the study. In group C there was greater than doubling of portal venous pressure by 1 wk which remained for 2 mo. Portal pressure then fell but remained elevated at greater than 30% above control values for 1 yr. Three systems of collateral circulation developed rapidly in response to this extrahepatic portal venous occlusion: (A) veins directly bridging across the occluding ameroid reestablishing hepatopetal flow which steadily increased; (B) spontaneous portosystemic shunts at the splenorenal area that occur early and then regress; and (C) retroperitoneal, paraesophageal and submucosal esophageal veins that develop late and remain stable. Quantitative assessment of the lumen size of the submucosal esophageal veins revealed a twofold increase in these veins in group B when compared to controls by 4 wk and a fivefold increase in these veins in group C by 8 wk that persisted for 1 yr. This model appears useful for studying the course and effects of extrahepatic portal hypertension and its gradual alteration by the spontaneous development of portosystemic collaterals in the rat. This model may have enough similarities to the extrahepatic portal hypertension seen in children that its use for future studies may be fruitful.

Baroreceptors and Hypertension

Baroreceptors are deformation receptors whose output is limited by wall strain. Experimental hypertension in animals is associated with a resetting of the baroreceptors such that the threshold pressure and set point are raised and gain decreased. These changes begin within a few days, are reversible, and are probably due to a splinting of the receptors by a stiffer arterial wall. The pulsatile pattern of impulse activity in the sinus nerve is maintained. Studies of the baroreflex arc in hypertensive man using the phenylephrine method have shown both resetting and a diminished sensitivity; the same changes occur with ageing. Neurogenic hypertension produced by baroreceptor denervation remains controversial, possibly due to species differences. Deafferentation may augment renal hypertension. Interaction between the baroreflex and the brain works both ways; situations where there is a heightened level of arousal may be associated with an inhibition of the cardiac limb of the reflex, while baroreceptor stimulation tends to lower the level of arousal. Malfunction of the baroreceptors might exacerbate hypertension by impairing the buffering of pressor stimuli and altering renal arterial resistance, resetting the relation between pressure and urine flow. Essential hypertension in human does not show the same degree of lability seen in experimental neurogenic hypertension in animals, but impairment of the reflex could be related to changes in distensibility of the sinus wall.