Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the Prague hypertensive rat (PHR), a strain of genetic hypertension derived from Wistar, administration of various antihypertensive drugs (AHD) during the developmental phase of hypertension (weeks 5-9 of life) prevents the rise of blood pressure. However, only drugs blocking the renin-angiotensin system (RAS, i.e. AT1-antagonist losartan and ACE inhibitor perindopril) have a long-term effect on blood pressure leading to values of systolic blood pressure (SBP) of 174.5+/-14.5 and 169.8+/-15.3 mmHg, respectively, at week 30. At this time, control, untreated PHR have a SBP of 222.0+/-16.6 mmHg (p<0.01 for both groups); age-matched PNR (Prague normotensive rat, bred in parallel with PHR from the same parent pair) exhibit values as low as 123.3+/-11.7 mmHg (p<0.01 from all other values). When losartan was administered to another group of PHR not only at weeks 5-9 but once more at weeks of 15-19 of age, the values of their SBP at week 30 were 156.8+/-12.64 mmHg, i.e., values significantly (p<0.01) different not only from 239.7+/-17.59 mmHg (value of the untreated PHR group) but also from 174.5+/-14.5 mmHg (value of PHR to which losartan was administered only once, at weeks 5-9). Thus, twice repeated administration of losartan in young age almost normalizes blood pressure deep into adult age. Proteinuria, a common finding in adult PHR, is also significantly lower in adult age in both groups receiving at weeks 5-9 drugs blocking RAS; the values at week 30 are 4.0+/-0.26 mg/24 h/rat in the losartan and 3.87+/-0.27 in the perindopril group, in contrast to 12.8+/-1.08 (p<0.01 for both groups) in control PHR. In conclusion, early brief administration (weeks 5-9 of life) of RAS-blocking agents to PHR led to long-term antihypertensive and antiproteinuric effects. These effects were significantly intensified by a second brief administration at weeks 15-19.
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PMID:Long-term effect on blood pressure of early brief treatment by different antihypertensive agents: a study in the prague hypertensive rat. 993 30

In the general population blood pressure varies along a continuum and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Epidemiological studies suggest that blood pressure variance is attributable to both genetic factors and environmental factors to the same magnitude. The molecular basis for three forms of sever hypertension transmitted on an autosomal basis has been recently elucidated: a) the glucocorticoid-suppressible aldosteronism (GSA), b) the Liddle's syndrome and c) the syndrome of apparent mineralocorticoid excess (AME). GSA is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. AME is caused by mutations of the 11 beta-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolises cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor from occupation by glucocorticoids. Apart from these rare genetic defects of the extended renin-angiotensin system, there are many susceptibility genes that might increase the risk of hypertension in a given environment. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension. One variant of angiotensinogen gene is associated with elevated plasma angiotensinogen levels and is more prevalent among hypertensive than among normotensive. This observation shows the relationship between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distant phenotype (i.e., blood pressure elevation). The identification of these genes as well as other informative genetic markers distributed along the genome could be used in the search for genetic links between arterial hypertension and a chromosomal locus.
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PMID:[Molecular genetics of hypertension in the human]. 1006 28

Dopamine modulates cardiovascular function by actions in the central and peripheral nervous system, by altering the secretion/release of prolactin, pro-opiomelanocortin, vasopressin, aldosterone, and renin, and by directly affecting renal function. Dopamine produced by the renal proximal tubule exerts an autocrine/paracrine action via two classes of dopamine receptors, D1-like (D1 and D5) and D2-like (D2, D3, and D4), that are differentially expressed along the nephron. The autocrine/paracrine function of dopamine, manifested by tubular rather than by haemodynamic mechanisms, becomes most evident during extracellular fluid volume expansion. This renal autocrine/paracrine function is lost in essential hypertension and in some animal models of genetic hypertension. The molecular basis for the dopaminergic dysfunction in hypertension may involve an abnormal post-translational modification of dopamine receptors.
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PMID:D1 dopamine receptor signalling defect in spontaneous hypertension. 1069 8

The purpose of this study was to determine whether activation of prostaglandin H(2)-thromboxane A(2) (PGH(2)-TxA(2)) receptors impedes vasodilation in the in situ peripheral microcirculation of spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Using intravital microscopy, we found that vasodilation elicited by suffusion of acetylcholine and vasoactive intestinal peptide (VIP), two neurotransmitters localized in perivascular nerves in the peripheral circulation, on the in situ cheek pouch was significantly attenuated in spontaneously hypertensive hamsters relative to age- and genetically matched normotensive hamsters (P < 0.05). However, nitroglycerin-induced vasodilation was similar in both groups. Pretreatment with SQ-29548, a selective and potent PGH(2)-TxA(2)-receptor antagonist, restored acetylcholine- and VIP-induced vasodilation in spontaneously hypertensive hamsters. SQ-29548 had no significant effects on resting arteriolar diameter and on nitroglycerin-induced vasodilation in both groups. SQ-29548 slightly but significantly potentiated VIP- but not acetylcholine-induced vasodilation in normotensive hamsters. Collectively, these data indicate that activation of PGH(2)-TxA(2) receptors impedes agonist-induced vasodilation in the in situ cheek pouch of spontaneously hypertensive hamsters. We suggest that this model is suitable for studying the role of prostanoids in mediating vasomotor dysfunction observed in genetic hypertension.
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PMID:PGH(2)-TxA(2)-receptor blockade restores vasoreactivity in a new rodent model of genetic hypertension. 1084 9

The antihypertensive agent omapatrilat represents a novel approach to antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure-lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.
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PMID:Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. 1085 67

Left ventricular hypertrophy (LVH) is an adaptive change in response to hypertensive pressure overload. Some evidence indicates that the decrease in sarcoplasmic reticulum (SR) Ca2+-ATPase mRNA expression, which may contribute to a diastolic dysfunction of the heart, occurs in the experimental pressure overload model. Also, recent studies have demonstrated that angiotensin II (Ang II) and angiotensin II receptor type 1 (AT1) play important roles in LVH. The purpose of this study was to investigate the function of the SR and the role of AT1 in genetic hypertension in spontaneously hypertensive rats (SHR) at ages 10 and 18 weeks. In SHR, cardiac hypertrophy has already developed at 10 weeks of age. SR Ca2+-ATPase activity and mRNA expression were significantly lower in SHR than in Wistar-Kyoto rats (WKY). Plasma renin activity in SHR was unchanged compared with WKY, whereas the Ang II concentration in SHR was significantly higher than that in WKY. AT1 mRNA expression in SHR was similar to that in WKY. These results suggest that in the early stage of hypertension in SHR Ang II may stimulate hypertrophy in the cardiomyocytes through the AT1, which is not downregulated by a high concentration of Ang II.
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PMID:Alterations in sarcoplasmic reticulum and angiotensin II receptor type 1 gene expression in spontaneously hypertensive rat hearts. 1094 16

During the past decade, it has become evident that dopamine plays an important role in the regulation of fluid and electrolyte balance and blood pressure. Dopamine exerts its actions through two families of dopamine receptors, designated D1-like and D2-like, which are identical in the brain and in peripheral tissues. The two D1-like receptors--D1 and D5 receptors--expressed in mammals are linked to stimulation of adenylyl cyclase. The three D2-like receptors--D2, D3, and D4,--are linked to inhibition of adenylyl cyclase. Dopamine affects fluid and electrolyte balance by regulation of renal excretion of electrolytes and water through actions on renal hemodynamics and tubular epithelial transport and by modulation of the secretion and/or action of vasopressin, renin, aldosterone, catecholamines, and endothelin B receptors (ETB) receptors. It also affects fluid and sodium intake by way of "appetite" centers in the brain and alterations of gastrointestinal tract transport. The production of dopamine in neural and non-neural tissues and the presence of receptors in these tissues suggest that dopamine can act in an autocrine or paracrine fashion. This renal autocrine-paracrine function, which becomes most evident during extracellular fluid volume expansion, is lost in essential hypertension and in some animal models of genetic hypertension. This deficit may be caused by abnormalities in renal dopamine production and polymorphisms or abnormal post-translational modification and regulation of dopamine receptor subtypes.
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PMID:Renal dopamine and sodium homeostasis. 1098 Nov 46

The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.
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PMID:Studies of prevention, treatment and mechanisms of heart failure in the aging spontaneously hypertensive rat. 1179 Sep 24

The precise role of nitric oxide (NO) in hypertension is still not fully understood, although this vasodilator system represents the main counterbalance of major pressor systems. The aim of our study was to determine the contributions of superoxide anions, the renin-angiotensin system (RAS), the sympathetic nervous system (SNS) and NO to the maintenance of blood pressure (BP) in Prague hereditary hypertriglyceridaemic (HTG) rats with genetic hypertension. Conscious chronically cannulated rats were subjected to the consecutive blockade of the RAS (losartan, 10 mg/kg), the SNS (pentolinium, 5 mg/kg) and NO synthase [N(omega)-nitro-L-arginine (L-NAME), 30 mg/kg]. Some additional rats were pretreated with tempol (a membrane-permeable mimetic of superoxide dismutase). A subsequent genetic study in HTG x Lewis F(2) hybrid rats (n=284) was designed to reveal potential associations of particular BP components with baseline BP. The progenitor study indicated that BP elevation was more pronounced in male than female HTG rats (as compared with normotensive Lewis controls). Higher BP in HTG rats was due to the increased residual BP (measured after combined RAS and SNS blockade) and the augmentation of BP responses to tempol or losartan. In contrast, BP responses to pentolinium or l-NAME were similar in all experimental groups. It should, however, be noted that the baseline BP of progenitor animals was correlated positively with both residual BP and the magnitude of the BP response to pentolinium, but not with BP response to L-NAME. Similarly, the baseline BP of F(2) hybrid rats was positively associated with residual BP, the BP response to pentolinium and the relative SNS contribution to BP maintenance [expressed as a percentage of baseline mean arterial pressure (MAP) values], as well as with the ratio of BP changes elicited by ganglion blockade and NO synthase inhibition (Delta MAP(pentolinium)/Delta MAP(L-NAME) ratio), reflecting the balance of main vasopressor and vasodepressor systems. Thus our studies, performed in progenitor and F(2) hybrid rats, revealed that changes in BP induced by L-NAME do not keep pace with the progressive augmentation of pentolinium-induced changes in BP occurring over a wide range of increasing BP. The altered balance between enhanced SNS-dependent vasoconstriction and unchanged NO-dependent vasodilation ('relative NO deficiency' in rats with high BP) might result in BP elevation in this form of genetic hypertension.
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PMID:Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia. 1186 67

Maitake mushroom has been reported to favorably influence hypertension and diabetes mellitus. The purpose of this study was to compare the effects of whole Maitake mushroom powder and two extracts designated as ether soluble (ES) and water soluble (WS) on Zucker fatty rats (ZFR), a model of insulin resistance, and on spontaneously hypertensive rats (SHR), a model of genetic hypertension. In the initial study, we followed four groups of eight ZFR and SHR receiving special diets: a baseline diet (BD), BD + whole Maitake mushroom powder (20% w/w), BD + fraction ES (0.10% w/w), and BD + WS (0.22% w/w). Different effects of these dietary regimens on the 2 rat strains were found. At 35 days, only consumption of the ES diet significantly decreased systolic BP (SBP) in SHR (average 197 vs. 176 mm Hg, p < 0.001), while in ZFR only the groups consuming the whole Maitake and WS diets showed significantly decreased SBP (138 vs. 120-125 mm Hg, p < 0.001). A challenge test with losartan (an angiotensin II receptor blocker) indicates that angiotensin II does not play a major role in SBP regulation of ZFR, but does in SHR where consumption of ES relative to other groups significantly lowered activity of this system. In SHR, glucose, cholesterol, circulating insulin and HbA1C were virtually similar among all dietary groups; but whole Maitake (-22%), ES (-120%) and WS (-80%) diets were associated with decreased triglycerides, and the ES diet with lowered serum creatinine (-29%). In ZFR, circulating insulin and HbA1C were significantly decreased in the whole Maitake powder and ES groups, and tended to be lower in the WS group compared to control. In the ensuing studies, we gavaged ZFR once daily with water (control), 44 mg fraction WS, or 44 mg fraction WS plus 100 microg niacin-bound chromium (NBC). Oral gavage of WS clearly lowered SBP and circulating glucose concentrations, more so with the addition of chromium. We conclude that the examined forms of Maitake mushroom have antihypertensive and antidiabetic potential which differ among rat strains. The ES fraction may decrease SBP in SHR via alteration in the renin-angiotensin system.
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PMID:Antihypertensive and metabolic effects of whole Maitake mushroom powder and its fractions in two rat strains. 1223 80


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