Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We propose that inadequate sympathetic bias and Th2 bias in the uterine environment contributes to the formation of fibroids, independent of the sex steroid status. We also propose that fibroids represent a modern maladaptation that partly results from decreasing exposure to seminal fluid, which contains catecholalmines, transforming growth factor beta1 (TGFbeta1), aldosterone, prostaglandins, and other factors that shift the uterine environment to sympathetic and T helper (Th)2 bias. Lower risk of fibroids is associated with pre-menarche, post-menopause, pregnancy, exposure to contraceptives, smoking, earlier age of first pregnancy, shorter interval since last pregnancy, higher parity, and non-obesity. These associations are currently attributed to alterations of sex steroids. However, the association may also be explained by the observation that pre-menarche, post-menopause, pregnancy, and smoking represent periods of sympathetic and Th2 bias. Furthermore, use of contraceptives, early age of first pregnancy, short interval since last pregnancy, high parity, abnormal pap smear, and non-obesity may represent surrogates for increased sexual activity and increased exposure to seminal fluid. Catecholalmines, aldosterone, TGF, and prostaglandins are among the seminal fluid components that promote sympathetic and Th2 bias. Vasectomized copulations protect against fibroids, an observation that undermines the steroid hypothesis and supports our hypothesis. The putative mechanism of action of uterine artery embolization (UAE) for fibroid treatment is starvation of blood supply, but the extensive collaterals that protect uterine perfusion would presumably also buffer against fibroid hypoperfusion. Instead, the sympathetic and Th2 responses to UAE-related ischemia may contribute to fibroid regression. A potential explanation for the association of fibroids with intrauterine devices may be a Th1 cell-mediated immune response to the foreign body, which may also enhance the contraceptive effect. Novel methods of preventing and treating fibroids by promoting sympathetic and Th2 shift through natural, pharmacologic, and neuromodulatory means are envisioned. Fibroids are likely a modern dysfunction given the high Darwinian fitness cost of fibroid-related infertility, and may be attributable to reduced intercourse frequency. Fibroids have been observed among animals in captivity that are presumably reproductively isolated.
 ...
PMID:Sympathetic and T helper (Th)2 bias may ameliorate uterine fibroids, independent of sex steroids. 1621 89

Hypertension is a major risk factor for cardiovascular mortality and morbidity through its effects on target organs like the brain, heart, and kidney. Structural alterations in the microcirculation form a major link between hypertension and target organ damage. In this review, we describe damages related to hypertension in these target organs and the mechanisms involved in the pathogenesis of hypertension-induced cardiovascular diseases such as dementia, cardiac ischemia and remodeling, or nephropathy. We also focus on the therapeutical potential on the basis of such mechanisms. Several antihypertensive agents like diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II (Ang II) receptor antagonists, beta-blockers, or calcium channel blockers (CCBs) have been shown to reduce effectively hypertension associated cardiovascular events and to improve end organ damage. More recently, aldosterone antagonism has also shown beneficial effects. Part of the favorable effects of these agents is due to blood pressure lowering as such. Other mechanisms such as oxidative stress, inflammation, or endothelial dysfunction have appeared to play a key role in the pathogenesis of target organ damage and therefore represent another important pathway for therapy. In this review, we discuss the different therapeutic approaches aiming at reducing cardiovascular events and damages induced by hypertension.
 ...
PMID:Mechanisms of target organ damage caused by hypertension: therapeutic potential. 1628 9

The pharmacologic management of the patient post myocardial infarction (MI) aims to achieve several goals. Chief among these is to prevent subsequent events, which include death, reinfarction, and rehospitalization. Secondary goals include preventing arrhythmias, minimizing left ventricular (LV) remodeling, and preventing progression to heart failure. This review describes practical algorithms for use in the pharmacologic management of the patient post MI based on American Heart Association/American College of Cardiology guidelines. The intensity of drug treatment is determined guided by the degree of LV dysfunction and the presence or absence of ischemia and arrhythmic risk markers. All patients post MI require an angiotensin-converting enzyme (ACE) inhibitor and antiplatelet therapy, usually with aspirin. In individuals who cannot tolerate an ACE inhibitor, an angiotensin receptor blocker (ARB) is an adequate substitute. Numerous studies document the efficacy of ACE inhibitors, which decrease mortality and the risk of heart failure and stroke. Aldosterone blockade is recommended long-term for patients post MI with an LV ejection fraction < or = 40% and either symptomatic heart failure or diabetes. Use of a beta blocker is an important addition to most post-MI drug regimens. Beta blockers decrease mortality and are especially effective in patients with impaired LV function. Among the beta blockers, carvedilol, which also has alpha-adrenergic receptor blocking activity, was found to decrease mortality significantly in patients with low ejection fractions and heart failure. Another drug therapy of value in post-MI treatment is use of calcium-channel blockers. These are restricted to patients with conserved LV function in whom congestion is absent and in whom beta blockers are contraindicated. Current guidelines also recommend that patients post MI with elevated cholesterol levels should be prescribed lipid therapy with a statin at hospital discharge.
 ...
PMID:Practical algorithms for pharmacologic management of the post myocardial infarction patient. 1645 Aug 10

Mineralocorticoid receptor antagonism with eplerenone reduces mortality in heart failure, possibly because of blockade of the deleterious effects of aldosterone. To investigate these effects, rat Langendorff hearts were exposed to aldosterone and/or eplerenone. Under normal conditions, aldosterone increased left ventricular pressure and decreased coronary flow. Eplerenone did not block these effects. Eplerenone reduced infarct size (from 68+/-2% to 53+/-4%; P<0.05) and increased left ventricular pressure recovery (from 44+/-2% to 60+/-5%; P<0.05) after 45 minutes of coronary artery occlusion and 3 hours of reperfusion, whereas aldosterone did not affect these parameters. To verify the origin of cardiac aldosterone, hearts were perfused with 3 to 30 nmol/L aldosterone and either frozen immediately or exposed to washout. Without washout, cardiac aldosterone was 1.5 times aldosterone in coronary effluent (CE), that is, too high to be explained on the basis of its presence in extracellular fluid. The cardiac levels of aldosterone correlated with its CE levels (r=0.81; P<0.01), and both were unaffected by eplerenone. During washout, tissue aldosterone disappeared monophasically (half life, 9+/-1 minutes), and CE aldosterone disappeared biphasically (half life 1+/-0 and 8+/-1 minutes, respectively). During buffer perfusion, cardiac aldosterone was at or below the detection limit. In conclusion, eplerenone improves the condition of the heart after ischemia and reperfusion. This does not relate to interference with the inotropic and vasoconstrictor effects of aldosterone. The majority of cardiac aldosterone, if not all, is derived from the circulation. The rapid, mineralocorticoid receptor-independent kinetics of aldosterone suggest that its accumulation in the heart involves cell surface binding rather than internalization.
 ...
PMID:Cardioprotective effects of eplerenone in the rat heart: interaction with locally synthesized or blood-derived aldosterone? 1649 Aug 40

Zofenopril is a specific ACE inhibitor with antihypertensive, remarkable antioxidant, and cardioprotective properties, including the ability to improve endothelial function and protect against ischemia. These beneficial properties of zofenopril are believed to be due primarily to the presence of a sulfhydryl group and the highly lipophilic nature of the agent. As a potent, long-acting ACE inhibitor with tissue selectivity, it is a useful agent for the treatment of a number of cardiovascular diseases. ACE inhibitors block the renin-angiotensin-aldosterone system (RAAS) and are recommended in the management of hypertension with associated risk factors because of their renoprotective and cardioprotective effects. There is a robust body of comparative data supporting zofenopril as an effective and well tolerated ACE inhibitor for treating hypertension. Hypertensive patients frequently require combination therapy to adequately control BP. ACE inhibitors combined with a diuretic make a very effective combination, as a result of the synergistic mechanisms of these two drug classes that allow good efficacy and favorable tolerability at low doses. The combination of zofenopril and hydrochlorothiazide is effective and superior to monotherapy with either agent. Clinical studies have demonstrated that early administration of zofenopril in patients with acute myocardial infarction is effective and well tolerated for reducing the incidence of major cardiovascular events in at-risk patients, and it is believed that much of the benefit is a result of the primary cardioprotective effect of zofenopril.
 ...
PMID:Defining the role of zofenopril in the management of hypertension and ischemic heart disorders. 1735 63

Renal ischemia and reperfusion (I/R) injury is the major cause of acute renal failure and may also be involved in the development and progression of some forms of chronic kidney disease. We previously showed that a mineralocorticoid receptor (MR) blockade prevents renal vasoconstriction induced by cyclosporine that leads to acute and chronic renal failure (Feria I, Pichardo I, Juarez P, Ramirez V, Gonzalez MA, Uribe N, Garcia-Torres R, Lopez-Casillas F, Gamba G, Bobadilla NA. Kidney Int 63: 43-52, 2003; Perez-Rojas JM, Derive S, Blanco JA, Cruz C, Martinez de la Maza L, Gamba G, Bobadilla NA. Am J Physiol Renal Physiol 289: F1020-F1030, 2005). Thus we investigated whether spironolactone administration prevents the functional and structural damage induced by renal ischemia-reperfusion (I/R). Five groups were studied: sham-operated animals, rats that underwent 20 min of ischemia and 24 h of reperfusion, and three groups that received spironolactone 1, 2, or 3 days before I/R, respectively. Renal I/R produced significant renal dysfunction and tubular damage. Spironolactone administration completely prevented a decrease in renal blood flow, the development of acute renal failure, and tubular apoptosis. The protection conferred by spironolactone was characterized by decreasing oxidative stress, as evidenced by a reduction in kidney lipoperoxidation, increasing expression of antioxidant enzymes, and restoration of urinary NO(2)/NO(3) excretion. Endothelial nitric oxide synthase expression was upregulated by a mineralocorticoid receptor blockade in I/R groups; in addition, an increase in activating phosphorylation of this enzyme at residue S1177 and a decrease in inactivating phosphorylation at T497 were observed. In conclusion, our study shows that spironolactone administration prevents the renal injury induced by I/R, suggesting that aldosterone plays a central role in this model of renal injury.
 ...
PMID:Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. 1737 67

Eplerenone, a mineralocorticoid receptor antagonist, is reported to be effective to prevent end-stage cardiovascular damage induced by aldosterone. However, the effect of eplerenone on brain damage is not fully understood. Here, we investigated whether pretreatment with eplerenone attenuates stroke size in mice subjected to middle cerebral artery occlusion. Middle cerebral artery occlusion with a microfilament technique induced focal ischemia, to approximately 25% of the total area in a coronal section of the brain. Treatment with eplerenone at a dose of 1.67 mg/g chow significantly reduced the ischemic area, ischemic volume, and neurological deficit, without a blood pressure-lowering effect. Laser-Doppler flowmetry analysis showed a decrease in surface cerebral blood flow in the peripheral region after 1 h of middle cerebral artery occlusion. This decrease was smaller in mice treated with eplerenone. Superoxide production evaluated by staining with dihydroethidium was attenuated in the ischemic area of the brain in eplerenone-treated mice. Taken together, our findings suggest that eplerenone has a protective effect on ischemic brain damage, at least partly due to improvement of cerebral blood flow in the penumbra and reduction of oxidative stress.
 ...
PMID:Pretreatment with eplerenone reduces stroke volume in mouse middle cerebral artery occlusion model. 1747 37

Although great progress has been made in reducing renarrowing of the lumen after stenting of coronary arteries, a considerable number of patients develop recurrent in-stent stenosis. Several studies suggest that neointimal proliferation is the crucial pathophysiological process underlying restenosis after stenting. The renin-angiotensin-aldosterone system (RAS) has been implicated in the development of neointimal hyperplasia. We tested the hypothesis that polymorphisms of the RAS genes are associated with recurrent in-stent restenosis (ISR). Coronary stent implantation was performed in 272 patients with clinical symptoms or objective signs of ischemia. At follow-up angiography 6 months after stenting, 81 patients (29.8%) revealed in-stent restenosis. These patients underwent balloon angioplasty and were scheduled for a further 6 months of follow up. One year after initial stenting of the coronary artery, 39 patients displayed no significant angiographic ISR, whereas 42 patients developed recurrent in-stent restenosis (RISR). The survey of specific functional polymorphisms of the RAS, namely the angiotensin-I converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence RISR in the high-risk cohort was not associated with any of the polymorphisms examined in this study.
 ...
PMID:Recurrent in-stent restenosis is not associated with the angiotensin-converting enzyme D/I, angiotensinogen Thr174Met and Met235Thr, and the angiotensin-II receptor 1 A1166C polymorphism. 1754 Nov 27

The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in rats with ischemia-induced HF and sham-operated controls. Brain ALDO levels were proportional to plasma ALDO levels across the spectrum of rats studied. Compared with sham-operated controls rats, HF rats had higher plasma and hypothalamic tissue levels of ALDO. HF rats also had higher expression of mRNA and protein for angiotensin-converting enzyme and angiotensin type 1 receptors in the hypothalamus, increased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide generation in the paraventricular nucleus of the hypothalamus, increased excitation of paraventricular nucleus neurons, and increased plasma norepinephrine. HF rats treated for 4 weeks with intracerebroventricular RU28318 (1 microg/h), a selective mineralocorticoid receptor antagonist, had less hypothalamic angiotensin-converting enzyme and angiotensin type 1 receptor mRNA and protein, less reduced nicotinamide-adenine dinucleotide phosphate-induced superoxide in the paraventricular nucleus, fewer excited paraventricular nucleus neurons, and lower plasma norepinephrine. RU28318 had no effect on plasma ALDO or on angiotensin-converting enzyme or angiotensin type 1 receptor expression in brain cortex. The data demonstrate that ALDO of adrenal origin enters the hypothalamus in direct proportion to plasma levels and suggest that ALDO contributes to the upregulation of hypothalamic RAS activity and sympathetic drive in heart failure.
 ...
PMID:Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure? 1821 62

Hypokalemia (serum K+ < 3.5 mEq/1) is a potentially serious adverse effect of diuretic ingestion. We report a 27 year-old woman admitted with muscle weakness, a serum potassium of 2.0 mEq/1, metabolic alkalosis and EKG abnormalities simulating cardiac ischemia, that reverted with potassium chloride administration. She admitted high dose furosemide self-medication for edema. Glomerular filtration rate, tubular sodium reabsorption, potassium secretion, the renin-aldosterone system, total body water distribution and capillary permeability, were studied sequentially until 90 days after her admission. There was hyperactivity of the renin-aldosterone axis, reduction in extracellular and intracellular volumes, normal capillary permeability and high sodium tubular reabsorption, probably explained by a "rebound" salt retention associated with her decreased extracellular volume.
 ...
PMID:[Hypokalemia, hypovolemia and electrocardiographic changes due to furosemide abuse. Report of one case]. 1825 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>