Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt sensitive humans and rats develop hypertension even on a normal salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes. These aldehydes bind sulfhydryl groups of membrane proteins, altering calcium channels, increasing cytosolic free calcium ([Ca2+]i) and blood pressure. Treatment with lipoic acid, an endogenous sulfur-containing fatty acid, normalizes insulin resistance and lowers tissue aldehyde conjugates, cytosolic [Ca2+]i, and blood pressure in spontaneously hypertensive rats (SHR). The objective of this study was to investigate the effects of a normal salt diet on tissue aldehyde conjugates, cytosolic [Ca2+]i and blood pressure in DSS rats and to determine whether lipoic acid supplementation prevents the increase in blood pressure and biochemical changes. Starting at 7 weeks of age, DSS rats were divided into three groups of six animals each and treated for 6 weeks with diets as follows: DSS-low salt, 0.4% NaCl; DSS-normal salt, 0.7% NaCl, and; DSS-normal salt + lipoic acid, 0.7% NaCl + lipoic acid 500 mg/kg feed. At completion, animals in the normal salt group had elevated systolic blood pressure, cytosolic [Ca2+]i and tissue aldehyde conjugates as compared to the low salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary lipoic acid supplementation attenuated the increase in systolic blood pressure and associated biochemical and histopathological changes.
 ...
PMID:Dietary lipoic acid supplementation attenuates hypertension in Dahl salt sensitive rats. 1633 93

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.
 ...
PMID:Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. 1641 45

Acrolein, a major lipid peroxidation product, has been associated with both CNS trauma and neurodegenerative diseases. Because of its long half-life, acrolein is a potent endogenous toxin capable of killing healthy cells during the secondary injury process. Traditionally, attempts to intervene in the process of progressive cell death after the primary injury have included scavenging reactive oxygen species (so-called free radicals). The animal data supporting such an approach have generally been positive, but all human clinical trials attempting a similar outcome in human CNS injury have failed. New drugs that might reduce toxicity by scavenging the products of lipid peroxidation present a promising, and little investigated, therapeutic approach. Hydralazine, a well-known treatment for hypertension, has been reported to react with acrolein, forming hydrazone in cell-free systems. In the companion paper, we have established an acrolein-mediated cell injury model using PC12 cells in vitro. Here we test the hypothesis that the formation of hydrazone adducts with acrolein is able to reduce acrolein toxicity and spare a significant percentage of the population of PC12 cells from death. Concentrations of approximately 1 mM of this aldehyde scavenger can rescue over 80% of the population of PC12 cells. This study provides a basis for a new pharmacological treatment to reduce the effects of secondary injury in the damaged and/or diseased nervous system. In particular, we describe the need for new drugs that possess aldehyde scavenging properties but do not interfere with the regulation of blood pressure.
 ...
PMID:Hydralazine rescues PC12 cells from acrolein-mediated death. 1661 36

Low alcohol intake in humans lowers the risk of coronary heart disease and may lower blood pressure. In hypertension, insulin resistance with altered glucose metabolism leads to increased formation of aldehydes. We have shown that chronic low alcohol intake decreased systolic blood pressure (SBP) and tissue aldehyde conjugates in spontaneously hypertensive rats and demonstrated a strong link between elevated tissue aldehyde conjugates and hypertension in salt-induced hypertensive Wistar-Kyoto (WKY) rats. This study investigated the antihypertensive effect of chronic low alcohol consumption in high salt-treated WKY rats and its effect on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca2+]i, and renal vascular changes. Animals, aged 7 weeks, were divided into three groups of six animals each. The control group was given normal salt diet (0.7% NaCl) and regular drinking water; the high salt group was given a high salt diet (8% NaCl) and regular drinking water; the high salt + ethanol group was given a high salt diet and 0.25% ethanol in drinking water. After 10 weeks, SBP, platelet [Ca2+]i, and tissue aldehyde conjugates were significantly higher in rats in the high salt group as compared with controls. Animals on high salt diets also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Ethanol supplementation prevented the increase in SBP and platelet [Ca2+]i and aldehyde conjugates in liver and aorta. Kidney aldehyde conjugates and renal vascular changes were attenuated. These results suggest that chronic low ethanol intake prevents salt-induced hypertension and attenuates renal vascular changes in WKY rats by preventing an increase in tissue aldehyde conjugates and cytosolic [Ca2+]i.
 ...
PMID:Low ethanol intake prevents salt-induced hypertension in WKY rats. 1668 63

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.
 ...
PMID:Acrolein generation stimulates hypercontraction in isolated human blood vessels. 1709 30

Reactive aldehydes and ketones are produced as a result of oxidative stress in several disease processes. Considerable evidence is now accumulating that these reactive carbonyl products are also involved in the progression of diseases, including neurodegenerative disorders, diabetes, atherosclerosis, diabetic complications, reperfusion after ischemic injury, hypertension, and inflammation. To counter carbonyl stress, cells possess enzymes that can decrease aldehyde load. These enzymes include aldehyde dehydrogenases (ALDH), aldo-keto reductases (AKR), carbonyl reductase (CBR), and glutathione S-transferases (GST). Some of these enzymes are inducible by chemoprotective compounds via Nrf2/ARE- or AhR/XRE-dependent mechanisms. This review describes the metabolism of reactive carbonyls and discusses the potential for manipulating levels of carbonyl-metabolizing enzymes through chemical intervention.
 ...
PMID:Reactive carbonyls and oxidative stress: potential for therapeutic intervention. 1757 May 31

We investigated the effects of 4% fructose plus moderately high salt (MHS) (4% NaCl) treatment on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca2+]i), renal morphology, and systolic blood pressure (SBP) in Wistar-Kyoto rats, and whether these effects were reversible (R) after withdrawal of treatment. At age 7 weeks, rats were divided into 4 groups: NS group, given normal salt (NS) diet (0.7% NaCl) for 18 weeks; NS+F(R) group, NS diet and fructose in water for 14 weeks, then 4 weeks fructose withdrawal; MHS+F group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 12 weeks; and MHS+F(R) group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 8 weeks, then MHS and fructose withdrawal for 4 weeks. SBP in the NS+F(R) group increased during fructose treatment, but normalized within 1 week of withdrawal. Tissue aldehyde conjugates and platelet [Ca2+]i were normal at completion. Adverse renal vascular changes did not reverse to normal and were similar to those of the salt plus fructose-treated groups. This may have implications for future development of hypertension. MHS did not cause any additional increase in SBP or associated tissue alterations when added to fructose treatment. However, the SBP and tissue changes persisted even after discontinuation of treatment. The fructose and salt combination may result in long-lasting vascular alterations leading to hypertension.
 ...
PMID:Fructose-induced hypertension in Wistar-Kyoto rats: interaction with moderately high dietary salt. 1761 50

The vascular diseases, hypertension and atherosclerosis, affect millions of individuals worldwide, and account for a large number of deaths globally. A better understanding of the mechanism of these conditions will lead to more specific and effective therapies. Hypertension and atherosclerosis are both characterized by insulin resistance, and we suggest that this plays a major role in their etiology. The cause of insulin resistance is not known, but may be a result of a combination of genetic and lifestyle factors. In insulin resistance, alterations in glucose and lipid metabolism lead to the production of excess aldehydes including glyoxal and methylglyoxal. These aldehydes react non-enzymatically with free amino and sulfhydryl groups of amino acids of proteins to form stable conjugates called advanced glycation end products (AGEs). AGEs act directly, as well as via receptors to alter the function of many intra- and extracellular proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation and oxidative stress. All these changes are characteristic of hypertension and atherosclerosis. Human and animal studies have demonstrated that increased AGEs are also associated with these conditions. A pathological role for AGEs is substantiated by studies showing that therapies that attenuate insulin resistance and/or lower AGEs, are effective in decreasing oxidative stress, lowering blood pressure, and attenuating atherosclerotic vascular changes. These interventions include lipoic acid and other antioxidants, AGE breakers or soluble receptors of AGEs, and aldehyde-binding agents like cysteine. Such therapies may offer alternative specific means to treat hypertension and atherosclerosis. An adjunct therapy may be to implement lifestyle changes such as weight reduction, regular exercise, smoking cessation, and increasing dietary intake of fruits and vegetables that also decrease insulin resistance as well as oxidative stress.
 ...
PMID:Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. 1787 39

Captopril, a thiol-containing antihypertensive drug, and lisinopril, an amino-containing antihypertensive drug, will both prolong the prothrombin time (PT) of Level I plasma. Acetaldehyde, a product of ethanol metabolism, also prolongs PT. In a study to examine the interrelationship between hypertension, hemostasis, and alcoholism, an examination of the impact of acetaldehyde on the effects of captopril and lisinopril upon PT was undertaken. It was observed that the pre-mixing of 7.7 x 10(-3) M captopril with 40.6 mM acetaldehyde for 30 min at R.T. prior to the addition to plasma results in a prolongation of PT which is less than that caused by acetaldehyde alone. Successive additions of captopril and acetaldehyde to plasma also yield a PT which is less than that of acetaldehyde alone. These data suggest that captopril may partially inactivate and detoxify the acetaldehyde effect on hemostasis upon interaction to form a thiohemiacetal. Captopril may prolong PT by the reduction of the S-S bridges in the coagulation factors. Lisinopril behaves similarly to captopril, prolonging PT. Successive additions of lisinopril and acetaldehyde, or pre-mixtures thereof, to plasma result in a lesser prolongation of clotting time relative to acetaldehyde alone. Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde, these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma, albeit by different mechanisms.
 ...
PMID:Captopril and lisinopril decrease acetaldehyde effects upon the prothrombin time. 1793 66

Hypertension is commonly observed in alcoholics. Both the renin-angiotensin system (RAS) and the non-renin-angiotensin system (NRAS) have been implicated in the dynamics of blood pressure maintenance. In bilaterally nephrectomized rats, acetaldehyde has been reported to enhance the generation of the rate-limiting angiotensin I (ANG I) in the plasma, and in humans it inhibits the activity of several angiotensinases (A, B, and M) in the serum, thereby promoting a hypertensive set of reactions. We report here the results of a study on the effect of acetaldehyde upon cathepsin G and mast cell chymase. Acetaldehyde enhanced cathepsin G activity at all of the concentrations tested between 11.2 and 223.5 mM in a statistically significant manner. Since cathepsin G is one of several enzymes transforming ANG I into ANG II and is also capable of cleaving ANG II directly from angiotensinogen, we suggest that alcoholism, which will generate exogenous acetaldehyde from ingested alcohol, may be a contributory factor for an elevated cathepsin G activity and, consequently, hypertension via the NRAS. Chymase activity also is elevated in the presence of 440 mM acetaldehyde and diminished in the presence of 27 mM acetaldehyde. Since both enzymes also degrade ANG II, the degradative effects of each enzyme on ANG II may neutralize one another.
 ...
PMID:Effect of acetaldehyde upon cathepsin G and chymase. NRAS implications. 1793 68


<< Previous 1 2 3 4 5 6 7 Next >>