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)

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.
Hypertension 2000 Feb
PMID:Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. 1067 17

During essential and secondary arterial hypertension it is possible to observe changes in microcirculation perfusion associated with a reduction in tissue oxygenation due in part to hemorheological changes such as an increase in blood viscosity or the formation of the red blood cell "rouleaux" which favour an increase in peripheral resistance and can cause or worsen arterial hypertension. We studied 21 healthy subjects (11 male and 10 female aged 42 +/- 4) and 26 hypertensive subjects (14 male and 12 female aged 49 +/- 3). The patients were non smokers and non suffering from respiratory or haemathological pathologies. They were not undergoing antihypertensive or vasodilatory pharmaceutical treatment. The patients suffered from mild hypertension (II WHO) with Peripheral Occlusive Arterial Disease (POAD II "a" acc. to Leriche-Fontaine class.). The patients showed an increase in cholesterolaemia (6.42 +/- 0.81 mmol/l) and trygliceridaemia (2.73 +/- 0.09 mmol/l) at an average level. The patients were studied in standard conditions with a constant temperature of 22 degrees C. We measured SBP, DBP, MBP, and the HR. We also measured the elongation index (EI) (with shear stress range 0.30 to 30 pascals) using LORCA, acc. to Hardeman method (1994), in order to study the erythrocyte deformability and aggregation kinetics in dynamic condition. To evaluate deformability in static conditions we calculated the Erythrocyte Morphologic Index (EMI), acc. to Forconi method, via the bowl/discocyte ratio (for 100 red blood cells fixed in glutaraldehyde at 0.3% and observed with an optical microscope under immersion in glycerol). Peripheral oxygenation was taken transcutaneously (TcpO2). To establish the level of vascular disease we used the Regional Perfusion Index (RPI = TcpO2 foot/TcpO2 subclavean) and doppler guided Winsor Index (WI). The Student "t" test and linear regression were used for the statistical analysis. Our data confirm a reduction in peripheral tissue oxygenation in hypertensives especially if suffering from vascular disease which correlates significantly (p < 0.01) with a reduction in red blood cell deformability. This itself can increase peripheral resistances and favour the onset of hemorheological complications, at a cerebral-vascular level, which are frequent in hypertensives.
 ...
PMID:Hemorheology in complicated hypertension. 1071 62

1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin, following work with Theophile-Jules Pelouze. Sobrero first noted the 'violent headache' produced by minute quantities of NG on the tongue. 2. Constantin Hering, in 1849, tested NG in healthy volunteers, observing that headache was caused with 'such precision'. Hering pursued NG ('glonoine') as a homeopathic remedy for headache, believing that its use fell within the doctrine of 'like cures like'. 3. Alfred Nobel joined Pelouze in 1851 and recognized the potential of NG. He began manufacturing NG in Sweden, overcoming handling problems with his patent detonator. Nobel suffered acutely from angina and was later to refuse NG as a treatment. 4. During the mid-19th century, scientists in Britain took an interest in the newly discovered amyl nitrite, recognized as a powerful vasodilator. Lauder Brunton, the father of modern pharmacology, used the compound to relieve angina in 1867, noting the pharmacological resistance to repeated doses. 5. William Murrell first used NG for angina in 1876, although NG entered the British Pharmacopoeia as a remedy for hypertension. William Martindale, the pharmaceutical chemist, prepared '...a more stable and portable preparation': 1/100th of a grain in chocolate. 6. In the early 20th century, scientists worked on in vitro actions of nitrate-containing compounds although little progress was made towards understanding the cellular mode of action. 7. The NG industry flourished from 1900, exposing workers to high levels of organic nitrites; the phenomena of nitrate tolerance was recognized by the onset of 'Monday disease' and of nitrate-withdrawal/overcompensation by 'Sunday Heart Attacks'. 8. Ferid Murad discovered the release of nitric oxide (NO) from NG and its action on vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized the importance of the endothelium in acetylcholine-induced vasorelaxation (in 1980) and Louis Ignarro and Salvador Moncada identified endothelial-derived relaxing factor (EDRF) as NO (in 1987). 9. Glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of NG and its established efficacy make it the mainstay of angina pectoris relief.
 ...
PMID:A short history of nitroglycerine and nitric oxide in pharmacology and physiology. 1077 31

We induced ischemia, hypertension and hypotension in 15 rabbits in order to evaluate the ischemic changes in the optic nerve and the effect of hypertension and hypotension on ischemia. We cauterized the right internal and external carotid arteries of 15 rabbits and applied dopamine hydrochloride and glycerol trinitrate to 5 each of these rabbits. Two rabbits were used as controls. We enucleated both eyes of all animals at the 24th hour. All of the optic nerves underwent biochemical, histopathological and ultrastructural examination. Histopathological and transmission electron-microscopic changes were found to be more prominent in the hypotensive group. We observed decreased superoxide dismutase levels in all groups, but it was more evident in the third group. In comparison to hypertension, hypotension is found to be a more important factor in the development of early degenerative changes.
 ...
PMID:Early ultrastructural findings and superoxide dismutase levels in experimental ischemic optic neuropathy: effect of hypertension and hypotension on ischemic changes. 1112 71

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.
 ...
PMID:NO-independent regulatory site on soluble guanylate cyclase. 1124 81

In Western society, the triad of hypertension, metabolic syndrome and obesity (which caries a high risk for renal disease) is increasing, as is the intake of caffeine. However, no information is available regarding the metabolic or renal consequences of caffeine consumption in this complex disease entity. The purpose of this study was to investigate the effects of chronic caffeine consumption on renal function and metabolic status in obese ZSF1 rats, an animal model of obesity, hypertension and the metabolic syndrome. Fifteen, 18-week-old male, obese ZSF1 rats were randomized to drink tap water (Cont, n = 8) or 0.1% solution of caffeine (Caff, n = 7) for 8 weeks. Metabolic and renal function measurements were performed at baseline and after 4 and 8 weeks of treatment. Caffeine treatment significantly (p < 0.05) reduced body weight, food, and fluid consumption and improved insulin sensitivity (fasting insulin 129.6+/-8.1 vs 97.5+/-3.6 microIU/mL; fed insulin 146.3+/-8.5 vs 110.6+/-3.4 microIU/mL; fasting glucose 138.7+/-13.4 vs 145+/-8.0 mg/dL; fed glucose 373+/-19.4 vs 283.3+/-19.6 mg/dL, Cont vs Caff, respectively). After 8 weeks of caffeine treatment, animals were less glycosuric as compared with control group. Area under glucose curves (AUC-glucose) in oral glucose tolerance test did not differ between the two groups (AUC- glucose: 592.5+/-42.7 vs 589.5+/-20.5 mg/dL x h, Cont vs Caff), whereas caffeine treatment significantly decreased AUC of insulin (AUC-insulin: 257.77+/-12.9 vs 198.0+/-5.9 microIU/mL x h, Cont vs. Caff, p<0.05). No differences were found with regard to plasma triglycerides and glycerol levels; however, caffeine significantly increased cholesterol levels after 4 and 8 weeks (2F-Anova, p<0.001). Moreover, caffeine significantly decreased creatinine clearance after 4 and 8 weeks (CrCl, Cont: 3.5+/-0.4, Caff: 2.2+/-0.2 L/kg/day, p<0.05) and increased protein/CrCl ratio (Cont: 323+/-30, Caff: 527+/-33 mg/L/day). Caffeine treatment for 8 weeks tended to increase plasma norepinephrine levels (p<0.06), but the two groups did not differ with regard to plasma renin activity, blood pressure, renal blood flow or and renal vascular resistance. The study indicates that caffeine improves insulin sensitivity but increases plasma cholesterol levels and impairs renal function in obesity with the metabolic syndrome and hypertension. Our results imply that the health consequences of chronic caffeine consumption may depend heavily on underlying pathophysiology process.
 ...
PMID:Renal and metabolic effects of caffeine in obese (fa/fa(cp)), diabetic, hypertensive ZSF1 rats. 1141 48

The recently discovered C825T polymorphism of the G-protein beta 3 subunit has been reported to be associated with the development of hypertension and obesity. The aim of our study was to investigate the relationship between the C825T polymorphism and functional aspects of human adipose cells, particularly with regard to adipose differentiation and lipolysis. Adipose tissue samples were collected from 65 women with a BMI ranging from 19.7 to 39.7 kg/m 2 undergoing surgical mammary reduction. The stromal cells were allowed to undergo differentiation in primary culture using adipogenic media of defined composition. No significant difference was observed between the CC carriers and the carriers of the T allele under all adipogenic conditions with differentiation capacity related to the genotype. In a subgroup of patients (n = 20), lipolysis in isolated fat cells was determined by measurement of glycerol in the culture medium upon catecholamine exposure. Glycerol release after 10(-7) mmol/l isoproterenol was significantly higher in fat cells from the 10 CC carriers than in adipocytes from the T allele carriers when expressed as percentage of basal glycerol release (increase above baseline: CC: 809 +/- 174 %, T allele carriers: 247 +/- 88 %, p = 0.01), while basal glycerol concentrations were no different according to genotype after controlling for either age or BMI. In conclusion, this study provides the first evidence that the GNB3 825T allele is associated with an impairment of the beta-adrenergic control of lipolysis.
 ...
PMID:Effects of the G-protein beta3 subunit 825T allele on adipogenesis and lipolysis in cultured human preadipocytes and adipocytes. 1238 23

Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 micro mol/L angiotensin II in the presence of the L- or D-isomer of N(G)-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (P<0.0438) but decreased in muscle (P<0.007). In muscle, dialysate pyruvate increased (P<0.0002), whereas lactate/pyruvate ratio decreased (P<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.
Hypertension 2003 Jan
PMID:Tissue-specific response to interstitial angiotensin II in humans. 1251 27

The aquaporins are a family of small, integral membrane proteins that function as plasma membrane transporters of water and in some cases small polar solutes such as glycerol. There are at least 10 distinct aquaporins in mammals with specific patterns of expression in epithelial, endothelial and other tissues. Recent studies in aquaporin-null mice have indicated key roles for certain aquaporins in the urinary concentrating mechanism, fluid secretion by glands, brain swelling, skin moisture, hearing and vision, and gastrointestinal absorption. The only known inhibitors of some aquaporins are mercurial sulfhydryl-reactive compounds, which are too toxic and nonspecific for use in vivo. Small-molecule or peptide aquaporin blockers have potential applications in the treatment of disorders of fluid/pressure homeostasis such as heart failure, hypertension, brain swelling and glaucoma.
 ...
PMID:Applications of aquaporin inhibitors. 1281 84

1. Free radicals mediate cerebral ischaemic injury associated with heatstroke. Magnolol, an active component of Magnolia officinalis, is 1000-fold more potent than alpha-tocopherol in inhibiting lipid peroxidation in rat mitochondria. The aim of the present study was to ascertain whether magnolol attenuated cerebral ischaemic injury and free radical formation associated with heatstroke. 2. Urethane-anaesthetized rats were exposed to heat stress (ambient temperature 42 degrees C) to induce heatstroke. Controlled rats were exposed to 24 degrees C. Mean arterial pressure, cerebral perfusion pressure and cerebral blood flow after the onset of heatstroke were all significantly lower than in control rats. However, colonic temperature, intracranial pressure, heart rate, cerebral free radicals, lipid peroxidation and the neuronal damage score were greater after the onset of heatstroke. 3. Magnolol (20 or 40 mg/kg, i.v.) significantly attenuated the heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral ischaemia and neuronal damage and increased free radical formation and lipid peroxidation in the brain. The extracellular concentrations of ischaemic (e.g. glutamate and lactate/pyruvate ratio) and damage (e.g. glycerol) markers in the corpus striatum were increased after the onset of heatstroke. Magnolol significantly attenuated the increase in striatal ischaemia and damage markers associated with heatstroke. 4. Thus, it appears that magnolol has impressive effects against heatstroke reactions.
 ...
PMID:Magnolol protects against cerebral ischaemic injury of rat heatstroke. 1285 31


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