Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension.
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Data obtained during the last two decades show that spontaneously hypertensive rats, an acceptable experimental model of primary human hypertension, possess increased activity of both ubiquitous and renal cell-specific isoforms of the Na+/H+ exchanger (NHE) and Na+-K+-2Cl- cotransporter. Abnormalities of these ion transporters have been found in patients suffering from essential hypertension. Recent genetic studies demonstrate that genes encoding the beta- and gamma-subunits of ENaC, a renal cell-specific isoform of the Na+-K+-2Cl- cotransporter, and alpha3-, alpha1-, and beta2-subunits of the Na+-K+ pump are localized within quantitative trait loci (QTL) for elevated blood pressure as well as for enhanced heart-to-body weight ratio, proteinuria, phosphate excretion, and stroke latency. On the basis of the homology of genome maps, several other genes encoding these transporters, as well as the Na+/H+ exchanger and Na+-K+-2Cl- cotransporter, can be predicted in QTL related to the pathogenesis of hypertension. However, despite their location within QTL, analysis of cDNA structure did not reveal any mutation in the coding region of the above-listed transporters in primary hypertension, with the exception of G276L substitution in the alpha1-Na+-K+ pump from Dahl salt-sensitive rats and a higher occurrence of T594M mutation of beta-ENaC in the black population with essential hypertension. These results suggest that, in contrast to Mendelian forms of hypertension, the altered activity of monovalent ion transporters in primary hypertension is caused by abnormalities of systems involved in the regulation of their expression and/or function. Further analysis of QTL in F2 hybrids of normotensive and hypertensive rats and in affected sibling pairs will allow mapping of genes causing abnormalities of these regulatory pathways. (+info)
Sympathetic nervous system activity and alpha-adrenergic responsiveness in older hypertensive humans.
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We have previously demonstrated in normotensive humans an age-associated increase in sympathetic nervous system (SNS) activity combined with appropriate downregulation of alpha-adrenergic responsiveness. Impaired downregulation of alpha-adrenergic responsiveness, despite a comparable level of SNS activity, could contribute to higher blood pressure in older hypertensive humans. We measured arterial plasma norepinephrine (NE) levels and the extravascular NE release rate (NE2) derived from [3H]NE kinetics (to assess systemic SNS activity), and platelet and forearm arterial adrenergic responsiveness in 20 normotensive (N) and in 24 hypertensive (H), otherwise healthy, older subjects (60-75 yr). Although plasma NE levels were similar (N 357 +/- 27 vs. H 322 +/- 22 pg/ml; P = 0.37), NE2 tended to be greater in the hypertensive group (H 2.23 +/- 0.21 vs. N 1.64 +/- 0.20 microgram. min-1. m-2; P = 0. 11), and the NE metabolic clearance rate was greater (H 1,100 +/- 30 vs. N 900 +/- 50 ml/m2; P = 0.004). In the hypertensive group, there was a greater alpha-agonist-mediated inhibition of platelet membrane adenylyl cyclase activity and a NE- but not ANG II-mediated decrease in forearm blood flow. Compared with normotensive subjects, in older hypertensive subjects 1) NE metabolic clearance rate is increased, 2) systemic SNS activity tends to be increased, and 3) arterial and platelet alpha-adrenergic responsiveness is enhanced. These results suggest that heightened SNS activity coupled with enhanced alpha-adrenergic responsiveness may contribute to elevated blood pressure in older hypertensive humans. (+info)
5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats.
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We previously demonstrated a change in the receptors mediating 5-hydroxytryptamine (5-HT)-induced contraction in arteries of deoxycorticosterone acetate (DOCA)-salt-hypertensive rats. Specifically, contraction to 5-HT is mediated primarily by 5-HT2A receptors in arteries from normotensive sham rats and by both 5-HT2A and 5-HT2B receptors in arteries from hypertensive rats. We hypothesized that the 5-HT2B receptor may play a role in maintaining the high blood pressure of DOCA-salt-hypertensive rats, and herein we provide data connecting in vitro and in vivo findings. The endothelium-denuded isolated superior mesenteric artery of DOCA-salt rats displayed a marked increase in maximum contraction to the newly available 5-HT2B-receptor agonist BW-723C86 compared with that of arteries from sham rats, confirming that the 5-HT2B receptor plays a greater role in 5-HT-induced contraction in arteries from DOCA-salt rats. In chronically instrumented rats, the 5-HT2B-receptor antagonist LY-272015 (0.3, 1.0, and 3.0 mg/kg iv at 30-min intervals) was given cumulatively 1 time/wk during 4 wk of continued DOCA-salt treatment. LY-272015 did not reduce blood pressure of the sham-treated rats at any time or dose. However, LY-272015 (1.0 and 3. 0 mg/kg) significantly reduced mean blood pressure in a subgroup of week 3 (-20 mmHg) and week 4 DOCA-salt (-40 mmHg) rats that had extremely high blood pressure (mean arterial blood pressure approximately 200 mmHg). Blockade of 5-HT2B receptors by in vivo administration of LY-272015 (3.0 mg/kg) was verified by observing reduced 5-HT-induced contraction in rat stomach fundus, the tissue from which the 5-HT2B receptor was originally cloned. These data support the novel hypothesis that 5-HT2B-receptor expression is induced during the development of DOCA-salt hypertension and contributes to the maintenance of severe blood pressure elevations. (+info)
Epidermal growth factor: a potent vasoconstrictor in experimental hypertension.
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We have tested the hypothesis that growth factor signaling pathways are augmented in hypertension, a disease associated with vascular smooth muscle cell growth. Thoracic aorta was dissected from deoxycorticosterone acetate-salt (DOCA-salt) and one kidney, one clip (1K, 1C) hypertensive rats and from sham normotensive rats for use in isolated tissue bath experiments. Systolic blood pressure was significantly higher in DOCA-salt and 1K, 1C than in normotensive sham rats: 192 +/- 7, 185 +/- 10, and 117 +/- 4 mmHg, respectively. Although virtually no contraction to epidermal growth factor (EGF) was observed in endothelium-denuded sham rat aorta [1 +/- 1% phenylephrine (PE) (10 micromol/l)-induced contraction], the maximal EGF-induced contraction was 45 +/- 7% in endothelium-denuded aorta from DOCA-salt hypertensive rats and 39 +/- 7% in aorta from 1K, 1C rats. Although slightly attenuated, a contraction to EGF was still observed in endothelium-intact aortic strips from 28-day DOCA-salt hypertensive rats. We also conducted concentration-response curves to EGF on days 1, 3, 5, 7, 14, and 21 of DOCA-salt therapy. A significant contraction to EGF in aorta from DOCA-salt rats was observed on day 14, when DOCA-salt rats had significantly higher blood pressure than sham rats: 188 +/- 6 and 122 +/- 3 mmHg, respectively. Transforming growth factor-alpha, an agonist of the EGF receptor, contracted DOCA-salt rat aorta (30 +/- 7% PE-induced contraction) but not sham aorta (3 +/- 3%). The EGF receptor tyrosine kinase inhibitor 4,5-dianilinophthalimide (10 micromol/l), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 micromol/l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol/l), but not the cyclooxygenase inhibitor indomethacin (10 micromol/l), virtually abolished EGF-induced contraction (85, 98, and 99% reduction, respectively). These data support a striking difference in EGF signaling between normotensive and hypertensive animals. Furthermore, they provide evidence that growth factors should be considered vasoconstrictors as well as growth modulators in hypertension. (+info)
Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension.
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Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 +/- 6 mmHg by day 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg. kg-1. 24 h-1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 +/- 17 to 277 +/- 104 pg. 100 g body wt-1. 24 h-1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng. 100 g body wt-1. 24 h-1 (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA. (+info)
Genetic control of renal thiazide receptor response to dietary NaCl and hypertension.
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Excess NaCl increases blood pressure in some strains of animals but not others. An 8% NaCl diet did not change renal thiazide receptor (TZR) density in two salt-resistant normotensive rat strains (Wistar-Kyoto and Sprague-Dawley) [Fanestil, D. D., D. A. Vaughn, and P. Blakely. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1241-R1245, 1997]. However, the renal response to salt differs in normal and hypertensive kidneys [Rettig, R., N. Bandelow, O. Patschan, B. Kuttler, B. Frey, and A. Uber. J. Hum. Hypertens. 10: 641-644, 1996]. Therefore, we examined two strains with salt-aggravated hypertension. Renal TZR did not change when Dahl-S (salt sensitive) animals became hypertensive with 8% dietary NaCl. In contrast, renal TZR decreased 34%, whereas blood pressure increased further, in SHR with 8% dietary NaCl. Blood pressure increased after NG-nitro-L-arginine in SHR, but renal TZR did not change, indicating the salt-induced decrease in TZR in SHR cannot be attributed nonspecifically to elevated arterial pressure. We conclude that the renal response to NaCl-induced increases in blood pressure can be genetically modulated independently of the genes that mediate either the primary hypertension or the salt sensitivity of the hypertension. This finding may be of use in future studies directed at identifying genotypes associated with salt-dependent hypertension. (+info)
Pharmacokinetic-pharmacodynamic modeling of metoprolol stereoisomers in spontaneously hypertensive rat.
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AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of metoprolol stereoisomers, and compare their inhibitory effects on cardiovascular system in the spontaneously hypertensive rats (SHR). METHODS: The drug concentration in plasma was measured by the reversed phase HPLC and the drug effects were recorded by polygraph. The pharmacokinetic parameters and the PK-PD model parameters were calculated. RESULTS: The plasma concentration-time profiles were adequately described by two-compartment model. Differences of Vd between (+)-Met and (-)-Met were found. The relationships between effects and concentration of effect compartment were represented by the sigmoid-Emax model. The Css50 of Vmax, dp/dtmax, and HR inhibitory effects of (+)-Met were larger than those of (-)-Met. CONCLUSION: Stereo-selective drug distribution and different potencies of the inhibitory effects of (+)-Met and (-)-Met existed in SHR. (+info)
A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP).
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AIMS: Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use. METHODS: A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme's (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy. RESULTS: 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%S) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs. CONCLUSIONS: In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin. (+info)