摘要:

Liddle's syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel beta- or gamma-subunits. These mutations delete or alter a conserved proline-rich amino acid sequence referred to as the PY-motif. We report here a Liddle's syndrome family with a beta Arg564X mutation with a premature stop codon deleting the PY-motif of the beta-subunit. This family shows marked phenotypic variation in blood pressure, serum potassium levels, and age of onset of hypertension. Given the similarity with primary hypertension, changes in the C termini of the beta- or gamma-subunits may contribute to the development of primary hypertension or to hypertension associated with diabetic nephropathy. Accordingly, the coding sequences for the cytoplasmic C termini of the beta- and gamma-subunits were screened for mutations with the use of polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing in 105 subjects with primary hypertension and 70 subjects with diabetic nephropathy. One frequent polymorphism was identified, but its frequency did not differ among subjects with primary hypertension, subjects with diabetic nephropathy, or control subjects. Two of the 175 subjects with primary hypertension or diabetic nephropathy showed variants that were not present in 186 control subjects. None of the variants changed the PY-motif sequence. In conclusion, a beta Arg564X mutation is the likely cause of Liddle's syndrome in this Swedish family, but it is unlikely that mutations in the beta- and gamma-subunit genes of the epithelial sodium channel play a significant role in the pathogenesis of primary hypertension or diabetic nephropathy. (Hypertension. 1998;31:1118-1124.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The amplitude of the whole-cell L-type Ca2+channel current recorded from vascular smooth muscle cells is reportedly greater in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). However, no study has examined properties of single Ca2+channels in arterial cells from these strains. To further test the hypothesis that activation of L-type Ca2+channels in arterial smooth muscle cells would be enhanced in SHR, we recorded single Ca2+channel currents in resistance mesenteric artery cells from SHR and WKY (8 to 9 weeks of age) using a cell-attached patch clamp technique. With 50 mmol/L Ba2+in the recording pipette, the depolarizing pulse from a holding potential of -40 mV evoked the single L-type Ca2+channel current. Opening of the single channels was more frequent in cells from SHR than from WKY. Single-channel conductance (20 pS) and open time (1 ms at 0 mV) did not differ in the two strains. The results suggest that an increased amplitude of the whole-cell current can be attributed to the enhanced opening of single Ca2+channels in the arterial smooth muscle cells from SHR compared with WKY. (Hypertension. 1998;31:1125-1129.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

or=to160/95 mm Hg and/or taking antihypertensive medication) over 7 years of follow-up was nearly identical: 25.7% in African Americans and 25.3% in whites. Baseline age, gender, blood pressure, and heart rate were all associated with the incidence of hypertension. Even after adjustment for these covariables, the risk of hypertension was not higher in African Americans compared with whites. These results indicate that middle-aged African Americans and whites have a similar risk of developing hypertension given the same age, initial blood pressure, and body mass index at baseline. (Hypertension. 1998;31:1130-1135.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

or=to160/95 mm Hg or taking antihypertensive medication) was 36% in men and 25% in women aged 25 to 64 years. Among hypertensive persons, 50% were aware of the condition, 34% were treated, and 10% had controlled BP (ie, BP <160/95 mm Hg). Most persons, whether nonhypertensive, unaware hypertensive, or aware hypertensive, had good basic knowledge related to hypertension determinants and consequences, possibly an effect of a nationwide cardiovascular disease prevention program over the last years. However, favorable outcome expectation, positive attitudes, and appropriate practices for hypertension and relevant healthy lifestyles were found in smaller proportions of participants, with little difference between aware hypertensives, unaware hypertensives, and nonhypertensives. Furthermore, hypertensive persons with other concurrent cardiovascular risk factors affecting the overall heart risk knew well the detrimental effects of these other factors but reported making little actual change to control them (particularly regarding overweight and sedentary habits). These data point to the need to maximize the efficiency of hypertension prevention and control programs so that delay in achieving effective hypertension control is minimized in countries experiencing recent emergence of hypertension as a major public health problem. (Hypertension. 1998;31:1136-1145.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The cardiovascular system shares numerous anatomic and functional pathways with the antinociceptive network. The aim of this study was to investigate whether angiotensin-converting enzyme (ACE) inhibitor treatment could affect hypertension-related hypalgesia. Twenty-five untreated hypertensive patients, together with a control group of 14 normotensive subjects, underwent dental pain perception evaluation by means of a pulpar test (graded increase of test current applied to healthy teeth). After the evaluation of the dental pain threshold (occurrence of pulp sensation) and tolerance (time when the subjects asked for the test to be stopped), all the subjects underwent a 24-hour ambulatory blood pressure monitoring. The hypertensive group then was treated with 20 mg/d enalapril, whereas the normotensive subjects remained without any treatment. After a time interval of 6 +/- 2 months, the dental pain sensitivity was retested in all the subjects, and ambulatory blood pressure was recorded during treatment in the hypertensive patients. At the first assessment, hypertensive patients showed a higher pain threshold than normotensive subjects (P<.001). On retesting of pain sensitivity in hypertensive patients, a significant decrease of both pain threshold and tolerance, leading to their normalization, was observed during treatment (P<.001 and P<.005, respectively), in the presence of reduced 24-hour and office blood pressure values. A slight, though significant, correlation was observed between variations in pain tolerance and baseline blood pressure changes occurring during treatment. During follow-up, the normotensive subjects did not show any significant pain perception or office blood pressure changes. Hypertension-related hypalgesia was confirmed. Mechanisms acting both through lowering of blood pressure and specific pharmacodynamic properties may account for the normalization of pain sensitivity observed in hypertensive patients during treatment with ACE inhibitors. (Hypertension. 1998;31:1146-1150.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The activation of mitogen-activated protein (MAP) kinase and increase in intracellular free calcium concentration ([Ca2+]i) are discussed in reference to activation of different protein kinases and growth of vascular smooth muscle cells (VSMCs). The aim of the present study was to investigate the role of angiotensin (Ang) II-induced increase in [Ca2+]ifor activation of 44-kD/42-kD MAP kinase (p44mapk/p42mapk) and DNA synthesis in VSMCs. Experiments were performed by chelation of [Ca2+]iby the intracellular chelator 1,2-bis-(o-amino-5-methylphenoxy)ethane-N,N,N[prime],N[prime]-tetraacetic acid tetraacetoxymethyl ester (MAPTAM). Ca2+was measured by the fura 2 method. MAP kinase activation was determined by the Western blotting method. DNA synthesis was determined by measurement of [(3) H]thymidine incorporation into the cell DNA. Treatment of VSMCs with 20 [micro sign]mol/L MAPTAM for 30 minutes resulted in a complete abolishment of the maximal Ang II-induced increase at 10 seconds. Ang II phosphorylated the p44mapk/p42mapkin a time-dependent manner, showing a maximum at 3 minutes. In MAPTAM-treated cells, the maximal phosphorylation of MAP kinase isoforms was shifted to 5 minutes, and dephosphorylation was delayed compared with untreated cells. In concordance with this finding, the induction of the MAP kinase phosphatase-1 was markedly impaired in MAPTAM-treated cells. Ang II induced a 2.3-fold increase in [(3) H]thymidine incorporation into DNA synthesis in untreated cells. This effect was not reduced in MAPTAM-treated cells. Treatment of the cells with PD 98059 (10 [micro sign]mol/L), a MAP kinase kinase inhibitor, caused 85% inhibition of the Ang II-induced activation of MAP kinases but did not inhibit the Ang II-induced DNA synthesis. In conclusion, the Ang II-induced stimulation of the MAP kinase is a Ca2+-dependentprocess. Furthermore, blockade of the Ang II-induced stimulation of the early intracellular events, such as increase in [Ca2+]ior phosphorylation of the MAP kinase, is not accompanied by an inhibition of the Ang II-induced DNA synthesis. (Hypertension. 1998;31:1151-1156.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In transgenic rats harboring the mouse Ren-2dgene [TG(mREN2)27], downregulation of the myocardial beta-adrenergic receptor adenylyl cyclase system has been demonstrated previously. Because a reduced vasodilatory reactivity may significantly contribute to hypertension in this model of an activated tissue renin-angiotensin system, the present study investigated alterations of the vascular beta-adrenergic receptor adenylyl cyclase system. In freshly harvested aortas from transgenic rats, the activity of adenylyl cyclase was reduced significantly (P<.05) in the presence of isoprenaline (10 [micro sign]mol/L; -28 +/- 4.5%), guanosine 5[prime]-triphosphate, 5[prime]-guanylylimidodiphosphate [Gpp(NH)p] (100 [micro sign]mol/L; -29 +/- 4.7%), and forskolin (100 [micro sign]mol/L) with (-42 +/- 6%) and without (-40 +/- 4.3%) MnCl2. Densities of beta-adrenoceptors were similar in both strains. In situ hybridization demonstrated the expression of the transgene in aortic smooth muscle cells. These data indicate a reduced catalyst function as a major contributing factor involved in the maintenance of high blood pressure in TG(mREN2)27. However, in cultivated aortic smooth muscle cells, cAMP production after stimulation with isoprenaline, forskolin, and Gpp(NH)p in the presence or absence of MnCl2was not different. Affinities and densities of beta-adrenoceptors and amounts of immunochemically detected inhibitory and stimulatory G-protein alpha-subunits were unchanged. Desensitization after incubation with 10 [micro sign]mol/L isoprenaline for 72 hours was identical in smooth muscle cells from both strains. Cell cultivation and isoprenaline treatment had no effect on transgene expression. We concluded that in transgenic rats the downregulation of the aortic beta-adrenergic adenylyl cyclase system is due to humoral and hemodynamic factors present in vivo rather than to transgenicity itself. (Hypertension. 1998;31:1157-1165.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In the renin-angiotensin system, renin is known to cleave angiotensinogen to generate angiotensin I, which is the precursor of angiotensin II. Angiotensin II is a vasoactive peptide that plays an important role in blood pressure. On the other hand, the liver is the major organ responsible for the production of angiotensinogen in spontaneously hypertensive rats (SHR). To test the hypothesis that a reduction of angiotensinogen mRNA in the liver by antisense oligodeoxynucleotides (ODNs) may affect both plasma angiotensinogen and angiotensin II levels, as well as blood pressure, we intravenously injected antisense ODNs against rat angiotensinogen coupled to asialoglycoprotein carrier molecules, which serve as an important regulator of liver gene expression, into SHR via the tail vein. The SHR used in the present study were studied at 20 weeks of age and were fed a standard diet throughout the experiment. Plasma angiotensinogen, angiotensin II concentrations, and blood pressure all decreased from the next day until up to 5 days after the injection of antisense ODNs. These concentrations thereafter returned to baseline by 7 days after injection. A reduction in the level of hepatic angiotensinogen mRNA was also observed from the day after injection until 5 days after injection with antisense ODNs. However, in the SHR injected with sense ODNs, plasma angiotensinogen, angiotensin II concentrations, and blood pressure, as well as hepatic angiotensinogen mRNA, did not significantly change throughout the experimental period. Although the exact role of angiotensinogen in hypertension still remains to be clarified, these findings showed that intravenous injection with antisense ODNs against angiotensinogen coupled to asialoglycoprotein carrier molecules targeted to the liver could thus inhibit plasma angiotensinogen levels and, as a result, induce a decrease in blood pressure in SHR. (Hypertension. 1998;31:1166-1170.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1Areceptors stimulate changes in cytosolic calcium concentration ([Ca2+]i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT1A/AT1Breceptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1Breceptor mRNA but not that for the AT1Areceptor. In wild-type cells with AT1Apresent, Ang II (10-7mol/L) produces a characteristic rapid peak increase in [Ca2+]iof 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca2+]i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca2+]ichanges produced by Ang II were similar in cells that lacked AT1Areceptors but possessed AT1Breceptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT1Areceptors suggests that non-AT1Areceptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT1Aand non-AT1Areceptors share common signal transduction pathways. The AT2receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2receptors and/or an absence of their linkage to [Ca2+]ipathways. The nonpeptide AT1receptor blocker losartan antagonizes Ang II-induced [Ca2+]iincreases in both cell groups, supporting mediation by native AT1Breceptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT (1A-deficient) VSMCs that is mediated by an endogenous losartan-sensitive AT1Breceptor. (Hypertension. 1998;31:1171-1177.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked NN-nicotinicreceptors with intravenous trimethaphan (6 +/- 0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32 +/- 3 years, 68 +/- 4 kg, 171 +/- 5 cm). NN-Nicotinicreceptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1 +/- 0.12 nmol/L (180 +/- 20 pg/mL) at baseline to 0.23 +/- 0.05 nmol/L (39 +/- 8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of NN-cholinergicreceptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute NN-cholinergicblockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. NN-Cholinergicblockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes. (Hypertension. 1998;31:1178-1184.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID