ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo investigate the hypotensive effect and mechanism of action of chronic administration of ketanserin in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats.Methods and resultsSHR and WKY rats were given chronic ketanserin infusions via osmotic minipumps to minimize fluctuations in drug concentrations and receptor responsiveness. In SHR treated with intravenous infusions of 3.0 (n =9) or 6.0 mg/kg per day (n=8) ketanserin for 7 days, significant dose-dependent falls in systolic blood pressure (SBP) were observed during the infusion period. Heart rate did not change in either the vehicle- or the ketanserin-treated groups of SHR. In WKY rats intravenously infused with 3.0 (n=9) or 6.0 mg/kg per day (n=10) ketanserin, dose-dependent falls in SBP were also observed during the infusion period, with the changes reaching statistical significance at the 6.0 mg/kg per day dose. The changes in heart rate were not different from those in control rats. Pressor responses to the type 2 5-hydroxytryptamine (5HT2)-receptor agonist (±)-α-methyl-5-hydroxytryptamine (5.0–125.0 μg/kg), as assessed on day 7, were reduced dose-dependently in all ketanserin-infused rats. αl-Adrenoceptor responses to 1.0–10.0μg/kg intravenous phenylephrine were attenuated in only the WKY rats infused with 6.0 mg/kg per day ketanserin. In the SHR treated with ketanserin there was no change in the pressor responsiveness to phenylephrine. Baroreflex sensitivity on day 7 was significantly greater in the ketanserin-infused SHR than in their respective controls. Changes in baroreflex sensitivity were not significantly different in WKY rats following ketanserin infusion.ConclusionsThese results show that chronic administration of ketanserin lowers blood pressure in both SHR and WKY rats. In SHR the al-adrenoceptor-blocking effects of ketanserin are compensated for, and the reduction in blood pressure by day 7 is maintained predominantly by, 5HT2-receptor blockade. In WKY rats ketanserin-induced hypotension is associated with concomitant blockade of 5HT2− and al-receptors. The present study therefore suggests a differential mechanism of action of ketanserin in hypertensive and normotensive rats during chronic treatment.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveDysfunctional cellular Ca2+handling has been proposed to underlie the heightened vascular reactivity observed in the spontaneously hypertensive rat (SHR) model of genetic hypertension. We tested the hypothesis that basal or agonist-induced mobilization of intracellular Ca2+is elevated in mesenteric resistance arteries of SHR compared with the normotensive Wistar-Kyoto (WKY) rat.DesignA method using fura-2 for the simultaneous measurement of intracellular Ca2+and isometric force generation in isolated mesenteric resistance arteries was employed to measure agonist-induced changes in Ca2+and force during activation with 100 μol/I K+or 10 μmol/I norepinephrine. Arteries with normalized diameter 220–240μm from male rats aged 14–15 weeks were examined.ResultsNo differences were detected between the rat strains in basal Ca2+ concentration or the steady-state concentration of Ca2+achieved in response to either 100 mmol/I K+or 10 μmol/I norepinephrine. The relationship between Ca2+ and force during the contractile responses to K+and norepinephrine was analyzed. No differences between the strains in the level of active stress, normalized to unit intracellular Ca2+, were detected in the steady-state responses to K+or norepinephrine.ConclusionsThe present results do not support the hypothesis that alterations in either the basal concentration of intracellular Ca2+or the amount of intracellular Ca2+mobilized in response to high levels of norepinephrine or K+are present in resistance arteries of SHR compared with those of WKY rats. Moreover, these findings suggest that elevations in Ca2+do not contribute to heightened peripheral resistance in SHR.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundIn contrast to studies in isolated blood vessels, results from whole-animal studies are ambiguous regarding differences in pressor responsiveness between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, possibly related to the measurement of blood pressure instead of total peripheral resistance (TPR) and to differences in compensatory mechanisms.Objective and designWe evaluated responses of blood pressure and TPR to two doses of the αl-agonist phenylephrine during the development of hypertension and cardiovascular hypertrophy in SHR aged 8–26 weeks compared with age-matched WKY rats before and after ganglionic blockade. At 16 weeks of age more-complete dose-response curves to the αl-agonist methoxamine were also constructed.ResultsOver the age range studied, the SHR developed marked hypertension, related to a significant rise in TPR, and concomitantly significant cardiac hypertrophy, as well as hypertrophy of the mesenteric arterial bed. The blood pressure responses to phenylephrine were diminished in the SHR compared with the WKY rats at all ages studied, but this effect was significant only in the absence of ganglionic blockade. TPR responses were significantly less in the SHR than in the WKY rats, both with and without concomitant ganglionic blockade. In contrast, both blood pressure and TPR responses to low doses, but not higher doses, of methoxamine were enhanced in the SHR compared with the WKY rats.ConclusionThese results indicate that the development of hypertension in SHR in vivo is associated with variable changes in blood pressure and TPR responses to al-receptor stimulation, depending on the αl-agonist employed.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundIn the kidney carbenoxolone impairs inactivation of glucocorticoids and facilitates their access to mineralocorticoid receptors by inhibiting 11β-hydroxysteroid dehydrogenase (11β-OHSD). 11β-OHSD is also expressed in vascular smooth muscle, and, in humans, carbenoxolone potentiates vasoconstrictor sensitivity to cortisol and noradrenaline.ObjectiveTo establish invitrowhether the vascular effects of carbenoxolone are mediated by inhibition of 11β-OHSD.MethodsNoradrenaline-induced vasoconstriction was measured in helical de-endothelialized rat aortic strips following 2–5 h exposure to one or more of: carbenoxolone, corticosterone, a mineralocorticoid-receptor antagonist (spironolactone) and a glucocorticoid- and progesterone-receptor antagonist (RU 38486).ResultsCarbenoxolone potentiated noradrenaline-induced vasoconstriction in aortae from adrenalectomized rats, an effect which was prevented by spironolactone but not by RU 38486. By contrast, when corticosterone was added or when aortae from non-adrenalectomized rats were studied, carbenoxolone attenuated noradrenaline-induced vasoconstriction.ConclusionsCarbenoxolone has a direct effect, independent of 11β-OHSD, which potentiates noradrenaline-induced vasoconstriction and might be mediated by activation of mineralocorticoid receptors. Carbenoxolone also has an indirect effect, attenuating noradrenaline-induced vasoconstriction dependent on corticosterone and, therefore, mediated by inhibition of 11β-OHSD. Although experiments with carbenoxolone must be interpreted with caution because of its direct effect, the present data confirm that 11β-OHSD modulates vascular sensitivity to glucocorticoids and noradrenaline. Therefore, 11β-OHSD activity might influence blood pressure by effects in both the kidney and the vasculature.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveStudies of aortas from hypertensive and diabetic rats and rabbits have demonstrated impairment of endothelium-dependent relaxations, which were associated with increased release of endothelium-derived thromboxane A2(TXA2). This implicates enhanced release of TXA2or its precursor prostanoid, prostaglandin endoperoxide (PGH2), or both, as factors mediating the endothelial cell dysfunction.MethodsThe interaction of vasoconstrictor prostanoids (PGH2, PGF2αand U-46619, a stable thromboxane-receptor agonist) and oxygen-derived free radicals with the release of nitric oxide was examined in isolated aortas from Sprague-Dawley rats.ResultsExogenously applied PGH2or U-46619 caused concentration-dependent contractions of aortic rings, these contractions being blocked by the newly developed, potent and selective PGH2- and TXA2-receptor antagonist BMS-180291, but not by inhibition of TXA synthase or cyclo-oxygenase (using dazoxiben and indomethacin, respectively). In aortic rings contracted sub-maximally with phenylephrine, brief exposure to a subthreshold concentration of PGH2caused impairment of acetylcholine- and ADP-induced, but not of nitroprusside-induced, relaxations. The impairment was restored towards normal by BMS-180291 or by superoxide dismutase (SOD), a superoxide anion scavenger, but not by dazoxiben or indomethacin. In contrast, treatment of aortic rings with U-46619 or PGF2αdid not impair the relaxations. Oxygen-derived free radicals generated by xanthine oxidase caused contractions and impaired acetylcholine relaxations which were reversed by SOD but not by BMS-180291.ConclusionsThese findings indicate that activation of PGH2receptors causes contractions and selective impairment of endothelium-dependent relaxations by a mechanism involving generation of oxygen-derived free radicals in the endothelium.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo evaluate the sensitivity to ischaemia of rat hearts made hypertrophic by pressure overload [two-kidney, one clip (2-K,1C) rats], volume overload (aortocaval arteriovenous shunt), minoxidil or isoproterenol.MethodsIschaemia was induced in the isolated perfused hearts by a stepwise lowering of the perfusion pressure; at each step the coronary effluent was assessed for the products of ATP breakdown.ResultsHypertension increased cardiac weight by 35 and 56% after 2.5 and 12 weeks, respectively. Volume overload increased heart weight by 25 and 55% after 1 and 12 weeks, respectively. Minoxidil (for 5 weeks) or isoproterenol (for 1 week) increased cardiac weight by 22 and 16%, respectively. The hearts from 2-K,1 C rats started to release ATP catabolites in the coronary effluent at a substantially higher perfusion pressure, and with significantly higher maximal levels, than the control hearts. In contrast, in volume overload cardiac ATP breakdown was similar to that in the controls, and isoproterenol administration caused significantly lower levels of ATP breakdown. At identical flow rates, normalized per gram dry tissue, the purine concentration in the coronary effluent was similar in all of the models of cardiac hypertrophy studied and in the respective controls, and was even lower in the long-term volume-overloaded and isoproterenol-induced hypertrophic hearts.ConclusionsWe conclude that hearts from hypertensive rats are more sensitive to ischaemic ATP breakdown during lowering of perfusion pressure than hearts from volume-overloaded or control rats. This is independent of the duration of the hypertrophic process, and can be explained by a lower coronary flow per gram heart tissue at a given perfusion pressure. This conclusion is strengthened by the observation that hypertrophic hearts from volume-overloaded rats had similar amounts of cardiac hypertrophy to the hearts from the hypertensive rats, without a change in flow, coronary vascular resistance or ischaemic sensitivity, whereas the hearts from isoproterenol-treated rats had lower ischaemic sensitivity and coronary vascular resistance.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundIn order to determine whether alterations in membrane lipids affect transmembrane cationic transport systems in erythrocytes and platelets, cationic fluxes and intracellular cationic concentrations were measured in hypercholesterolaemic patients before and during administration of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.MethodsAfter a 1-month run-in placebo period on a lipid-lowering diet the patients were treated, in a double-blind manner, with either placebo (n=25) or pravastatin (n=25) for 6 months. Placebo or pravastatin (10 mg during the first month, 20 mg during the second month and 40 mg during the remaining 4 months) was administered once a day in the evening.ResultsCompared with the placebo group, the erythrocyte and platelet membrane cholesterol content was reduced in the patients treated with pravastatin. The intra-erythrocyte and intraplatelet Na+concentration was reduced during pravastatin administration, whereas the activity of the erythrocyte and platelet Na+-K+pump was increased. However, the intra-erythrocyte and intraplatelet K+, Mg2+and cytosolic Ca2+concentrations, and water content, as well as the activities of the erythrocyte Na+-Li+countertransporter and Na+, K+cotransporter, and Na+ and K+ leakage, were not changed during pravastatin treatment.ConclusionsThe present data show that cholesterol lowering in hypercholesterolaemic patients may result in a significant decrease in erythrocyte and platelet membrane cholesterol content. These changes in membrane cholesterol are accompanied by an increase in activity of the Na+-K+pump and a decrease in intra-erythrocyte and intraplatelet Na*concentrations.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine whether treatment of borderline hypertension reverses the cardiac 'amplifier' effect associated with increased left ventricular mass.DesignRandomized, double-blind, placebo-controlled trial involving treatment for 6 months.SettingAmbulant outpatients in a teaching hospital.ParticipantsRecruited by local doctor referral or worksite screening. Average of two readings of entry blood pressures taken 1 week apart 140–160 mmHg (systolic) or 90–95 mmHg diastolic, or both. Twenty-six previously untreated males, mean±SD age 33±9.2 years with mean±SD blood pressure 138±7.4/ 90 7.0 mmHg entered and completed the study.InterventionsTwelve subjects received captopril, average dose 72 mg/day for 24 weeks, the remainder receiving placebo.Main outcome measures: Echocardiographic left ventricular dimensions, mass and transmitral Doppler flow, as well as office, ambulatory and exercise blood pressure.ResultsIn the captopril group blood pressure was reduced significantly. Left ventricular mass decreased significantly from 205 to 195 g at 8 weeks and to 202 g at 24 weeks, returning to 232g 4 weeks after treatment. Interventricular septum thickness fell significantly at 24 weeks. Doppler parameters did not alter. Baseline 8-h ambulatory blood pressure did not change with treatment. The reduction in peak exercise systolic blood pressure in the captopril group was not different from the change in the placebo group.ConclusionBlood pressure can be effectively lowered using captopril in young subjects with borderline hypertension. Treatment is well tolerated and leads to regression of left ventricular wall thickness and mass, suggesting that treatment of blood pressure elevations may be advisable at lower levels than currently recommended.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveUltrasonic backscatter from the myocardial walls is directly related to the morphometrically or biochemically evaluated collagen content in man, and shows a normal pattern of quantitatively assessed ultrasonic backscatter in hypertensive patients, even in the presence of left ventricular hypertrophy. Whether the pharmacologically induced regression of left ventricular hypertrophy in hypertensive patients is accompanied by a disproportionate increase in relative connective tissue content is not yet known. The objective of the present study was to assess the effects of regression of left ventricular hypertrophy on the quantitatively evaluated myocardial reflectivity in essential hypertensives.DesignWe evaluated 19 mild-to-moderate essential hypertensives with echo-cardiographically assessed left ventricular hypertrophy, before and after 8 months' effective antihypertensive therapy with 20–40 mg enalapril once a day, associated with diuretics or calcium antagonists, or both, in six patients to achieve optimal blood pressure control. Using a modified echo machine developed in the Institute of Clinical Physiology, Pisa, an on-line radio-frequency analysis was performed to obtain quantitative operator-independent measurements of the integrated backscatter signal of the ventricular septum and the posterior wall. The integrated values of the radio-frequency signal from the myocardial walls were normalized for those from the pericardial interface and were expressed as percentages (integrated backscatter index).ResultsIn comparison with baseline, the treated hypertensives showed significant decreases in mean blood pressure, left ventricular mass index, and septal and posterior wall thickness. However, integrated backscatter index values were similar at baseline and after therapy for both the septum and the posterior wall.ConclusionAntihypertensive therapy with enalapril does not increase myocardial reflectivity, although it does induce regression of left ventricular hypertrophy. This suggests that, in accord with experimental data, regression of hypertrophy is achieved by enalapril through a proportionate regression of the myocyte and connective tissue components of the myocardium.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID