|
11. |
Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 203-207
Martin Pfaffendorf,
Marie-Jeanne Mathy,
Robin van der Lee,
Pieter van Zwieten,
Preview
|
PDF (191KB)
|
|
摘要:
ObjectiveThe T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug.MethodsTo evaluate the sympathoinhibitory action, the effects of 3 and 10 μmol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 μmol/kg verapamil (VER).ResultsThe maximal increase in heart rate in response to electrical nerve stimulation was 96 ± 7 bpm (control,n= 6), 70 ± 6 bpm (3 μmol/kg MIB,n= 8), 57 ± 6 bpm (l0 μmol/kg MIB,n= 5), 93 ± 5 bpm (3 μmol/kg VER,n= 6) and 46 ± 7 bpm (10 μmol/kg VER,n= 5). The tachycardic response to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 ± 4 bpm (control,n= 6), 103 ± 6 (3 μmol/kg MIB,n= 6), 42 ± 9 bpm (10 μmol/kg MIB,n= 5), 73 ± 5 bpm (3 μmol/kg VER,n= 5) and 40 ± 7 bpm (10 μmol/kg VER,n= 6). Under control conditions and in the presence of 3 μmol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 μmol/kg whereas in the presence of 10 μmol/kg MIB and VER it was reached at a dose of 1 μmol/kg.MIBat a dose of 3 μmol/kg was significantly more effective in reducing the chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 μmol/kg MIB and VER.ConclusionMibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
12. |
Cicletanine reverses vasoconstriction induced by the endogenous sodium pump ligand, marinobufagenin, via a protein kinase C dependent mechanism |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 209-215
Alexei Bagrov,
Renata Dmitrieva,
Natalia Dorofeeva,
Olga Fedorova,
Denis Lopatin,
Edward Lakatta,
Marie-Therese Droy-Lefaix,
Preview
|
PDF (281KB)
|
|
摘要:
RationaleCicletanine (CIC), an anti-hypertensive compound with direct vascular and natriuretic actions, is especially effective in salt-sensitive hypertension, in which dysregulation of the sodium pump plays an important pathogenic role, and digitalis-like cardiotonic steroids contribute to increased vascular tone. The purpose of the present study was to investigate whether, and by what mechanisms, cicletanine antagonizes the vasoconstrictor effects of cardiotonic steroids in isolated human arteries.MethodsThe effects of cicletanine on vascular tone were studied in isolated, endothelium-denuded rings of 2nd-3rd-order branches of human mesenteric arteries pre-contracted with bufodienolide marinobufagenin (MBG), an Na/K-ATPase inhibitor, or endothelin-1 (ET-1). Na/KATPase activity was measured in sarcolemmal membranes from the mesenteric artery. Activity of rat brain protein kinase C (PKC) was measured using the PepTag phosphorylation assay.ResultsMBG and ET-1 both induced sustained vasoconstriction in human mesenteric artery rings, and cicletanine relaxed rings pre-contracted with either MBG (EC50=11 ± 2 μmol/l) or ET-1 (EC50= 6.4 ± 1.1 μmol/l). Although 8-Br-cGMP (100 μmol/l) caused complete vasorelaxation of arterial rings pre-contracted with ET-1, it did not affect the MBG-induced vasoconstriction. An activator of PKC, phorbol diacetate (PDA) (50 nmol/l), attenuated CIC-induced vasorelaxation of mesenteric artery rings pre-contracted with MBG (EC50>100 μmol/l), but not rings pre-contracted with ET-1 (EC50= 6.5 ± 1.2 μmol/l). In mesenteric artery sarcolemma, 100 nmol/l MBG inhibited the Na/K-ATPase by 68 ± 5% and cicletanine (100 μmol/l) attenuated this Na/K-ATPase inhibition by 85 ± 6%. In the PepTag PKC assay, cicletanine produced a concentration-dependent inhibition of rat brain PKC activity (IC5045 ± 11 μmol/l). In the presence of 50 nmol/l PDA, 100 μmol/l cicletanine did not antagonize the Na/K-ATPase inhibition by MBG, and did not inhibit the PKC from rat brain.ConclusionsCicletanine antagonizes vasoconstriction induced by Na/K-ATPase inhibition via a PKC-dependent mechanism that does not involve inhibition of cyclic GMP phosphodiesterase (cGMP-PDE). This mechanism of action may be relevant to the greater potency of cicletanine in salt-sensitive hypertension in which plasma levels of endogenous digitalis-like cardiotonic steroids are elevated. Our findings also suggest that PKC is an important factor for cardiotonic steroid–Na/K-ATPase interactions on the vascular tone, and is therefore a potential target for therapeutic intervention in hypertension.
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
13. |
Platelet α2‐adrenoceptor alterations in patients with essential hypertension are normalized after treatment with doxazosin but not propranolol |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 217-221
Francesco Portaluppi,
Roberto Manfredini,
Katia Varani,
Stefania Gessi,
Alberto Caiazza,
Pier Borea,
Preview
|
PDF (172KB)
|
|
摘要:
ObjectiveMarked alterations have been demonstrated to occur in the platelet α2-adrenoceptors of patients with essential hypertension. The purpose of this study was to determine whether antihypertensive treatment with α-adrenergic blocker doxazosin or β-adrenergic blocker propranolol can affect the af(r)nity and the density of platelet α2-adrenoceptors in such patients.Subjects and methodsIn two groups of 22 previously untreated, essential hypertensive patients, the mean affinity (Kd) and density (Bmax) of platelet α2-adrenoceptors were studied by [3H]-UK 14304 binding assays; the first assays were performed before any medication was begun, the second were performed after treatment for up to 13 weeks with doxazosin or propranolol. A third group of 22 healthy normotensive volunteers matched by age, sex and body mass index was used as control.ResultsBlood pressure did not differ significantly in the two hypertensive groups, and treatment with the two drugs resulted in closely similar, normal blood pressure levels.KdandBmaxvalues were significantly higher in the two hypertensive groups than in controls. After treatment with propranolol the binding parameters did not change significantly, whereas after treatment with doxazosinKdandBmaxreturned to normotensive values.ConclusionsIn previously untreated, essential hypertensive patients platelet α2-adrenoceptors have a lower affinity but a higher density than in normotensive subjects. Despite similar effects on blood pressure, the treatment with the α2-adrenergic blocker doxazosin is followed by restoration of normal findings in the binding assays of platelet α2-adrenoceptors whereas the treatment with the β-adrenergic blocker propranolol does not alter theKdandBmaxvalues.
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
14. |
Myocardial bradykinin B2‐receptor expression at different time points after induction of myocardial infarction |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 223-228
Carsten Tschöpe,
Silvia Heringer-Walther,
Matthias Koch,
Frank Spillmann,
Michael Wendorf,
Dorian Hauke,
Michael Bader,
Heinz-P Schultheiss,
Thomas Walther,
Preview
|
PDF (582KB)
|
|
摘要:
ObjectiveTo characterize the regulation of the myocardial bradykinin B2receptor after induction of myocardial infarction (MI), we studied its expression at different time points in the left ventricle (LV), right ventricle (RV) and interventricular septum (S) of the heart.DesignMale Sprague-Dawley rats were submitted to permanent occlusion of the left descending coronary artery. Six hours, 24 h or 6 days after MI induction or a sham operation, a Millar-tip catheter was placed in the LV. Left ventricular pressure (LVP) and contractility [(dP/dt)max] were measured. The LV, RV and S of all animals were isolated, and total RNA was extracted. B2-receptor expression was analysed by an RNase-protection assay. In addition, Western blot analysis was used to determine protein levels of the B2receptor in the infarcted area of the LV.ResultsWe observed a decrease in LVP and contractility at all time points after MI in comparison with sham-operated animals. Basal B2-receptor expression was detected in the LV and RV, but not in the S of sham-operated rats. In the LV of infarcted hearts, we found a time-dependent up-regulation of the B2-receptor expression, which was increased twofold and fivefold, respectively, 6 h and 24 h after induction of MI compared with controls. This increase was maintained for at least 6 days. Similarly, we also found an up-regulation of the B2-receptor expression in the RV and S. Both reached a peak 24 h after induction of MI. The protein level of the receptor gradually increased up to day 6.ConclusionWe conclude that myocardial ischaemia triggers B2-receptor up-regulation in both the infarcted and non-infarcted areas of the heart.
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
15. |
Effects of oral administration of L‐arginine on renal function in patients with heart failure |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 229-234
Gohki Watanabe,
Hirofumi Tomiyama,
Nobutaka Doba,
Preview
|
PDF (170KB)
|
|
摘要:
ObjectivesAlthough the beneficial effects of L-arginine on systemic haemodynamics have been reported in patients with heart failure, its effect on renal function has not been examined. We evaluated the effects of oral administration of L-arginine on renal haemodynamics, sodium and water handling, and various hormonal factors in patients with chronic heart failure.Subjects and methodsA double-blind crossover trial was performed in 17 patients with chronic congestive heart failure (NYHA II–III, 56 ± 12 years of age) who were randomly assigned to receive oral L-arginine (15 g/day) and placebo or placebo and arginine sequentially for 5 days each. Twenty-four hour creatinine clearance (Ccr), and 24-h urinary cyclic guanosine 5-monophosphate (GMP) excretion were determined. Saline loading was performed on day 5 of each treatment. Renal blood flow, glomerular filtration rate (GFR), and urinary sodium excretion rate (UNa) were assessed before and after saline loading.ResultsTwenty-four hour GMP excretion (1.4 ± 1.1 versus 0.8 ± 0.5 μmol/day,P< 0.01) and Ccr (150 ± 43 versus 125 ± 42 ml/min,P< 0.05) were higher and plasma endothelin level (2.5 ± 0.6 versus 3.1 ± 0.8 pg/ml,P< 0.05) was lower with L-arginine treatment compared to placebo treatment. In addition, the relative increase of UNa and GFR after saline loading were significantly higher in L-arginine treatment (UNa, 47 ± 12%; GFR, 44 ± 31%) than in placebo treatment (UNa, 34 ± 9%; GFR, 22 ± 29%) (P< 0.05).ConclusionsOral administration of L-arginine has beneficial effects on glomerular filtration rate, natriuresis, and plasma endothelin level in patients with chronic congestive heart failure.
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
16. |
Structure and the resistance amplifier in hypertensionreply to the dissenters |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 235-239
Paul Korner,
James Angus,
Christine Wright,
Preview
|
PDF (160KB)
|
|
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
17. |
Structure and the resistance amplifier in hypertensionreply to the dissenters |
|
Journal of Hypertension,
Volume 18,
Issue 2,
2000,
Page 239-239
A Izzard,
A Heagerty,
F Leenen,
Preview
|
|
ISSN:0263-6352
出版商:OVID
年代:2000
数据来源: OVID
|
|