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)
Maintenance of blood pressure in normotensive dogs by endothelin.
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The role of endothelin (ET)-1 in blood pressure homeostasis and the interaction with the renin-angiotensin system (RAS) was investigated in normotensive conscious dogs. ETA receptors were blocked by LU-135252 (1-30 mg/kg); trandolapril (2 mg/kg) or losartan (10 mg/kg) was used to inhibit the RAS. LU-135252 in oral doses of 3-30 mg/kg significantly reduced mean arterial pressure (MAP) by approximately 10 mmHg maximally, whereas trandolapril or losartan were without any effect. MAP reduction was more pronounced when LU-135252 was combined with either losartan (-15.5 +/- 3.2 mmHg; 2 h postadministration; P < 0.05) or trandolapril (-30.9 +/- 3.6 mmHg; P < 0.05). When endogenous nitric oxide (NO) generation was blocked but NO concomitantly infused, this synergistic effect on MAP was prevented. The data show that ET-1 contributes to the maintenance of blood pressure via ETA receptors. Furthermore, ET-1 and ANG II play a prominent role in the control of blood pressure by opposing the effects of NO. The pronounced blood pressure fall after combined blockade of ETA receptors and the RAS may be mediated by an enhanced release of NO. (+info)
Trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the anaesthetized cat: role of endothelin(B) receptors in carotid vasodilatation.
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1. The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001-10.0 mg kg(-1)), SB-217242, SB-234551 (0.01-10.0 mg kg(-1)) and BQ-788 (0.001-1.0 mg kg(-1)) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003-3.0 mg kg(-1)) and alpha-CGRP8-37 (0.001-0.1 mg kg(-1)). 2. Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non-frequency related increases in blood pressure. Guanethidine (3 mg kg(-1), i.v.) blocked trigeminal nerve ganglion-induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation-induced responses in guanethidine treated cats. 3. Saline, alpha-CGRP8-37 SB-209670 and BQ-788 had little or no effect on resting haemodynamic parameters. SB-217242 (10 mg kg(-1), n=3) produced a 56% reduction in arterial blood pressure whereas SB-233451 (10 mg kg(-1), n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose-related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg(-1), n = 5) in vascular resistance. 4. SB-209670 (n=6-7), SB-217242 (n=3) and BQ-788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation-induced reductions in carotid vascular resistance. Saline, SB-234551, alpha-CGRP8-37 and sumatriptan had no effect. 5. These data demonstrate ET(B) receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats. (+info)
Role of K+ channels in A2A adenosine receptor-mediated dilation of the pressurized renal arcuate artery.
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1. Adenosine A2A receptor-mediated renal vasodilation was investigated by measuring the lumenal diameter of pressurized renal arcuate arteries isolated from the rabbit. 2. The selective A2A receptor agonist CGS21680 dilated the arteries with an EC50 of 130 nM. The CGS21680-induced vasodilation was, on average, 34% less in endothelium-denuded arteries. 3. The maximum response and the EC50 for CGS21680-induced vasodilation in endothelium-intact arteries were not significantly affected by incubation with the K+ channel blockers apamin (100 nM), iberiotoxin (100 nM), 3,4-diaminopyridine (1 mM), glibenclamide (1 microM) or Ba2+ (10 microM). However, a cocktail mixture of these blockers did significantly inhibit the maximum response by almost 40%, and 1 mM Ba2+ alone or 1 mM Ba2+ in addition to the cocktail inhibited the maximum CGS21680-response by 58% and about 75% respectively. 4. CGS21680-induced vasodilation was strongly inhibited when the extracellular K+ level was raised to 20 mM even though the dilator response to 1 microM levcromakalim, a K(ATP) channel opener drug, was unaffected. 5. CGS21680-induced vasodilation was inhibited by 10 microM ouabain, an inhibitor of Na+/K(+)-ATPase, but ouabain had a similar inhibitory effect on vasodilation induced by 30 nM nicardipine (a dihydropyridine Ca2+ antagonist) or 1 microM levcromakalim. 6. The data suggest that K+ channel activation does play a role in A(2A) receptor-mediated renal vasodilation. The inhibitory effect of raised extracellular K+ levels on the A(2A) response may be due to K(+)-induced stimulation of Na+/K(+)-ATPase. (+info)
Modulation of ET-1-induced contraction of human bronchi by airway epithelium-dependent nitric oxide release via ET(A) receptor activation.
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1. The purpose of this work was to investigate whether endothelin-1 (ET-1) was able to induce the release of an inhibitory factor from the airway epithelium in isolated human bronchi and to identify this mediator as well as the endothelin receptor involved in this phenomenon. 2. In intact bronchi, ET-1 induced a concentration-dependent contraction (-logEC50 = 7.92+/-0.09, n = 18) which was potentiated by epithelium removal (-logEC50 = 8.65+/-0.11, n = 17). BQ-123 , an ET(A) receptor antagonist, induced a significant leftward shift of the ET-1 concentration-response curve (CRC). This leftward shift was abolished after epithelium removal. 3. L-NAME (3 x 10(-3) M), an inhibitor of nitric oxide (NO) synthase, induced a significant leftward shift of the ET-1 CRC, and abolished the potentiation by BQ-123 (10(-8) M) of ET-1-induced contraction. 4. In intact preparations, the ET(B) receptor antagonist BQ-788 induced only at 10(-5) M a slight rightward shift of the ET-1 CRC. In contrast, in epithelium-denuded bronchi or in intact preparations in the presence of L-NAME, BQ-788 displayed a non-competitive antagonism toward ET-1-induced contraction. 5. IRL 1620, a selective ET(B) receptor agonist, induced a contraction of the isolated bronchus (-logEC50=7.94+/-0.11, n= 19). This effect was not modified by epithelium removal or by BQ-123. BQ-788 exerted a competitive antagonism against IRL 1620 which was similar in the presence or absence of epithelium. 6. These results show that ET-1 exerts two opposite effects on the human airway smooth muscle. One is contractile via ETB-receptor activation, the other is inhibitory and responsible of NO release which counteracts via ETA-receptor activation the contraction. (+info)
Cardiac baroreflex during the postoperative period in patients with hypertension: effect of clonidine.
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BACKGROUND: Patients with essential hypertension show altered baroreflex control of heart rate, and during the perioperative period they demonstrate increased circulatory instability. Clonidine has been shown to reduce perioperative circulatory instability. This study documents changes in measures of heart rate control after surgery in patients with essential hypertension and determines the effects of clonidine on postoperative heart rate control in these patients. METHODS: Using a randomized double-blind placebo-controlled design, 20 patients with essential hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg for > or =1 yr) were assigned to receive clonidine (or placebo), 6 microg/kg orally 120 min before anesthesia and 3 microg/kg intravenously over 60 min before the end of surgery. The spontaneous baroreflex ("sequence") technique and analysis of heart rate variability were used to quantify control of heart rate at baseline, before induction of anesthesia, and 1 and 3 h postoperatively. RESULTS: Baroreflex slope and heart rate variability were reduced postoperatively in patients given placebo but not those given clonidine. Clonidine resulted in greater postoperative baroreflex slope and power at all frequency ranges compared with placebo (4.9+/-2.9 vs. 2.2+/-2.1 ms/mm Hg for baroreflex slope, 354+/-685 vs. 30+/-37 ms2/Hz for high frequency variability). Clonidine also resulted in lower concentrations of catecholamine, decreased mean heart rate and blood pressure, and decreased perioperative tachycardia and hypertension. CONCLUSIONS: Patients with hypertension exhibit reduced heart rate control during the recovery period after elective surgery. Clonidine prevents this reduction in heart rate control. This may represent a basis for the improved circulatory stability seen with perioperative administration of clonidine. (+info)
A signaling pathway for stimulation of Na+ uptake induced by angiotensin II in primary cultured rabbit renal proximal tubule cells.
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The aim of the present study was to examine the signaling pathways for a low dose of angiotensin II (ANG II) on Na+ uptake of primary cultured rabbit renal proximal tubule cells (PTCs) in hormonally defined serum-free medium. The results were as follows; ANG II (10(-11) M) stimulated the proliferation of PTCs. 10(-11) M ANG II stimulated Na+ uptake by 20%, whereas 10(-9) M ANG II inhibited it by 20% (p < 0.05). The stimulatory effect of 10(-11) M ANG II on Na+ uptake was inhibited by amiloride (10(-3) M) and by losartan (ANG II receptor subtype 1 antagonist, 10(-8) M) but not by PD123319 (ANG II receptor subtype 2 antagonist, 10(-8) M). Pertussis toxin (PTX, 50 ng/ml) prevented the ANG II-induced stimulation of Na+ uptake (p < 0.01). 8-Bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cAMP, 10(-6) M) did not affect Na+ uptake. SQ 22536 (adenylate cyclase inhibitor, 10(-6) M) also did not change the ANG II-induced stimulation of Na+ uptake. ANG II did not stimulate cAMP production. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.01 ng/ml) produced significant increase in Na+ uptake. When ANG II and TPA were added together to the PTCs, there was no additive effect on Na+ uptake. Staurosporine (calcium-dependant protein kinase C inhibitor, 10(-6) M) led to a complete inhibition of ANG II-induced stimulation of Na+ uptake. ANG II-treatment resulted in a 26% increase in total protein kinase C (PKC) activity. However, 10(-11) M ANG II did not change [Ca2+]i mobilization and [3H]-AA release while 10(-9) M ANG II increased both of them. In conclusion, the PTX-sensitive PKC pathway may be the main signaling cascade in the stimulatory effects of low dose of ANG II (10(-11) M) on Na+ uptake in the primary cultured rabbit renal proximal tubule cells in hormonally defined serum-free medium. (+info)
Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.
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Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects. (+info)