Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats (original) (raw)
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Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
Endothelin-1 (ET-1) is released on stimulation by shear stress of the vascular wall. In several pathological situations, an involvement of ET-1 is suspected. Nevertheless, the effect of a chronic increase in circulating ET-1 on vascular tone in resistance arteries is not yet fully understood. We investigated the response to tensile stress (pressure-induced myogenic tone) and shear stress (flow-induced dilation, FD) of rat mesenteric resistance arteries cannulated in an arteriograph. Intraluminal diameter was measured continuously. Rats (normotensive Wistar-Kyoto rats [WKYs] and spontaneously hypertensive rats [SHRs]) were treated for 2 weeks with ET-1 (5 pmol. kg(-1). min(-1) SC; n=8 to 16 per group). Systolic arterial blood pressure increased significantly in ET-1-treated rats (171+/-7 versus 196+/-6 mm Hg in WKYs and 216+/-8 versus 245+/-6 mm Hg in SHRs, P<0.05). Passive arterial diameter in isolated resistance arteries ranged from 78+/-9 to 169+/-4 microm in WKYs and from 62+/-6 to 149+/-7 microm in SHRs (pressure from 10 to 150 mm Hg). Myogenic tone was not significantly affected by chronic ET-1. Flow (9 to 150 microL/min) significantly increased the arterial diameter by 2+/-0.5 to 22+/-2 microm in WKYs and by 1.3+/-0. 7 to 8.3+/-0.8 microm in SHRs (P<0.001 versus WKYs). The NO synthesis blocker N(G)-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L) attenuated FD in WKYs (eg, 22+/-2 versus 15+/-3 microm after L-NAME, flow=150 microL/min) and, to a lesser extent, in SHRs (P<0.001 versus WKYs). The cyclooxygenase inhibitor indomethacin (3 micromol/L) attenuated the remaining FD in WKYs (eg, 15+/-3 versus 8+/-3 microm, flow=150 microL/min) and in SHRs (eg, 7.5+/-0.5 versus 5.0+/-0.6 microm). Chronic ET-1 significantly increased FD in SHRs but not in WKYs. In both strains, NO-dependent FD was significantly increased by chronic ET-1. Furthermore, indomethacin-sensitive FD was increased by chronic ET-1 in SHRs only. Thus, chronic ET-1 increased NO-dependent FD in resistance mesenteric arteries from both WKYs and SHRs and increased indomethacin-sensitive FD in SHRs only.
Hypertension, 1999
Pressure-induced tone (myogenic, MT) and flow (shear stress)-induced dilation (FD) are potent modulators of resistance artery tone. We tested the hypothesis that locally produced angiotensin II interacts with MT and FD. Rat mesenteric resistance arteries were perfused in situ. Arterial diameter was measured by intravital microscopy after a bifurcation on 2 distal arterial branches equivalent in size (150 microm, n=7 per group). One was ligated distally and thus submitted to pressure only (MT, no FD). The second branch was submitted to flow and pressure (MT and FD). The difference in diameter between the 2 vessels was considered to be FD. Flow-diameter-pressure relationship was established in the absence and then in the presence of 1 of the following agents. In the nonligated segment (MT+FD), angiotensin II type 1 (AT(1)) receptor blockade (losartan) had no significant effect, whereas angiotensin II type 2 (AT(2)) receptor blockade (PD123319) or saralasin (AT(1)+AT(2) blocker) decreased the diameter significantly, by 9+/-1 and 10+/-0.8 microm, respectively. Angiotensin II in the presence of losartan increased the diameter by 18+/-0.6 microm (inhibited by PD123319). PD123319 or saralasin had no effect after NO synthesis blockade or after endothelial disruption. In the arterial segment ligated distally (MT only), AT(1) or AT(2) receptor blockade had no significant effect. AT(2)-dependent dilation represented 20% to 39% of FD (shear stress from 22 to 37 dyn/cm(2)), and AT(2)-receptor mRNA was found in mesenteric resistance arteries. Thus, resistance arterial tone was modulated in situ by locally produced angiotensin II, which might participate in flow-induced dilation through endothelial AT(2) receptor activation of NO release.
British Journal of Pharmacology, 2000
The contribution of endothelin-1 (ET-1) to angiotensin II (Ang II)-mediated contraction of the isolated rat tail artery was assessed with measurements of tension, and cytosolic calcium ([Ca 2+ ] i). The distribution of the AT 1 receptor was studied with RT ± PCR and immunohistochemistry. 2 Ang II induced an endothelium-independent contraction (pEC 50 7.95+0.06 and E max : 0.46 g+0.05 with endothelium vs 7.81+0.02 and 0.41 g+0.07 without endothelium; P40.05). Ang II (0.003 ± 0.3 mM)-induced a non-sustained contraction of endothelium-intact preparations which was not antagonized by BQ-123 (1 mM), but was inhibited by losartan (10 nM). In addition, the maximal contraction induced by ET-1 (0.1 mM) could be further increased by the addition of 0.1 mM Ang II. 3 Ang II (0.001 ± 0.3 mM) elevated [Ca 2+ ] i in single vascular smooth muscle cells (VSMCs) in a dose-dependent manner (pEC 50 9.12+0.26) and the Ang II-induced increases in [Ca 2+ ] i were not aected by a Ca 2+-free solution, but were abolished by pretreatment with caeine (5 mM). Ang II did not increase [Ca 2+ ] i in endothelial cells. ET-1 (0.1 mM) increased [Ca 2+ ] i in single VSMCs in a normal Ca 2+ containing physiological saline solution (PSS), but not in a Ca 2+-free solution. 4 Ang II-induced contraction was insensitive to inhibition by nifedipine (0.1 mM), an antagonist of L-type voltage-gated Ca 2+ channels, and SK&F96365 (10 mM), which blocks non-selective cation channels, whereas that to ET-1 was inhibited by SK&F69365. 5 RT ± PCR data indicate the expression of AT 1A and AT 1B on both VSMCs and endothelial cells, but immunohistochemical evidence illustrates that the AT 1 is located primarily on VSMCs. 6 These results indicate that endothelium-derived ET-1 is not involved in the Ang II-mediated vasoconstriction of the rat tail artery and that Ang II-and ET-1-mediated VSM contractions utilize distinct pathways.
Characterization of angiotensin-(1–7) receptor subtype in mesenteric arteries
Peptides, 2003
Mesenteric arteries from male Sprague-Dawley rats were mounted in a pressurized myograph system. Ang-(1-7) concentration-dependent responses were determined in arteries preconstricted with endothelin-1 (10 −7 M). The receptor(s) mediating the Ang-(1-7) evoked dilation were investigated by pretreating the mesenteric arteries with specific antagonists of Ang-(1-7), AT 1 or AT 2 receptors. The effects of Ang-(3-8) and Ang-(3-7) were also determined. Ang-(1-7) caused a concentration-dependent dilation (EC 50 : 0.95 nM) that was blocked by the selective Ang-(1-7) receptor antagonist D-[Ala 7 ]-Ang-(1-7). Administration of a specific antagonist to the AT 2 receptor (PD123319) had no effect. On the other hand, losartan and CV-11974 attenuated the Ang-(1-7) effect. These results demonstrate that Ang-(1-7) elicits potent dilation of mesenteric resistance vessels mediated by a D-[Ala 7 ]-Ang-(1-7) sensitive site that is also sensitive to losartan and CV-11974.
British Journal of Pharmacology, 1997
1. We investigated the response to pressure (myogenic tone) and flow of rat mesenteric resistance arteries cannulated in an arteriograph which allowed the measurement of intraluminal diameter for controlled pressures and flows. Rats were treated for 3 weeks with NG-nitro-L-arginine methyl ester (L-NAME, 50 mg kg-1 day-1) or L-NAME plus the angiotensin I converting enzyme inhibitor (ACEI) quinapril (10 mg kg-1 day-1). 2. Mean blood pressure increased significantly in chronic L-NAME-treated rats (155 +/- 4 mmHg, n = 8, vs control 121 +/- 6 mmHg, n = 10; P < 0.05). L-NAME-treated rats excreted significantly more dinor-6-keto prostaglandin F1 alpha (dinor-6-keto PGF1 alpha), the stable urinary metabolite of prostacyclin, than control rats. The ACEI prevented the rise in blood pressure and the rise in urinary dinor-6-keto PGF1 alpha due to L-NAME. 3. Isolated mesenteric resistance arteries, developed myogenic tone in response to stepwise increases in pressure (42 +/- 6 to 847 +/- 10 mN mm-1, from 25 to 150 mmHg, n = 9). Myogenic tone was not significantly affected by the chronic treatment with L-NAME or L-NAME + ACEI. 4. Flow (100 microliters min-1) significantly attenuated myogenic tone by 50 +/- 6% at 150 mmHg (n = 10). Flow-induced dilatation was significantly attenuated by chronic L-NAME to 22 +/- 6% at 150 mmHg (n = 10, p = 0.0001) and was not affected in the L-NAME + ACEI group. 5. Acute in vitro NG-nitro-L-arginine (L-NOARG, 10 microM) significantly decreased flow-induced dilation in control but not in L-NAME or L-NAME + ACEI rats. Both acute indomethacin (10 microM) and acute NS 398 (cyclo-oxygenase-2 (COX-2) inhibitor, 1 microM) did not change significantly flow-induced dilatation in controls but they both decreased flow-induced dilatation in the L-NAME and L-NAME + ACEI groups. Acute Hoe 140 (bradykinin receptor inhibitor, 1 microM) induced a significant contraction of the isolated mesenteric arteries which was the same in the 3 groups. 6. Immunofluorescence analysis of COX-2 showed that the enzyme was expressed in resistance mesenteric arteries in L-NAME and L-NAME + ACEI groups but not in control. COX-1 expression was identical in all 3 groups. 7. We conclude that chronic inhibition of nitric oxide synthesis is associated with a decreased flow-induced dilatation in resistance mesenteric arteries which was compensated by an overproduction of vasodilator prostaglandins resulting in part from COX-2 expression. The decrease in flow-induced dilatation was prevented by the ACEI, quinapril.
British Journal of Pharmacology, 1996
1 The involvement of cyclo-oxygenase (COX) products and nitric oxide (NO) in contractile responses of resistance arteries to angiotensin II (All) were investigated in small mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. 2 In endothelium intact vessels, All induced concentration-dependent responses without any significant difference between the two strains. However, removal of functional endothelium resulted in enhanced sensitivity to All, the pD2 value increasing from 8.4 + 0.2 to 8.9 + 0.2 (P< 0.05) in WKY and from 8.2 + 0.1 to 8.6 + 0.1 (P< 0.05) in SHR (not significantly different between strains, n = 9-12). In addition, endothelium removal enhanced maximal contractions elicited by All in SHR (1.4+ 0.1 to 2.1+0.2 mN mm-', n=5; P<0.01) but not in WKY (1.0+0.1 to 1.2+0.1 mN mm-l, n=5) vessels.
Different regulation of vascular tone by angiotensin II and endothelin-1 in rat aorta
European Journal of Pharmacology, 1991
The effects of moderate cooling and of phenylarsine oxide on the contraction induced by two vasoactive peptides, angiotensin II (AII) and endothelin (ET-1), were investigated on endothelium-free rings of rat aortas. At 37 degrees C, the contraction induced by AII (0.1 microM) was transient. This decline in tension is unlikely to be due to rapid degradation of AII. In contrast, ET-1 (10 nM) induced a slowly developing and sustained contraction similar to the one observed with phorbol 12-13 dibutyrate (PDB, 22 nM). Moderate cooling (25 degrees C) significantly potentiated and prolonged the effect of AII but reduced the velocity of the ET-1 and PDB contraction, although the rate of the phenylephrine (1 microM) response remained unchanged. Phenylarsine oxide (100 microM) reduced the decline in tension in response to AII but inhibited the contraction elicited by ET-1 and PDB. In rings incubated in calcium-free medium (37 degrees C), AII induced a phasic contraction. This was followed by a second phasic contraction after calcium (2.5 mM) had been restored to the bath. The intensity of this second contraction decreased as the time between AII and calcium injection increased. This method, using regression analysis, permitted us to determine the time taken to reduce the contraction by half (4.8 min; r: 0.96), which may reflect the half-time of receptor sequestration. In calcium-free medium, the contractions induced by ET-1 and PDB were slow and sustained. Thus, rapid AII-receptor internalization leads to a short-term regulation of vascular tone whereas activation of protein kinase C by ET-1 may induce a long-term regulation.
Effect of angiotensin receptor blockade in the rabbit aorta: influence of the endothelium
Canadian Journal of Physiology and Pharmacology, 1996
Contractile responsiveness of the rabbit aorta (endothelium intact and denuded) to angiotensin I, II, and III was compared. The effects of converting-enzyme inhibition with enalapril, the selective AT 1-receptor antagonist (losartan), and the AT 2-receptor antagonist (PD 123319) on these contractile profiles were examined. In all preparations, it was found that the angiotensins produced concentration-dependent increases in tension. Differences in sensitivity were encountered; in endothelium-intact preparations, the mean EC 50 values (nM with 95% confidence interval in parentheses) for angiotensin I, II, and III were 9 (95% CI 7-11), 40 (20-60), and 30 (10-40), respectively, and for denuded preparations they were 20 (11-29), 0.8 (0.7-0.9), and 30 (20-40), respectively. Enalapril decreased the maximal tension developed to angiotensin I and II, which was greater in endothelium-intact preparations. Losartan was a competitive antagonist against angiotensin I and angiotensin II in both intact and denuded preparations, with pA 2 values as follows: against angiotensin I, 9.0 and 9.3 for intact and denuded, respectively; against angiotensin II, 8.3 and 8.9 for intact and denuded, respectively. Losartan antagonized angiotensin III, but the slopes of the Schild analysis were significantly less than unity. In endothelium-intact preparations, PD 123319 failed to significantly antagonize responsiveness to angiotensin I. Against angiotensin II, PD 123319 was a competitive antagonist with a pA 2 of 8.3. The antagonism for PD 123319 against angiotensin III was insurmountable. In endothelium-denuded preparations, PD 123319 failed to antagonize angiotensin I and angiotensin III. Although PD 123319 appeared to inhibit the responsiveness of the rabbit aorta by angiotensin II, the slope of the Schild plot was significantly less than unity. These experiments provide evidence that angiotensin I possesses different actions from angiotensin II and III and that a functional endothelium modulates the underlying vascular response to angiotensin. In addition, the endothelium modulates the antagonism by losartan and PD 123319, supporting the notion that the endothelium possesses distinct angiotensin receptors.
Journal of Vascular Research, 2000
Converting-enzyme inhibition reduces cardiovascular hypertrophy in hypertensive subjects. Whether the blockade of angiotensin II type 1 (AT1) receptors reduces arterial hypertrophy has never been investigated. In a double-blind study versus placebo in subjects with essential hypertension, the effect of the AT1 blocker irbesartan (150 mg/day for 8 weeks) on blood pressure, wall thickness, diameter and stiffness of the common carotid and radial arteries was studied, using echotracking techniques of high resolution. With irbesartan, mean blood pressure decreased significantly and proportionally to the baseline levels of active renin, and angiotensin I and II. There was a significant decrease in radial artery wall thickness. The percent change from baseline (± SEM) was –10.51 ± 3.42 versus 6.18 ± 4.77. There was no significant change in diameter or distensibility. This effect was correlated neither to blood pressure changes nor to hormonal baseline levels of the renin-angiotensin system...