Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats

Abstract

In resistance arteries pressure-induced (myogenic) tone (MT) and flow (shear stress)-induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin-1 in FD and MT in resistance arteries and their potential change in hypertension. Flow - diameter - pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 microM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously. External diameter (with flow) ranged from 150+/-3 to 191+/-7 microM in WKY (n=28) rats and from 168+/-6 to 186+/-6 microM in SHR (n=28). Flow induced a dilation of the non-ligated arteries which was lower in SHR (13+/-5 - 31+/-4 microM vs WKY: 5+/-5 - 44+/-4 microM). In the ligated artery, the diameter did not significantly change, due to MT. In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 micromol L(-1)) increased the diameter in SHR (+11+/-2 microM) significantly more than in WKY (+2+/-1 microM). Angiotensin type 1 receptor (AT(1)R) blockade (losartan, 10 micromol L(-1)) increased the diameter in the vessels with flow in SHR only (+6+/-1 microM). Angiotensin type 2 receptor (AT(2)R) blockade (PD 123319, 1 micromol L(-1)) decreased arterial diameter in WKY only (9+/-2). Endothelin-1 type A receptor (ET(A)R) blockade (LU135252, 0.1 micromol L(-1)) increased the diameter only in SHR in the artery submitted to flow (by 6+/-1 microM). Thus FD was counteracted by a flow-dependent AT(1) and ET(A) receptors-activation in SHR whereas in WKY FD AT(2)-dependent dilation is involved.

Figure 1

Changes in diameter in responses to increases in flow and pressure in mesenteric resistance artery isolated from SHR (n=28) and WKY rats (n=28). The arterial diameter was measured in arteries segments with or without flow (ligated arteries). Changes in diameter are represented as a function of flow rate (upper panel) or pressure (middle panel). Flow-induced dilation (lower panel) was estimated as the difference in diameter between arteries submitted to flow and pressure and arteries submitted to pressure only in SHR and WKY rats. Mean±s.e.mean are represented. ^*P<0.001, ANOVA for repeated measures.

Figure 2

Effect of angiotensin I converting enzyme inhibition with perindoprinol (10 μmol L⁻¹) on the arterial diameter measured in resistance mesenteric artery segments with or without flow (ligated arteries) isolated from SHR or WKY rats. Results are expressed as changes in diameter (μM) due to perindopril. (n=7). Mean±s.e.mean are represented. ^*P<0.01, 2-way ANOVA for repeated measures, SHR vs WKY. #P<0.01, 2-way ANOVA for repeated measures, vessels with versus vessels without flow.

Figure 3

Effect of the angiotensin II type 1 receptor blocker losartan (10 μmol L⁻¹) on the arterial diameter measured in rat resistance mesenteric arteries with or without flow (ligated arteries) isolated from SHR or WKY rats. Results are expressed as changes in diameter due to losartan (μM). Mean±s.e.mean are represented (n=7 per group). ^*P<0.001, 2-way ANOVA for repeated measures. #P<0.01, 2-way ANOVA for repeated measures, vessels with versus vessels without flow.

Figure 4

Effect of the angiotensin II type 2 receptor blocker PD 123319 (1 μmol L⁻¹) on the arterial diameter measured in rat resistance mesenteric arteries with or without flow (ligated arteries) isolated from SHR or WKY rats. Results are expressed as changes in diameter due to PD 123319 (μM). Mean±s.e.mean are represented (n=7 per group). ^*P<0.001, 2-way ANOVA for repeated measures. #P<0.01, 2-way ANOVA for repeated measures, vessels with versus vessels without flow.

Figure 5

Effect of the endothelin type A receptor blocker LU 13525 (0.1 μmol L⁻¹) on the arterial diameter measured in rat resistance mesenteric arteries with or without flow (ligated arteries) isolated from SHR or WKY rats. Results are expressed as change in diameter (μM). Mean±s.e.mean are represented (n=7 per group). ^*P<0.01, 2-way ANOVA for repeated measures, vessels with versus vessels without flow.

Figure 6

Effect of exogenous angiotensin II (Ang II, 10 nmol L⁻¹) on the internal diameter of mesenteric resistance arteries from SHR or WKY rats submitted to pressure and flow. Vessels were pretreated with losartan (10 μmol L⁻¹). Sodium nitroprusside (SNP, 100 μmol L⁻¹) was added at the end of the experiment in order to induce a full vessel relaxation.