We determined the structure of mesenteric small arteries after chronic elevation and chronic reduction of blood flow. In 6-wk-old rats, we ligated second-order side branches of every other first-order side branch of the superior mesenteric artery. This persistently reduced blood flow (−90%) in the vessels feeding into the ligated trees and elevated blood flow (+80%) in the nonligated mesenteric artery side branches. Four weeks after surgery, vessels that had been exposed to high blood flow (HF) or low blood flow (LF) and vessels from sham-operated rats (Sham) were isolated and mounted in a pressure myograph system. At an intraluminal pressure of 100 mmHg, the internal diameter at rest was larger in HF (533 ± 23 μm) and smaller in LF (262 ± 14 μm) than in Sham vessels (427 ± 15 μm). Also, wall and media cross-sectional areas were larger in HF and smaller in LF than in Sham vessels (media: 22 ± 1, 11 ± 2, and 16 ± 1 × 103μm2, respectively), but circumferential wall stress did not differ among groups. DNA content was significantly increased in HF vessels (+100%) and was not modified in LF vessels. Maximal vasoconstrictions elicited by high potassium or norepinephrine were slightly increased in HF vessels but were reduced by 50% in LF vessels. Thus chronic changes in blood flow give rise to structural changes that normalize circumferential wall stress. Elevated blood flow resulted in outward hypertrophic remodeling involving hyperplasia. Reduced blood flow resulted in inward hypotrophic remodeling accompanied by hyporeactivity of the arterial smooth muscle.

Abstract-To obtain information on the molecular and cellular mechanisms of flow-induced arterial remodeling, we analyzed the morphology and smooth muscle cell (SMC) characteristics in rat mesenteric resistance arteries after interventions that decreased and increased flow. Juvenile male Wistar Kyoto rats were subjected to surgery that, compared with control arteries, provided arteries with chronic low flow and chronic high flow. Low flow resulted in a decreased passive lumen diameter, hypotrophy of the artery wall, and both loss and decreased size of SMCs. Time course studies, with intervention length ranging from 2 to 32 days of altered blood flow, showed that the narrowing of the lumen diameter in low-flow arteries appeared within 2 days and that an early dedifferentiation of SMC phenotype was indicated by markedly reduced levels of desmin mRNA. High flow resulted in an increased passive lumen diameter and in hypertrophy of the artery wall. The hypertrophy resulted from SMC proliferation because SMC number, measured by the 3D-dissector technique, was increased and immunohistochemical assessment of proliferating cell nuclear antigen also showed an increase. The widening of high-flow arteries required 16 days to become established, at which time desmin mRNA was reduced. This time was also required to establish changed wall mass in both low-flow and high-flow arteries. Apoptotic cells detected by TdT-mediated dUTP-biotin nick end labeling staining were mainly located in the medial layer, and evaluation of DNA fragmentation indicated that increased apoptosis occurred in both low flow and high flow. This study shows for the first time direct evidence that reduced and elevated blood flow in resistance arteries produce, respectively, decrease and increase in SMC number, with dedifferentiation of the SMCs in both cases.

1 This study investigates the role of nitric oxide (NO) and reactive oxygen species (ROS) on endothelial function of pulmonary arteries in a mice model of hypoxia-induced pulmonary hypertension. 2 In pulmonary arteries from control mice, the NO-synthase inhibitor N o -nitro-L-arginine methyl ester (L-NAME) potentiated contraction to prostaglandin F 2a (PGF 2a ) and completely abolished relaxation to acetylcholine. In extrapulmonary but not intrapulmonary arteries, acetylcholine-induced relaxation was slightly inhibited by polyethyleneglycol-superoxide dismutase (PEG-SOD) or catalase. 3 In pulmonary arteries from hypoxic mice, ROS levels (evaluated using dihydroethidium staining) were higher than in controls. In these arteries, relaxation to acetylcholine (but not to sodium nitroprusside) was markedly diminished. L-NAME abolished relaxation to acetylcholine, but failed to potentiate PGF 2a -induced contraction. PEG-SOD or catalase blunted residual relaxation to acetylcholine in extrapulmonary arteries, but did not modify it in intrapulmonary arteries. Hydrogen peroxide elicited comparable (L-NAME-insensitive) relaxations in extra-and intrapulmonary arteries from hypoxic mice. 4 Exposure of gp91phox -/-mice to chronic hypoxia also decreased the relaxant effect of acetylcholine in extrapulmonary arteries. However, in intrapulmonary arteries from hypoxic gp91phox -/-mice, the effect of acetylcholine was similar to that obtained in mice not exposed to hypoxia. 5 Chronic hypoxia increases ROS levels and impairs endothelial NO-dependent relaxation in mice pulmonary arteries. Mechanisms underlying hypoxia-induced endothelial dysfunction differ along pulmonary arterial bed. In extrapulmonary arteries from hypoxic mice, endothelium-dependent relaxation appears to be mediated by ROS, in a gp91phox-independent manner. In intrapulmonary arteries, endothelial dysfunction depends on gp91phox, the latter being rather the trigger than the mediator of impaired endothelial NO-dependent relaxation.

We evaluated the reactivity of small arteries after remodeling induced by elevated or reduced blood flow. In 6-wk-old rats, every other first-order side branch of the superior mesenteric artery was ligated near the bifurcation of second-order branches. Four weeks after surgery, vessels that had been exposed to high flow (HF) or low flow (LF) were isolated and mounted in a pressure myograph at 100 mmHg and were compared with vessels from sham-operated rats (Sham). In HF: 1) basal lumen diameter was increased; 2) sensitivity to norepinephrine, arginine vasopressin, and perivascular nerve stimulation was not modified; 3) maximal constrictor responses (Δ diameter) to these stimuli and 125 mM K+ were increased; and 4) sensitivity and maximal dilator responses to sodium nitroprusside, acetylcholine, and flow were not modified. In LF: 1) basal diameter was reduced; 2) sensitivity to constrictor stimuli was not altered; 3) maximal responses to all vasoconstrictors except arginine vasopressin were reduced; and 4) sensitivity but not maximal dilator responses to sodium nitroprusside and acetylcholine was reduced. During acute flow-induced dilatations, lower shear stress was maintained in HF (48 ± 7 dyn/cm2) than in Sham (63 ± 10 dyn/cm2), but no shear stress regulation was observed in LF. These observations indicate that arterial structural responses to altered blood flow are accompanied by modified reactivity of the arterial smooth muscle, which entails changes in responsiveness to neurogenic and endothelium-dependent stimuli.

The aim of this study was to analyze beta-adrenoceptor (beta-AR)-mediated relaxation in rat intralobar pulmonary artery. The relaxant responses of beta-AR agonists were characterized using beta-AR antagonists in prostaglandin F2alpha (PGF2alpha)-precontracted arteries. The role of nitric oxide (NO) and endothelium in beta-AR-mediated relaxation was also investigated. Isoprenaline (a non-selective beta-AR agonist) and salbutamol (a selective beta2-AR agonist) induced vasorelaxation. ICI 118551 (a selective beta2-AR antagonist) antagonized the effect of both isoprenaline and salbutamol (pA2 values of 9.57 and 9.51 respectively). In contrast, atenolol (1 microM) and CGP 20712A (0.1 microM), two beta1-AR antagonists, did not modify the relaxing effect of isoprenaline. The response to isoprenaline obtained in the presence of nadolol (10 microM, a beta1/beta2-AR antagonist) was not further inhibited by SR 59230A (1 microM, a selective beta3-AR antagonist). The non-beta1/beta2-AR agonists studied (BRL 37344, SR 58611A, and CGP 12177A) did not elicit vasorelaxation. Relaxation to isoprenaline and salbutamol was unaffected by L-N(G)-nitro-arginine methyl ester (100 microM, an inhibitor of NO synthase) or after endothelium removal. These results demonstrate the role of beta2-AR in mediating relaxation in rat intralobar pulmonary artery precontracted with PGF2alpha. They indicate that beta2-AR-mediated relaxation in this artery is NO- and endothelium-independent. Furthermore, they do not provide evidence of a relaxant role of either beta1- or beta3-AR in PGF2alpha-precontracted rat intrapulmonary artery.

The study was designed to compare the effects of agonists and flow on endothelial reactivity in perfused coronary arteries of spontanously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. To this end, coronary arteries were cannulated at both ends using an arterio-graph system. In the absence of flow and under an intraluminal pressure of 30 mm Hg, SHR arteries had larger internal diameters compared to those of WKY rats (275 ± 10 vs. 239 ± 7 µm, p < 0.01). In preparations preconstricted with serotonin HT, concentration-effect curves were constructed by adding acetylcholine or bradykinin in the bath. On the other hand, the effect of a stepwise increase in intraluminal flow (50–450 µl/min) of physiological salt solution was observed. Agonist-induced dilations were significantly smaller in arteries of SHRs compared to those of WKY rats. Starting flow at the plateau of constriction led to dilations that were also weaker in SHR compared to WKY vessels: 27 ± 6 vs. 61 ± 3, p < 0.001, when expressed as percentage of maximal initial constrictions. The maximal dilation induced by flow in SHR arteries was obtained for a greater value of shear stress compared to that determined in WKY preparations: 81 ± 6 vs. 60 ± 4 dyn/cm², p < 0.01. After endothelium destruction, flow-induced dilation was totally abolished in SHR arteries but only reduced in those of WKY rats. Subsequent additions of sodium nitroprusside induced complete dilations in vessels from both strains. The same protocol was performed in arteries submitted to a perfusion pressure of 90 mm Hg. In these conditions, impairments of agonist-and flow-induced dilations were also evidenced in SHR arteries. These results show that both the endothelium-dependent dilation induced by acetylcholine or bradykinin and the flow-induced dilation are impaired in coronary arteries of SHRs compared to WKY rats. These alterations appear to be due to a deterioration of endothelial cell function in the presence of a normal reactivity of the smooth muscle cells.

This study investigates the effect of the aryloxypropanolamines

We have recently shown that the beta-adrenoceptor ligands CGP 12177, bupranolol, and SR 59230A (aryloxypropanolamines), but not BRL 37344 and CL 316243 (phenylethanolamines), exhibit significant affinity for alpha1-adrenoceptors and that CGP 12177 displays partial agonist properties at alpha-adrenoceptors in rat pulmonary artery. In this study, bupranolol and SR 59230A were further evaluated for their potential alpha-adrenoceptor mediated effects (i.e., agonist and/or antagonist properties) in rat intralobar pulmonary artery and compared with BRL 37344 and CL 316243. Bupranolol induced a relaxation in phenylephrine-precontracted arteries, but had no effect in prostaglandin F2alpha(PGF2alpha) -precontracted ones. SR 59230A also elicited a relaxation in phenylephrine-precontracted arteries. In PGF2alpha -precontracted arteries, SR 59230A induced a contractile response that was insensitive to the irreversible alpha-adrenoceptor antagonist phenoxybenzamine. BRL 37344 at high concentrations, but not CL 316243, produced slight relaxation in both phenylephrine- and PGF2alpha -precontracted arteries. The contractile response to phenylephrine was antagonized by bupranolol and SR 59230A in a competitive manner (pA2: 6.38 and 7.08 respectively). The concentration-response curve to phenylephrine was also shifted to the right by BRL 37344 (mean pKb: 4.45), but not by CL 316243 (100 microM). This study indicates that the aryloxypropanolamine derivatives bupranolol and SR 59230A exhibit competitive antagonist, but no agonist properties on alpha1-adrenoceptors, SR 59230A also inducing alpha-adrenoceptor-independent contraction. Among the phenylethanolamines, BRL 37344 but not CL 316243, also exerts an antagonist effect on alpha1-adrenoceptors, with a much lower potency than the aryloxypropanolamines studied.