Chronic Increase In Blood Flow Research Articles

FLOW-INDUCED DILATION IN RAT SOLEUS FEED ARTERIES AFTER ALTERED PHYSICAL ACTIVITY 997

Flow-induced dilation (FID) in conduit arteries and skeletal muscle arterioles has been reported to be enhanced after exercise training or chronic increases in blood flow. We tested the hypothesis that rat soleus feed arteries (SFA), which contribute a significant proportion of the total vascular resistance to a muscle, would 1) exhibit enhanced FID following exercise training, and 2) exhibit attenuated FID following hindlimb unweighting. SFA from exercise trained (EX; n=7) (treadmill running: 30m/min, 15% incline, 1 hr/d,5d/wk, 10-12 wks), hindlimb unweighted (HLU; n=5)(14 days), and sedentary control (CON; n=10) rats were isolated and cannulated with two glass pipettes connected to independent reservoirs in two different sets of experiments. Intraluminal pressure was maintained at 90 cmH2O throughout the experiment. Flow was induced through SFA by raising one reservoir while lowering the other an equal distance. SFA from all groups dilated markedly to flows of 10-60 ul/min, but dilation of SFA from EX and HLU did not differ from dilation of SFA from CON (maximal dilation: CON: 61±8%, EX: 55±9%, HLU: 56±19%). Thus chronic changes in blood flow induced by EX or HLU did not alter FID in rat SFA. Since SFA blood flow in the resting rat (-90 ul/min) is well above that necessary to produce maximal FID (Physiologist 39:A-45, 1996), changes in flow associated with EX and HLU may not provide an adequate stimulus for alteration of flow signalling mechanisms.

Role of NO in flow-induced remodeling of the rabbit common carotid artery.

Flow-induced changes in vessel caliber tend to restore baseline wall shear stress (WSS) and have been reported to be endothelium-dependent. To investigate the role of endothelium-derived nitric oxide (NO) in the adaptive increase in artery diameter in response to a chronic increase in blood flow, an arteriovenous fistula was constructed between the left common carotid artery (CCA) and the external jugular vein in 22 New Zealand White rabbits, and NO synthesis was inhibited in 14 animals by long-term administration of NG-nitro-L-arginine-methyl ester (L-NAME) in drinking water given for 4 weeks. The remaining 8 animals served as controls. Mean arterial blood pressure was not significantly altered by L-NAME treatment (91 +/- 2 in control versus 98 +/- 3 mm Hg in L-NAME-treated rabbits). Blood flow significantly increased in the left CCA in both groups but was lower in L-NAME-treated than control animals (106.1 +/- 10.7 versus 196.2 +/- 32.3 mL/min, P < .003). The diameter of the flow-loaded left CCA also increased significantly in both groups compared with the right CCA (2.15 +/- 0.12 and 2.54 +/- 0.1 mm, respectively, P < .02), but the increase was less in the L-NAME-treated than the control group (3.24 +/- 0.09 and 4.64 +/- 0.17 mm, respectively, P < .0001). The diameter of the anastomosed veins was also increased but to a much lesser degree in L-NAME-treated animals than in controls (4.14 +/- 0.29 versus 7.94 +/- 0.51 mm, P < .0001). As a result of artery enlargement, WSS was normalized in the flow-loaded left CCA of the control group (8.87 +/- 0.77 dynes/cm2) regardless of blood flow values. In L-NAME-treated animals, however, WSS was only partially regulated, the mean value being significantly increased (18.7 +/- 2.2 dynes/cm2, P < .006). Moreover, a highly significant positive correlation between WSS and blood flow was obtained in L-NAME-treated animals (r = .84, P < .0001). We also found remodeling of the artery wall, with a larger increase in the medial cross-sectional area associated with an increased number of smooth muscle cells, in the control group compared with the L-NAME-treated group (0.75 +/- 0.09 versus 0.49 +/- 0.04 mm2 and 4504 +/- 722 versus 2717 +/- 282 cells/mm2, P < .03). We conclude that NO plays a role in the increase of vessel caliber in response to chronic increase in blood flow. As yet unidentified additional metabolic processes appear to be necessary for a complete regulatory response.

Modulation of endothelium-derived nitric oxide in canine femoral veins.

Experiments were designed to determine whether nitric oxide was the mediator of increased endothelium-dependent relaxations in veins proximal to an arteriovenous fistula. A fistula was prepared between femoral arteries and veins in dogs. After 6 wk, veins proximal to the fistula were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers. In some rings the endothelium was removed deliberately. NG-monomethyl-L-arginine (L-NMMA) caused contraction in three of six fistula-operated veins with and without endothelium. In rings contracted submaximally with prostaglandin F2 alpha, acetylcholine and the alpha 2-adrenergic agonist UK-14,304 cause e tylcholine and the alpha 2-adrenergic agonist UK-14,304 caused endothelium-dependent, concentration-dependent relaxations that were greater in fistula compared with sham-operated veins. These relaxations were reduced by L-NMMA. Calcium ionophore A23187 caused comparable endothelium-dependent relaxations in fistula- and sham-operated veins that were unaffected by L-NMMA. There were no differences in either calcium-dependent or -independent activity of nitric oxide synthase isolated from fistula- and sham-operated veins. Positive staining for nitric oxide synthase was present in both the endothelium and media of fistula-operated veins. These results indicate that nitric oxide mediates increased endothelium-dependent relaxations to acetylcholine and alpha 2-adrenergic agonists in fistula-operated veins. Therefore, chronic increases in blood flow and oxygen tension modify selectively receptor-coupled production of nitric oxide in endothelium and smooth muscle of veins.

Remodeling of the Radial Artery in Response to a Chronic Increase in Shear Stress

Chronic changes in large artery blood flow rates induce corresponding adjustments in arterial diameter, but little is known about structural adaptations of the vessel wall in humans. We used a high-resolution echo-tracking system to measure radial artery internal diameter, wall thickness, and mean blood flow on both arms of 11 patients with end-stage renal disease. Measurements were performed on the wrist side of the arteriovenous fistula. The contralateral radial artery was investigated as control. Wall cross-sectional area, circumferential wall stress, and mean wall shear stress were calculated. Results indicate a sixfold increase in blood flow on the side of the arteriovenous fistula compared with the control side, with a 1.4-fold increase in internal diameter. The diameter enlargement was sufficient to normalize wall shear stress. Changes in diameter were not associated with arterial wall hypertrophy because wall cross-sectional area was not increased and rather suggest a "remodeling" of the arterial wall. For the same level of blood pressure, circumferential wall stress was increased on the side of the arteriovenous fistula. These results suggest that the structural adaptations of the arterial wall to a chronic increase in blood flow normalize wall shear stress and overcome stretch-induced changes in the particular circumstance of arteriovenous fistula.

Chronic increases in blood flow upregulate endothelin-B receptors in arterial smooth muscle.

Experiments were designed to characterize endothelin receptors in arteries after chronic increases in blood flow. A fistula was created between the femoral artery and vein in one hindlimb of dogs; contralateral blood vessels were sham operated. Sham- and fistula-operated arteries were removed 6 wk postoperatively. Some arteries were prepared for measurement of isometric force or for isolation of membrane proteins. Other arteries were used for histological staining with an endothelin-B (ETB) receptor antibody. In arteries suspended for the measurement of isometric force, endothelin-1 produced concentration-dependent increases in tension that were significantly greater in fistula- than in sham-operated arteries without endothelium. The ETB-receptor-selective peptide sarafotoxin S6c produced concentration-dependent increases in tension only in fistula-operated arteries. In receptor-binding studies of membrane proteins, Scatchard analysis of saturation binding with 125I-labeled endothelin-1 (125I-endothelin-1) indicated that the total number of receptors was greater in fistula-operated arteries; affinity was threefold less in fistula- than in sham-operated arteries. Competitive displacement of 125I-endothelin-1 by endothelin-3 was significant for a two-site model in membranes prepared from sham-and fistula-operated arteries. Competitive inhibition of 125I-endothelin-1 binding by sarafotoxin S6c was significant for a one-site binding model in all arteries. Sarafotoxin S6c binding sites were elevated significantly in fistula-operated arteries. Immunohistochemical staining for the ETB receptor was significantly greater in both the endothelium and smooth muscle of fistula- than in sham-operated arteries. These results suggest that chronic increases in blood flow upregulate endothelin receptors, including ETB receptors in arterial smooth muscle.

Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries.

Experiments were designed to determine whether chronic increases in arterial blood flow alter production of or response to nitric oxide and endothelin. Canine femoral arteries proximal to an arteriovenous fistula- and from the contralateral sham-operated blood vessels were removed, cut into rings, and suspended for measurement of isometric force in organ chambers. The remainder of the artery was homogenized for measurement of endothelin content by radioimmunoassay. NG-monomethyl-L-arginine (10(-4) M) caused concentration-dependent increases in tension only in fistula-operated arteries. Endothelium-dependent relaxations to acetylcholine and BHT-920 were greater in fistula- compared with sham-operated arteries. These differences were reduced by the arginine analogue. Pertussis toxin (100 ng/ml) inhibited relaxations to acetylcholine only in fistula-operated arteries and to BHT-920 only in sham-operated arteries. Contractions to endothelin-1 were greater in fistula- compared with sham-operated arteries. These results suggest that chronic increases in blood flow enhance the tonic and receptor-stimulated production of nitric oxide and its release by receptors coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins. Furthermore, chronic increases in blood flow may either inhibit the production of endothelin or promote its depletion from endothelial cells while simultaneously increasing the sensitivity of the smooth muscle to its contractile effects.

Modulation of arterial endothelin-1 receptors following chronic increases in blood flow.

Experiments were designed to determine whether or not increased contractions to endothelin-1 (ET-1) in arteries chronically exposed to increased blood flow were due to a change in the subtype, number, or affinity of ET receptors on the smooth muscle. A fistula was created between one femoral artery and vein in dogs; contralateral blood vessels were operated as shams. After 6 weeks, the femoral arteries were removed. In both fistula- and sham-operated arteries suspended for the measurement of isometric force in organ chambers, the contractile potency was ET-1 > ET-2 > ET-3. Specific binding of [125I]ET-1 as a function of membrane protein was significantly greater in fistula compared to sham-operated arteries (Bmax = 184.8 +/- 35.9 and 117.4 +/- 25.6 fmol/mg, n = 6, respectively). Affinity of binding was the same in each group of arteries. These results suggest that ETA receptors mediate contraction on canine femoral arterial smooth muscle. These receptors may be upregulated when the artery is exposed chronically to increased blood flow.

Enhanced release of endothelium-derived factor(s) by chronic increases in blood flow.

Chronic increases in blood flow caused by an arteriovenous fistula augment endothelium-dependent relaxations to acetylcholine. To determine whether endothelial muscarinic receptors are altered, concentration-response curves to acetylcholine were obtained in the presence of pirenzepine in fistula- and sham-operated canine femoral arteries. Pirenzepine inhibited the response to acetylcholine in both arteries. The pA2 (log Kb) for the antagonist was the same. A bioassay system was used to assess release of endothelium-derived relaxing factor. Rings of femoral artery (without endothelium) from unoperated dogs relaxed more when superfused with perfusate derived from endothelium of fistula-operated arteries during acetylcholine stimulation. Rings without endothelium of sham- and fistula-operated arteries relaxed to the same extent when superfused with perfusate derived from the endothelium of unoperated femoral arteries. These results suggest that augmented relaxations to acetylcholine in canine arteries where blood flow is chronically elevated do not result from changes in the subtype of endothelial muscarinic receptors or in the sensitivity of the underlying smooth muscle to endothelium-derived relaxing factor(s). They are likely due to increased release of endothelium-derived relaxing factor(s) on muscarinic activation.

Decreased pulmonary vascular responses in dogs with increased pulmonary blood flow.

We wished to determine whether high pulmonary blood flow alters the pulmonary vascular responses to the vasoconstrictors, hypoxia and prostaglandin F2alpha (PGF2alpha). Acute or chronic left pulmonary artery (PA) occlusion was performed in dogs in order to create high pulmonary blood flow conditions. Right lung pulmonary vascular resistance (PVR) during normoxia was reduced by both acute and chronic left PA occlusion, suggesting passive vasodilatation. Increases in right lung PVR induced by hypoxia (10--15% O2) and PGF2alpha (0.8-4 microgram kg-1 min-1) were attenuated both in acute and chronic left PA occluded dogs. Since the reductions in responsiveness were similar with acute and chronic increases in blood flow, the attenuating effect of high blood flow was not dependent upon morphologic changes in the vasculature. Pulmonary vascular responsiveness was probably reduced in these animals due to their dilated pulmonary vascular beds, consequent to the increased blood flow, thereby decreasing the effectiveness of smooth muscle contraction.