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. 1999 Jul 1;518(Pt 1):239–245. doi: 10.1111/j.1469-7793.1999.0239r.x

Impaired flow-dependent dilatation in distal mesenteric arteries from the spontaneously hypertensive rat

Ashley S Izzard 1, Anthony M Heagerty 1
PMCID: PMC2269414  PMID: 10373705

Abstract

  1. The aim of the study was to examine the hypothesis that flow-dependent dilatation is impaired in distal mesenteric arteries from adult spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rat (WKY) controls and to assess the role of nitric oxide (NO).

  2. Arterial segments were cannulated, pressurized to 80 mmHg and allowed to develop spontaneous myogenic tone. Flow was increased incrementally in vessels from both strains and responses were also assessed before and after incubation with the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). Responses to flow in control vessels were also assessed before and after intraluminal perfusion with antibody-complement to disrupt the endothelium.

  3. At a flow rate of 5 μl min−1, arteries from the WKY dilated significantly (22 ± 5 %, P < 0·01, n = 29) compared with the diameter at zero flow, whereas arteries from the SHR did not (4 ± 4 %, n.s., n = 16). Incubation with L-NAME had no inhibitory effect on the responses to flow in either rat strain. In control arteries, antibody-complement treatment abolished the dilatation in response to both flow and acetylcholine (ACh, 1 μM).

  4. We conclude that flow-dependent dilatation is impaired in distal mesenteric arteries from adult SHR compared with WKY controls. Furthermore, flow-dependent dilatation is endothelium dependent, but L-NAME insensitive, thus excluding the NO pathway in this abnormality. Impaired flow-dependent dilatation may contribute to the increased peripheral resistance in hypertension.

Throughout the vasculature, blood flow exerts shear stress on the endothelial cells and this is the physical stimulus for endothelium-dependent relaxation of the underlying vascular smooth muscle, a process known as flow-dependent dilatation (Smeisko & Johnson, 1993). Resistance vessels have been shown to be particularly sensitive to flow-dependent dilatation, compared with conduit vessels, which has led to the suggestion that this stimulus may contribute to the regulation of blood flow and hence peripheral vascular resistance (Smeisko et al. 1989; Koller & Kaley, 1990; Kuo et al. 1990). In fact, several studies have demonstrated that flow-dependent dilatation opposes and competes with pressure-induced myogenic constriction in setting resistance vessel tone (Griffith & Edwards, 1990; Kuo et al. 1991; Pohl et al. 1991; Koller et al. 1993; Juncos et al. 1995). Flow-dependent dilatation has been shown to be mediated by nitric oxide (NO) (Kuo et al. 1991; Juncos et al. 1995; Ngai & Winn, 1995), dilator prostaglandins (Koller et al. 1993) and a combination of both (Koller & Huang, 1994; Yashiro & Ohhashi, 1997), apparently depending on the species and vascular bed under study.

Thus, it is a reasonable hypothesis that impaired flow-dependent dilatation in the resistance vasculature may lead to an elevation in tone and contribute to the elevated peripheral resistance observed in hypertension. In support of this, in vitro studies of pressurized gracilis muscle arterioles from the spontaneously hypertensive rat (SHR) have demonstrated impaired flow-dependent dilatation compared with control vessels because of the loss of the NO-mediated component of flow-dependent dilatation; a prostaglandin component was preserved (Koller & Huang, 1994). However, it is not known if this abnormality is limited to the gracilis muscle arterioles or if it is a more general feature of the resistance vasculature in hypertension. Therefore the aim of our study was to compare flow-dependent dilatation in distal mesenteric arteries from the SHR with vessels from the normotensive Wistar-Kyoto rat (WKY), and to assess the role of the NO pathway in these responses.

METHODS

Male SHR and WKY (Charles River, UK) were obtained at 4 weeks of age, housed four to six per cage and maintained on tap water and standard laboratory food ad libitum. All procedures were performed in accordance with our Institutional Guidelines and the UK Animals (Scientific Procedures) Act 1986. At 20 weeks a subgroup of each rat strain was anaesthetized with a 3.3 ml (kg body wt)−1 intraperitoneal injection of 1:1:2 fentanyl citrate- fluanisone (Hypnorm), midazolam (Hypnovel) and water. Following induction of anaesthesia, supplemental doses (0.3 ml (kg body wt)−1) of the above mixture were administered intraperitoneally when necessary, as assessed by the flexion withdrawal reflex. Polyethylene cannulae (Portex tubing, 0.61 mm o.d., 0.28 mm i.d.) were inserted into the left femoral artery. The distal region of the cannula was exteriorized between the scapulae, flushed with saline containing 100 u ml−1 heparin, and closed with a stainless steel spigot. The cannula was secured to the femoral artery with a 4-0 silk suture. Analgesia was provided by 0.3 mg (kg body wt)−1 buprenorphine given intramuscularly. Then rats were housed singly and 24 h later, blood pressure recordings were made. To record the blood pressure, the cannula was clamped, the spigot removed and the cannula connected to a pressure transducer (Spectramed, Swindon, UK) which was connected to a chart recorder. The clamp was then removed and pressure recorded. The rat was free to move in the cage. Movements were associated with large fluctuations in blood pressure, and therefore recording continued until a period of inactivity occurred during which the blood pressure stabilized and was used for analysis. The time between connecting the catheter to the transducer and such a quiet period varied between recordings, but was typically within 20 min. The length of these quiet periods were also variable. After a steady recording had been made, the cannula was clamped, disconnected from the transducer and reclosed with the spigot.

Rats that underwent cannulation were used within 1 week of blood pressure measurement. The remainder were 20-24 weeks old. On the day of study rats were killed by stunning followed by cervical dislocation. An abdominal incision was made and a segment of the proximal jejunum with attached mesentery was excised and placed in ice-cold physiological solution (PSS) of the following composition (mM): 119 NaCl, 4.7 KCl, 25 NaHCO3, 1.18 KH2PO4, 1.17 MgSO4, 1.6 CaCl2, 0.026 EDTA and 5.5 glucose.

Distal mesenteric arteries (6th generation branches) of 1-2 mm length were freed from adherent adipose tissue, removed and placed in the arteriograph chamber (Living Systems Instrumentation, Burlington, VT, USA). The artery segments were cannulated as previously described (Halpern et al. 1984; Izzard et al. 1996) and initially pressurized to 20 mmHg. A three-way tap, which connected the proximal cannula to the pressure servo, was then closed off and the pressure servo reconnected, via a three-way tap, to the distal cannula and a windkessel. The proximal cannula was reconnected to a micro-infusion syringe pump (KD Scientific, Boston, MA, USA) which was primed and then set to ‘off’ prior to opening the tap. This arrangement established intraluminal flow in the in vivo direction, when the syringe pump was turned on, as the proximal artery segment was cannulated first. ‘In line’ pressure transducers were connected proximally and distally, allowing the pressure gradient to be determined for a given flow rate. Intraluminal pressure was then increased to 80 mmHg and the artery checked for leaks. A stable pressure recording when the pressure servo system was turned to manual confirmed the absence of leaks. Any artery that leaked was discarded. Lumen diameter was continuously monitored using a Video Dimension Analyser (Living Systems). Signals from the pressure transducers and Video Dimension Analyser were digitized and stored on a computer loaded with WINDAQ data acquisition system software (Dataq Instruments, Akron, OH, USA). The arteriograph bath chamber was superfused with PSS from a reservoir gassed with 5 % CO2 in air (pH 7.4-7.45) and the temperature increased to 37°C. Arteries were equilibrated for 1 h; by this time they developed a stable level of spontaneous myogenic tone.

In the first series of experiments, intraluminal flow was started at a rate of 1 μl min−1, increased to 2, 5, 10 and 20 μl min−1 in sequence, and then returned to zero-flow conditions. Using the pressure servo system, distal pressure was reduced by 50 % of the total pressure gradient generated at each flow rate and returned to 80 mmHg when flow was stopped, thereby maintaining constant intraluminal pressure. Flow was maintained for at least 3 min at each flow rate and changes in diameter were allowed to plateau for 1 min. Approximately 30 min later, vessels were superfused with PSS containing acetylcholine (ACh; 1 μM) to assess the integrity of endothelium-dependent dilatation in control conditions in both of the rat strains.

A second series of experiments was carried out to assess the reproducibility of flow-dependent dilatation. Only WKY rat vessels were used for this study. Intraluminal flow was increased up to 20 μl min−1 as described above and the procedure repeated 30 min later. A separate series of experiments was carried out as above except the maximum flow rate was reduced to 5 μl min−1.

A third series of experiments was carried out to examine the effect of NO synthase inhibition on flow-dependent dilatation of distal mesenteric vessels from both strains. After control responses to flow (maximum 5 μl min−1) were assessed, arteries were superfused with PSS containing Nω-nitro-L-arginine methyl ester (L-NAME, 10−4 M) for 30 min and the responses to flow reassessed. Afterwards, arterial responsiveness to ACh (1 μM) was routinely assessed in the continued presence of L-NAME.

A final series of experiments was carried out to assess the effect of endothelial disruption on flow-dependent dilatation. Only WKY rat vessels were used in this study. We adopted the antibody- complement strategy to disrupt the endothelium as described by Juncos et al. (1994). After control responses to flow (maximum 5 μl min−1), arteries were perfused intraluminally for 1 h with medium 199 (M199)-5 % bovine serum albumin (BSA) containing anti-human factor VIII-related antigen antibody (13.4 μg ml−1, Atlantic Antibodies, DiaSorin, Wokingham, UK) and 4 % guinea-pig complement (Sigma Chemical Co.) referred to below as antibody-complement, at a rate of 5 μl min−1 using the syringe pump. This was followed by 20 min washout with PSS after which flow was stopped and the vessels allowed to develop a stable level of myogenic tone. Responses to flow were reassessed and then the vessels were challenged with ACh (1 μM) to confirm endothelial disruption.

At the end of all experimental protocols, arteries were superfused in Ca2+-free PSS containing 2 mM EGTA for 20 min to determine passive lumen diameter.

Salts and chemicals were purchased from Sigma Chemical Co. L-NAME was prepared on the day of the experiment (10−1 M stock dissolved in PSS). ACh was prepared in 1 ml aliquots (10−2 M dissolved in distilled water) and kept frozen until required.

Statistics

The data are presented as means ±s.e.m.n represents the number of arteries studied. One artery was studied from each rat. Mean arterial blood pressure was calculated as diastolic pressure plus one third pulse pressure. Shear stress (τ) was calculated from τ= 4ηQ/πr3, where η is perfusate viscosity (0.007 poise for PSS at 37°C), Q is perfusate flow rate and r is vessel radius. Statistical analyses were carried out using Student's two-tailed unpaired and paired t test with Bonferroni correction where appropriate. In all cases P < 0.05 was considered significant.

RESULTS

A total of 16 SHR and 29 WKY arteries were studied. One vessel was studied from each rat. Mean arterial blood pressure was significantly increased in SHR compared with WKY (178 ± 8 vs. 124 ± 1 mmHg, P < 0.001, n = 6 in each group). Mean body weight was significantly reduced in the SHR compared with the WKY (345 ± 11 vs. 380 ± 8 g, P < 0.05, n = 6 in each group).

In Ca2+-free PSS at 80 mmHg, passive lumen diameter of arteries from the SHR was significantly reduced compared with controls (135 ± 4 vs. 161 ± 3 μm, P < 0.001, n = 16 and 29, respectively). The active lumen diameter in the presence of spontaneous myogenic tone was not significantly different between strains (94 ± 4 vs. 104 ± 4 μm SHR vs. WKY, respectively, n.s.). Expressing active diameter as a percentage of the corresponding passive diameter indicated that there were comparable levels of myogenic tone in the two strains (70 ± 3 vs. 65 ± 2 %, SHR and WKY vessels, respectively, n.s.).

Figure 1 shows the mean diameter of arteries from SHR and WKY (n = 8 in each group) with intraluminal flow ranging from 0 to 20 μl min−1. At 1 and 2 μl min−1 there was no change in diameter in either rat strain. At 5 μl min−1, arteries from WKY rats began to dilate after a latent period of 55 ± 18 s and reached a plateau by 1-2 min, resulting in a 16 ± 4 μm (P < 0.01) increase in diameter compared with control (zero-flow) conditions. Arteries from the SHR did not demonstrate significant dilatation (6 ± 3 μm, n.s., n = 8) compared with control conditions and this response was significantly impaired compared with WKY arteries (P < 0.05). Further increases in flow to 10 and 20 μl min−1 did not result in further dilatation in arteries from either strain. As a result of impaired flow-dependent dilatation, the lumen diameter of SHR vessels was significantly reduced at intraluminal flow rates of 5 and 10 μl min−1 compared with WKY vessels (P < 0.05, Fig. 1). Representative recordings of the response of an SHR and WKY vessel to intraluminal flow are shown in Fig. 2. Calculated wall shear stress ranged from 0 to 38 ± 0.98 dyn cm−2 in SHR arteries and from 0 to 23 ± 0.47 dyn cm−2 in controls. At 5 μl min−1, impaired dilatation resulted in a doubling of the wall shear stress compared with controls (8.0 ± 0.16 vs. 4.4 ± 0.09 dyn cm−2, P < 0.01, SHR vs. WKY, respectively).

Figure 1. Effect of intraluminal flow on the diameter of distal mesenteric arteries from the SHR compared with WKY controls.

Figure 1

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Flow-diameter relation of distal mesenteric arteries from SHR (□) and WKY controls (○). * P < 0.01 lumen diameter with intraluminal flow compared with zero flow; † P < 0.05 lumen diameter of SHR vs. WKY (n = 8 in each group).

Figure 2. Representative recordings of the response to flow in a distal mesenteric artery from the SHR and WKY control.

Figure 2

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Proximal pressure, distal pressure and diameter recording as intraluminal flow is increased incrementally to 20 μl min−1, followed by dilatation in response to ACh (1 μM), in a distal mesenteric artery from the SHR (A) and WKY control (B).

Experiments to test the reproducibility of flow-dependent dilatation demonstrated a 50 ± 18 % reduction in the maximum response when flow was increased up to 20 μl min−1 (the change in diameter attained was reduced from 25 ± 6 to 12 ± 4 μm, n = 4, P < 0.05). However, another series of time control experiments carried out with the maximum flow rate reduced to 5 μl min−1 showed the effect of flow to be reproducible (n = 6, Fig. 3).

Figure 3. Reproducibility of flow-dependent dilatation.

Figure 3

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Time control experiments using distal mesenteric arteries from WKY, demonstrating reproducibility of flow-dependent dilatation when the maximum flow rate is 5 μl min−1 (n = 6). ○, first response; □, second response.

Lumen diameter was not significantly different after 30 min incubation in 100 μM L-NAME, to inhibit NO synthase, compared with the control condition for either SHR (107 ± 6 vs. 98 ± 5 μm, n = 8) or WKY (113 ± 7 vs. 113 ± 7 μm, n = 7). Incubation in L-NAME did not reduce artery dilatation to intraluminal flow in the WKY control; in fact arteries treated with the NO synthase inhibitor were significantly dilated at 1 and 2 μl min−1 compared with control conditions (Fig. 4). The lack of flow dilatation in arteries from the SHR was unaltered in the presence of L-NAME (Fig. 4).

Figure 4. Effect of L-NAME on the response to intraluminal flow in distal mesenteric arteries from the SHR and WKY.

Figure 4

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Flow-diameter relation before (○) and after (□) 30 min incubation in L-NAME (10−4 M). A, SHR (n = 8); B, WKY (n = 7). * P < 0.05, L-NAME vs. control.

The lumen diameter of WKY vessels was not significantly different after perfusion for 1 h with antibody-complement compared with control conditions (115 ± 9 vs. 117 ± 6 μm, n = 4, n.s.). This treatment completely abolished artery dilatation in response to intraluminal flow (Fig. 5).

Figure 5. Effect of endothelial disruption on flow-dependent dilatation.

Figure 5

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Flow-diameter relation in distal mesenteric arteries from the WKY rat before (○) and after (□) endothelial disruption by intraluminal perfusion with M199-5 % BSA containing anti-human factor VIII-related antigen antibody (13.4 μg ml−1) and 4 % guinea-pig complement (n = 4). * P < 0.05 endothelial disruption vs. control.

Dilatation in response to ACh (1 μM), expressed as a percentage of maximum dilatation (Ca2+-free PSS), was not different for vessels incubated in L-NAME compared with untreated vessels in either SHR (75 ± 4 vs. 85 ± 13 %, n.s., n = 5 and 8) or WKY (99 ± 6 vs. 96 ± 8 %, n.s., n = 6 and 8). Vessels treated with antibody-complement did not dilate in response to ACh (12 ± 0.05 %, n.s.), thus confirming endothelial disruption.

DISCUSSION

The major findings of this study are that endothelium-dependent flow-induced dilatation is impaired in distal mesenteric arteries from the SHR compared with those from normotensive WKY. Our results suggest that this impairment is independent of the NO pathway, as L-NAME was without effect on the response to flow in either rat strain.

Flow-dependent dilatation was first reported in rat mesenteric arteries in vivo, using the technique of ‘parallel occlusion’, and the flow-dependent dilatation reached maximal dilatation (Smeisko et al. 1989). In the present study, flow-dependent dilatation increased the diameter of WKY controls from 104 ± 4 to 123 ± 4 μm (n = 29, pooled data) which is 33 % maximum dilatation (161 ± 3 μm). The larger dilatation observed in the study of Smeisko et al. (1989) may be a consequence of using younger rats: we used adult rats (20-24 weeks) weighing 380 g whereas young rats (age not given but weighing only 62 g) were used in the previous study. Other factors to be considered include the strain of rat used (Sprague-Dawley vs. WKY), and the methodology employed (parallel occlusion in vivovs. incremental increases in intraluminal perfusion in vitro). Using cannulated vessels in vitro, flow-dependent dilatation has been shown to be absent in mesenteric arteries from adult Wistar rats with a lumen diameter of ∼200 μm in the presence of myogenic tone (Cockell & Poston, 1996), although it was present when tone was increased with noradrenaline (Tribe et al. 1998). Mesenteric arteries with a resting lumen diameter of ∼100 μm with myogenic tone have been reported to demonstrate flow-dependent dilatation (Henrion et al. 1997), as in the present study. The higher levels of myogenic tone which develop in the smaller calibre mesenteric vessels (∼100 μm) may enable flow-dependent dilatation to be detected, whereas upstream vessels may require additional agonist-induced constriction to reveal this response. Alternatively or in addition, a gradient for flow-dependent dilatation in the adult mesenteric vasculature, as has been demonstrated in the pig coronary microvasculature (Kuo et al. 1995), may be the explanation for the difference.

In the study of Henrion et al. (1997) on 100 μm mesenteric arteries, peak flow-dependent dilatation occurred at a flow rate of 100 μl min−1, compared with 5 μl min−1 in the present study. In fact, graded increases in flow did not result in a clearly graded dilatation in the present study, rather an attenuation of the response was observed at higher flow rates. A similar finding has been observed in rat cerebral arterioles using similar techniques (Ngai & Winn, 1995). Nevertheless, smaller increments in flow, especially at the lower range employed in this study, might have revealed graded dilatation since the flow-diameter relation can be steep, as observed in pig coronary microvessels (Kuo et al. 1990) and rat soleus feed arteries (Jasperse & Laughlin, 1997).

The time control experiments of the present study demonstrated diminished flow-dependent dilatation when the maximum flow rate was 20 μl min−1, but reproducible dilatation when the maximum flow rate was 5 μl min−1 (Fig. 3). Thus, we speculate that a shear stress of 4 dyn cm−2, generated at the flow rate of 5 μl min−1, is within the physiological range for rat distal mesenteric arteries, whereas the shear stresses obtained at the higher flow rates are not and this causes damage to the endothelium which results in loss of flow sensitivity. Maximum flow-dependent dilatation also occurs at shear stresses of < 5 dyn cm−2 in pig coronary arterioles (Kuo et al. 1995) and rat soleus feed arteries (Jasperse & Laughlin, 1997), although higher levels of shear stress (∼30 dyn cm−2) are associated with dilatation of rat gracilis muscle arterioles (Kollar & Huang, 1995). Shear stress was not calculated in the study of Henrion et al. (1997) so the results cannot be fully compared with those of the present study.

A characteristic of flow-dependent dilatation both in vivo (Smeisko et al. 1989; Koller & Kaley, 1990) and in vitro (Kuo et al. 1990; Koller et al. 1993) is a latent period between the increase in flow and the ensuing dilatation. This finding is consistent with the concept that an elevation in shear stress is indeed the stimulus for flow-dependent dilatation. In our study, distal mesenteric arteries from the WKY dilated 7-166 s (mean 44 ± 8 s, n = 29, pooled control data) after an increase in flow from 2 to 5 μl min−1 and at 80 mmHg intraluminal pressure. Similarly, using cannulated vessels in vitro, this latent period was 7-51 s for rat cremaster arterioles (Koller et al. 1993), whereas a latent period of less than 5 s has been observed for pig coronary arterioles (Kuo et al. 1990).

In our study, L-NAME did not inhibit flow-dependent dilatation, indicating an apparent lack of NO dependence. A role for prostaglandins seems unlikely as preliminary studies demonstrated that indomethacin was without effect on flow-dependent dilatation in these vessels (Izzard & Heagerty, 1998). In addition, L-NAME did not inhibit the dilatation in response to ACh in these vessels from either strain of rat. This suggests or raises the possibility that prostaglandins and/or endothelial derived hyperpolarizing factor (EDHF) was responsible for the ACh-induced dilatation: the latter can play a substantial role in the relaxation of resistance vessels in response to endothelial agonists, especially in rat mesenteric resistance vessels (Taylor & Weston, 1988; Garland et al. 1995). As a consequence we do not have an index of the efficacy of NO synthase inhibition. However, arginine analogues used at the same concentration and for the same incubation time as in the present study have been shown to inhibit NO synthase and flow-dependent dilatation in resistance arteries from several other beds (Kuo et al. 1991; Koller & Huang, 1994; Juncos et al. 1995; Ngai & Winn, 1995). Thus the present results suggest that flow-dependent dilatation in WKY control vessels is not dependent on NO. On the other hand, the present study showed that endothelial disruption, by antibody-complement perfusion, had no effect on myogenic tone, but almost abolished the dilatation in response to ACh, indicating selective impairment of the endothelium. This treatment also eliminated flow-dependent dilatation (Fig. 5), and is therefore in agreement with the known endothelium dependence of the response (Kuo et al. 1990; Koller et al. 1993; Juncos et al. 1995). Thus in distal mesenteric arteries from WKY controls, flow-dependent dilatation appears to involve an endothelium-dependent, but an NO-independent, mechanism. This leaves the possibility that either there is an interaction between NO and prostaglandins such that, in the presence of L-NAME, flow-dependent dilatation is mediated by prostaglandins as in arteries from the spinal cord of the rabbit (Yashiro & Ohhashi, 1997), or that flow-dependent dilatation is mediated by a non-NO, non-prostaglandin mechanism, i.e. EDHF. Given the predominant role of EDHF in ACh-induced dilatation in rat mesenteric small arteries, a flow (shear stress) coupled EDHF system seems a likely candidate. Thus, the finding that flow-dependent dilatation is augmented at the lower flow rates after nitric oxide synthase inhibition (Fig. 4B) could be due to loss of inhibition of EDHF activity by NO (Bauersachs et al. 1996; McCulloch et al. 1997). These possibilities require further investigation.

To date, only one other study has investigated flow-dependent dilatation in the resistance vasculature of the SHR in vitro (Koller & Huang, 1994). These investigators observed impaired flow dilatation in gracilis muscle arterioles from 12-week-old SHR compared with those from Wistar rats. Now we can extend this observation to the distal mesenteric vasculature of adult (20-24 weeks) SHR compared with WKY controls (Fig. 1). In gracilis muscle arterioles from the SHR, an NO-mediated flow-dependent dilatation was absent, a residual dilatation remained which was prostaglandin mediated, whereas in control arterioles, flow-dependent dilatation was mediated by both NO and prostaglandins. Thus, these investigators concluded that the impaired flow-dependent dilatation in the SHR was a consequence of a selective defect in flow-induced NO synthesis (Koller & Huang, 1994). Given our current findings in mesenteric arteries, it appears that the impairment of shear stress signalling in the endothelium is common to both NO-dependent and an NO-independent system in the resistance vasculature of the SHR.

Impaired flow-dependent dilatation will increase shear stress for a given flow rate. In the current study, shear stress was increased at all flow rates greater than 2 μl min−1 in SHRs compared with controls. This is similar to observations from gracilis muscle arterioles from the SHR compared with controls (Koller & Huang, 1995). Elevated shear stress in the resistance vasculature will increase the power loss within this region of the circulation thereby necessitating greater pressure gradients across the resistance vasculatures, as has been confirmed by micropuncture measurements in the SHR (Bohlen, 1983).

In conclusion, the present study demonstrates impaired endothelium-dependent flow-induced dilatation of distal mesenteric arteries from the SHR compared with WKY controls. An abnormality in the NO pathway cannot account for this difference. We propose that impaired flow-dependent dilatation may contribute to the elevated peripheral resistance in hypertension.

Acknowledgments

This work was supported by the British Heart Foundation. We thank Dr Stuart Bund for the blood pressure measurements.

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