Active Wall Tension Research Articles

Isometric myography is a feasible method to identify and quantify endothelial dysfunction in dogs with myxomatous mitral valve disease.

To assess the feasibility of isometric myography in pet dogs with myxomatous mitral valve disease (MMVD) to determine its use in quantifying endothelial dysfunction. 9 dogs euthanized for medical reasons. Femoral, renal, and mesenteric arteries were collected postmortem and stored in physiological saline solution at 4 °C for myography. Mitral valves were scored for myxomatous degeneration (grades 1 to 4). Sections of arteries were mounted in wells, immersed in physiological saline solution perfused with 95% O2 and 5% CO2 at 37 °C, and stretched to an internal circumference (IC) that generated the maximal difference between active and passive wall tension (IC1). Normalization factors were calculated by dividing the IC1 by the IC at which the passive wall tension was 100 mm Hg (IC100). Vasoconstriction to phenylephrine and vasodilation to acetylcholine (endothelial dependent) and sodium nitroprusside (endothelial independent) were assessed by cumulative dose-response curves. Median MMVD grade was 3. Mean values of normalization factors were 1.00 ± 0.14 (renal, n = 15), 1.00 ± 0.10 (femoral, 8), and 1.05 ± 0.12 (mesenteric, 6). Responses to phenylephrine were similar between dogs (P = .14). Reduced responses to acetylcholine compared with sodium nitroprusside were identified in 15 arteries, suggesting endothelial dysfunction. Isometric myography of arteries from pet dogs is feasible and can identify loss of endothelial-dependent relaxation in dogs with MMVD postmortem. Its use in further research can lead to a better understanding of the pathophysiology mechanisms of this disease.

Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress.

Because superoxide dismutase (SOD) knockout enhances arteriolar remodeling and contractility, we hypothesized that remodeling enhances contractility. In the isolated and perfused renal afferent arterioles from SOD wild type (+/+) and gene-deleted mice, contractility was assessed from reductions in luminal diameter with perfusion pressure from 40 to 80 mm Hg (myogenic responses) or angiotensin II (10(-6) mol/L), remodeling from media:lumen area ratio, superoxide (O2 (·-)) and hydrogen peroxide (H2O2) from fluorescence microscopy, and wall stress from wall tension/wall thickness. Compared with +/+ strains, arterioles from SOD1-/-, SOD2+/-, and SOD3-/- mice developed significantly (P<0.05) more O2 (·-) with perfusion pressure and angiotensin II and significantly increased myogenic responses (SOD1-/-: -20.7±2.2% versus -12.7±1.6%; SOD2+/-: -7.4±1.3% versus -12.6±1.4%; and SOD3-/-: -9.1±1.9% versus -15.8±2.2%) and angiotensin II contractions and ≈2-fold increased media:lumen ratios. Media:lumen ratios correlated with myogenic responses (r(2) =0.23; P<0.01), angiotensin II contractions (r(2)=0.57; P<0.0001), and active wall tension (r(2) =0.19; P<0.01), but not with active wall stress (r(2)=0.08; NS). Differences in myogenic responses among SOD3 mice were abolished by bath addition of SOD and were increased 3 days after inducing SOD3 knockout (-26.9±1.7% versus -20.1±0.7%; P<0.05), despite unchanged media:lumen ratios (2.01±0.09 versus 2.02±0.03; NS). We conclude that cytosolic, mitochondrial, or extracellular O2 (·-) enhance afferent arteriolar contractility and remodeling. Although remodeling does not enhance contractility, it does prevent the potentially damaging effects of increased wall stress.

Abstract 539: Remodeling Of Afferent Arterioles From Mice With Oxidative Stress Does Not Enhance Contractility But Does Limit Excessive Wall Stress

Background: Remodeling of resistant vessels in hypertension is postulated to enhance their contractility. We showed that knockout of SOD increased superoxide (O 2 .- ), contractility and remodeling of afferent arterioles (Affs). Therefore, we tested the hypothesis that the remodeling causes the enhanced contractility. Methods: Myogenic responses (MRs) were assessed from the slope of the regression of active wall tension (AWT) on perfusion pressure (PP) in wild type and knockout SOD-1,-2 or -3 mice and in mice 3 days after induction of SOD-3 knockout before remodeling had developed. Contractions to 10 -6 M Ang II were tested also. O 2 .- was assessed from PEG-SOD inhibitable ethidium:dihydroethidium fluorescence and remodeling from media:lumen area ratio (M:L). Results: 1. Compared to +/+, increasing PP or 10 -6 M Ang II increased O 2 .- of Affs more in SOD1-/-, SOD2+/- and SOD3-/- (P&lt;0.01). 2. Compared to +/+, MRs (dynes.cm -1 .mmHg -1 ) were significantly (P&lt;0.05) increased in SOD1-/- (3.49 ± 0.30 vs 2.30 ± 0.27), in SOD2+/- (3.85 ± 0.48 vs 1.80 ± 0.34), and in SOD3-/- (3.51 ± 0.20 vs 2.43 ± 0.15). 3. Compared to +/+, Ang II contractions were also stronger in knockout mice (P&lt;0.001). 4. Compared to +/+, M:L ratio of Affs were significantly (P&lt;0.001) greater in SOD1-/- (4.0 ± 0.2 vs 1.8 ± 0.2), in SOD2+/- (3.7 ± 0.4 vs 1.8 ± 0.4), and in SOD3-/- (4.5 ± 0.2 vs 1.9 ± 0.1). 5. Across genotypes, MR (r 2 =0.32, P&lt;0.005) and Ang II contractions (r 2 = 0.56, P&lt;0.005) were strongly correlated with M:L ratios. 6. Changes in AWT (T physiol - T passive ) during increase in PP were dependent on SOD genotype (P&lt;0.01) yet changes in vessel wall stress (AWT/wall thickness) were independent (P=NS). 7. Compared to controls , MRs and Ang II contractions were increased 3 days after inducing SOD3 knockout (MR, 3.76 ± 0.55 vs 2.26 ± 0.01, P&lt;0.05; Ang II, -66 ± 4% vs -49 ± 4%, P&lt;0.01) and were not significantly different from SOD3-/- mice. However, the M:L ratio of these Affs was unchanged (2.0 ± 0.1 vs 1.8 ± 0.2, NS). Conclusions: lifetime increases in cytosolic, mitochondrial or extracellular O 2 .- enhances afferent arteriolar contractility and remodeling. The remodeling is not required for the enhanced contractility, but does prevent the damaging effects of increased wall stress.

Postnatal kidney maturation regulates renal artery myogenic constriction.

Intravascular pressure-induced vasoconstriction (myogenic constriction) is central to renal blood flow autoregulation. At term, kidney maturation is functionally incomplete. Premature neonates are at risk of kidney dysfunction. However, it is unclear whether renal artery myogenic constriction is altered after preterm birth. Here, we compared renal artery myogenic constriction in full-term and preterm pigs during the first week of life. We investigated myogenic constriction in small interlobular arteries isolated from the kidneys of pigs delivered at term and at 91% of term (with and without 96 h of neonatal intensive care). Cross-sectional area, media/lumen ratio, and luminal diameter measured under passive conditions were similar in arteries from full-term and preterm pig kidneys. An acute elevation in intravascular pressure from 20 to 100 mm Hg increased arterial wall tension and induced steady-state constriction of the arteries. However, arteries isolated from newly born preterm pigs (within 24 h) developed greater myogenic tone and lower active wall tension compared with arteries from full-term and 4-day-old preterm neonates. Pressure-induced elevation in intracellular Ca2+ was also larger in arteries from newly born preterm pigs compared with full-term and 4-day-old preterm pigs. Myogenic constriction is elevated in newly born preterm pigs. Our data also suggests that postnatal kidney maturation may modulate renal blood flow autoregulation.

Abstract 376: Prolonged Excess of Superoxide in Mouse Afferent Arterioles Causes Remodeling and Enhances Myogenic and Angiotensin II Contractions

Background: Superoxide (O 2 .- ) is associated with cardiovascular disease (CVD) and inactivating SNIPs of the EC-SOD gene increased CVD, but the mechanisms are unclear. Superoxide dismutases (SODs) have three isoforms: cytoplasmic Cu/ZnSOD (SOD1), mitochondrial MnSOD (SOD2) and extracellular Cu/ZnSOD (SOD3). Complete SOD2-/- was lethal. We tested the hypothesis that these isoforms of SOD modulate angiotensin II (Ang II), myogenic responses (MRs) and remodeling of afferent arterioles (Affs). Methods and Results: MRs were assessed from the slope of the regression of active wall tension on perfusion pressure (PP) and Ang II contractions from incubation with 10 -6 M Ang II. O 2 .- was assessed from PEG-SOD inhibitable ethidium:dihydroethidium fluorescence and remodeling from media:lumen area ratio (M:L). Results: 1. Compared to +/+, increasing PP from 40 to 80 mmHg or applying 10 -6 M Ang II in Affs increased O 2 .- more in SOD1-/- (PP, 8 ± 1% vs 5 ± 1% , P&lt;0.05; Ang II, 29 ± 7 vs 10 ± 2%, P&lt;0.05), in SOD2+/- (PP, 15 ± 2% vs 7 ± 1%, P&lt;0.01; Ang II, 32 ± 5 % vs 7 ± 1%, P&lt;0.01), and in SOD3-/- ( PP, 20 ± 4% vs 7 ± 1%, P&lt;0.05; Ang II, 32 ± 5% vs 12 ± 3%, P&lt;0.05). However, O 2 .- did not increase in SOD1+/- and SOD3+/-. 2. Compared to +/+, MRs (dynes.cm -1 .mmHg -1 ) were significantly increased in SOD1-/- (3.49 ± 0.30 vs 2.30 ± 0.27, P&lt;0.05), in SOD2+/- (3.85 ± 0.48 vs 1.80 ± 0.34, P&lt;0.05), and in SOD3-/- (3.51 ± 0.20 vs 2.43 ± 0.15, P&lt;0.01), with no increase in SOD1+/- and SOD3+/-. 3. Compared to +/+, Ang II contractions were stronger in SOD1-/- (-68 ± 2% vs -33 ± 3%, P&lt;0.0001), in SOD2+/- (-66 ± 6% vs -42 ± 3%, P&lt;0.01), and in SOD3-/- (-75 ± 3% vs -34 ± 3%, P&lt;0.0001) 4. Compared to +/+, M:L ratio of Affs were greater in SOD1-/- (4.0 ± 0.2 vs 1.8 ± 0.2, P&lt;0.0001), in SOD2+/- (3.7 ± 0.4 vs 1.8 ± 0.4, P&lt;0.001), and in SOD3-/- (4.5 ± 0.2 vs 1.9 ± 0.1, P&lt;0.0001), but were unchanged in SOD1+/- and SOD3+/-. M:L ratio was strongly correlated to MR (r 2 =0.32, P&lt;0.005) and Ang II contractions (r 2 = 0.56, P&lt;0.005) across genotypes. 5. There were no compensatory changes in expression of other SOD isoforms. Conclusions: Lifetime increases in cytosolic, mitochondrial or extracellular O 2 .- enhanced afferent arteriolar myogenic and Ang II contractions that were closely related to vascular remodeling.

Abdominoplasty with Mesh Reinforcement Ventral Herniorrhaphy

Sir: Ventral hernias occur postoperatively in 10 to 20 percent of laparotomies from failed healing or develop spontaneously from architectural deterioration of the abdominal wall.1 Hernias unload the muscle-aponeurosis, allowing it to retract, atrophy, and scar beyond the defect. Occluding only the fascial defect has proven insufficient, and herniorrhaphy has evolved from suture plication to mesh repair. As a result, the reoccurrence rate has been reduced to 12.1 percent in open ventral herniorrhaphy2 and 4.3 percent in laparoscopic ventral herniorrhaphy. An alternate open technique uses an abdominoplasty incision remote from the hernia site. After the flap is elevated, a thorough evaluation of the entire abdominal wall is performed. All hernias are identified, but local suture plication is not required. Instead, the linea alba is plicated uniformly from the sternum to the pubic symphysis, preserving the umbilicus whenever possible. Large mesh is cut into a pentagon shape and sutured under tension to the fascia overlying the anterior superior iliac spine, pubic symphysis, and in the midline cephalad to the umbilicus (Fig. 1). Running sutures attach the mesh inferiorly along the inguinal ligament, transversely along the cephalad edge, and lateral to a vertical line through the anterior superior iliac spine.Fig. 1.: Static mesh lies within the rigid triangle defined by the anterior superior iliac spine (ASIS) bilaterally and the pubic symphysis (PS). Dynamic mesh is powered by the transversalis muscle.A retrospective review of ventral herniorrhaphies in 14 women over 8 years was performed by the authors. There were no reoccurrences, new hernias, or enterotomies. The complications were transient dyspnea in two women and seroma in two others. Weight loss after abdominoplasty with mesh has been reported previously,3 and in this study, 93 percent of patients lost weight postoperatively. Abdominoplasty with mesh reinforcement ventral herniorrhaphy has advantages compared with laparoscopic ventral herniorrhaphy or open ventral herniorrhaphy. Laparoscopic ventral herniorrhaphy requires laparoscopy with possible intraabdominal organ injury, wall injury, adhesions, and mesh erosions. The mesh in abdominoplasty with mesh reinforcement ventral herniorrhaphy increases passive wall tension directly and active wall tension indirectly (Starling's law) over the entire lower abdominal wall, which is subjected to the greatest pressure. Abdominoplasty with mesh reinforcement ventral herniorrhaphy restores lost muscle-aponeurosis function by a dynamic in situ transversalis–to-mesh transfer placed under tension (Fig. 1). The tension in the mesh generates a perpendicular pressure vector directed inward overlying the hernia by the law of Laplace (p = T/r). The mesh in laparoscopic ventral herniorrhaphy or open ventral herniorrhaphy is not placed under muscle tension4 and deforms with loading, which creates shearing at the mesh wall junction and possible recurrence (Fig. 2). The large mesh in abdominoplasty with mesh reinforcement ventral herniorrhaphy treats the hernia abnormality extending beyond the fascial defect and decreases the shearing vector. Ventral hernias are biomechanically analogous to chronic flexor tendon rupture in the hand. Both require interposition grafting under muscle-generated tension to restore function.Fig. 2.: The pressure vectors Pw generated by the wall and Pm generated by the mesh have bisecting (b) and shearing (s) components. Pwb and Pmb are in the same direction and add to opposed intraabdominal pressure. Pms pulls the mesh away from the wall and Pws pulls the wall away from the mesh, causing shearing and possible hernia recurrence. Large mesh, sutured farther from the fascial defect and under tension, increases angle θ. As θ approaches 180 degrees, the shearing vectors Pms and Pws approach 0.Obesity is believed to be a cause of ventral hernia and a risk factor for recurrence.5 An alternate to the cause-and-effect theory postulates that hernias and obesity are two clinical presentations of a single pathologic condition. Hernias are localized, complete wall failure with secondary changes. Obesity may result from generalized wall weakness.3 The authors recommend abdominoplasty with mesh reinforcement for biomechanical failure presenting as hernia or obesity. Gary Horndeski, M.D. Elisa Gonzalez, P.A.-C. Mainland Medical Center Texas City, Texas

Myogenic Responses of Mouse Isolated Perfused Renal Afferent Arterioles

Because defects in renal autoregulation may contribute to renal barotrauma in chronic kidney disease, we tested the hypothesis that the myogenic response is diminished by reduced renal mass. Kidneys from 5/6 nephrectomized mice had only a minor increase in the glomerular sclerosis index. The telemetric mean arterial pressure (108+/-10 mm Hg) was unaffected after 3 months of high-salt intake (6% salt in chow) or reduced renal mass. Afferent arterioles from 5/6 nephrectomized mice and sham-operated controls were perfused ex vivo during step changes in pressure from 40 to 134 mm Hg. Afferent arterioles developed a constriction and a linear increase in active wall tension above a perfusion pressure of 36+/-6 mm Hg, without a plateau. The slope of active wall tension versus perfusion pressure defined the myogenic response, which was similar in sham mice fed normal or high-salt diets for 3 months (2.90+/-0.22 versus 3.22+/-0.40 dynes x cm(-1)/mm Hg; P value not significant). The myogenic response was unaffected after 3 days of reduced renal mass on either salt diet (3.39+/-0.61 versus 4.04+/-0.47 dynes x cm(-1)/mm Hg) but was reduced (P<0.05) in afferent arterioles from reduced renal mass groups fed normal and high salt at 3 months (2.10+/-0.28 and 1.35+/-0.21 dynes x cm(-1)/mm Hg). In conclusion, mouse renal afferent arterioles develop a linear increase in myogenic tone around the range of ambient perfusion pressures. This myogenic response is impaired substantially in the mouse model of prolonged reduced renal mass, especially during high salt intake.

Myogenic Responses of Mouse Isolated Perfused Renal Afferent Arterioles: Effect of Salt Intake and Reduced Renal Mass

Renal autoregulation is mediated by myogenic vasoconstriction and tubuloglomerular feedback. Since defects may contribute to renal barotrauma in salt‐sensitive hypertension and chronic kidney disease, we tested the hypothesis that the myogenic response is diminished by dietary salt or the reduced renal mass (RRM). Afferent arterioles (Af) were dissected from 1 2/3 nephrectomized RRM mice and sham‐operated controls and perfused during step changes in pressure from 0 to 140 mmHg. The active wall tension (AWT) was the differences with physiologic perfusate, compared to zero calcium + EGTA. The MAP of conscious mice by telemetry (85 ± 4 mmHg) was unaffected by salt intake or RRM. Af developed a linear increase in AWT above a perfusion pressure of 60 ± 6 mmHg without plateau. The slope of AWT vs perfusion pressure defined the myogenic response. This response was similar in mice fed normal or high salt for 3 months (3.5±0.3 vs 3.9 ± 0.5 dynes μcm−1/mmHg, p&gt;0.05). It was unaffected after 3 days or 3 weeks of RRM but was reduced by 28±3% and 60±7% (p&lt;0.05) in the normal and high salt RRM groups at 3 months (2.5 ± 0.3 and 1.6 ± 0.3 dynes·cm−1/mmHg). We conclude that the mouse renal Af develops a linear increase in myogenic tone above ambient perfusion pressure that could safeguard against renal barotrauma. The normal myogenic response is not dependent on salt intake, but is impaired substantially in RRM, especially during high salt intake.

The critical closing pressure of the cerebral circulation

The critical closing pressure (CrCP) of the cerebral circulation indicates the value of arterial blood pressure (ABP) at which cerebral blood flow (CBF) approaches zero. Measurements in animals and in humans, have shown that the CrCP is significantly greater than zero. A simple mathematical model, incorporating the effects of arterial elasticity and active wall tension, shows that CrCP can be influenced by several structural and physiological parameters, notably intracranial pressure (ICP) and active wall tension. Due to the non-linear shape of the complete ABP-CBF curve, most methods proposed for estimation of CrCP can only represent the linear range of the pressure-flow (or velocity) relationship. As a consequence, only estimates of apparent CrCP can be obtained, and these tend to be significantly higher than the true CrCP. Estimates of apparent CrCP have been shown to be influenced by arterial PCO 2, ICP, cerebral autoregulation, intra-thoracic pressure, and mean ABP. There is a lack of investigation, under well-controlled conditions, to assess whether CrCP is altered in disease states. Studies of the cerebral circulation need to take CrCP into account, to obtain more accurate estimates of cerebrovascular resistance changes, and to reflect the correct dynamic relationship between instantaneous ABP and CBF.

Contractility Studies on Isolated Bovine Choroidal Small Arteries: Determination of the Active and Passive Wall Tension–Internal Circumference Relation

Studies on isolated choroidal arteries could help to understand the regulatory mechanisms in the choroidal circulation. The aim of the present study was therefore to assess whether contractility studies on isolated choroidal arteries were feasible and to determine the active and passive wall tension–internal circumference relation of these arteries. This relation is essential for reliable further pharmacodynamic studies on these vessels. Isolated choroidal arteries were mounted on a wire myograph for isometric tension recording. After the vessel was mounted, theL100 (the circumference of the vessel at a transmural pressure of 100 mmHg) was determined. Then the passive and active wall tension–internal circumference relation of the choroidal vessels was obtained by stepwise increasing the internal circumference. The changes in the internal circumference were expressed as a percentage ofL100 . After each increase in circumference, the passive tone (in a calcium free medium), the spontaneous tone (in a Krebs--Ringer bicarbonate solution) and the active tone (in a solution containing K+ 120 m M and prostaglandin F2α 30 μM) was measured. The passive tone of the vessel increased exponentially with the circumference of the vessel. Both the spontaneous tone and the active tone also increased when the vessel was stretched. They peaked when the internal circumference approached 90% of theL100 and diminished again when the circumference was further increased. The peak value of the active tension curve averaged 2.24 ± 0.47 N m−1 (n = 10). The passive tension was 0.57 ± 0.08 N m−1 (n = 10) at this circumference. The peak value of the spontaneous tension curve averaged 0.37 ± 0.08 N m−1 (n = 10). It can be concluded that in vitro contractility studies on isolated choroidal arteries are feasible. The optimal length or preload of the choroidal arteries is attained when the internal circumference of the artery is set to 90% of the L100.

Contractility Studies on Isolated Bovine Choroidal Small Arteries: Determination of the Active and Passive Wall Tension–Internal Circumference Relation

Studies on isolated choroidal arteries could help to understand the regulatory mechanisms in the choroidal circulation. The aim of the present study was therefore to assess whether contractility studies on isolated choroidal arteries were feasible and to determine the active and passive wall tension–internal circumference relation of these arteries. This relation is essential for reliable further pharmacodynamic studies on these vessels. Isolated choroidal arteries were mounted on a wire myograph for isometric tension recording. After the vessel was mounted, the L 100 (the circumference of the vessel at a transmural pressure of 100 mmHg) was determined. Then the passive and active wall tension–internal circumference relation of the choroidal vessels was obtained by stepwise increasing the internal circumference. The changes in the internal circumference were expressed as a percentage of L 100 . After each increase in circumference, the passive tone (in a calcium free medium), the spontaneous tone (in a Krebs--Ringer bicarbonate solution) and the active tone (in a solution containing K + 120 m M and prostaglandin F 2α 30 μ M) was measured. The passive tone of the vessel increased exponentially with the circumference of the vessel. Both the spontaneous tone and the active tone also increased when the vessel was stretched. They peaked when the internal circumference approached 90% of the L 100 and diminished again when the circumference was further increased. The peak value of the active tension curve averaged 2.24 ± 0.47 N m −1 ( n = 10). The passive tension was 0.57 ± 0.08 N m −1 ( n = 10) at this circumference. The peak value of the spontaneous tension curve averaged 0.37 ± 0.08 N m −1 ( n = 10). It can be concluded that in vitro contractility studies on isolated choroidal arteries are feasible. The optimal length or preload of the choroidal arteries is attained when the internal circumference of the artery is set to 90% of the L 100.

Contractility and Endothelium-Dependent Relaxation of Resistance Vessels in Polycystic Kidney Disease Rats

Hypertension and vascular disease are common complications in autosomal-dominant polycystic kidney disease (ADPKD). The role of changes in morphology and reactivity of resistance vessels in this disease have not previously been studied. Mesenteric resistance arteries were dissected from 8- to 14-week-old heterozygous Han:SPRD polycystic kidney disease (PKD) rats, homozygous normal Han:SPRD littermates (HSPRD) and Sprague-Dawley rats (SD). The morphology, noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) relaxation before and after incubation with L^G-nitro-L-arginine methyl ester (L-NAME), and endothelium-independent 3-morphollino-sydnonimine (SIN-1) relaxation were studied with the Mulvany-Halpern myograph. Blood pressure and morphology of vessels were the same in all groups of rats, apart from a slightly higher media/lumen ratio in heterozygous PKD rats (p < 0.05). Active wall tension and contractile sensitivity to NA were higher in both heterozygous PKD rats and HSPRD than SD rats (p < 0.05). The maximum endothelium-dependent relaxation rate was markedly decreased in heterozygous PKD (19 ± 9%) and HSPRD (34 ± 12%) compared to SD rats (75 ± 11%) (p < 0.05). After incubation with L-NAME, ACh-induced relaxation was significantly attenuated in SD rats, less attenuated in HSPRD, and not significantly changed in heterozygous PKD rats. SIN-1-induced endothelium-independent relaxation was similar in all three groups. In conclusion, hyperreactivity to NA and impaired endothelium-dependent relaxation were present in resistance vessels from Han:SPRD rats, especially in animals with PKD. These abnormalities in resistance vessels from PKD rats may be important for the development of hypertension and vascular disease.

Cholesterol enhances contractile responses in isolated small mesenteric arteries of normotensive and spontaneously hypertensive rats.

In order to examine possible mechanisms by which hypercholesterolemia may contribute to the development of cardiovascular disease, we investigated the effect of cholesterol enrichment on contractility in isolated small rat mesenteric arteries. Contractile responses of cholesterol-enriched isolated small mesenteric arteries of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were compared with control groups. First- to second-order mesenteric arteries (327-349 microm internal lumen diameter) were dissected from the mesenteric bed of 10-20-week-old male WKY rats and SHR, and incubated in cholesterol-free and cholesterol-rich (150 microg/ml) medium. Isolated arteries were mounted on a Mulvany-Halpern myograph for measurement of isometric tension. Cholesterol significantly increased active wall tension and active wall pressure in WKY rat arteries and active wall tension in SHR arteries in response to potassium chloride, norepinephrine and serotonin (P < 0.05). In addition, contractile responses to all agonists were significantly higher in cholesterol-enriched SHR arteries compared with cholesterol-enriched WKY rat vessels (P < 0.05). These findings suggest that elevated cholesterol content enhances agonist-stimulated contractility in small mesenteric resistance arteries, providing a possible mechanism by which hypercholesterolemia may contribute to the development of hypertension.

Myogenic activation and calcium sensitivity of cannulated rat mesenteric small arteries.

Pressure-induced activation of vascular smooth muscle may involve electromechanical as well as nonelectromechanical coupling mechanisms. We compared calcium-tone relations of cannulated rat mesenteric small arteries during pressure-induced activation, depolarization (16 to 46 mmol/L K+), and alpha1-adrenergic stimulation (1 micromol/L phenylephrine). The intracellular calcium concentration was expressed as the fura-2 ratio, normalized to the maximal and minimal ratios. In order to compare activation levels at various pressures, tone was expressed as the ratio of active wall tension to the maximal active tension. The passive and maximal active pressure-diameter relations needed for the calculation of tone were determined in a separate set of experiments, using isometric loading of cannulated vessels. Pressure steps from 20 to 60 and then to 100 mm Hg caused a modest rise of calcium. Nifedipine (1 micromol/L) blocked both the calcium rise and the resulting myogenic responses. Electromechanical coupling could not fully account for the myogenic response: the calcium sensitivity, defined as the slope of the calcium-tone relation, was five times higher during pressure-induced activation compared with potassium stimulation and twice as high as the sensitivity during alpha1-adrenergic stimulation. We therefore conclude that the myogenic response involves a small but necessary rise in calcium due to influx through L-type calcium channels, as well as a nonelectromechanical coupling mechanism that greatly enhances the calcium sensitivity of the contractile machinery.

Mechanical properties and effects of sympathetic co-transmitters on human coronary arteries and veins.

Active isometric wall tension was studied at different levels of passive wall tension in isolated circular 2 mm long segments of human epicardial coronary arteries and veins, and maximum active wall tension was calculated to 6.60 mN/ mm for arteries and 0.86 mN/mm for veins. Vasomotor responses to sympathetic co-transmitters were studied at resting tension and after precontraction with U46619. Noradrenaline (NA) and adenosine 5'-triphosphate (ATP) induced strong contractions of veins, whereas relaxant responses dominated in arteries. Isoprenaline potently relaxed all arteries and veins. Prazosin and rauwolscine in a concentration of 10(-7) M both competitively antagonized NA-induced contraction of arteries and veins. For uridine 5'-triphosphate (UTP), relaxant responses were demonstrated in most arteries but only some veins. Neuropeptide Y (NPY) elicited no observable vasomotor responses in either arteries or veins. Mechanical removal of the arterial endothelium did not significantly alter relaxant responses to NA, ATP, UTP or isoprenaline. In conclusion, alpha 1- and alpha 2-adrenoceptors mediating contraction and beta-adrenoceptors mediating relaxation seem to be present in both human epicardial coronary arteries and veins. When applied to isolated epicardial coronary vessels, NA and ATP had a stronger influence on vasomotor tone than NPY and UTP, mediating strong contraction of veins but mainly relaxation of coronary arteries, that was independent of an intact endothelium.

Coronary arterial hyperreactivity and mesenteric arterial hyporeactivity after myocardial infarction in the rat.

After myocardial infarction, several neurohumoral systems become activated to maintain systemic perfusion pressure. We evaluated whether this leads to alterations of wall structure and contractile reactivity in the thoracic aorta, coronary septal artery, and mesenteric resistance arteries. In male Wistar rats, myocardial infarction (MI) was induced by permanent ligation of the left coronary artery. At 5 weeks after MI or sham operation, vessel segments were isolated, chemically sympathectomized, and mounted in a myograph for recording of isometric force development. Contractile reactivity to high potassium, norepinephrine, phenylephrine, serotonin, and Arg-vasopressin was determined. At the end of the experiments, vessels were fixed for morphometric analysis (cross-sectional area, media thickness, radius, and wall-to-lumen ratio). At 5 weeks after myocardial infarction, no alterations of contractile reactivity or wall structure were observed in the thoracic aorta of MI rats. In mesenteric resistance arteries, a nonselective reduction of maximal active wall tension and of active wall stress in response to vasoconstrictors was observed, whereas vessel wall structure and sensitivity to stimuli were not modified. On the other hand, coronary septal arteries displayed hyperreactivity to all strong contractile stimuli. These observations demonstrate a heterogeneity of arterial reactivity changes at 5 weeks after MI in the rat: (a) no alterations in thoracic aorta, (b) hyporeactivity of mesenteric resistance arteries despite maintenance of media mass, and (c) hyperreactivity of coronary vessels obtained from the hypertrophic remnant myocardium. This could result from the complex regional hemodynamic and neurohumoral changes associated with heart failure and may contribute to the further deterioration of cardiovascular function in this setting.

Age and Hypertension Differently Affect Coronary Contractions to Endothelin-1, Serotonin, and Angiotensins

Endothelium-derived substances and the renin-angiotensin system are important regulators of vascular tone. This study was designed to evaluate the effects of age and hypertension on vascular function of rat coronary arteries. Rings of the left anterior descending coronary artery were isolated from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at 12 (younger) and 72 (older) weeks of age and suspended in myographs (37 degrees C, 95% O2/5% CO2) for isometric tension recording. Systolic blood pressure was higher in SHR than in WKY rats (P < .05) but was unaffected by age in both strains. Active wall tension to KCl 100 mmol/L (mN/mm) was decreased in younger (0.28 +/- 0.03, n = 9) and older SHR (0.49 +/- 0.06, n = 13) compared with age-matched WKY rats (0.87 +/- 0.05, n = 9 and 1.51 +/- 0.11, n = 11, respectively, P < .05). In both strains, active wall tension to endothelin-1 and serotonin increased with age (n = 6 to 10, P < .05) but was decreased in younger and older SHR compared with WKY rats (P < .05). Active wall tension induced by angiotensin I 10(-7) mol/L was increased in older SHR (0.19 +/- 0.04, n = 7) compared with younger SHR (0.04 +/- 0.01, n = 9) but was similar in younger and older WKY rats (0.10 +/- 0.02 versus 0.15 +/- 0.03, n = 6 to 9) and younger SHR. In younger WKY rats and SHR, pretreatment of coronary arteries with benazeprilat 10(-5) mol/L (n = 5 for each) almost completely abolished the contractions to angiotensin I 10(-7) mol/L. Active wall tension to angiotensin II 10(-7) mol/L was comparable in all four groups, but compared with the contraction to KCl 100 mmol/L, the response was already increased in younger SHR (29 +/- 3%, n = 9) compared with the younger WKY rats (14 +/- 3%, n = 9, P < .05), but it was unaffected by age in both strains. In vitro treatment of younger WKY rat and SHR coronary arteries with the nonpeptide angiotensin II (AT1) receptor antagonist valsartan 10(-5) mol/L (n = 3 for each) fully suppressed contractions to angiotensin II 10(-7) mol/L. In contrast, endothelium-independent relaxations to the nitrovasodilator sodium nitroprusside, endothelium-dependent relaxations to acetylcholine, and endothelium-dependent contractions to N omega-nitro-L-arginine methyl ester were comparable in all four groups of rats. In summary, in rat coronary arteries, contractile responses to endothelin-1, serotonin, and KCl increase with age but are decreased by hypertension. In contrast, the L-arginine/nitric oxide pathway remains unaffected. The contractions to angiotensin I markedly increased with increasing duration of hypertension in the SHR only. Despite overall reduced contractile responses of SHR coronary arteries, contractions to angiotensin II were maintained. Hence, aging and hypertension affect contractile responses of rat coronary arteries to vasoconstrictor agonists differently.

29 Prospective trial of effects of an angiotensin I-converting enzyme inhibitor and a beta-blocker on structure and function of resistance arteries in mild essential hypertension

Methods: Seventeen male untreated mild essential hypertensive patients with a mean age of 41 years agreed to participate in a double-blind randomized trial to test the effects of treatment with cilazapril, an inhibitor of angiotensin I converting enzyme, in comparison with treatment with atenolol, a beta-blocker, on the structure and function of subcutaneous resistance arteries. Patients were randomized to receive either 2.5–5 mg cilazapril or 25–100 mg atenolol per day. Results: Systolic/diastolk blood pressure was 147/99 and 148/99 mmHg before treatment and 132/86 and 131/85 mmHg at 1 year of treatment in the two groups, respectively. Cilazapril treatment for 1 year resulted in a reduction in the media: lumen ratio of resistance arteries (150–400 μm lumen diameter) dissected from subcutaneous gluteal biopsies from 7.5±0.3% before treatment to 6.3±0.2% 1 year later (P<0.05), still slightly but significantly larger (P<0.05) than the media: lumen ratio of resistance arteries of normotensive controls (5.1 ±0.3%). In arteries from patients treated with atenolol there was no significant change with treatment (8.0±0.6% before and 8.1 ±0.5% after 1 year of treatment). Active wall tension responses to endothelin-1 were blunted in hypertensive patients and normalized in the cilazapril-treated patients, but unchanged in those taking atenolo). Relaxation in response to acetylcholine of norepinephrine pre-contracted arteries was stiD significantly reduced after 1 year (P<0.05) in normotensive participants treated with atenolol, but not in those who had received cilazapril. Conclusion: Treatment for 1 year with the converting enzyme inhibitor cilazapril thus corrects some structural and functional abnormalities of resistance arteries from mild essential hypertensive patients.

Reactivity and Sensitivity of the Mesenteric Artery in Adult Spontaneously Hypertensive Rats After Chronic Treatment with Indapamide

The effects of chronic treatment with indapamide (3 mg/kg/day) on the structure and function of the mesenteric artery were studied in two groups of spontaneously hypertensive rats (SHRs) using an experimental model of in situ localized mesenteric artery. Indapamide (n = 12) or placebo (n = 12) were given to 8-week-old rats for 4 weeks. After anesthesia and laparotomy, a segment of mesenteric artery (external diameter, 300-400 microns) was exposed for video-microscopic measurements. The diameter-pressure relationships were established under active conditions (phenylephrine, 10(-6) M) and passive conditions (potassium cyanide, KCN) for transmural pressure ranging from atmospheric pressure to 200 mm Hg. These studied arterial segments were then fixed and their wall cross-sectional areas (CSA) measured in transverse sections. Active wall stress and tension were defined as the differences in wall stresses and wall tensions calculated for active and passive conditions. Systolic arterial pressure and mesenteric CSA were decreased in treated rats (197 +/- 15 mm Hg vs. 211 +/- 12 mm Hg, p < 0.05; 16,230 +/- 1048 microns2 vs. 19,033 +/- 1082 microns2, p < 0.05). In both groups, mesenteric diameters were smaller under active than under passive conditions without significant differences in treated vs. untreated group under active conditions. The active wall tension was lower in treated (0.4 +/- 0.19 N/m) than in untreated rats (1.19 +/- 0.62 N/m, p < 0.05). However, there were no differences in active wall stress in both groups (103 +/- 47 kPa and 134 +/- 30 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypertension induced by nitric oxide synthase inhibition on structure and function of resistance arteries in the rat.

To determine whether inhibition of generation of endothelium-derived relaxing factor or nitric oxide (NO) resulted in elevated blood pressure and its effect on resistance arteries, rats were offered NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase, in their drinking water. Blood pressure (BP) rose slightly from 100 +/- 2 mmHg in controls to 130 +/- 5 mmHg with 25 mg/Kg L-NAME per day and to 173 +/- 9 mmHg with 100 mg/Kg per day for 2 1/2 to 4 weeks. Rats were studied after 1-2 weeks of hypertension (BP > 150 mmHg). The concentration of cyclic guanosine monophosphate, the intracellular second messenger of NO, was significantly depressed in aorta and in the mesenteric vascular bed in L-NAME-treated rats. Mesenteric resistance arteries studied on a wire-myograph exhibited similar external and lumen diameters, whereas media width and media/lumen ratio were greater (p < 0.01). Cross-sectional area of the media was similar. Active wall tension in response to norepinephrine tended to be greater in blood vessels from L-NAME-treated rats, while responses to vasopressin and endothelin-1 were unaltered. Sensitivity to norepinephrine was significantly enhanced in L-NAME-treated rats (p < 0.001), while that to endothelin-1 and arginine8 vasopressin was similar. In conclusion, administration of an NO synthase inhibitor produces hypertension, with exaggerated media/lumen ratio in resistance arteries and enhancement of response to norepinephrine, which together with decreased NO generation may contribute to elevation of blood pressure.