Coronary Resistance Arteries Research Articles

Asymmetric Dimethylarginine Enables Depolarizing Spikes and Vasospasm in Mesenteric and Coronary Resistance Arteries.

Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance arteries, declining NO enhances vascular smooth muscle (VSM) reactivity partly by enabling rapid depolarizing Ca2+-based spikes that underlie vasospasm. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is metabolized by DDAH1 (dimethylarginine dimethylaminohydrolase 1) and elevated in cardiovascular disease. We hypothesized ADMA might enable VSM spikes and vasospasm by reducing NO bioavailability, which is opposed by DDAH1 activity and L-arginine. Rat isolated small mesenteric arteries and myogenic rat-isolated intraseptal coronary arteries (RCA) were studied using myography, VSM intracellular recording, Ca2+ imaging, and DDAH1 immunolabeling. Exogenous ADMA was used to inhibit NO synthase and a selective DDAH1 inhibitor, NG-(2-methoxyethyl) arginine, to assess the functional impact of ADMA metabolism. ADMA enhanced rat-isolated small mesenteric arteries vasoreactivity to the α1-adrenoceptor agonist, phenylephrine by enabling T-type voltage-gated calcium channel-dependent depolarizing spikes. However, some endothelium-dependent NO-vasorelaxation remained, which was sensitive to DDAH1-inhibition with NG-(2-methoxyethyl) arginine. In myogenically active RCA, ADMA alone stimulated depolarizing Ca2+ spikes and marked vasoconstriction, while NO vasorelaxation was abolished. DDAH1 expression was greater in rat-isolated small mesenteric arteries endothelium compared with RCA, but low in VSM of both arteries. L-arginine prevented depolarizing spikes and protected NO-vasorelaxation in rat-isolated small mesenteric artery and RCA. ADMA increases VSM electrical excitability enhancing vasoreactivity. Endothelial DDAH1 reduces this effect, and low levels of DDAH1 in RCAs may render them susceptible to endothelial dysfunction contributing to vasospasm, changes opposed by L-arginine.

Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment.

To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

Alterations in Coronary Resistance Artery Network Geometry in Diabetes and the Role of Tenascin C.

Geometrical alterations in the coronary resistance artery network and the potential involvement of Tenascin C (TNC) extracellular matrix protein were investigated in diabetic and control mice. Diabetes was induced by streptozotocin (STZ) injections (n = 7-11 animals in each group) in Tenascin C KO (TNC KO) mice and their Wild type (A/J) littermates. After 16-18 weeks the heart was removed and the whole subsurface network of the left coronary artery was prepared (down to branches of 40 m outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 m pixel resolutions. Diabetes induced abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed retrogradely (p 0.001 by the 2 test). Networks of TNC KO mice tended to form early divisions producing parallelly running larger branches (p 0.001 by the 2 probe). Networks of coronary resistance arteries were substantially more abundant in 100-180 m components, appearing in 2-5 mm flow distance from orifice in diabetes. This was accompanied by thickening of the wall of larger arterioles ( 220 m) and thinning of the wall of smaller (100-140 m) arterioles (p 0.001). Blood flow should cover larger distances in diabetic networks, but interestingly STZ-induced diabetes did not generate further geometrical changes in TNC KO mice. Diabetes promotes hypertrophic and hypotrophic vascular remodeling and induces vasculogenesis at well defined, specific positions of the coronary vasculature. TNC plays a pivotal role in the formation of coronary network geometry, and TNC deletion causes parallel fragmentation preventing diabetes-induced abnormal vascular morphologies.

ADDITIVE DAMAGE IN THE CONTRACTILITY OF INTRAMURAL CORONARY ARTERIOLES IN A RAT MODEL OF ANDROPAUSAL HYPERTENSION

Objective: Hypertension accelerates vascular aging, and changes associated with vascular aging play a role in hypertension. Andropause also contributes to age – related vascular damage and increases cardiovascular risk. Our aim is to investigate the combined effect of hypertension and androgen deficiency on the contractility of intramural coronary resistance arteries. Design and method: Male Sprague-Dawley rats were distributed into 4 groups: control (Co, n = 10); orchidectomized (OCT, n = 13), angiotensin II infused (AII, n = 10) and AII infused plus orchidectomized (AII+OCT, n = 8). Early hypertension was established using osmotic minipumps containing angiotensin II (100 ng / min / kg), while testosterone deficiency achieved via orchidectomy. After 4 weeks, spontaneous, thromboxane- and bradykinin-induced tones of intramural coronary resistance arterioles were investigated by in vitro pressure microarteriography. Results: Inner radius was reduced in the AII+OCT group compared to all other groups. Spontaneous tone was significantly higher in AII and AII+OCT groups than in Co and OCT groups. U46619-induced vasoconstriction was significantly smaller in OCT and AII+OCT groups compared to Co and AII rats. Bradykinin-induced relaxation was also significantly reduced in orchidectomized rats (OCT and AII+OCT groups) to a greater extent than in Co and AII animals. Conclusions: Spontaneous vascular tone is increased in AII hypertension. As a result of orchidectomy, adaptation range of the blood vessels narrows both regarding vasoconstriction and vasodilation. Therefore, the reactivity of the coronary arterioles deteriorates due to testosterone deficiency. In case of parallel manifestation of hypertension and testosterone deficiency, these two effects add up, which may increase age-related cardiovascular risk significantly in men.

Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality control

ABSTRACT The coronary arteries mainly function to perfuse the myocardium. When coronary artery resistance increases, myocardial perfusion decreases and myocardial remodeling occurs. Mitochondrial damage has been regarded as the primary cause of microvascular dysfunction. In the present study, we explored the effects of mitophagy activation on microvascular damage. Hypoxia/reoxygenation injury induced mitochondrial oxidative stress, thereby promoting mitochondrial dysfunction in endothelial cells. Mitochondrial impairment induced apoptosis, reducing the viability and proliferation of endothelial cells. However, supplementation with the mitophagy inducer urolithin A (UA) preserved mitochondrial function by reducing mitochondrial oxidative stress and stabilizing the mitochondrial membrane potential in endothelial cells. UA also sustained the viability and improved the proliferative capacity of endothelial cells by suppressing apoptotic factors and upregulating cyclins D and E. In addition, UA inhibited mitochondrial fission and restored mitochondrial fusion, which reduced the proportion of fragmented mitochondria within endothelial cells. UA enhanced mitochondrial biogenesis in endothelial cells by upregulating sirtuin 3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These results suggested that activation of mitophagy may reduce hypoxia/reoxygenation-induced cardiac microvascular damage by improving mitochondrial quality control and increasing cell viability and proliferation.

Correlation between the Level of Inflammatory Cytokines and Prognosis in Children with IVIG-sensitive Kawasaki Disease and IVIG-resistant Kawasaki Disease.

Objectives:To investigate whether the levels of interleukin 1β (IL-1β), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) in children with Kawasaki disease (KD) are correlated with coronary artery lesion (CAL) and resistance to intravenous immunoglobulin (IVIG) treatment.Methods:A total of 216 children in line with KD diagnostic criteria were continuously included as subjects, and 50 healthy children at the same period were selected as the control group, and their levels of IL-1β, IFN-γ, and TNF-α were detected.Results:Subjects were subdivided according to the presence or absence of CAL: 42 cases (19.4%) of 216 children with KD developed CAL and were subdivided into the CAL group, while 174 (80.6%) of those who did not develop CAL were subdivided into the NCAL group. The levels of IL-1β, IFN-γ, and TNF-α in the CAL group and the NCAL group were higher than those in the control group (P<0.05), and the levels of those in the CAL group were higher than those in the NCAL group (P<0.05). Subjects were subdivided according to the effect of IVIG treatment: 194 cases (89.8%) of 216 children with KD had a good control of inflammation after the initial IVIG treatment, and were considered to have IVIG-sensitive KD and divided into the IVIG-sensitive group; 22 cases (10.2%) could not get good control of inflammation after the initial IVIG treatment, and were considered to have IVIG-resistant KD and divided into the IVIG-resistant group. The levels of IL-1β, IFN-γ, and TNF-α in the IVIG-sensitive group and the IVIG-resistant group were higher than those in the control group; The levels of IL-1β, IFN-γ, and TNF-α in the IVIG-resistant group were higher than those in the IVIG-sensitive group (P<0.05), while the fever time of the IVIG-sensitive group was lower than that of the IVIG-resistant group (P<0.05).Conclusion:Children with KD may experience changes in IL-1β, IFN-γ, and TNF-α levels in the acute phase. Such a significant increase in levels may be a risk factor for CAL and resistance to IVIG treatment in children with KD, while the prolonged fever time is a risk factor for resistance to IVIG treatment in children with KD.

Differential vasodilator effect of Dioclea rostrata lectin in conductance and resistance arteries: Mechanisms and glycoconjugate binding relationships.

Lectins are proteins that recognize specific carbohydrates, and the vasorelaxant effect of legume lectins has been previously reported, for example the Dioclea rostrata lectin (DRL). This study evaluated major pathways of DRL-induced relaxation in different artery segments and the possible molecular interactions involved. Rat thoracic aorta, coronary and mesenteric resistance arteries were tested "in vitro" with concentration-response curves to DRL (0.01-100µg/mL). L-NAME, indomethacin and high KCl were used to evaluate nitric oxide, cyclooxygenase and hyperpolarization-dependent effects. DRL promoted relaxation of all vessels throughout different mechanisms. L-NAME blunted DRL-induced effects only in the aorta and mesenteric resistance artery. By the use of depolarizing KCl solution, vasodilation was reduced in all arteries, while incubation with indomethacin indicated a role of cyclooxygenase-derived factors for DRL effects in mesenteric and coronary arteries, but not in the aorta. Molecular docking results suggested interactions between DRL and heparan sulphate, CD31 and other glycans present on the membrane surface. These data indicate that the mechanisms involved in DRL-mediated vasodilation vary between conductance and resistance arteries of different origins, and these effects may be related to the capacity of DRL to bind a diversity of glycans, especially heparan sulphate, a proposed mechanoreceptor for nitric oxide synthase and cyclooxygenase activation.

Network analysis of the left anterior descending coronary arteries in swim-trained rats by an in situ video microscopic technique

BackgroundWe aimed to identify sex differences in the network properties and to recognize the geometric alteration effects of long-term swim training in a rat model of exercise-induced left ventricular (LV) hypertrophy.MethodsThirty-eight Wistar rats were divided into four groups: male sedentary, female sedentary, male exercised and female exercised. After training sessions, LV morphology and function were checked by echocardiography. The geometry of the left coronary artery system was analysed on pressure-perfused, microsurgically prepared resistance artery networks using in situ video microscopy. All segments over > 80 μm in diameter were studied using divided 50-μm-long cylindrical ring units of the networks. Oxidative-nitrative (O-N) stress markers, adenosine A2A and estrogen receptor (ER) were investigated by immunohistochemistry.ResultsThe LV mass index, ejection fraction and fractional shortening significantly increased in exercised animals. We found substantial sex differences in the coronary network in the control groups and in the swim-trained animals. Ring frequency spectra were significantly different between male and female animals in both the sedentary and trained groups. The thickness of the wall was higher in males as a result of training. There were elevations in the populations of 200- and 400-μm vessel units in males; the thinner ones developed farther and the thicker ones closer to the orifice. In females, a new population of 200- to 250-μm vessels appeared unusually close to the orifice.ConclusionsPhysical activity and LV hypertrophy were accompanied by a remodelling of coronary resistance artery network geometry that was different in both sexes.

Aerobic exercise training reduces cardiac function and coronary flow-induced vasodilation in mice lacking adiponectin.

We tested the hypothesis that adiponectin deficiency attenuates cardiac and coronary microvascular function and prevents exercise training-induced adaptations of the myocardium and the coronary microvasculature in adult mice. Adult wild-type (WT) or adiponectin knockout (adiponectin KO) mice underwent treadmill exercise training or remained sedentary for 8-10 wk. Systolic and diastolic functions were assessed before and after exercise training or cage confinement. Vasoreactivity of coronary resistance arteries was assessed at the end of exercise training or cage confinement. Before exercise training, ejection fraction and fractional shortening were similar in adiponectin KO and WT mice, but isovolumic contraction time was significantly lengthened in adiponectin KO mice. Exercise training increased ejection fraction (12%) and fractional shortening (20%) with no change in isovolumic contraction time in WT mice. In adiponectin KO mice, both ejection fraction (-9%) and fractional shortening (-12%) were reduced after exercise training and these decreases were coupled to a further increase in isovolumic contraction time (20%). In sedentary mice, endothelium-dependent dilation to flow was higher in arterioles from adiponectin KO mice as compared with WT mice. Exercise training enhanced dilation to flow in WT mice but decreased flow-induced dilation in adiponectin KO mice. These data suggest that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice lacking adiponectin; however, in the absence of adiponectin, cardiac and coronary microvascular adaptations to exercise training are compromised.NEW & NOTEWORTHY We report that compensatory mechanisms contribute to the maintenance of cardiac and coronary microvascular function in sedentary mice in which adiponectin has been deleted; however, when mice lacking adiponectin are subjected to the physiological stress of exercise training, beneficial coronary microvascular and cardiac adaptations are compromised or absent.

MICROVASCULAR ANGINA IS ASSOCIATED WITH SYSTEMIC DYSFUNCTION OF PERIPHERAL RESISTANCE ARTERIES

Objective: Microvascular angina (MVA) is characterized by functional and structural alterations of resistance coronary arteries without any significant alterations of epicardial coronary arteries. Whether MVA patients present also dysfunction of peripheral resistance arteries is still a matter of debate. We sought to evaluate whether MVA is associated with parameters of systemic microvascular dysfunction. Design and method: Thirteen patients with MVA and 13 healthy control subjects were enrolled in this study. The diagnosis of MVA was based on the presence of typical symptoms of ischemic heart disease, evidence of myocardial ischemia on exercise stress testing and normal epicardial coronary arteries at angiography. Parameters of peripheral microvascualar alterations, arterial stiffness (Pulse Wave Velocity, PWV), and central blood pressure (cBP) and Subendocardial Viability Ratio (SEVR, and index of subendocardial microvascular dysfunction), were evaluated by applanation tonometry. Results: Patients and controls were similar with respect to metabolic parameters, BMI, and renal function. MVA patients were on therapy with beta-blockers (50%), calcium channel blockers (37%), nitrates (12%), renin-angiotensin-blockers (44%), and statins (25%). MVA patients were slightly older than controls (63.6 ± 1.9 vs 53.1 ± 2.0 years, p &lt; 0.05). Albeit in the normal range, peripheral (pSBP) and central (cSBP) systolic BP were significantly higher in MVA patients as compared to controls (pSBP:134.3 ± 2.9 vs 118.5 ± 3.5 mmHg, p &lt; 0.002; and cSBP:124.8 ± 2.9 vs 109.7 ± 2.9 mmHg, p &lt; 0.001). Diastolic BP was similarly preserved in both groups. SEVR, an index of subendocardial microvascular dysfunction, was lower in MVA patients as compared to controls (139.7 ± 4.1 vs 160.4 ± 8.5 %, p &lt; 0.05). Augmentation index (AI), reflected (RPH), and forward (FPH) pulse height, all parameters of peripheral microvascular dysfunction, were also altered in MVA patients as compared to controls (AI:29.0 ± 1.0 vs 19.9 ± 2.4%, p &lt; 0.003; RPH:22.3 ± 1.4 vs 15.3 ± 0.9 mmHg, p &lt; 0.001; FPH:31.0 ± 1.4 vs 24.2 ± 1.4 mmHg p &lt; 0.005). The index of aortic stiffness PWV was similar in both groups (7.20 ± 07 vs 6.6 ± 0.2 m/sec, NS). Conclusions: Patients with MVA on optimal anti-schemic therapy exhibit alterations of parameters of both subendocardial and peripheral microvascular dysfunction, suggesting that coronary microvascular dysfunction is part of a more generalized disorder also involving peripheral resistance arteries.

Association of 8p22-23-rs2254546 Genotypes with Coronary Artery Status and Resistance to Intravenous Immunoglobulin in Iranian Children with Kawasaki Disease

Background: Kawasaki disease (KD) is a frequent cause of acquired heart disease in infants and young children, which may be triggered by infectious agents, with the highest incidence in Asian countries. Several genotypes are identified as susceptibility genes for KD, but none is known in the Iranian population. Objectives: Due to the racial differences in the frequency and significance of the identified genes, we aimed to investigate the 8p22-23-rs2254546 genotypes in a sample of Iranian children and their association with aneurysm and resistance to treatment. Methods: In this prospective cross-sectional study, 100 children with KD as the sample group were compared with 100 matched unrelated healthy Iranian children with no history of KD or immune-related disease. The control subjects were ethnically recruited from the same hospital at the time of a routine physical examination. The 8p22-23-rs2254546 genotypes were analyzed using the polymerase chain reaction (PCR) and direct sequencing techniques, and the frequency of the three genotypes (GA, AA, and GG) was reported. Finally, the frequency of aneurysm and IVIG resistance was reported, and their associations with 8p22-23-rs2254546 genotypes were tested by SPSS software. Results: Of 100 patients with a mean age of 1.9 ± 1.7 (0.1 - 10.2) years, 57% were boys and 43% were girls. Of them, 62% had GG, 30% GA, and 8% AA genotypes. Besides, 21% of the studied patients were resistant to IVIG, and 19% had aneurysm, but resistance to IVIG and aneurysm was not associated with GG and GA genotypes of 8p22-23-rs2254546 (P = 0.29 and 0.88, respectively). Conclusions: The majority of the children with KD were shown to have this genetic susceptibility, which shows the importance of the 8p22-23-rs2254546 genotype in Iranian children. However, this genotype was not associated with the risk of resistance to IVIG and aneurysm.

Risk Factors of Coronary Artery Abnormalities and Resistance to Intravenous Immunoglobulin Plus Corticosteroid Therapy in Severe Kawasaki Disease: An Analysis of Post RAISE.

Coronary artery abnormalities (CAAs) still occur in patients with Kawasaki disease receiving intensified treatment with corticosteroids. We aimed to determine the risk factors of CAA development and resistance to intensified treatment in Post RAISE (Prospective Observational Study on Stratified Treatment With Immunoglobulin Plus Steroid Efficacy for Kawasaki Disease)-the largest prospective cohort of Kawasaki disease patients to date. In Post RAISE, 2648 consecutive patients with Kawasaki disease were enrolled. The present study analyzed 724 patients predicted to be intravenous immunoglobulin (IVIG) nonresponders (Kobayashi score ≥5) who received intensified treatment consisting of IVIG plus prednisolone. The association between the baseline characteristics and CAA at 1 month after disease onset was examined. The association between the baseline characteristics and treatment resistance was also investigated. Maximum Z score at baseline ≥2.5 (odds ratio, 3.4 [95% CI, 1.5-7.8]), age at fever onset <1 year (odds ratio, 3.4 [95% CI, 1.6-7.4]), and nonresponsiveness to IVIG plus prednisolone treatment (odds ratio, 6.8 [95% CI, 3.3-14.0]) were independent predictors of CAA development. Nonresponsiveness to IVIG plus prednisolone was significantly associated with 8 baseline variables. Baseline total bilirubin (odds ratio, 1.4 [95% CI, 1.2-1.7]) was the only significant independent predictor other than the variables included in the Kobayashi score, enabling treatment resistance to be identified at diagnosis. The area under the ROC curve was 0.74 (95% CI, 0.69-0.79). At a cutoff point of 1.0, the sensitivity and specificity for predicting treatment resistance were 71% and 65%, respectively. In Post RAISE, younger age at fever onset, a larger maximum Z score at baseline, and nonresponsiveness to IVIG plus prednisolone were risk factors significantly associated with CAA development. Nonresponders were able to be identified at diagnosis based on the total bilirubin value. To prevent CAA, more intensified or adjunctive therapies using other agents, such as pulsed methylprednisolone, ciclosporin, infliximab, and Anakinra, should be considered for patients with these risk factors. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000007133.

Effects of Testosterone Deficiency and Angiotensin II–Induced Hypertension on the Biomechanics of Intramural Coronary Arteries

BackgroundAndropause and hypertension also increase the risk of coronary artery damage. AimTo investigate the effect of testosterone deficiency and hypertension on intramural coronary vessels. Methods4 groups of 8-week-old Sprague-Dawley rats were studied: control male (Co, n=10), orchidectomized male (OCT, n=13), angiotensin (AII) hypertensive male (AII, n=10), and AII hypertensive and OCT (AII + OCT, n=8). Surgical orchidectomy was performed, and an osmotic minipump was inserted for chronic angiotensin II infusion (100 ng/min/kg). After 4 weeks, spontaneous tone and biomechanical properties of the intramural coronary resistance artery were investigated in vitro, by pressure microarteriography. OutcomesMorphology and biomechanics of the intramural coronaries were evaluated: the outer diameter, wall thickness–to–lumen diameter ratio, and tangential wall stress in the contracted and relaxed states. ResultsThe outer diameter was reduced in OCT and AII + OCT groups (on 50 mmHg 315 ± 20 Co; 237 ± 21 OCT; 291 ± 16 AII, and 166 ± 12 μm AII + OCT). The increased wall thickness–to–lumen diameter ratio resulted in lower tangential wall stress in AII + OCT rats (on 50 mmHg 19 ± 2 Co; 24 ± OCT; 26 ± 5 AII, and 9 ± 1 kPa AII + OCT). Spontaneous tone was increased in the hypertensive rats (AII and AII + OCT groups) (on 50 mmHg 7.7 ± 1.8 Co; 6.1 ± 1.4 OCT; 14.5 ± 3.0 AII, and 17.4 ± 4.1 % AII + OCT). Clinical ImplicationsAndropause alone can be considered as a cardiovascular risk factor that will further exacerbate vascular damage in hypertension. Strengths & LimitationsA limitation of our study is that it was performed on relatively young rats, and the conclusions might not apply to coronary remodelling in older animals with slower adaptation processes. ConclusionsTestosterone deficiency and hypertension damage the mechanical adaptation of the vessel wall additively: double noxa caused inward eutrophic remodeling and increased tone.Jósvai A, Török M, Mátrai M, et al. Effects of Testosterone Deficiency and Angiotensin II–Induced Hypertension on the Biomechanics of Intramural Coronary Arteries. J Sex Med 2020;17:2322–2330.

Chronic swimming training resulted in more relaxed coronary arterioles in male and enhanced vasoconstrictor ability in female rats.

Exercise training is associated with hypertrophy of left ventricle (LV). The aim of the present study is to evaluate sex differences in the adaptation of the coronary contractile function in physiological left ventricular hypertrophy induced by long-term swim training. Thirty-two Wistar rats were randomly divided into 4 groups: exercised male (ExM), exercised female (ExF), untrained control male (CoM), and untrained control female (CoF). The trained animals underwent a 12-week-long swim training program. After finishing the training program, LV morphology and function were checked by echocardiography. The spontaneous tone, thromboxane (TxA<inf>2</inf>) agonist-induced vascular contractility and non-endothelial dilatation of the isolated intramural coronary resistance artery were examined by pressure microangiometry. The thromboxane receptor (TxA<inf>2</inf>R) protein expression in the wall of coronary arteries was examined using immunohistochemistry. The LV mass index was significantly higher in the ExM and ExF groups, furthermore the LV mass index was significantly higher in female than in male animals. ExM animals had lower spontaneous tone than ExF. TxA<inf>2</inf> agonist-induced tone was raised only in ExF animals. The resistance coronary artery of exercised male animals had a significantly lower level of TxA<inf>2</inf>R positivity compared to exercised females. Both sexes broaden their range of contractility following chronic swimming, but the vessel tone shifted toward contraction in exercised female rats, while these values shifted toward relaxation in males. These observations underline the significance of identifying potential gender differences in the chronic exercise-induced coronary vascular remodeling in human athletes.

Morphological remodeling of the intramural coronary resistance artery network geometry in chronically Angiotensin II infused hypertensive female rats

Segmental remodeling of resistance arteries, inhibition of angiogenetic processes, their rarefaction by AngiotensinII and hypertension are accepted facts. Less is known about alterations in resistance artery network geometry potentially induced by them. Female rats were infused with 100 ng/kg/min AngiotensinII with osmotic minipumps for four weeks that raised mean arterial blood pressure from 98 ± 3 to 125 ± 7 mmHg. Geometry of the left coronary artery system was studied on plastic casts and on in situ microsurgically prepared, saline infused video-microscoped networks (n = 13 and 11 controls and hypertensives, respectively). Parallel running branches, broken course of larger branches, multiple branchings and branch crossings have been identified (13 and 74 such deformities, in control and hypertensive networks, respectively, p < 0.01). Bifurcation angles increased with increasing asymmetry of daughter branches but not in hypertensives. Dividing the whole network (theoretically) into several hundreds of 50μm long ring units, ring frequency peaked at 200μm diameter in normal networks. This peak diminished and was replaced by a peak at 300μm in hypertensives (p < 0.01). In controls, diameter of vascular units decreased at a fairly even rate with flow distance from the orifice. The 350, 200, 150μm diameter units were found with highest frequencies at flow distances around 2.5, 5.5 and 7.5mm, respectively. This regular pattern disintegrated in hypertensives. Higher blood flow routes were needed to cover the same distance from the orifice (p < 0.01). Shrinkage and diminishment of many parallel connected 200μm segments, concomitant enlargement of many larger segments accompanied with morphological deformities can be expected to contribute to elevated vascular resistance.

Long-term exercise results in morphological and biomechanical changes in coronary resistance arterioles in male and female rats

BackgroundBiomechanical remodeling of coronary resistance arteries in physiological left ventricular hypertrophy has not yet been analyzed, and the possible sex differences are unknown.MethodsWistar rats were divided into four groups: male and female sedentary controls (MSe and FSe) and male and female animals undergoing a 12-week intensive swim training program (MEx and FEx). On the last day, the in vitro contractility, endothelium-dependent dilatation, and biomechanical properties of the intramural coronary resistance arteries were investigated by pressure microarteriography. Elastica and collagen remodeling were studied in histological sections.ResultsA similar outer radius and reduced inner radius resulted in an elevated wall to lumen ratio in the MEx and FEx animals compared to that in the sedentary controls. The wall elastic moduli increased in the MEx and FEx rats. Spontaneous and TxA2 agonist-induced tone was increased in the FEx animals, whereas endothelium-dependent relaxation became more effective in MEx rats. Arteries of FEx rats had stronger contraction, while arteries of MEx animals had improved dilation.ConclusionsAccording to our results, the coronary arterioles adapted to an elevated load during long-term exercise, and this adaptation depended on sex. It is important to emphasize that in addition to differences, we also found many similarities between the sexes in the adaptive response to exercise. The observed sport adaptation in the coronary resistance arteries of rats may contribute to a better understanding of the physiological and pathological function of these arteries in active and retired athletes of different sexes.

Terminalia avicennioides causes redox-sensitive endothelium-dependent relaxation involving nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing in porcine coronary artery and different conductance and resistance vessels from rats

Background: Our work is part of the enhancement of plants of Senegalese pharmacopeia with cardiovascular aim, among which Terminalia avicennioides. Aim and Objective: The aim of this study was to determine whether a hydroethanolic bark extract of T. avicennioides (TAE) is able to induce a relaxant effect in porcine coronary, rat mesenteric artery, carotid, femoral arteries, and thoracic aorta and to determine the mechanism underlying this effect. Materials and Methods: Porcine coronary, rat mesenteric, carotid, femoral arteries, and thoracic aorta rings were suspended in organ chambers for the recording of changes in isometric forces. Rings with endothelium were incubated or not with L-Nitro Arginine to block nitric oxide (NO) synthase, MnTMPyP, polyethylene glycol catalase (CAT), an inhibitors of intracellular production reactive oxygen species; CAT, an inhibitor of extracellular reactive oxygen species; Wortmannin, an inhibitor of redox-sensitive pathway PI3 kinase/Akt; PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine), an inhibitor of Src kinase; apamin (APA) an inhibitor of small conductance potassium channels calcium-dependent (SKCa) and Tram-34 an inhibitor of intermediary conductance potassium channels calcium-dependent (IKCa); and indomethacin (INDO), an inhibitor of cyclooxygenase before contraction with U46619 or phenylephrine (PE) and a concentration relaxation curve to TAE. In some experiments, the endothelium was removed before contraction with U46619 or PE and concentration relaxation to TAE. The phosphorylation level of Akt and eNOS was assessed by Western blot analysis. Results: The hydroethanolic bark TAE induces a vasodilatory effect in porcine coronary artery precontracted with U46619. This effect is endothelium-dependent and is mediated by NO, prostaglandin, and endothelium-derived hyperpolarizing. TAE also induces vasorelaxant effects in superior mesenteric arteries, carotid arteries, thoracic aorta, and femoral arteries from rat. Conclusion: TAE-induced sustaining phosphorylation of Akt and eNOS in endothelial cells. T. avicennioides induces vascular relaxation which can explain the benefic effect of this plant in the treatment of high blood pressure in Senegal.

Vasoactive properties of Ceiba pentandra in porcine coronary artery and different conductance and resistance vessels from rats: A role of nitric oxide

Background: Ceiba pentandra (L.) Gaertner (Malvaceae) a plant widely spread in the world, particularly in sub-Saharan Africa where it is used to handle several pathologies like high blood pressure without scientific evidence by experimental scientific works. Aim and Objective: The purpose of this study is to show how a hydroethanolic leaves extract of Ceiba pentandra (FCP) produces relaxant effects in porcine coronary, rat mesenteric artery, carotid, femoral arteries, and thoracic aorta and to determine the mechanisms which lie beneath this effect. Materials and Methods: Porcine coronary, rat mesenteric, carotid, and femoral arteries and thoracic aorta rings were suspended in organ chambers for recording of changes in isometric forces. Rings with endothelium were incubated or not with L-nitroarginine to block nitric oxide (NO) synthase, manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin, polyethylene glycol catalase (CAT), an inhibitors of intracellular production reactive oxygen species (ROS); CAT, an inhibitor of extracellular ROS; wortmannin, an inhibitor of redoxsensitive pathway phosphoinositide 3-kinase (PI3 kinase)/Akt; (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d] pyrimidine), an inhibitor of Src kinase; apamin, an inhibitor of small conductance potassium channels calcium dependent (SKCa) and tram-34, an inhibitor of intermediary conductance potassium channels calcium dependent (IKCa); and indomethacin, an inhibitor of cyclooxygenase before contraction with U46619 or phenylephrine and a concentration-relaxation curve to FCP. Results: Some experiments show that endothelium was taken away before contraction with U46619 and concentration relaxation to FCP. The hydroethanolic leaves extract of C. pentandra produces a vasodilatory result in porcine coronary artery pre-contracted with U46619. This effect is endothelium dependent and is mediated by NO. FCP generates, as well, vasorelaxant results in superior mesenteric arteries, carotid arteries, thoracic aorta, and femoral arteries from rat. C. pentandra generates vascular relaxation which can be the explanation of the benefic effect of this plant in the treatment of high blood pressure (HBP) in Africa. Conclusion: C. pentandra holds vasorelaxants properties on pig coronary artery, thoracic aorta, the main superior mesenteric artery, and femoral and carotid artery from rat justifying its utilization in the treatment of the arterial HBP. This effect necessitates the presence of a functional endothelium and passes by the redox-sensitive pathway Src kinase and PI3-kinase/Akt.

HDL preserves mitochondrial complex I activity during myocardial reperfusion injury

Introduction. Myocardial reperfusion injury answers for half of final infarct size following myocardial infarction, although no effective therapy has yet been discovered. Modulation of mitochondrial activity stands as an attractive target, as its impairment following reperfusion impairs ATP generation and henceforth turns cardiac recovery less prone to occur. HDL reduced final infarct size in different ischemia-reperfusion injury models for unknown mechanisms. Whether this effect involves mitochondrial activity modulation is unknown. Hypothesis. HDL post-conditioning preserves mitochondrial activity. Methods. Hearts extracted from male adult Wistar rats were subjected to 35min of regional ischemia, followed by 90min of reperfusion in a Langendorff apparatus. HDL (200ug/mL) or saline solution (PBS) was administered during the 7 first minutes of reperfusion. Infarct size was determined as percentage of total ventricular area, considering area at risk (AAR) as the delineated by Evans Blue. Cardiac samples underwent high-resolution oxygraph, and maximal oxygen consumption rate was calculated after the addition of saturating concentrations of ADP (1mM). Mitochondrial viability and complex I activity were assessed by colorimetric assays. Statistical analysis. Data are mean ± standard error. Means were compared by Student`s t test and p value &lt; 0,05 was considered significant. Results. Treatment with HDL improved cardiac recovery, as indicated by better recovery of LVDP and dP/dT, and reduction of coronary artery resistance in comparison to control group (30,5 vs. 46,7%, 26 vs. 54,7% and 144±30 Vs. 98±14mmHg/mL, respectively; p&lt;0.01). Treatment with HDL reduced final infarct size by 30% in comparison to control (69.2±3.7% Vs. 49.2±13%; p&lt;0.001). The HDL group showed higher ADP-stimulated oxygen consumption rate (7.1±2.2 Vs. 33.8±6.6pmol/s.mg; p&lt;0.05; n=6) and greater complex I activity (12.7±4.2 vs. 30.7±4.4mOD/min; p&lt;0.05; n=3 per group) compared to control, though mitochondrial content was comparable (1.1±0.8 vs. 1.1±0.8AU; n=3; ns). Conclusions. Ischemic postconditioning with HDL reduces infarct size and preserves complex I activity, improving myocardial recovery following reperfusion injury.

Modeling of cardiovascular circulation for the early detection of coronary arterial blockage

Coronary arteries are responsible for maintaining blood supply to the heart. When these arteries get blocked due to plaque deposition, the corresponding pathological condition is referred to as coronary artery disease. This disease develops gradually over the years and consequently, the function of the heart deteriorates, leading to a heart attack in many cases. As the symptoms manifest themselves only when it has become severe, detection of the disease often gets delayed. In order to detect it early and take preventive action, this work is aimed at detecting the arterial blockage in its early stage via cardiovascular modeling. To achieve this, the cardiovascular circulation has been modeled as a sixth order nonlinear system. Blood circulation in a body is viewed as an electrical system using the pressure-voltage analogy. In this case, the heart is considered as a self-excited generator. The rest of the body tissues form a systemic load. In the models reported in the literature, coronary circulation has been assumed to be a part of the systemic load. However, this circulation path has its own importance as it is responsible for the blood supply to the heart. Therefore, in our work, the coronary path is separated out from the rest of the body tissues. This enables us to explicitly model the coronary arterial resistance and thereby helps us to detect coronary arterial blockage condition by estimating this parameter from blood pressure measurements. Increase in the coronary resistance is found to reduce the left ventricular ejection fraction; this information can therefore be used as an index for coronary arterial blockage. It has been shown that the systolic function of the heart deteriorates when the resistance of the coronary path increases beyond a critical value; the situation can be related to a severe blockage condition. The model has been tested on a chosen sample of 20 subjects suffering from coronary artery disease and the results are found to be quite promising.