Systemic Vascular Reactivity Research Articles

Role of pterygopalatine ganglion in regulating isoflurane-induced cerebral hyper-perfusion.

Cerebral perfusion is functionally regulated by neural mechanisms in addition to the systemic hemodynamic variation, vascular reactivity and cerebral metabolism. Although anesthesia is generally esteemed to suppress the overall brain neural activity and metabolism, a few inhalation anesthetics, such as isoflurane, can increase cerebral perfusion, thus heightening the risks of higher intracranial pressure, bleeding, and brain edema during surgery. With the aid of laser speckle contrast imaging, we observed a transient yet limited effect of cerebral perfusion enhancement in mice from awake to anesthetized conditions with different concentration of isoflurane. Retrograde and antegrade tracing revealed a higher proportion of parasympathetic control more than sympathetic innervation for the blood vessels. Surprisingly, isoflurane directly activated pterygopalatine ganglion (PPG) explants and induced FOS expression in the cholinergic neurons. Chemogenetic activation of cholinergic PPG neurons reduced isoflurane-related cerebral perfusion. On the contrary, ablation of the cholinergic PPG neurons resulted in further enhancement of cerebral perfusion induced by isoflurane. While blocking muscarinic cholinergic receptors resulted in the overall reduction upon isoflurane stimulation, the blockage of nicotinic cholinergic receptors enhanced the isoflurane-induced cerebral perfusion only when PPG neurons exist. Collectively, these results suggest that PPG play important roles in regulating cerebral perfusion under isoflurane inhalation.

Hypocholesterolemia is a risk factor for reduced systemic vascular resistance reactivity during hemodialysis.

Intradialytic hypotension (IDH) is associated with high mortality. Peripheral vascular resistance and circulating blood volume are important factors in IDH; however, the effects of hemodialysis (HD) on vascular resistance in IDH remain unclear. We herein performed a retrospective observational cohort study to investigate changes in and factors related to vascular resistance during HD. A total of 101 HD patients were divided into two groups (Decreased blood pressure (BP) during HD group: N = 19, Nondecreased BP group: N = 82), and cardiac output was measured with electrical velocimetry (AESCLON) for 3 h. The systemic vascular resistance index (SVRI) was significantly decreased in the Decreased BP group, while the cardiac index was similar in both groups. A multivariate regression analysis identified hypocholesterolemia as a predictor of reduced vascular resistance reactivity during HD. Furthermore, a correlation was found between changes in the SVRI and cholesterol levels in patients with a higher Geriatric Nutritional Risk Index (GNRI) but not in those with a lower GNRI. The present results suggest that hypocholesterolemia contributes to reducing systematic vascular resistance reactivity during HD, which is an important predictor of a reduction in BP during HD. The relationship between hypocholesterolemia and vascular resistance may involve mechanisms other than malnutrition.

Proton magnetic resonance spectroscopy (1H-MRS) in rheumatic autoimmune diseases: A systematic review.

Proton magnetic resonance spectroscopy (1H-MRS) has been shown to be an important non-invasive tool to quantify neuronal loss or damage in the investigation of central nervous system (CNS) disorders. The purpose of this article is to discuss the clinical utility of 1H-MRS in determining CNS involvement in individuals with rheumatic autoimmune diseases. This study is a systematic review of the literature, conducted during the month of November and December of 2019 of articles published in the last 16 years (2003-2019). The search for relevant references was done through the exploration of electronic databases (PubMed/Medline and Embase). We searched for studied including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), juvenile idiopathic arthritis, rheumatoid arthritis (RA), psoriasis, Sjögren's syndrome (pSS), vasculitis and Behçet. Only studies published after 2003 and with more than 20 patients were included. We included 26 articles. NAA/Cr ratios were significant lower and Cho/Cr ratios increased in several brain regions in SLE, SS, RA, SSc. Associations with disease activity, inflammatory markers, CNS manifestations and comorbidities was variable across studies and diseases. The presence of neurometabolite abnormalities in patients without ouvert CNS manifestations, suggests that systemic inflammation, atherosclerosis or abnormal vascular reactivity may be associated with subclinical CNS manifestations. MRS may be a usefull non-invasive method for screening patients with risk for CNS manifestations.

Contribution of systemic vascular reactivity to variability in pulse volume amplitude response during reactive hyperemia.

The aim of the present study was to investigate why the magnitude of reactive hyperemia (RH) observed by pulse volume amplitude (PVA) after arm occlusion differs greatly among study subjects. Healthy subjects (n = 12) in the age range of 22-30years participated in this study. Vascular reactivity was assessed by measuring the changes in finger PVA simultaneously in the test (occluded arm) and control arm (contralateral non-occluded arm) using two separate Photoplethysmographic sensors. Short-term HRV was computed from simultaneously acquired lead II ECG signal to monitor the changes in cardiac sympathetic nervous activity. The observed coefficient of variation for inter-subject variability in PVA response in test arm during second minute of RH was 115.3%. In the control arm, significantly reduced PVA was observed during the period of occlusion as well as RH. This observation was corroborated by simultaneously acquired short-term HRV which showed a significant rise in total power (p value < 0.005) and low-frequency (LF) power (p value < 0.05) during release of occlusion when compared to the baseline. A significant positive correlation (Spearman r = 0.33; p = 0.02) was observed between % change in PVA in the control arm and in the test arm for first 3min of RH. Sympathetic activation possibly plays an important role in mediating the inter-subject variability of vascular responses during reactive hyperemia which warrants simultaneous recording of both the test and the control arm responses during RH to accurately assess endothelial function.

Impaired systemic vascular reactivity & raised high-sensitivity C reactive protein levels in chronic obstructive pulmonary disease.

Background & objectives:Chronic obstructive pulmonary disease (COPD) is characterized by slowly progressive airflow limitaion, chronic lung inflammation and associated systemic manifestations. The objective of this preliminary study was to investigate the levels of high sensitivity C reactive protein (hs CRP) and tumour necrosis factor-α (TNF-α) as markers of systemic inflammation and assessment of systemic vascular reactivity that may play an important role in development of cardiovascular disease in COPD patients.Methods:Systemic vascular reactivity was assessed non-invasively by measuring peripheral pulse waveform changes during reactive hyperemia (RH) in 16 COPD patients and 14 controls by photoplethysmography technique (PPG). Parameters measured were pulse wave amplitude (PWA), slope and pulse transit time (PTT). Tumour necrosis factor-α (TNF-α) and hs CRP were measured as markers of inflammation.Results:PWA during the 1st, 2nd and 3rd minutes post release of occlusion were significantly higher than the baseline means in controls, whereas in the patient group there was no significant change in the PWA during any of the observed time periods following release of occlusion, in comparison to the baseline means. Similar results were observed in slope values for patients and controls. Maximum percentage change in PWA during RH with reference to baseline was significantly lower in patients as compared to controls (26.78±20.19 vs 57.20±19.80%, P<0.001). Maximum percentage change in slope during RH with reference to baseline was significantly lower in patients as compared to controls (19.77±10.73 vs 39.25±13.49%, P<0.001). A vascular tone response as represented by PTT was also impaired in the 3rd minute of RH as compared to baseline mean values in COPD patients only.Interpretation & conclusions:Our findings showed raised hs CRP levels and impaired systemic vascular reactivity in COPD patients. Whether these may increase the risk of cardiovascular disease in COPD patients need to be confirmed in future studies with large sample size and appropriate study design.

Correlations between endothelial function in the systemic and cerebral circulation and insulin resistance in type 2 diabetes mellitus.

Insulin resistance is associated with endothelial dysfunction in type 2 diabetes mellitus, which can lead to impaired vascular reactivities of both systemic and cerebral circulations. Appropriate 'correction' of vascular reactivity results for non-endothelium-dependent systemic effects avoids misinterpretation of endothelial function. Therefore, we 'corrected' vascular reactivity results and explored the potential correlations between systemic vascular reactivity, cerebrovascular reactivity and insulin resistance. In 34 patients, 'systemic vascular reactivity' was assessed by quantifying reactive hyperaemia. Cerebrovascular reactivity was assessed by quantifying changes in cerebral blood flow velocity during hypercapnia. To minimize the influence of non-endothelium-dependent systemic effects on vascular reactivity results, 'corrected systemic vascular reactivity' was calculated by normalizing systemic vascular reactivity using the measurements from the contralateral side; and cerebrovascular reactivity results were corrected by calculating percentage and absolute changes in cerebrovascular conductance index ('percent cerebrovascular conductance index' and 'delta cerebrovascular conductance index', respectively). Insulin resistance was estimated by homeostatic model assessment. Correlation between conventional cerebrovascular reactivity and systemic vascular reactivity was not significant. But correlations between 'corrected systemic vascular reactivity' and 'percent cerebrovascular conductance index' (r = 0.51; p = 0.002) and 'corrected systemic vascular reactivity' and 'delta cerebrovascular conductance index' (r = 0.50; p = 0.003) were significant. Among all vascular reactivity parameters, only 'delta cerebrovascular conductance index' was significantly correlated with homeostatic model assessment of insulin resistance (r = -0.38; p = 0.029). In conclusion, endothelial function in the systemic and cerebral circulations is moderately correlated, provided that vascular reactivity estimates are corrected for non-endothelium-dependent influences.

Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease

AbstractTricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia.

Amelioration of Endothelial Dysfunction in Middle Cerebral Arteries (MCA) of Fawn‐Hooded Rats by Antioxidant Treatment and Chromosomal Substitution

The Fawn‐Hooded Hypertensive (FHH) rat is a genetic model of spontaneous high‐renin systemic hypertension and multiple other disorders. As such, it is important to gain an increased understanding of genetic factors controlling systemic vascular reactivity in this strain. We evaluated vascular function in isolated middle cerebral arteries (MCA) from 8–10 week old FHH rats and 3 consomic panels carrying Brown Norway (BN) chromosomes (1,5, and 13) shown to be important in regulating vascular reactivity. All rats were maintained on a low salt (0.4% NaCl) diet since weaning. MCA's from FHH failed to dilate to acetylcholine (ACh, 10−10M to 10−5M). Introgression of BN chromosomes 1 and 13 partially restored ACh‐induced dilation. Introgression of BN chromosome 5 (carrying CYP4A alleles), acute addition of the superoxide (O2• −) scavenger tempol, and scavenging of mitochondrial O2• − with mito‐Q caused a dramatic restoration of ACh‐induced vascular relaxation. Mitochondrial O2• − levels (evaluated with the specific fluorescent probe MitoSOX) were significantly higher in MCA of FHH vs. the well characterized Sprague‐Dawley rat. These findings indicate that chronic elevations in oxidant stress disrupt cerebral vascular reactivity in FHH rats, and that different genes and chromosomes are likely to contribute to vascular dysregulation in different forms of hypertension. (NIH #HL‐65289; #HL‐72920, #HL‐92026).

Central, peripheral and resistance arterial reactivity: fluctuates during the phases of the menstrual cycle

The purpose of this study was to document the temporal changes in vascular reactivity occurring simultaneously in central, peripheral and microvascular resistance arteries in the same cohort of women during the normal menstrual cycle. Twenty-three (n = 23) women (mean age (+/-SD) = 19 +/- 1 y) were tested during four phases of a normal menstrual cycle. Delineation of the four phases occurred as follows: (1) the early follicular phase; (2) the late follicular (LF) phase; (3) the early luteal (EL) phase; and (4) the late luteal phase. Non-invasive measurement of central hemodynamics and peripheral artery pulse wave velocity (PWV) were performed using applanation tonometry. Measurement of peripheral endothelial function was determined by flow-mediated dilation (FMD) testing in the brachial artery and venous occlusion plethysmography in the forearm and calf resistance arteries. Additionally, plasma NOx and 17beta-estradiol (E) concentrations were measured. Both central (aortic) and peripheral blood pressure (BP) were lowest (P < 0.05) during the LF phase and BP reduction was sustained (P < 0.05) into the EL phase. The timing and amplitude of the reflected pressure wave were attenuated only during the LF phase (P < 0.05). No temporal changes were observed in either central (carotid-femoral) or peripheral PWV (femoral-dorsalis pedis, carotid-radial). Peak forearm and calf blood flow during reactive hyperemia were greatest in LF. Brachial FMD was greatest during the LF phase (P < 0.05). Plasma E and NOx concentrations were highest during the LF phase (P < 0.05). Young premenopausal women experienced an overwhelming pattern of reduced BP and increased systemic vascular reactivity during the LF phase prior to ovulation.

Vitamin E supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats

An altered vascular reactivity is an important manifestation of the hemodynamic and renal dysfunction during liver cirrhosis. Oxidative stress-derived substances and nitric oxide (NO) have been shown to be involved in those alterations. In fact, both can affect vascular contractile function, directly or by influencing intracellular signaling pathways. Nevertheless, it is unknown whether oxidative stress contributes to the impaired systemic and renal vascular reactivity observed in cirrhosis. To test this, we evaluated the effect of vitamin E supplementation (5,000 IU/kg diet) on the vasoconstrictor and vasodilator responses of isolated perfused kidneys and aortic rings of rats with cirrhosis induced by bile duct ligation (BDL), and on the expression of renal and aortic phospho-extracellular regulated kinase 1/2 (p-ERK1/2). BDL induced a blunted renal vascular response to phenylephrine and ACh, while BDL aortic rings responded less to phenylephrine but normally to ACh. Cirrhotic rats had higher levels of oxidative stress-derived substances [measured as thiobarbituric acid-reactive substances (TBARS)] and NO (measured as urinary nitrite excretion) than controls. Vitamin E supplementation normalized the renal hyporesponse to phenylephrine and ACh in BDL, although failed to modify it in aortic rings. Furthermore, vitamin E decreased levels of TBARS, increased levels of NO, and normalized the increased kidney expression of p-ERK1/2 of the BDL rats. In conclusion, BDL rats showed a blunted vascular reactivity to phenylephrine and ACh, more pronounced in the kidney and reversed by vitamin E pretreatment, suggesting a role for oxidative stress in those abnormalities.

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg.kg-1.day-1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver (n=6 in each group). Resting mean arterial blood pressure (MABP; 77+/-1 vs. 74+/-3 mmHg) and heart rate (HR; 249+/-9 vs. 226+/-21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 microg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; -30+/-3 vs. -20+/-3 mmHg, P<0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-L-arginine (25 mg/kg; 23+/-3 vs. 13+/-2 mmHg, P<0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups (n=4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.

Effect of Chronic Administration of Aminoguanidine on Vascular Reactivity of the Greater Circulation in Rats with Monocrotaline-induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a severe disease affecting both the pulmonary and systemic circulation. One of possible factors of these disturbances can be nitric oxide (NO) overproduction by inducible NO synthase (iNOS). To examine the effect of iNOS on systemic vascular reactivity, we used aminoguanidine (AG), a selective iNOS inhibitor. Using the model of monocrotaline-induced pulmonary hypertension, we demonstrated that chronic AG administration restores the decreased arterial pressure responses to NO donor and to nonspecific inhibitor of NO synthase as well as the decreased endothelium-dependent relaxation of isolated systemic artery. This points to an important role of iNOS in systemic pathogenesis of PH.

Maintenance of Renal Vascular Reactivity Contributes to Acute Renal Failure during Endotoxemic Shock

Septic shock is characterized by hypotension and decreased systemic vascular resistance and impaired vascular reactivity. Renal vasoconstriction markedly contrasts with sepsis-induced generalized systemic vasodilation, which is strongly dependent on nitric oxide. Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice. LPS-injected mice displayed lower MAP, RBF, and GFR than controls (P < 0.001). Despite a lower MAP, basal renal vascular resistance (RVR) was higher during endotoxemia (P < 0.02). Angiotensin II infusion produced a weaker MAP response in septic mice (24 versus 37%; P < 0.005), suggesting impaired vasoconstriction and hyporeactivity. A similar MAP increase was observed between groups during norepinephrine (NE) infusion. The MAP increase to nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) was much greater in LPS-treated mice (41 versus 15%, P = 0.01), indicating a strong influence of nitric oxide in sepsis. In contrast, the RBF and RVR responses to angiotensin II, NE, or L-NAME were similar in both groups. Moreover, vasopressin produced greater changes in MAP, RBF, and RVR in septic mice than in controls. Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection. The in vivo results demonstrate that the renal microvasculature displays a normal or enhanced reactivity to constrictor agents as compared with nonrenal circulatory beds. Such responsiveness may contribute to reduced RBF and GFR during endotoxemia.

Abnormal systemic and ocular vascular response to temperature provocation in primary open-angle glaucoma patients: a case for autonomic failure?

To assess systemic and ocular vascular reactivity in response to warm and cold provocation in untreated patients with primary open-angle glaucoma and normal control subjects. Twenty-four patients with primary open-angle glaucoma and 22 normal control subjects were subjected to a modified cold pressor test involving immersion of the right hand in 40 degrees C warm water followed by 4 degrees C cold water exposure, and finger and ocular blood flow were assessed by means of peripheral laser Doppler flowmetry and retinal flowmetry, respectively. Finger and body temperature as well as intraocular pressure, systemic blood pressure, systemic pulse pressure, heart rate, and ocular perfusion pressure were also monitored. The patients with glaucoma demonstrated an increase in diastolic blood pressure (P = 0.023), heart rate (P = 0.010), and mean ocular perfusion pressure (P = 0.039) during immersion of the tested hand in 40 degrees C water. During cold provocation, the patients demonstrated a significant decrease in finger (P = 0.0003) and ocular blood flow (the parameter velocity measured at the temporal neuroretinal rim area; P = 0.021). Normal subjects did not demonstrate any blood flow or finger temperature changes during immersion of the tested hand in 40 degrees C water (P > 0.05); however, they exhibited increases in systolic blood pressure (P = 0.034) and pulse pressure (P = 0.0009) and a decrease in finger blood flow (P = 0.0001) during cold provocation. In normal subjects, the ocular blood flow was unchanged during high- and low-temperature challenge. Cold provocation elicits a different blood pressure, and ocular blood flow response in patients with primary open-angle glaucoma compared with control subjects. These findings suggest a systemic autonomic failure and ocular vascular dysregulation in POAG patients.

Systemic vascular reactivity in an aortic coarctation model of preeclampsia in the rat

Preeclampsia (preECL), a hypertensive disorder of pregnancy, which occurs only in humans, is dangerous for mother and fetus. It may be caused by placental hypoxia triggering the release of a circulating factor that damages the maternal endothelium leading to vasoconstriction and hypertension. Our primary objective was to determine if systemic vascular reactivity is altered in a rat aortic coarctation (ACOR) model of preECL. We hypothesized that reduced blood flow to the rat utero-placental unit would lead to increased responsiveness to vasoconstrictors. On day 8 of pregnancy, rats were anesthetized and subjected to sham (SHAM) or aortic coarctation (ACOR) surgery by placing a 0.4 mm diameter silver clip distal to the renal arteries. Systemic pressor responses to bolus doses of phenylephrine (PE), angiotensin II (AII), and 5-hydroxytryptamine (5-HT) were determined in these animals on gestation days 14–15 (mid-pregnancy) or 19–20 (late pregnancy). Virgin rats were subjected to sham or ACOR surgery and arterial pressure measured 10–11 days after surgery. Arterial pressure was elevated in late pregnant ACOR animals (mean of 120±4 mmHg) compared with SHAM (mean of 101±6), but mid-pregnant and virgin groups were not different. Proteinuria was present more frequently in late pregnant ACOR animals (86%) than in SHAM (41%), but there were no differences in average fetal weight, fetal number, or number of reabsorbed fetuses. Pressor responses were not different in ACOR and SHAM groups in mid- or late pregnancy. These data indicate that the aortic coarctation to 0.4 mm in the rat mimics the clinical presentation of mild preECL in humans.

Mechanisms regulating angiotensin II responsiveness by the uteroplacental circulation

Pregnancy is associated with increases in cardiac output and uterine blood flow (UBF) and a fall in systemic vascular resistance. In ovine pregnancy, UBF rises from approximately 3% of cardiac output to approximately 25% at term gestation, reflecting a >30-fold rise in UBF by term. This increase in UBF supports exponential fetal growth during the last trimester and maintains fetal well-being by providing excess oxygen and nutrient delivery. These hemodynamic changes are associated with numerous hormonal changes, including increases in placental steroid hormones and enhanced activation of the renin-angiotensin and sympathetic nervous systems, all of which are believed to modulate systemic and uterine vascular adaptation and vascular reactivity. Systemic pressor responses to infused ANG II are attenuated in normotensive pregnancies and the uteroplacental vasculature is even less sensitive, suggesting development of mechanisms to maintain basal UBF and permit the rise in UBF necessary for fetal growth and well-being. The effects of ANG II on the uteroplacental vasculature are reviewed, and the mechanisms that may account for attenuated vascular sensitivity are examined, including ANG II metabolism, vascular production of antagonists, ANG II-receptor subtype expression, and the role of indirect mechanisms.

Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation.

Hypercholesterolemia impairs systemic vascular reactivity in response to endothelium-dependent vasodilators, which may be mediated partly through increased formation of lipid peroxides. However, it is unclear whether these pathophysiological mechanisms play a role in renal vascular impairment in experimental hypercholesterolemia. Hence, pigs were studied after a 3-mo normal (n = 7) or high cholesterol (HC) (n = 7) diet, HC diet supplemented daily with antioxidant vitamins E (100 IU/kg) and C (1000 mg; HC+vitamins, n = 5), or normal diet supplemented with vitamins (N+vitamins, n = 5). Renal blood flow was measured with electron-beam computed tomography before and during infusion of acetylcholine (Ach). Endothelial function, endothelial and inducible nitric oxide synthase (NOS), and nitrotyrosine immunoreactivity were studied in renal arteries ex vivo. Despite similar cholesterol levels, LDL oxidizability (lag time, malondialdehyde, and relative electrophoretic mobility) was increased in pigs that were fed the HC diet but was significantly decreased in pigs that were fed the HC+vitamins diet. Renal blood flow response to Ach was blunted in pigs that were fed the HC diet but was preserved in pigs that were fed the HC+vitamins diet. Maximal relaxation to Ach was attenuated in pigs that were fed the HC diet compared with those that were fed the normal diet (51.5 +/- 6.4% versus 97.0 +/- 2.9%; P < 0.01) but was preserved in pigs that were fed the HC+vitamins diet (103.1 +/- 3.0%; P = 0.39) and N+vitamins diet (87.7 +/- 3.0%; P = 0.1), as were relaxation responses to calcium ionophore A23187. Vascular smooth-muscle relaxation to diethylamine was enhanced in endothelium-denuded HC vessel but was restored in pigs that were on the HC+vitamins regimen. In HC, immuno-reactivity of endothelial NOS was decreased, that of inducible NOS was increased, and both were preserved in pigs that were fed the HC+vitamins and N+vitamins diets, whereas nitrotyrosine was not detected. The present study demonstrates that antioxidant intervention in experimental HC reduces LDL oxidizability and preserves renal vascular responses to endothelium-dependent vasodilators. Therefore, this beneficial effect potentially can protect the kidney from hypercholesterolemia-induced damage.

Impaired renal vascular endothelial function in vitro in experimental hypercholesterolemia

Hypercholesterolemia (HC) induces alterations in systemic vascular reactivity, which can manifest as an attenuated endothelium-dependent relaxation, partly consequent to an impairment in nitric oxide (NO) activity. To determine whether experimental HC has a similar effect on renal vascular function, renal artery segments obtained from pigs fed a HC ( n=5) or normal ( n=5) diet were studied in vitro. Endothelium-dependent relaxation was examined using increasing concentrations of acetylcholine (Ach), calcium ionophore A23187, and Ach following pre-incubation with N G-monomethyl- l-arginine or l-arginine (L-ARG). The NO-donor diethylamine (DEA) was used to examine smooth muscle relaxation response and cyclic GMP generation in endothelium-denuded vessels. The expression of endothelial NO synthase (eNOS) in the renal arteries was examined using Western blotting. Endothelium-dependent relaxation to Ach was significantly attenuated in the HC group compared to normal (53.3±9.1 vs. 98.8±3.7%, P<0.005), but normalized after pre-incubation with L-ARG (82.3±13.8%, P=0.21). Receptor-independent endothelium-dependent relaxation to A23187 was also significantly blunted in HC (75.2±10.5 vs. 115.5±4.2%, P<0.017). Smooth muscle relaxation and cyclic GMP generation in response to DEA were greater in denuded HC vessels, while relaxation of intact vessels to nitroprusside was unaltered. In the HC vessels eNOS was almost undetectable. In conclusion, experimental HC attenuates in vitro endothelium-dependent relaxation of the porcine renal artery, possibly due to low bioavailability of NO. These vascular alterations in HC could play a role in the pathogenesis of renal disease or hypertension, supporting a role for HC as a risk factor for renovascular disease.

Decreased Endothelium-Dependent Vascular Relaxation During Reduction of Uterine Perfusion Pressure in Pregnant Rat

Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to 4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0. 7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/-0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0. 1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100 micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3) N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium-intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3) N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.

Endothelin-1 and relaxation of the rat aorta during pregnancy in nitroarginine-induced hypertension.

In pregnant rats during hypertension induced by NO synthase inhibition, endothelin (ET) plasma levels are increased as in some preeclamptic women. Previously, the enhanced vasodepressor effect of endothelin-1 (ET-1) has been observed in this model, thus we decided to study the relaxation induced by ET-1 on the aorta. Non-pregnant or pregnant Wistar rats (n = 7 by group) were fed for 7 days (day 13-day 20) on a nitroarginine-enriched diet (L-NNA, 0.063% i.e. 30 mg/kg/day) or a control diet. Systolic blood pressure, measured by the tail cuff method on conscious rats at day 20 of gestation, was raised by the chronic L-NNA treatment (mean +/- s.e.m., mmHg, p < 0.001: pregnant L-NNA treated, 145 +/- 1.84 vs. pregnant control, 101 +/- 2.00 and non-pregnant L-NNA treated, 148 +/- 3.11 vs. non-pregnant control, 119 +/- 1.80). On day 20 ex vivo aortic ring relaxation was produced by ET-1 in vessels previously precontracted with norepinephrine only when endothelium was present. In control rats, ET-1 (10(-8) to 5 x 10(-8) M) produced a short but significant relaxation (mean value between 4 to 19%) followed by a long-lasting contracting phase, and a higher ET-1 concentration (10(-7) M) only produced contraction. Chronic L-NNA treatment decreased the level of relaxation (at least p < 0.05, in non-pregnant and pregnant rats) and with a 30 min L-NAME (10(-4) M) preincubation, relaxation was completely inhibited in non-pregnant and pregnant rats. BQ-123, an ETA receptor antagonist, did not produce any effect on ET-1 induced relaxation. BQ-788, an ETB receptor antagonist, significantly decreased it. In conclusion, in female rats, as in male rats, ET-1 induces a transient relaxation in the preconstricted aorta which involves endothelial ETB receptors. Despite a decrease in the systemic vascular reactivity during late gestation, the vasodilating and vasoconstricting properties of ET-1 on the aorta are not changed.