Decrease In Vascular Reactivity Research Articles

Functional State of the Mesenteric Arteries and Vessels of the Skin Microcirculation Bed in Rats with Experimental Kidney Dysfunction

Chronic kidney disease is accompanied by cardiovascular complications, including endothelial dysfunction, arterial hypertension, and atherosclerosis. The aim of this work is to compare the reactivity of the vessels of the microcirculatory bed (MCR) of the skin, assessed by laser Doppler flowmetry (LDF) and mesenteric arteries in rats with resection of 5/6 of the mass of the kidneys, and to evaluate the possibility of using LDF analysis as a method that reflects the functional state of large resistive vessels. Wistar rats were divided into two groups: animals of the NE-group (n = 15) had 5/6 of the mass of kidney tissue removed, control animals of the SO-group (n = 15) underwent a sham operation. After 8 weeks, the reactivity of rat skin microvessels to acetylcholine (ACh) and sodium nitroprusside (NP) iontophoresis was assessed. A week later, in rats, the effect of NE on the reactivity of mesenteric arteries preconstricted with phenylephrine was evaluated in vivo using microphotographic and video recording of the diameter. It has been shown that NE does not affect the average value of perfusion in the skin of rats at rest, however, it changes the structure of the frequency range of the spectrum of fluctuations in the MCR index, increasing the value of endothelial, neurogenic, and myogenic tone. NE led to the development of endothelial dysfunction of the mesenteric arteries and MCR vessels of the skin, which was expressed in a decrease in vascular reactivity to the action of endothelium-dependent (ACh) and endothelium-independent (NP) vasodilators. Thus, the development of experimental kidney dysfunction led to changes in the spectral components of fluctuations in the MCR index in the skin, indicating an increase in tonic effects of various genesis on the vessels. NE was accompanied by a decrease in the reactivity of microvessels of the skin and mesenteric arteries, however, there was no correlation between an increase in the MCR index and dilatation of the mesenteric arteries under the action of vasodilator agonists.

Role of the angiotensin type 1 receptor in modulating the carotid chemoreflex in an ovine model of renovascular hypertension.

The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear. Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. In both hypertensive and sham animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure but a reduction in renal vascular conductance. These responses were not different between groups. Infusion of angiotensin II led to an increase in arterial pressure and reduction in renal blood flow. The sensitivity of the renal vasculature to angiotensin II was significantly attenuated in hypertension compared with the sham animals. Systemic inhibition of the AT1R did not alter blood pressure in either group. Interestingly carotid body-evoked arterial pressure responses were attenuated by AT1R blockade in renovascular hypertension but not in shams. Taken together, our findings indicate a decrease in vascular reactivity of the non-clipped kidney to angiotensin II in hypertension. The CB-evoked increase in blood pressure in hypertension is mediated in part, by the AT1R. These findings indicate a differential role of the AT1R in the carotid body versus the renal vasculature.

Ipomoea hederacea Jacq.: A plant with promising antihypertensive and cardio-protective effects

Ethnopharmacological relevanceSeeds of Ipomoea hederacea Jacq. (family: Convolvulaceae) are traditionally used to treat high blood pressure and cardiac diseases.Aim of the study: Present study was conducted to validate the traditional claim and explore the possible mechanism(s) of antihypertensive effects of I. hederacea. Materials and methodsAqueous-ethanolic extract and activity based fractions of I. hederacea were evaluated using invasive blood pressure measuring technique, isolated tissue experiments, fructose induced hypertension/metabolic syndrome and biochemical analysis.Phytochemical analysis of active fraction was performed with aim to identify chemical composition of I. hederacea seeds. LC-MS analysis was also performed to identify the compounds proposed to be present in active fraction of I. hederacea seeds. ResultsCrude extract/fractions of I. hederacea showed dose (0.01–100 mg/kg) dependent significant hypotensive effect in normotensive anesthetized rats, similar to verapamil (0.01–30 mg/kg). Pretreatment with hexamethonium and atropine mediated no significant changes in hypotensive effect of butanol fraction of I. hederacea (Ih.Bn) at 3 mg/kg dose. However, a significant decrease in the hypotensive effect of Ih.Bn 3 mg/kg (−34.82 ± 3.36%; p < 0.05) was observed in the presence of L-NAME (20 mg/kg). Similarly, Ih.Bn (3 mg/kg) showed no significant effect on angiotensin-II response. However, response of phenylephrine (45.60 ± 9.63%; p < 0.05) and dobutamine (18.25 ± 2.10%; p < 0.01) was significantly decreased in the presence of Ih.Bn 3 mg/kg. Ih.Bn also exhibited dose dependent (0.01–100 mg/kg) antihypertensive effect in fructose induced hypertensive rats, similar to verapamil (0.01–30 mg/kg). Concomitant treatment with Ih.Bn (3, 10 and 30 mg/kg) for six weeks showed a dose dependent profound protection with significant (p < 0.01) effect at 30 mg/kg against fructose induced basal mean arterial pressure (142.2 ± 4.62 mmHg). Ih.Bn did not significantly change response of PE, Ang-II and Epi was observed in invasive and ex vivo techniques. However, Ih.Bn significantly (p < 0.01; p < 0.001) prevented against decrease in vascular response of acetylcholine in anesthetized rats and in isolated aorta of rat. A significant dose dependent decrease in triglyceride and glucose level (p < 0.001), and increase in HDL level (p < 0.05) was observed in Ih.Bn treated groups. Results of LC-MS analysis of Ih.Bn showed the presence of 24 compounds that belong to different chemical classes, including carboxylic acid, flavonoids, oligopeptides and tripeptide that are known to have antihypertensive and vasorelaxant properties. ConclusionsResults of present study indicate the presence of hypotensive/antihypertensive effect in crude extract/fractions of I. hederacea with most potent effect shown by butanol fraction (Ih.Bn), possibly mediated through α1 blocking, β blocking and iNOS/cGMP stimulating activity.

Exposure to total 36-hr sleep deprivation reduces physiological and psychological thermal strain to whole-body uncompensable passive heat stress in young adult men.

Total sleep deprivation (TSD) is associated with endothelial dysfunction and a consequent decrease in vascular reactivity and increase in peripheral vascular resistance. These effectors compromise the body's ability to thermoregulate in hot and cold stress conditions. We investigated heat-unacclimated young adult men (26±2years) to determine whether 36hr of TSD compared to an 8 or 4-hr sleep condition, would suppress the responses of the autonomic system (body rectal temperature [Tre ], heart rate [HR], root mean square of successive interbeat intervals, physiological strain, blood pressure [BP], circulating blood catecholamines, sweating rate and subjective sensations) to whole-body uncompensable passive heat stress in traditional Finnish sauna heat (Tair =80-90°C, rh=30%). Sauna bathing that induced whole-body hyperthermia had a residual effect on reducing BP in the 8-hr and 4-hr sleep per night conditions according to BP measurements. By contrast, 36hr of total wakefulness led to an increase in BP. These observed sleep deprivation-dependent differences in BP modifications were not accompanied by changes in the blood plasma epinephrine and norepinephrine concentrations. However, during sauna bathing, an increase in BP following 36hr of TSD was accompanied by significant decreases in body Tre , HR and physiological strain, together with a diminished sweating rate, enhanced vagus-mediated autonomic control of HR variability, and improved thermal perception by the subjects. Our results suggest the impaired ability of the body to accumulate external heat in the body's core under uncompensable passive heat conditions following 36hr of TSD, because of the TSD-attenuated autonomic system response to acute heat stress.

In Vitro Effects of Eicosapentaenoic and Docosahexaenoic Acid on the Vascular Tone of a Human Saphenous Vein: Influence of Precontractile Agents

Cardiovascular effects of omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been widely reported. However, there are limited studies concerning their effects on human blood vessels. Therefore, the aim of this study was to investigate the direct vascular effects of EPA and DHA on the human saphenous vein (SV) precontracted with either prostaglandin F2α (PGF2α), or thromboxane A2 analogue (U46619), or norepinephrine (NE). Moreover, we aimed to investigate the protein expression of free fatty acid receptor 4 (FFAR4) in human SV. Pretreatment of human SV rings with EPA and DHA (100μM, 30min) was tested on vascular reactivity induced by PGF2α (10 nM to 5 μM), NE (10 nM to 100 μM), and U46619 (1nM to 100 nM). In addition, direct relaxant effects of EPA/DHA (1-100μM) were tested in human SV rings precontracted by PGF2α, NE, and U46619. Furthermore, the involvement of potassium channels on their vascular effects was investigated in the presence of the nonselective K+ channel inhibitor tetraethylammonium chloride. Pretreatment with EPA and DHA resulted in a significant decrease in vascular reactivity induced by U46619 and PGF2α compared to NE. In the presence of TEA, the relaxant effects of EPA and DHA were significantly decreased in SV preparations precontracted by U46619 and PGF2α for DHA. Furthermore, FFAR-4 protein was expressed in tissue extracts of humanSV. Our study demonstrates that both EPA and DHA reduce the increased vascular tone elicited by contractile agents on the human SV and that the direct vasorelaxant effect is likely to involve potassium channels.

Changes in the reactivity of vessels of rats with an experimental decrease in the mass of functioning nephrons

The aim : to evaluate changes in endothelium-dependent regulation of the tone of blood vessels (aorta and superior mesenteric artery) in rats 4 months after the removal of 5/6 renal tissue. Material and methods. An experimental CKD model was created by resection of 5/6 mass of renal tissue. The experimental group included animals (n = 12), subjected to nephrectomy (NE). The control group consisted of sham-operated (SO) rats (n = 10). Researches of vascular reactivity were performed on ring segments 2 mm long, which were excised from the aorta and superior mesenteric artery (SMA). A total of 23 segments of the aorta and 17 segments of SMA from rats after NE and 18 segments of the aorta and 15 segments of SMA from control animals were prepared. To measure the strength of contractions of the drugs, a FORT-10 sensor (WPI, USA) was used. The effects of acetylcholine (Ach, 1 x10 -6 M) on blood vessels, previously exposed to phenylephrine (1 x10 -5 M), and the response of vessels to Ach under conditions of prior exposure to TEA (1 x 10 -3 mol / l) and L-NAME (1 x10 -4 mol / l) were evaluated. Results. NE for a period of 4 months led to arterial hypertension - BP in the NE group of rats was higher (165, 0 ± 9.8 mm Hg) compared with SO (127.2 ± 9.7 mm Hg, р &lt;0,001), and to myocardial remodeling (LVMI in NE rat was 2.72 ± 0.11 mg / g compared to 2.35 ± 0.09 mg / in the SO group, р &lt;0,001 ). NE led to a decrease in dilatation of aortic and BWA fragments on the ACh compared with LO animals. Under the conditions of NO blocking, the NO synthase inhibitor — L-NAME — also had a lower response to ACh in rats with NE. The preliminary blockade of the Ca2 + -activated K + channels of high conductivity with the introduction of TEA resulted in a decrease in vasodilation caused by ACh in NE rat compared with the SO group. Conclusion. Resection of 5/6 of the kidney tissue mass in rats causes a decrease in vascular reactivity on the ACh. Endothelial dysfunction of rats after NE is associated with impairment of both NO-related and hyperpolarization-dependent endothelial cells in pathways of the vascular tone regulation.

Organ-specific changes in vascular reactivity and roles of inducible nitric oxide synthase and endothelin-1 in a rabbit endotoxic shock model.

Hemorrhagic shock-induced changes in vascular reactivity appear organ-specific. In the present study, we examined the hypothesis that vascular reactivity induced by septic shock similarly displays organ-specific differences and is regulated by inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1). Endotoxic shock was induced in rabbits by administration of lipopolysaccharide (LPS) (1 mg/kg), and organ specificity of vascular reactivity of superior mesenteric artery (SMA), celiac artery (CA), and left renal artery (LRA) as well as the potential involvement of iNOS and ET-1 examined. Vascular reactivity of SMA, CA, and LRA was increased at the early stages and decreased at the late stages after LPS administration. Superior mesenteric artery showed the greatest decrease in vascular reactivity in response to norepinephrine (NE) (34.9%) and acetylcholine (Ach; 32.3%), followed by LRA (NE, 33.7%; Ach, 30.5%) and CA (NE, 16.2%), whereas the relaxation reactivity of CA in response to Ach was increased to 159%. The mRNA and protein levels of iNOS and ET-1 in SMA, CA, and LRA were not affected at the early stages of endotoxic shock after LPS administration but significantly increased at the late stages. Expression levels were higher in SMA than CA and LRA and negatively correlated with the decrease in vascular reactivity. The iNOS and ET-1 inhibitors, aminoguanidine (20 mg/kg) and PD-142893 (0.02 mg/kg), respectively, induced significant improvements in vascular reactivity and organ perfusion and stabilized the hemodynamic parameters in rabbits subjected to endotoxic shock. Changes in vascular reactivity during endotoxic shock are organ-specific. Differential expression patterns of iNOS and ET-1 in different blood vessels contribute to the organ specificity of vascular reactivity. Therapeutic study, level II.

Anti-oxidative treatment with vitamin E improves peripheral vascular function in patients with diabetes mellitus and Haptoglobin 2-2 genotype: A double-blinded cross-over study.

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

Renal sympathetic nerve activity and vascular reactivity to phenylephrine after lipopolysaccharide administration in conscious rats

It has been proposed that sympathoexcitation is responsible for vascular desensitization to α 1‐adrenoceptor stimulation during lipopolysaccharide (LPS)‐induced systemic inflammation. The present study tested this hypothesis by examining the effects of sympatho‐deactivation with the α 2‐adrenoceptor agonist, dexmedetomidine, on mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and vascular reactivity to phenylephrine in conscious rats with cardiac autonomic blockade (methylatropine and atenolol) following LPS administration. In male, adult Sprague‐Dawley rats (n = 5 per group), RSNA and MAP were continuously recorded over 1‐h periods, before and after LPS administration (20 mg/kg iv), and finally after infusion of either saline or dexmedetomidine (5 μg/kg, then 5 μg/kg/h iv). A full dose–response curve to phenylephrine was constructed under each condition. After pooling data from both groups of rats (n = 10), LPS significantly (P = 0.005) decreased MAP (from 115 ± 1 to 107 ± 2 mmHg), increased RSNA (to 403 ± 46% of baseline values) and induced 4 to 5‐fold increases in the half‐maximal effective dose (ED 50) of phenylephrine (from 1.02 ± 0.09 to 4.76 ± 0.51 μg/kg). During saline infusion, RSNA progressively decreased while vascular reactivity did not improve. Treatment with dexmedetomidine decreased MAP, returned RSNA to near pre‐endotoxemic levels, but only partially restored vascular reactivity to phenylephrine (ED 50 was still threefold increased as compared with baseline values). These findings indicate that only part of the decrease in vascular reactivity to α 1‐adrenoceptor stimulation during endotoxemia can be accounted for by sympathetic activation, at least on a short‐term basis.

DIVERSITY OF VASCULAR REACTIVITY AND THE TREATMENT RESPONSE IN DIABETIC, HYPERTENSIVE, HYPERLIPIDEMIC, AND HEALTHY RATS SUBJECTED TO HEMORRHAGIC SHOCK.

The current diagnosis and treatment guidelines for severe trauma and shock are all for healthy population. Few studies focused on the pathophysiological features and treatments in metabolic diseases after severe trauma and shock. Vascular reactivity is significantly decreased after severe trauma and shock. Improving the vascular reactivity with arginine vasopressin (AVP) and phorbol-12 myristate-13-acetate (PMA) is beneficial to trauma and shock. Whether the cardiovascular function and treatment responses have the own features in hypertensive, diabetic, and hyperlipidemic patients after traumatic hemorrhagic shock is not known. Using hypertensive, diabetic, and hyperlipidemic and healthy rats, we compared the change patterns in cardiovascular function including vascular reactivity, tissue perfusion, and the hemodynamics after hemorrhagic shock and their responses to AVP, PMA, and common antishock agents including dopamine and norepinephrine. A same degree of hemorrhagic shock (40% hemorrhage or mean arterial pressure maintained at 40 mm Hg for 2 h) resulted in a more obvious decrease in vascular reactivity, hemodynamics, tissue perfusion, and mitochondrial function of liver and kidney in hypertensive, diabetic, and hyperlipidemic rats, and a more rapidly natural death than in healthy rats. The effectiveness of AVP and PMA in these diseased rats was lower than in healthy rats. The effective dosage of common antishock agents including norepinephrine, dopamine, and AVP in healthy rats was wider than that in these diseased rats. Among the antishock agents used in the current study, AVP had the best effect in improving animal survival and vascular reactivity both in healthy and in diseased rats. These findings suggest that hypertensive, diabetic, and hyperlipidemic rats have a worse vascular reactivity and organ function than the healthy rats after traumatic hemorrhagic shock, which result in the worse treatment responses and effects to vasoactive agents. Lower dose of AVP can be recommended as the first-line antishock agents for these diseased rats.

EFFECT OF OZONE THERAPY ON ISCHEMIC REPERFUSION INJURY OF THE HEART AND VASCULAR REACTIVITY IN ADULT MALE DIABETIC ALBINO RAT

Background: Ozone therapy is a form of complementary medicine treatment that aims to increase the amount of oxygen to the body through the introduction of ozone into the body. Objective: Studying the effects of diabetes mellitus, insulin and ozone on ischemic reperfusion (IR) injury on the heart and vascular reactivity in diabetic rat. Material and Methods: Two hundred and fifty adult male albino rats of local strain, weighing 120-150 ±10 grams each, were used in this investigation and divided into: Group I (Normal control group): 10 rats. Group II (Diabetic group -240 rats) were subdivided into 4 subgroups: Group II-a (Diabetic non-treated group - 40 rats), Group II-b (Diabetic insulin-treated group - 40 rats, and Group II-c (Diabetic ozone-treated group - 80 rats Group II-d (Diabetic ozone and insulin-treated group - 80 rats): Rats were submitted to ozone therapy with concomitant treatment with insulin. Supernatant serum was collected in a dry clean tube for estimation of fasting serum glucose, serum total cholesterol, triglycerides, HDL, LDL, LDH, catalase enzyme, glutathione peroxidase, and SOD. Rat aortic rings preparation were used for estimation of changes in vascular reactivity in response to norepinephrine (10-5), vasopressin (10-6 M), indomethacin (10-6 M) and relaxation of aortic rings (preconstricted by NE (10-5) in response to ACh (10-6) and Na+ nitroprusside (10-6) as estimated in different groups. The organ bath was washed out three times with fresh Krebs' solution before the next substance was added and the rings were allowed to stabilize for 1 hour. All results were presented as the mean ± SEM. The data were analyzed using SPSS program version 12. For comparison of statistical significance between different groups, a one way ANOVA with the post hoc of Tukey's multiple comparison test was used. A value of P ≤ 0.05 was considered statistically significant. Results: Ozone therapy caused significant decrease in fasting glucose, total cholesterol, triglycerides, LDL, and lactate dehydrogenase “LDH”, and significant increase in HDL and myocardial antioxidants (catalase, superoxide dismutase “SOD” and glutathione peroxidase). There were a significant increase in cardiac contractility and heart rate during pre-ischemic and ischemic periods. There was a significant decrease in heart rate accompanied by significant increase in cardiac contractility during reperfusion period. Also, ozone treatment produced a significant decrease in vascular reactivity of aortic rings to norepinephrine, vasopressin and indomethacin, with significant increase in percentage of relaxation to acetyl choline “ACh”. Conclusion: Diabetic complications are attributed to the oxidative stress in the body. Ozone activates the antioxidant system affecting the level of glycemia. Ozone prevents oxidative stress by normalizing the organic peroxide levels by activating superoxide dismutase.

Plasma asymmetric and symmetric dimethylarginine in a rat model of endothelial dysfunction induced by acute hyperhomocysteinemia.

Hyperhomocysteinemia induces vascular endothelial dysfunction, an early hallmark of atherogenesis. While higher levels of circulating asymmetric dimethylarginine (ADMA) and symmetric dimethyl arginine (SDMA), endogenous inhibitors of nitric oxide synthesis, have been associated with increased cardiovascular risk, the role that ADMA and SDMA play in the initiation of hyperhomocysteinemia-induced endothelial dysfunction remains still controversial. In the present study, we studied the changes of circulating ADMA and SDMA in a rat model of acutely hyperhomocysteinemia-induced endothelial dysfunction. In healthy rats, endothelium-related vascular reactivity (measured as acetylcholine-induced transient decrease in mean arterial blood pressure), plasma ADMA and SDMA, total plasma homocysteine (tHcy), cysteine and glutathione were measured before and 2, 4 and 6 h after methionine loading or vehicle. mRNA expression of hepatic dimethylarginine dimethylaminohydrolase-1 (DDAH1), a key protein responsible for ADMA metabolism, was measured 6 h after the methionine loading or the vehicle. Expectedly, methionine load induced a sustained increase in tHcy (up to 54.9 ± 1.9 µM) and a 30 % decrease in vascular reactivity compared to the baseline values. Plasma ADMA and SDMA decreased transiently after the methionine load. Hepatic mRNA expression of DDAH1, cathepsin D, and ubiquitin were significantly lower 6 h after the methionine load than after the vehicle. The absence of an elevation of circulating ADMA and SDMA in this model suggests that endothelial dysfunction induced by acute hyperhomocysteinemia cannot be explained by an up-regulation of protein arginine methyltransferases or a down-regulation of DDAH1. In experimental endothelial dysfunction induced by acute hyperhomocysteinemia, down-regulation of the proteasome is likely to dampen the release of ADMA and SDMA in the circulation.

Early changes in vascular reactivity in response to 56Fe irradiation in ApoE–/– mice

Epidemiological studies have established that radiation from a number of terrestrial sources increases the risk of atherosclerosis. The accelerated heavy ions in the galacto-cosmic radiation (GCR) that astronauts will encounter on in space, however, interact very differently with tissues than most types of terrestrial radiation, so the health consequences of exposure on deep-space missions are not clear. We demonstrated earlier that 56Fe, an important component of cosmic radiation, accelerates atherosclerotic plaque development. In the present study, we examined an earlier, pro-atherogenic event that might be predictive of later atherosclerotic disease. Decreased endothelium-dependent vasodilation is a prominent manifestation of vascular dysfunction that is thought to predispose humans to the development of structural vascular changes that precede the development of atherosclerotic plaques. To test the effect of heavy-ion radiation on endothelium-dependent vasodilation, we used the same ApoE–/– mouse model in which we previously demonstrated the pro-atherogenic effect of 56Fe on plaque development. Ten week old male ApoE mice (an age at which there is little atherosclerotic plaque in the descending aorta) were exposed to 2.6Gy 56Fe. The mice were then fed a normal diet and housed under standard conditions. At 4–5 weeks post-irradiation, aortic rings were isolated and endothelial-dependent relaxation was measured. Relaxation in response to acetylcholine was significantly impaired in irradiated mice compared to age-matched, un-irradiated mice. This decrease in vascular reactivity following 56Fe irradiation occurred eight weeks prior to the development of statistically significant exacerbation of aortic plaque formation and may contribute to the formation of later atherosclerotic lesions.

Effects of Kaempferia parviflora rhizomes dichloromethane extract on vascular functions in middle-aged male rat

Ethnopharmacological relevanceIn Thai traditional medicine, rhizomes of Kaempferia parviflora (KP) have been used for treating hypertension and for the promotion of longevity with good health and well being. Ageing is one of the most important risk factors for development of cardiovascular disease. To investigate whether a 6 weeks oral administration of a dichloromethane extract of fresh rhizomes of Kaempferia parviflora (KPD) had any effects on vascular functions, on the accumulation of lipid, as well as on any signs of gross organ toxicity in middle-aged rats. Materials and methodsFresh rhizomes of Kaempferia parviflora were first macerated twice with 95% ethanol to remove the dark color before extracting three times with 100% dichloromethane. The dichloromethane extract was evaporated under reduced pressure to obtain the dried Kaempferia parviflora dichloromethane extract (KPD). The rats were orally administered with the KPD at a dosage of 100mg/kg body weight, or with the same volume of the vehicle (tween 80, 0.2g: carboxy-methylcellulose sodium, 0.2g: distilled water 10ml) once or twice a day for 6 weeks. Vascular functions were studied on isolated thoracic aorta and the mesenteric artery. The vascular eNOS enzyme was measured by Western blot analysis. Blood chemistry was measured by enzymatic methods. Liver cell lipid accumulation was measured using oil red O staining. ResultsA 6 weeks treatment of KPD once a day had no significant effects on any of the studied parameters. When the KPD was given twice a day, the contractile responses to phenylephrine of the thoracic aorta and mesenteric artery were lower than the vehicle control group, and this effect was abolished by NG-nitro-l-arginine or by removal of the vascular endothelium. Vasorelaxation to acetylcholine, but not to glyceryl trinitrate, by the thoracic aortic and mesenteric ring precontracted with phenylephrine was higher from the KPD treated rats than those from the vehicle control groups. Western blot analysis showed a higher quantity of thoracic- and mesenteric-eNOS protein obtained from the KPD treated rats. In addition, the body weight, serum glucose and triglycerides levels, visceral and subcutaneous fat, as well as liver lipid accumulation were all significantly decreased in the KPD treated rats compared to those of the vehicle control. No differences were found between the KPD treated-, and the vehicle-control for animal food intake, internal organ weight, serum ALP, SGOT, SGPT, BUN and creatinine levels, serum cholesterol, HDL-C and LDL-C levels, nor total blood cell counts. ConclusionsThe chronic oral administration of KPD extract, to middle aged rats, caused a decrease in vascular responsiveness to phenylephrine with an increase in the acetylcholine induced vasorelaxation, due to an increase in nitric oxide production from their blood vessels. The extract also caused a decrease in visceral and subcutaneous fat, fasting serum glucose and triglyceride levels and liver lipid accumulation, with no changes to liver and kidney functions or to total blood cell counts. It is possible that these KPD extracts could be developed as a health product for mid-aged humans to reduce obesity, diabetes type II and cardiovascular disease.

Age and sex differences in vascular responsiveness in healthy and trauma patients: contribution of estrogen receptor-mediated Rho kinase and PKC pathways

Several medical conditions exhibit age- and sex-based differences. Whether or not traumatic shock exhibits such differences with regard to vascular responsiveness is not clear. In a cohort of 177 healthy subjects and 842 trauma patients (21-82 years) as well as different ages (4, 8, 10, 14, 18, and 24 wk; 1 and 1.5 years) and sexes of Sprague-Dawley normal and traumatic shock rats, the age- and sex-based differences of vascular responsiveness and the underlying mechanisms were investigated. Middle-aged and young women as well as female rats of reproductive age had higher vascular responsiveness in the normal condition and a lower decrease in vascular responsiveness after traumatic shock than older men and male rats of identical age. Exogenous supplementation of 17β-estrdiol increased vascular reactivity in both male and femal rats of 8-24 wk and preserved vascular responsiveness in rats following traumatic shock. No effect was observed in rats 1 to 1.5 years. These protective effects of estrogen were closely related to G protein-coupled receptor (GPR)30, estrogen receptor-mediated Rho kinase, and PKC pathway activation. Vascular responsiveness exhibits age- and sex-based differences in healthy subjects and trauma patients. Estrogen and its receptor (GPR30) mediated activation of Rho kinase and PKC using genomic and nongenomic mechanisms to elicit protective effects in vascular responsiveness. This finding is important for the personalized treatment for several age- and sex-related diseases involving estrogen.

Late preterm infants: lung and brain development

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2 DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8 weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

Angiopoietins regulate vascular reactivity after haemorrhagic shock in rats through the Tie2-nitric oxide pathway

Vascular reactivity shows biphasic changes after severe trauma or shock. Our aim was to elucidate the mechanisms of biphasic-changed vascular reactivity after haemorrhagic shock by observing the regulation of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) on it. Haemorrhagic-shock Sprague-Dawley rats, hypoxia-treated superior mesenteric arteries (SMAs) with intact endothelia, and a cell mixture of vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) were adopted to evaluate the regulatory effects of Ang-1 and Ang-2 on vascular reactivity and their relationship to Tie2 (receptor tyrosine kinase)-Akt-endothelial nitric oxide synthase (eNOS) and Tie2-extracellular signal-regulated kinase (Erk)-inducible nitric oxide synthase (iNOS) signal pathways. Ang-1 expression, Tie2 phosphorylation, and nitric oxide (NO) release were increased at early shock. Exogenous Ang-1 maintained the vascular reactivity of SMAs after early hypoxia. Tie2-blocking antibody and the antagonists of Akt and eNOS antagonized Ang-1-induced maintenance in vascular reactivity and a slight release in NO at the early stage of shock. Ang-2 expression, Tie2 phosphorylation, and NO release were greatly increased at late shock, but exogenous Ang-2 further decreased the vascular reactivity of SMAs after late hypoxia. Tie2-blocking antibody and the antagonists of Erk and iNOS andtagonized the Ang-2-induced decrease in vascular reactivity and a large release of NO at the late stage of shock. Ang-1 and Ang-2 participated in the regulation of vascular reactivity after haemorrhagic shock. Ang-1 was mainly responsible for the hyperreactivity at early shock through the Tie2-Akt-eNOS pathway and an appropriate amount of NO release. Ang-2 was mainly responsible for the hyporeactivity at late shock through the Tie2-Erk-iNOS pathway and the release of a large amount of NO.

Effect of early diabetes on the expression of alpha‐1 adrenoceptors in aorta of Wistar Kyoto and Spontaneously Hypertensive rats

Adrenergic receptors play an important role in the regulation of blood pressure. Diabetes and hypertension affect this mechanism producing changes in vascular responses and exacerbating cardiovascular diseases. Several studies have mentioned that vascular changes are different in the early versus advanced stages of diabetes. For instance, in a recent study by our work group, a decrease in the vasopressor response to noradrenaline was found at 4 weeks of the diabetes evolution in Wistar Kyoto (WKY) and Spontaneously Hypertensive rats (SHR). Among the changes that could take place in the early stages of diabetes to cause this decrease in vascular response is a decrease in the expression of alpha‐1 adrenergic receptors. Therefore, the aim of the present study was to assess the expression of the three subtypes of alpha‐1 adrenergic receptors (alpha‐1A, alpha‐1B, alpha‐1D) in the aorta of WKY and SHR with 4 weeks of the evolution of diabetes. The results showed that whereas the condition of diabetes in WKY rats did not modify significantly the expression of alpha‐1 adrenoceptors, in SHR led to a significative decrease in the expression of both alpha‐1A and alpha‐1B receptors, with no change observed in alpha‐1D expression. In conclusion, the early stages of diabetes produce modifications in the expression of alpha‐1 adrenergic receptors that could explain the decrease found in vascular responses.This work was supported by a CONACYT grant (#82599) and SIP grant (#20110176) COFAA‐ IPN.

Involvement of Nitric Oxide in Mesenteric Vascular Reactivity following Intraperitoneal Pancreatic Juice in Rats

The purposes of this study were to examine the protein expressions of endothelial and inducible nitric oxide synthase (eNOS and iNOS) of the rat intestinal smooth muscle, and to elucidate the role of nitric oxide (NO) in the reactivity of the superior mesenteric artery (SMA) to vasoconstrictors following intraperitoneal (i.p.) injection of pancreatic juice. Immunohistochemistry was used to observe the protein expressions of eNOS and iNOS in the intestinal tissues 15 h after i.p. injection of pancreatic juice (1 ml/100 g body weight). To test the vascular reactiveness, SMA was isolated and perfused with Tyrode's solution at a constant flow rate of 5 ml/min. The changes in perfusion pressure as the measure of contractile responses to phenylephrine (PE) were monitored. I.P. injection of pancreatic juice induced increases of plasma levels of tumor necrosis factor α (TNFα) (P < 0.001; N = 7) and NO (P < 0.001; N = 7). Nω-nitro-L-arginine methyl ester (L-NAME) reduced the release of TNFα and NO. There were 8.3 ± 1.2-fold and 11.4 ± 2.8-fold increases in the protein expressions of eNOS and iNOS, respectively, in the intestinal tissue after pancreatic juice injection. PE (10⁻⁸ ~ 10⁻⁴ M) produced a dose-dependent vasoconstrictive effects on the SMA bed. Contractile responses to PE were attenuated in pancreatic juice-treated group. Addition of L-NAME (10⁻⁴ M) resulted in full recovery of the responses to phenylephrine in SMA bed, while aminoguanidine (AG, 10⁻⁴ M) caused only partial recovery. Our results indicate that i.p. injection of pancreatic juice results in a decrease in vascular reactivity of mesenteric vessels that is dependent on both eNOS and iNOS expressions in the intestinal vascular bed. Overproduction of NO elicits intestinal low vascular reactivity.

Unveiling the vasodilatory actions and mechanisms of relaxin.

Relaxin is a 6-kDa peptide hormone that is secreted from the corpus luteum of the ovary and circulates in the blood during pregnancy in several species, including humans, rats, and mice1 (see Appendix for relaxin ligand and receptor nomenclature). Hisaw and colleagues,2,3⇓ who discovered the hormone, provided the first evidence, albeit structural in nature, that the vasculature is a relaxin target. In ovariectomized monkeys administered relaxin, they noted marked morphological changes in the endothelial cells of endometrial blood vessels consistent with hypertrophy and hyperplasia, as well as enlargement of arterioles and capillaries.4,5⇓ Functional evidence for a vasodilatory role of the hormone was initially reported by St-Louis and Massicotte,6 who demonstrated that chronic infusion of purified rat or porcine relaxin decreased systolic blood pressure in female spontaneously hypertensive rats but not Wistar-Kyoto rats. In another study, the same group of investigators showed that short-term administration of purified rat relaxin decreased mean arterial pressure in female spontaneously hypertensive rats as early as 8 hours after initiating the infusion, and the vasoconstrictor responses to norepinephrine and arginine vasopressin were blunted in the mesenteric circulation of these animals perfused in situ.7 Subsequently, some doubt about the physiological importance of the vascular role of relaxin was raised, when Ahokas et al8 found that the gestational decline in systolic blood pressure and decrease in vascular reactivity to angiotensin II were comparable in gravid spontaneously hypertensive rats with and without ovaries and, thus, with and without circulating relaxin. Further supportive evidence for vascular effects of relaxin was garnered by Bani-Sacchi et al,9 who reported that, in the Langendorff preparation, relaxin acutely increased coronary blood flow in rat and guinea pig hearts. This group also showed that the vasodilatory action of relaxin in the coronary circulation was prevented by …