scholarly journals Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

2012 ◽  
Vol 302 (9) ◽  
pp. L875-L890 ◽  
Author(s):  
Helen Christou ◽  
Ossama M. Reslan ◽  
Virak Mam ◽  
Alain F. Tanbe ◽  
Sally H. Vitali ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Ex Vivo ◽  
Systolic Pressure ◽  
Mesenteric Arteries ◽  
Hypoxic Exposure ◽  
Sprague Dawley ◽  
Vsmc Proliferation

Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH.

scholarly journals Vascular function in rats with adenine-induced chronic renal failure

2012 ◽  
Vol 302 (12) ◽  
pp. R1426-R1435 ◽  
Author(s):  
Lisa Nguy ◽  
Holger Nilsson ◽  
Jaana Lundgren ◽  
Maria E. Johansson ◽  
Tom Teerlink ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Vascular Function ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Severe Renal Failure ◽  
Stress Markers

The aim of the present study was to characterize the function of resistance arteries, and the aorta, in rats with adenine-induced chronic renal failure (A-CRF). Sprague-Dawley rats were randomized to chow with or without adenine supplementation. After 6–10 wk, mesenteric arteries and thoracic aortas were analyzed ex vivo by wire myography. Plasma creatinine concentrations were elevated twofold at 2 wk, and eight-fold at the time of death in A-CRF animals. Ambulatory systolic and diastolic blood pressures measured by radiotelemetry were significantly elevated in A-CRF animals from week 3 and onward. At death, A-CRF animals had anemia, hyperphosphatemia, hyperparathyroidism, and elevated plasma levels of asymmetric dimethylarginine and oxidative stress markers. There were no significant differences between groups in the sensitivity, or maximal response, to ACh, sodium nitroprusside (SNP), norepinephrine, or phenylephrine in either mesenteric arteries or aortas. However, in A-CRF animals, the rate of aortic relaxation was significantly reduced following washout of KCl (both in intact and endothelium-denuded aorta) and in response to ACh and SNP. Also the rate of contraction in response to KCl was significantly reduced in A-CRF animals both in mesenteric arteries and aortas. The media of A-CRF aortas was thickened and showed focal areas of fragmented elastic lamellae and disorganized smooth muscle cells. No vascular calcifications could be detected. These results indicate that severe renal failure for a duration of less than 10 wk in this model primarily affects the aorta and mainly slows the rate of relaxation.

Carbonic Anhydrase Inhibition Improves Pulmonary Artery Reactivity and Nitric Oxide-Mediated Relaxation in Sugen-Hypoxia Model of Pulmonary Hypertension

2021 ◽  
Author(s):  
Helen Christou ◽  
Zoe Michael ◽  
Fotios Spyropoulos ◽  
Yunfei Chen ◽  
Dan Rong ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Carbonic Anhydrase ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Vascular Function ◽  
Systolic Pressure ◽  
Mesenteric Arteries ◽  
Pulmonary Hemodynamics ◽  
Carbonic Anhydrase Inhibition

Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen5416 (20mg/kg, sc) and subjected to hypoxia (9%O2) (Su+Hx), or Su+Hx treated with acetazolamide (ACTZ, 100mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su+Hx and reduced in Su+Hx+ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su+Hx and improved in Su+Hx+ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su+Hx and improved in Su+Hx+ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su+Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su+Hx that was ameliorated in Su+Hx+ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation, and may enhance responsiveness to vasodilator therapies in PH.

Effect of pioglitazone on vascular reactivity in vivo and in vitro

1996 ◽  
Vol 270 (3) ◽  
pp. R660-R666 ◽  
Author(s):  
T. A. Kotchen ◽  
H. Y. Zhang ◽  
S. Reddy ◽  
R. G. Hoffmann
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Sprague Dawley ◽  
Vasoactive Agents ◽  
Sprague Dawley Rats ◽  
Pressor Responses

Pioglitazone (a thiazolidinedione derivative) increases insulin sensitivity and prevents hypertension in the Dahl-salt-sensitive (S) rat. The present study was undertaken to determine if pioglitazone modulates pressor responsiveness to vasoactive agents, both in vivo and in vitro. In vivo, pretreatment with pioglitazone inhibited (P < 0.02) pressor responses to both norepinephrine and angiotensin II in conscious Dahl-S, but not in Sprague-Dawley rats. In vitro, pioglitazone augmented the capacity of insulin to inhibit pressor responses of strips of thoracic aortas to norepinephrine, but not to angiotensin. Additionally, in vitro, incubation with insulin plus pioglitazone augmented acetylcholine-induced, but not nitroprusside-induced vasodilation. Pioglitazone pretreatment increased (P < 0.001) in vitro insulin-stimulated glucose uptake in adipose tissue, but not in thoracic aortas of Dahl-S. We hypothesize that pioglitazone attenuates hypertension by modulating the effects of insulin on vascular function, resulting in both blunted vasoconstriction and augmented acetylcholine-induced vasodilation. These alterations are not accounted for by an effect of pioglitazone on glucose uptake by vascular smooth muscle.

scholarly journals Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats

2018 ◽  
Vol 132 (14) ◽  
pp. 1513-1527 ◽  
Author(s):  
Alynne Carvalho-Galvão ◽  
Blessing Ogunlade ◽  
Jiaxi Xu ◽  
Cristiane R.A. Silva-Alves ◽  
Leônidas G. Mendes-Júnior ◽  
...  
Keyword(s):  
Vascular Function ◽  
Baroreflex Sensitivity ◽  
Vascular Reactivity ◽  
Mesenteric Arteries ◽  
Control Group ◽  
Ang Ii ◽  
Central Administration ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (AT1R), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT1R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg, P<0.05), sympathetic vasomotor activity (ΔMAP = −47.2 ± 2.8 compared with −64 ± 5.1 mmHg, P<0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg, P<0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside (SNP). In vitro, TRV027 prevented the Ang-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between AT1R and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the β-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones.

scholarly journals Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats

2016 ◽  
Vol 310 (11) ◽  
pp. L1088-L1097 ◽  
Author(s):  
C. M. Happé ◽  
M. A. de Raaf ◽  
N. Rol ◽  
I. Schalij ◽  
A. Vonk-Noordegraaf ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Endothelial Cell Proliferation ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
Sprague Dawley ◽  
Pulmonary Arterial ◽  
Severe Pulmonary Arterial Hypertension

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6. Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

A Novel Hemoglobin-Binding Agent Reduces Plasma Free Hemoglobin and Partially Improves Vascular Function In Murine Hemolytic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 267-267
Author(s):  
Nancy J. Wandersee ◽  
Timothy C. Flewelen ◽  
Anne C. Frei ◽  
Deron W. Jones ◽  
Dawn Retherford ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Function ◽  
Complex Disease ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Systolic Pressure ◽  
Free Hemoglobin ◽  
Ventricular Systolic Pressure ◽  
Vascular Bed

Abstract Abstract 267 Humans with sickle cell disease (SCD) and hereditary spherocytosis (HS) have been shown to have increased plasma free hemoglobin, vascular dysfunction, and pulmonary hypertension. Increased plasma free hemoglobin (Hb) levels are associated with multiple physiologic findings, including hemoglobinuria, increased blood pressure, platelet activation, and increased mortality. Previously, we showed that SCD and HS mice have impaired systemic vasodilation and mild pulmonary hypertension. Furthermore, there is evidence of increased plasma free hemoglobin and plasma oxidizing potential in mice with SCD and HS, and plasma oxidizing potential correlates with plasma free hemoglobin levels. We hypothesize that increased plasma free Hb impairs systemic vasodilation and increases pulmonary hypertension in SCD and HS mice. To test this hypothesis, we developed a peptide (hE-Hb-B10) that specifically binds human hemoglobin and removes it from the plasma via the heparan sulfate proteoglycan (HSPG)-associated lipoprotein pathway, rather than the haptoglobin-Hb-CD163 receptor pathway. SCD, HS, and control mice were treated with daily intraperitoneal (ip) injections of PBS or peptide hE-Hb-B10 dissolved in PBS (10-20 mg/mouse/day). At the end of three weeks of treatment, anesthetized mice were phlebotomized, as well as utilized for either ex vivo vasodilation studies using the facialis artery (a distal branch of the carotid artery) or assessment of right ventricular systolic pressure (RVsP) as a surrogate measure of pulmonary hypertension. In addition, plasma samples from the mice were analyzed for plasma free hemoglobin (PFH), lactate dehydrogenase (LDH, a marker of hemolysis), and oxidizing potential. PFH, LDH and oxidizing potential were significantly increased in the plasma of PBS-treated SCD and HS mice as compared with levels in control mice. Treatment with hE-Hb-B10 significantly reduced PFH levels in both SCD and HS mice compared to PFH levels in PBS-treated SCD and HS mice. In contrast, hE-Hb-B10 treatment did not reduce oxidizing potential in SCD and HS mice, suggesting that factors other than PFH contribute to the increased oxidizing potential of plasma in SCD and HS mice. hE-Hb-B10 treatment did not alter hematocrit, reticulocyte count, or plasma LDH levels in SCD and HS mice, suggesting that the overall hemolytic rate was unaltered by peptide treatment. Plasma from control mice had low levels of PFH, LDH and oxidizing potential; these levels did not change with hE-Hb-B10 treatment. Finally, facialis artery vasodilation in response to acetylcholine was significantly improved in hE-Hb-B10 treated as compared to PBS-treated SCD and HS mice. However, pulmonary hypertension, as measured by RVsP, in SCD mice was not altered by treatment with hE-Hb-B10, while hE-Hb-B10-treated HS mice showed mild improvement. These data demonstrate that hE-Hb-B10 effectively reduces plasma free hemoglobin in SCD and HS mice. Although reducing PFH improves vascular function in a systemic vascular bed (facialis artery), we found minimal beneficial effects in the pulmonary vascular bed (as measured by RVsP). Our findings confirm that the mechanisms impairing vascular function in SCD and HS are complex, and suggest that targeting only one mechanism (i.e., plasma free Hb) may be insufficient to achieve notable improvements in vascular function in these complex disease states. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses

2014 ◽  
Vol 306 (2) ◽  
pp. C143-C151 ◽  
Author(s):  
Subha Bhaskaran ◽  
Jeremy Zaluski ◽  
Amy Banes-Berceli
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Ex Vivo ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Contractile Responses ◽  
Endothelin 1

Elevated levels of serotonin (5-HT) and endothelin-1 (ET-1) may be involved in cardiovascular complications of diabetes mellitus. Data suggest supraphysiological concentrations of 5-HT (10−6 M) potentiate the ability of ET-1 to stimulate DNA synthesis and vascular smooth muscle cell (VSMC) proliferation in vitro via activation of mitogen-activated protein kinase (p42/44 MAPK) and Janus kinase 2 (JAK2) pathways. Additionally, 5-HT enhances agonist-induced contractions via p42/44 MAPK and an unknown tyrosine kinase. However, the exact mechanisms of the 5-HT/ET-1 interactions and whether these effects occur at physiological levels (10−9 M) are unknown. Therefore, we hypothesized that interactions between 5-HT and ET-1 at physiological concentrations in VSMC enhanced activation of both p42/44 MAPK and JAK2 pathways contributing to vascular growth and contractile responses. With the use of rat VSMC and Western blot analysis, our data suggest no effect of acute (30 min) preincubation with 5-HT (10−9 M) and/or ET-1 (10−9 M) on the activation of either pathway in normal or high glucose conditions. To determine if there was altered vascular reactivity in intact vessels we tested the effects of 5-HT and ET-1 interaction using myographs to measure isometric contractions of rat thoracic aortic rings. 5-HT (10−9 M) and ET-1 (10−12 M) stimulate enhanced contractile responses to each other that were inhibited by JAK2 and p42/44 MAPK antagonists. Our findings demonstrate that both 5-HT and ET-1 at physiological concentrations could interact with each other and activate p42/44 MAPK and JAK2 signaling pathways to cause an increase in smooth muscle contraction that could lead to altered vascular function.

scholarly journals Food Restriction Augmented Alpha1 Adrenergic Mediated Contraction in Mesenteric Arteries

2021 ◽  
Author(s):  
Rany Vorn ◽  
Hae Young Yoo
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Vascular Function ◽  
Food Restriction ◽  
Vascular Reactivity ◽  
Hypovolemic Shock ◽  
Mesenteric Arteries ◽  
Sprague Dawley ◽  
Underlying Mechanisms ◽  
Endothelial Nitric Oxide

Food restriction (FR) enhances the sensitivity to cardiopulmonary reflexes and alpha1 adrenoreceptors in the female, despite hypotension. The effect of male FR on cardiopulmonary and systemic vascular function is not well understood. This study examines the effects of FR on cardiopulmonary, isolated mesenteric arterial function and potential underlying mechanisms. We hypothesized that FR decreased eNOS activity in mesenteric arteries. Male Sprague Dawley (SD) rats were randomly divided into three groups: (1) control (n=30), (2) 20 percent of food reduction (FR20, n=30), and (3) 40 percent of food reduction (FR40, n=30) for five weeks. Non-invasive blood pressure was measured twice a week. Pulmonary arterial pressure (PAP) was measured using isolated/perfused lungs in rats. The isolated vascular reactivity was assessed in double-wire myograph. After five weeks, food restricted rats exhibited a lower mean arterial pressure and heart rate, however, only FR40 groups exhibited statistically significant differences. The basal tone of PAP and various vasoconstrictors did not show significant differences in pulmonary circulation between each group. We observed that food restriction were enhanced the sensitivity (EC50) in response to α1-adrenoreceptors (phenylephrine, PhE)-induced vasoconstriction, but not to serotonin, U46619, and high K+ in the mesenteric arteries. FR reduced endothelium-dependent relaxation via decreased function of endothelial nitric oxide synthase (eNOS)-nitric oxide (NO) pathway in the mesenteric arteries. PhE-mediated vasoconstriction in mesenteric arteries was eliminated in the presence of eNOS inhibitor (L-NAME). In addition, incubation with NOX2/4 inhibitors (apocynin, GKT137831, VAS2870) and reactive oxygen species (ROS) scavenger inhibitor (Tiron) were eliminated the differences of PhE-mediated vasoconstriction but not to cyclooxygenase inhibitor (indomethacin) in the mesenteric artery. Augmentation of alpha1 adrenergic mediated contraction via inhibition of eNOS-NO pathway by increased activation of ROS through NOX2/4 in response to FR. Reduced eNOS-NO signaling might be a pathophysiological counterbalance to prevent hypovolemic shock in response to FR.

scholarly journals Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 155
Author(s):  
Daniel Morales-Cano ◽  
Bianca Barreira ◽  
Beatriz De Olaiz Navarro ◽  
María Callejo ◽  
Gema Mondejar-Parreño ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Gas Exchange ◽  
Pulmonary Circulation ◽  
Pulmonary Arteries ◽  
Blood Perfusion ◽  
Mesenteric Arteries ◽  
Oxygen Sensitivity ◽  
Low Oxygen ◽  
Oxygen Selectivity

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

scholarly journals Endothelial dysfunction precedes hypertension in diet-induced insulin resistance

1998 ◽  
Vol 275 (3) ◽  
pp. R788-R792 ◽  
Author(s):  
Prasad V. G. Katakam ◽  
Michael R. Ujhelyi ◽  
Margarethe E. Hoenig ◽  
Allison Winecoff Miller
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Serum Insulin ◽  
Serum Glucose ◽  
Mesenteric Arteries ◽  
Control Group ◽  
Sprague Dawley ◽  
Insulin Resistant ◽  
Glucose Levels

The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined (in vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (∼250 μM). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by day 14 [mean percent maximal relaxation (Emax): 69 ± 10% of baseline] and becomes significant by day 18 (Emax: 52 ± 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 ± 1 ( day 28) vs. 116 ± 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.

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