15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Peripheral-Vascular-Diseases

A low-protein diet (LPD) during pregnancy induces vascular dysfunction and hypertension in the offspring, prevented by administration of an angiotensin II type 1 (AT(1)) receptor antagonist in early life to the offspring. Whether such protection extends to subsequent pregnancy is unknown; we therefore hypothesized that administration of a specific AT(1) receptor antagonist (losartan) in early life to offspring of LPD dams would improve vascular dysfunction in their uterine arteries when they, in turn, were pregnant.. Pregnant rats were randomly divided into two dietary groups fed a control (C) or protein-restricted (R) diet throughout pregnancy. Between two and 10 weeks postnatally, female offspring (F(1)) were randomly assigned to drink either pure tap water (CO, RO) or water with losartan (CL, RL). Offspring were mated and killed on gestational day 19 or 20 in order to investigate uterine artery function.. In pregnant offspring, vasoconstriction of the uterine arteries to phenylephrine (PE) and the thromboxane A2 mimetic U46619 was greater in RO than CO (F(1)). Responses to both antagonists were suppressed in RL (F(1)). Relaxation to sodium nitroprusside was increased in RO versus CO and suppressed in RL versus RO (F(1)).. Administration of an AT(1) receptor antagonist to offspring during the suckling and juvenile period improves the uterine vascular dysfunction in pregnancy induced by prior maternal LPD during their development. Such treatment may contribute to decreasing the transmitted risks of maternal malnutrition from offspring to the subsequent generation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II Type 1 Receptor Blockers; Animals; Diet, Protein-Restricted; Female; Hypertension; Losartan; Nitroprusside; Peripheral Vascular Diseases; Phenylephrine; Pregnancy; Pregnancy Complications, Cardiovascular; Random Allocation; Rats; Rats, Wistar; Uterine Artery; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The metabolic syndrome is associated with elevated peripheral vascular disease risk, characterized by mismatched blood flow delivery/distribution and local metabolism. The obese Zucker rat (OZR) model of the metabolic syndrome exhibits myriad vascular impairments, although their integrated impact on functional hyperaemia remains unclear. In this study, arterial pressor responses and skeletal muscle perfusion were assessed in lean Zucker rats (LZRs) and OZRs during adrenergic stimulation (phenylephrine), challenge with thromboxane (U46619) and endothelium-dependent dilatation (methacholine). The OZRs were hypertensive compared with the LZRs, but this was abolished by adrenoreceptor blockade (phentolamine); pressor responses to U46619 were similar between strains and were abolished by blockade with the prostaglandin H(2)/thromboxane A(2) receptor antagonist, SQ-29548. Depressor reactivity to methacholine was impaired in OZRs, but was improved by antioxidant treatment (TEMPOL). Across levels of metabolic demand, blood flow to in situ gastrocnemius muscle was restrained by adrenergic constriction in OZRs, although this diminished with increased demand. Oxygen extraction, reduced in OZRs compared with LZRs across levels of metabolic demand, was improved by TEMPOL or SQ-29548; treatment with phentolamine did not impact extraction, and neither TEMPOL nor SQ-29548 improved muscle blood flow in OZRs. While oxygen uptake and muscle performance were consistently reduced in OZRs versus LZRs, treatment with all three agents improved outcomes, while treatment with individual agents was less effective. These results suggest that contributions of vascular dysfunction to perfusion, oxygen uptake and muscle performance are spatially distinct, with adrenergic constriction impacting proximal resistance and endothelial dysfunction impacting distal microvessel-tissue exchange. Further, these data suggest that increasing skeletal muscle blood flow in OZRs is not sufficient to improve performance, unless distal perfusion inhomogeneities are rectified.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antioxidants; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hyperemia; Hypertension; In Vitro Techniques; Male; Metabolic Syndrome; Methacholine Chloride; Muscle Fatigue; Muscle, Skeletal; Obesity; Oxygen; Perfusion; Peripheral Vascular Diseases; Phenylephrine; Rats; Rats, Zucker; Vasoconstriction

Highly active antiretroviral therapy (HAART) including HIV protease inhibitor ritonavir may be associated with the clinical complications including accelerated atherosclerosis and pulmonary artery hypertension. The objective of this study was to determine whether capsaicin, a major ingredient of hot pepper with antioxidative property, could effectively inhibit ritonavir-induced oxidative injury in porcine pulmonary arteries.. Fresh porcine pulmonary artery rings were treated with ritonavir (15 microM), capsaicin (50 microM) or both for 24 hours and, then, subjected to myograph analysis in response to vasoactive drugs including thromboxane A2 analog U-46619, bradykinin, and sodium nitroprusside (SNP).. In response to U-46619 (3x10(-8) M), ritonavir-treated porcine pulmonary artery rings reduced the contraction by 15% compared with control rings. In response to bradykinin (10(-6) M), ritonavir-treated rings showed a significant reduction of endothelium-dependent vasorelaxation by 32% compared with untreated control vessels (P<0.05, n=5, Student t-test). However, ritonavir treatment did not change endothelium-independent vasorelaxation in response to SNP (10(-6) M). Capsaicin-treated vessel rings did not show any significant changes in response to U-46619, bradykinin, and SNP compared with untreated control vessels. More importantly, capsaicin co-cultured with ritonavir significantly blocked ritonavir-induced inhibition of endothelium-dependent vasorelaxation and contraction compared with ritonavir alone treatment in porcine pulmonary artery rings (P<0.05, n=5, Student t-test).. Capsaicin effectively inhibits the detrimental effects of HIV protease inhibitor ritonavir on vasomotor functions of porcine pulmonary arteries. These findings may suggest that capsaicin could have clinical applications to prevent vascular and pulmonary complications of HAART drugs in HIV patients.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Antiretroviral Therapy, Highly Active; Bradykinin; Capsaicin; Electromyography; Nitroprusside; Peripheral Vascular Diseases; Pulmonary Artery; Ritonavir; Swine; Vasodilation

This study was carried out to determine whether early failure of infrainguinal bypass grafts is associated with increased expression of platelet thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors. A prospective correlation of preoperative platelet TXA2/PGH2 receptor-mediated activity with lower extremity graft patency was sought.. Twenty-five patients who underwent infrainguinal bypass surgery for limb salvage were studied at an inpatient academic tertiary referral center and Department of Veterans Affairs Medical Center. Outcome measures were primary graft patency rate at 3 months, platelet TXA2/PGH2 receptor activity by equilibrium binding with 125I-BOP, and aggregation to the TXA2-mimetic U46619.. Preoperative platelet TXA2/PGH2 receptor density was higher (Bmax, 3100 +/- 1300 vs 1500 +/- 1100 sites/platelet [mean +/- SD]; p = 0.004) in the five patients who had graft thrombosis within 3 months. The EC50 for U46619 was lower (26 +/- 6 nmol/L vs 57 +/- 30 nmol/L; p < 0.05) in these patients as well, confirming the functional effect of the increased receptor density. Early graft thrombosis was more likely in patients with a platelet TXA2/PGH2 receptor density greater than 3000 sites/platelet (odds ratio, 76; 95% confidence interval, 3.9 to 1500) or an EC50 for U46619 less than 30 nmol/L (odds ratio, 16; 95% confidence interval, 1.4 to 180).. Elevated platelet TXA2/PGH2 receptor levels and enhanced sensitivity of platelet aggregation to TXA2 predict early arterial graft thrombosis. Specific TXA2/PGH2 receptor antagonism may prevent one of the mechanisms that contributes to early graft occlusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Blood Platelets; Female; Graft Occlusion, Vascular; Humans; Male; Peripheral Vascular Diseases; Platelet Aggregation; Prospective Studies; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thrombosis; Vascular Patency