The incidence of vasculitis is increased in female stroke-prone hypertensive rats compared to males

Background: Vascular changes in hypertension share common characteristics with inflammatory wall injury. Since it is known that chronic inflammatory diseases are frequently more prevalent in females, this study tested the hypothesis that vasculitis would be more evident in female stroke-prone spontaneously hypertensive rats (SHRSP) than in males.Methods: Arterial lesions were characterized in the gastrointestinal tract of necropsied SHRSP and normotensive Wistar-Kyoto rats (WKY). Systolic blood pressure was measured using the tail cuff method.Results: Vasculitis was present in 54% of SHRSP (n=357). None of the WKY rats had the vascular disease (n=373). Arterial lesions were not evident in young SHRSP (1-1.5 months of age) before the development of high blood pressure. The earliest appearance of vasculitis in SHRSP was at ~8 months of age after full establishment of elevated arterial pressure. Systolic blood pressures during the maintained phase were greater than 200mmHg for SHRSP and less than 130mmHg for WKY rats (ages: 8-18 months). Within SHRSP, lesions were more common in females, in spite of higher mean systolic pressure found in males (both p<0.05). Of the female SHRSP, 70% (n=234) had severe micronodular vasculitis whereas 24% of male SHRSP showed lesions (age matched).Conclusion: These observations indicate that in SHRSP: 1) inflammatory responses in arteries occur with greater incidence compared to WKY rats; 2) there is a relationship between incidence of vascular lesions and age, but not elevated arterial pressure; and 3) there is a higher incidence of vasculitic lesions in females compared to males.Keywords: Vasculitis, Stroke-prone, SHR, WKY, Blood pressure, Hypertensio

The Role of Uridine Adenosine Tetraphosphate in the Vascular System

The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up4A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up4A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up4A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up4A on vascular function and a potential role for Up4A in cardiovascular diseases

L-arginase induces vascular dysfunction in old spontaneously hypertensive rats

Background: Aging is a major non-modifiable risk factor for hypertension. Changes in aging are similar to those seen in hypertension in the vasculature. Also, aging increases the vascular dysfunction that occurs in hypertension. L-arginase action reduces substrate (L-arginine) availability for the formation of nitric oxide (NO). This reduces the level of NO and leads to reduced vasodilation and ultimately, vascular dysfunction. This study examines the hypothesis that age-dependent vascular dysfunction in SHRs is mediated by arginase.Methods: Young (12-14 weeks) and old (11-12 months) male Wistar and spontaneously hypertensive rats (SHR) were used. Mean arterial pressure (MAP) was measured in the rats. They were then euthanized and mesenteric resistance arteries (MRAs) and thoracic aortae were excised and placed in ice-cold physiological salt solution (PSS). Arterial segments were either snap-frozen in liquid nitrogen and stored for immunoblotting studies or cut into 2mm rings for reactivity studies. Cumulative concentration-response curves to acetylcholine (Ach; 10-9 – 3x10-5M) and sodium nitroprusside (SNP; 10-12 – 3x10-5 M) were performed in the absence or presence (30-minute exposure) of L-arginase, 0.05U/ML (MRA) or 0.5U/ML (aorta). Vessels were pre-contracted with phenylephrine (PE; 3x10-6M)Results: MAP increased during aging in the SHRs p<0.05 but not in the Wistar rats. Arginase impaired the endothelium-dependent relaxation responses of thoracic aortic and MRA arterial rings to Ach in the old Wistars and SHRs (Emax aorta: 29.42±2.19% vs 7.94±1.86%). Arginase also impaired endothelium-independent relaxation response to SNP in the old SHRs only (Emax aorta: 88.62±4.10% vs 31.45±10.61%). We also observed no differences in the serum arginase activity in the four groups of rats. On the contrary, arginase activity in the aortae of young Wistar rats was reduced compared to other groups.Conclusions: Arginase impairs both endothelium-dependent and –independent vasorelaxation responses, through the NO signaling pathway.Keywords: Hypertension, Arginase, aging, vascular dysfunction, endothelium, Nitric oxid

Cyclosporine augments reactivity of isolated blood vessels

Administration of cyclosporine (CS) as an immunosuppressive agent in clinical transplantation is associated with multiple side effects including nephrotoxicity and hypertension. These two effects could be related in that the renal changes may be secondary to alterations in organ blood flow. The present studies investigate the ability of CS to augment contractile responsiveness in blood vessels from normotensive rats. Isometric force generation was measured in isolated tail arteries and portal veins. CS (8.3 x 10-6M) potentiated tail artery contractile responses to sympathetic nerve stimulation, exogenous norepinephrine, and increases in extracellular potassium concentration. Portal veins undergo spontaneous contractions which are related to the firing of calcium-driven action potentials in the smooth muscle cells. CS significantly increased the frequency of these spontaneous contractile events. These results suggest that components of CS toxicity may involve a direct action on vascular smooth muscle and/or on vascular adrenergic neurotransmission.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26675/1/0000219.pd

Effect of cooling on vascular smooth muscle from the thirteen-lined ground squirrel

Peripheral vascular resistance in the ground squirrel (Spermophilus tridecemlineatus) increases when the animal enters hibernation. The goals of this study were (1) to determine if a change in vascular reactivity contributes to this hemodynamic response, and (2) to compare the effects of temperature on vascular responsiveness in a hibernator (ground squirrel) and a nonhibernating mammal (rat). Helically cut strips of aortae and femoral arteries were mounted in organ chambers (37 [deg]C) and isometric contractions were recorded. The arteries were made to contract in response to exogenous norepinephrine (5.9 x 10- 7 M). Cooling the organ chamber (11 [deg]C) potentiated contractions to norepinephrine (5-15% increase) in ground squirrel femoral arteries but depressed those (80-100% decrease) in ground squirrel aortae and rat aortae and femoral arteries. Contractions in response to depolarizing concentrations of potassium in ground squirrel femoral arteries were depressed by cooling (11 [deg]C), suggesting that the augmented response to norepinephrine at low temperature is specific. Treatment with indomethacin, propanolol, and ouabain did not alter the potentiating effect of temperature on contractions to norepinephrine in ground squirrel femoral arteries. Apparently, the potentiation is not related to prostaglandins generated in the vascular wall, to blockade of [beta]-adrenergic receptors, nor to inhibition of the electrogenic sodium pump. The observations are consistent with the hypothesis that a change in vascular responsiveness contributes to the regional control of blood flow in hibernation. This adaptive response is specific in that it does not occur in the aorta of the ground squirrel and the response is not present in the vasculature of the rat, a nonhibernating mammal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26819/1/0000377.pd

Characterization of o,p'-DDT-stimulated contraction frequency in rat uterus in vitro

Exposure to organochlorine pesticides, including DDT, has previously been associated with premature birth. Using an improved protocol to characterize dose and time dependent responses, the present report extends a preliminary finding by this laboratory that o,p'-DDT directly stimulates uterine contractility. Contraction frequency was determined in longitudinal uterine strips from pregnant rats under isometric force conditions. Following equilibration, the uterine strips were monitored for a 1-hr baseline period, then treated with o,p'-DDT or ethanol (solvent control) for 3 hr, followed by 3 hr without test substance. During exposure to 100 [mu] o,p'-DDT, the frequency of contraction significantly increased by 66% relative to matched controls. After removal of o,p'-DDT from the medium, the frequency of contraction continued to increase in uterine strips exposed to 50 and 100 [mu] o,p'-DDT. A dose effect was clearly observed during the post-treatment period, with 50 and 100 [mu] o,p'-DDT significantly increasing contraction frequency by 39 and 104% relative to controls. No significant differences in contraction frequency were observed with 10 [mu] o,p'-DDT during any test period. These data show that o,p'-DDT directly stimulated isometric contractions in rat uterine strips.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29112/1/0000150.pd

Long-term effects of brief antihypertensive treatment on systolic blood pressure and vascular reactivity in young genetically hypertensive rats

Recent studies have shown that angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR) reduces blood pressure into adulthood. This study explored changes in vascular reactivity in adult normotensive (WKY) rats and stroke-prone SHR (SHRSP) receiving the following treatments at 6–10 weeks of age: (a) ACE inhibitor (ramipril); (b) hydralazine/hydrochlorothiazide (hydral/HCTZ); or (c) no treatment. The hypothesis tested was that vascular changes and blood pressure would be reduced in adult SHRSP treated with ramipril during development. At 17 weeks of age, rats were anesthetized and vascular tissue was excised. Isolated experiments in the aorta included characterization of initial phasic and tonic contractions to 0.1 µM angiotensin II (AII). A phenylephrine (PE) concentration-response curve was performed on carotid arteries, and threshold values were determined. All WKY groups showed lower systolic blood pressure (131±4 mmHg) and reduced phasic AII induced contraction (7.4±4.7%) compared with SHRSP (217±4 mmHg; 37.2±4%). Antihypertensive treatment reduced blood pressure (ramipril: 168±2; hydral/HCTZ: 198±6 mmHg) but not phasic AII responses in adult SHRSP; adult WKY rats were unaffected by treatment. Threshold values for PE in carotid arteries were lower in SHRSP than in WKY, indicating increased sensitivity. However, SHRSP treated with ramipril did not demonstrate increased sensitivity to PE. These data support the hypothesis that blood pressure and sensitivity to PE but not contractile responsiveness to AII in adult SHRSP are determined by an AII-sensitive mechanism during development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44642/1/10557_2004_Article_BF00879031.pd