Thromboxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats.

Stier, Charles T.; Benter, İbrahim F.; Levine, Seymour

doi:10.1161/01.str.19.9.1145

Cited by 26 publications

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“…Histological examination revealed evidence of cerebrovascular lesions in all except one of the brains from control SHRSP. As previously observed, 21 these lesions included hematomas, hemorrhagic and anemic infarcts, edema and rarefaction of the cerebral cortex, and fibrinoid necrosis of vessels. There was no evidence of any of these lesions in the brains of enalapril-treated SHRSP.…”

Section: Analysessupporting

confidence: 78%

“…21 Despite lowering blood pressure by 15 to 29 mm Hg at 10 and 11 weeks of age during TXA 2 synthase inhibition, there was no effect on mortality; 70% of the animals with or without treatment died by 14 weeks of age. The ability of TXA 2 synthase inhibition to lower blood pressure without affecting mortality suggests that factors in addition to blood pressure may be important in causing stroke in these rats.…”

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confidence: 96%

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Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

et al. 1989

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The influence of chronic treatment with the angiotensin I converting enzyme (ACE) inhibitor enalapril on blood pressure, kidney function, and survival was examined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed a Japanese rat chow plus a 1% NaCl drinking solution beginning at 7-8 weeks of age developed severe hypertension and stroke; 14 of 18 untreated control SHRSP died by 14 weeks of age and exhibited evidence of cerebrovascular lesions. When enalapril (15 mg/kg/day) was included in the drinking solution of 15 SHRSP, blood pressure was initially reduced by only a slight degree, whereas survival unproved markedly; only one of 10 SHRSP died before the rest were killed at 18 to 21 weeks. The remaining five enalapril-treated SHRSP lived beyond 36 weeks and on histological examination exhibited no evidence of cerebrovascular lesions. Chronic enalapril treatment also prevented the greater urinary excretion of protein and severe renal lesions observed in untreated SHRSP but did not affect urinary salt and water excretion. In anesthetized rats, glomerular filtration rate and tubular reabsorption of water were lower hi untreated control SHRSP when compared with enalapril-treated SHRSP. Mean arterial pressure was comparable in both groups. These data support a possible role for ACE inhibition in the prevention of stroke and maintenance of kidney function independent of any marked change in blood pressure of SHRSP. Whether the protective effects of ACE inhibition relate to reduced angiotensin H formation, increased tissue kinins, or another mechanism remains to be determined. {Hyper-tension 1989;13:115-121) I n 1974 Okamoto and coworkers 1 reported the development of a stroke-prone substrain of the spontaneously hypertensive rat (SHRSP). These animals developed severe hypertension and a high incidence (80%) of cerebrovascular hemorrhage or infarction after 15 weeks of age. The pial arteries of SHRSP showed cellular hyperplasia or proliferation of adventitial cells and fibrinoid necrosis, 1 which resulted in microinfarction. 2 Parenchymal brain lesions were noted that were thought to be the result of vascular leakage.34 Similar abnormalities were observed in the microvasculature of the heart, kidney, and other organs. SHRSP From the Departments of Pharmacology, Pathology, and Medicine, New York Medical College, Valhalla, New York.Portions of this work were previously published in abstract form (FedProc 1987 ;46:1290).Supported by Grant HL-35522 (to C.T.S.) from the National Institutes of Health, Bethesda, Maryland.Address for reprints: Charles T. Stier Jr., PhD, Department of Pharmacology, Basic Science Building, New York Medical College, Valhalla, NY 10595.Received February 5, 1988; accepted October 14, 1988. fed a Japanese rat chow exhibited a higher incidence of stroke than SHRSP fed an American rat chow (88% vs. 30% by 9 months of age). 5 Elevation of sodium intake (by replacing normal drinking water with a 1% NaCl solution) also increased blood pressure and accelerated the onset ...

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Section: Analysessupporting

confidence: 78%

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confidence: 96%

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

et al. 1989

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“…ACE inhibition 15,21 and dietary potassium administration, 22 with no or only a small reduction in blood pressure, substantially prolonged survival in salt-loaded SHRSP. In contrast, a thromboxane A 2 synthase inhibitor, 23 hydralazine, and diuretics, 24 which all reduced blood pressure, did not prevent cerebral edema or significantly prolong survival.…”

Section: Early Therapymentioning

confidence: 90%

Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats

et al. 1999

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Abstract-The ability of endothelin receptor blockade to prevent and to treat established cerebral and renal injury was explored in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist A127722. SHRSP were subjected to 1% NaCl intake. The start of treatment with A127722 (35 and 70 mg ⅐ kg, respectively) was either synchronized with salt loading or initiated after the first observation of cerebral edema with T 2 -weighted magnetic resonance imaging. In untreated control animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset A127722 treatment increased median survival to 233 days (range, 92 to 407 days; PϽ0.05 versus controls) with 35 mg/kg and to 124 days (range, 97 to 169 days; PϽ0.05 versus control) with 70 mg/kg. The development of cerebral edema was prevented, and systolic blood pressure and proteinuria were dose-dependently reduced. However, all rats in the 70-mg/kg treatment group developed hemorrhages in the basal ganglia shortly before death. Late-onset A127722 treatment failed to affect survival, systolic blood pressure, or proteinuria. Nevertheless, cerebral edema was reduced but not as well as in early-onset treatment. Development of hypertension, cerebral edema, and proteinuria was prevented in SHRSP when A127722 treatment was initiated at the start of salt-loading. However, A127722 treatment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the development of increased blood pressure and initiation of organ damage but participates minimally in established malignant hypertension and progression of target-organ damage. (Hypertension. 1999;33:137-144.) Key Words: edema, cerebral Ⅲ rats, inbred strains Ⅲ magnetic resonance imaging Ⅲ endothelin Ⅲ receptors, endothelin Ⅲ proteinuria R ecently, endothelin (ET) receptor blockers have been advanced as possible antihypertensive drugs. 1 It has been suggested that ET blockers may be particularly beneficial in modulating target-organ damage because of their antiproliferative actions. 2 The predominant ET receptor expressed in vascular smooth muscle cells is the ET A subtype that is mainly responsible for the vasoconstrictor 3 and mitogenic 4 effects of ET-1. ET receptor blockade has proven to be effective in ameliorating the development of hypertension and renal damage in chronic rat models, including renal failure, 5 nitric oxide synthase inhibition, 6 deoxycorticosterone acetate-salt treatment, 7 deoxycorticosterone acetatesalt-treated spontaneously hypertensive rat (SHR), 8 and in stroke-prone SHR (SHRSP) with or without salt treatment, 9 but therapeutic effects on manifest target-organ damage, such as cerebral edema and renal injury, have not yet been reported.To explore the role of ET-1 in severe hypertension and related target-organ damage, we used the salt-loaded SHRSP, 10 a model in which we found consecutive development of hypertension, proteinuria, and cerebral e...

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“…6). Although we previously found that chronic administration of the selective TSI UK-38,485 (dazmegrel) to saline-drinking SHRSP was associated with a slight reduction in systolic blood pressure, this also did not protect against stroke (63,64). Thus, agents that inhibit either the action or the formation of TxA 2 do not exhibit anti-stroke activity in these rats.…”

Section: Strokementioning

confidence: 93%

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

Rosenfeld

Grover

Stier

2001

Cardiovascular Drug Reviews

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This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A 2 /prostaglandin H 2 receptor antagonist. Thromboxane A 2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A 2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A 2 levels in blood, urine, and tissues. The precursors to thromboxane A 2 , prostaglandin G 2 , and prostaglandin H 2 , also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A 2 /prostaglandin H 2 , rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A 2 -and prostaglandin H 2 -mediated processes.

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Thromboxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats.

Cited by 26 publications

References 26 publications

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats

Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist

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Thromboxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats.

Cited by 26 publications

References 26 publications

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats

Ifetroban Sodium: An Effective TxA2/PGH2 Receptor Antagonist

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Ifetroban Sodium: An Effective TxA₂/PGH₂ Receptor Antagonist