15-hydroperoxy-5-8-11-13-eicosatetraenoic-acid and Hypertension

Acute, severe increases in arterial blood pressure cause sustained cerebral arteriolar dilation, abnormal reactivity to carbon dioxide and to changes in blood pressure, abolition of endothelium-dependent dilation from acetylcholine, discrete morphological lesions of the endothelium and vascular smooth muscle, and breakdown of the blood-brain barrier to plasma proteins. The dilation, abnormal reactivity, and morphological abnormalities are inhibited by pretreatment with cyclooxygenase inhibitors or with free radical scavengers. Superoxide dismutase-inhibitable reduction of nitroblue tetrazolium applied to the brain surface was detectable both during hypertension and one hour after hypertension subsided. Nitroblue tetrazolium reduction is also reduced by inhibitors of the anion channel. The abnormalities seen after hypertension are reproduced by topical application of arachidonate. The results are consistent with the view that acute hypertension induces generation of superoxide anion radical in association with accelerated arachidonate metabolism via cyclooxygenase. This radical enters cerebral extracellular space via the anion channel and gives rise to hydrogen peroxide and hydroxyl radical. All three radicals are capable of causing vasodilation by relaxation of cerebral vascular smooth muscle. The hydroxyl radical is the most likely candidate for vascular wall damage. The significance of this mechanism in chronic experimental hypertension or its relevance to human disease is not known.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arterioles; Blood Proteins; Blood-Brain Barrier; Bradykinin; Brain; Brain Injuries; Cardiovascular Agents; Catalase; Cerebrovascular Circulation; Cerebrovascular Disorders; Cyclooxygenase Inhibitors; Endothelium; Free Radicals; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; Hypertension; Leukocytes; Leukotrienes; Lipid Peroxides; Muscle, Smooth, Vascular; Peroxidases; Prostaglandin-Endoperoxide Synthases; Prostaglandins G; Superoxide Dismutase; Superoxides; Vasodilation; Xanthine Oxidase

Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Brain; Epoprostenol; Free Radical Scavengers; Hypertension; Kidney; Leukotrienes; Lipid Peroxidation; Lipid Peroxides; Pyridines; Rats; Rats, Inbred Strains; Sodium, Dietary; Xanthine; Xanthine Oxidase; Xanthines

The effects of topical application of agents which produce oxygen radicals on cerebral arterioles were studied in anesthetized cats. Xanthine oxidase plus xanthine, which produced superoxide anion radical, hydrogen peroxide, and hydrogen peroxide plus ferrous sulfate, which produced the free hydroxyl radical, induced sustained dilation, reduced responsiveness to the vasoconstrictor effect of hypocapnia, and destructive lesions of the endothelium and of the vascular smooth muscle. Similar effects were produced by arachidonate, 15-HPETE, and PGG2. The effect of arachidonate was inhibited by mannitol, a free hydroxyl radical scavenger, the effect of PGG2 was inhibited by SOD, the effect of 15-HPETE was inhibited by either catalase or SOD. These results suggest that these cerebral vascular abnormalities were produced by a single destructive free radical, probably the hydroxyl free radical, generated via interaction of superoxide and hydrogen peroxide. Cerebral vascular abnormalities similar to those produced by oxygen radicals were also seen after experimental concussive brain injury or after acute hypertension. After brain injury, activation of phospholipase C and increased brain prostaglandin concentration were demonstrated. The vascular effects of brain injury and acute hypertension were inhibited by free radical scavengers. The results suggest that, in these conditions, vascular damage is induced by oxygen radicals generated from arachidonate in association with increased prostaglandin synthesis.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain Injuries; Cats; Cattle; Cerebral Arteries; Free Radicals; Hypertension; Leukotrienes; Lipid Peroxides; Muscle, Smooth, Vascular; Oxygen Consumption; Rabbits; Sarcoplasmic Reticulum; Vasomotor System; Xanthine Oxidase