Abstract: Premature vascular senescence is reversed or prevented in tissue or cells by contacting the tissue or cells with a hydroxyguanidine. This finds application in treatment of patients with a disorder associated with elevated levels of advanced glycation end products in blood or tissue, e.g., patients with end stage renal disease or poorly controlled diabetes, and in contacting vascular tissue or cells ex vivo to prevent occurrence of premature senescence.

Abstract: A patient with a disorder involving endothelial dysfunction associated with deficient nitric oxide bioactivity, e.g., coronary artery disease, atherosclerosis, hypertension, diabetes or neurodegenerative condition stemming from ischemia and/or inflammation, is treated by administering nitric oxide bioactivity increasing hydroxyguanidine.

Abstract: A patient with a disorder involving endothelial dysfunction associated with deficient nitric oxide bioactivity, e.g., coronary artery disease, atherosclerosis, hypertension, diabetes or neurodegenerative condition stemming from ischemia and/or inflammation, is treated by administering nitric oxide bioactivity increasing hydroxyguanidine.

Abstract: Premature vascular senescence is reversed or prevented in tissue or cells by contacting the tissue or cells with a hydroxyguanidine. This finds application in treatment of patients with a disorder associated with elevated levels of advanced glycation end products in blood or tissue, e.g., patients with end stage renal disease or poorly controlled diabetes, and in contacting vascular tissue or cells ex vivo to prevent occurrence of premature senescence.

Abstract: Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonist are administered to inhibit nitric oxide synthesis from arginine in vascular smooth muscle cells in a subject in need of such inhibition (e.g. for prophylactic or curative effect for cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension).

Abstract: Paraquat has been found to accept electrons from nitric oxide synthase (NOS) whereupon the reduced paraquat generates toxic O2− and prevents NOS from giving electrons to arginine and thereby inhibits NO production. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds inhibit nitric oxide synthase and kill cells including NOS by generating O2− and also by depriving the cells of the NO which they need. Applications include treating paraquat-induced injury and pathologically proliferating cells (tumors, restenosis benign prostatic hypertrophy, pulmonary hypertension, infective pathogens).

Abstract: Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.

Abstract: Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.

Abstract: Guanosine triphosphate pathway tetrahydrobiopterin synthesis antagonist and/or pterin salvage pathway tetrahydrobiopterin synthesis antagonists are administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylactic or curative effect for endotoxin- or cytokine-induced hypotension or for restoration of vascular contractile sensitivity to pressor agents in the treatment of such hypotension). The tetrahydrobiopterin synthesis antagonist may be administered with .alpha..sub.1 -adrenergic agonist or with nitric oxide synthase inhibitor. The tetrahydrobiopterin synthesis antagonists are also administered to attenuate inflammation caused by induced nitric oxide production in immune cells. Unwanted counterproductive or side effects can be eliminated or ameliorated by administration additionally of levodopa with or without carbidopa and L-5-hydroxytryptophane.

Abstract: Inhibitor of the use of tetrahydrobiopterin as a cofactor for nitric oxide synthase, e.g., substituted 4-phenyl(hydropyridines) such as 1-methyl-4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine or, 4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine) or tetrahydropterin analog which does not replace tetrahydrobiopterin as a substrate for nitric oxide synthase such as (6R,S)-6,7-dimethyl-tetrahydropterin or (6R,S)-tetrahydrofolic acid or 2,4-diamino-, 2,6-diamino, or 4,6-diamino mono- or disubstituted pyrimidines or the corresponding pyrimidine-3-oxides such as 2,4-diamino-6-(diethylamino)pyrimidine, 2,4-diamino-6-piperidino-pyrimidine-3-oxide, 2,4-diamino-6-hydroxypyrimidine, 4,6-diamino-2-hydroxypyrimidine or 2,5-diamino-4,6-dihydroxypyrimidine is administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylaxis or treatment of cytokine- or endotoxin-induced hypotension (e.g., septic shock).

Abstract: The present invention involves a method for prophylaxis or treatment of an animal for systemic hypotension induced by endotoxin and/or a biological response modifier such as the cytokines, IFN, TNF, IL-1 or IL-2 and the like. The method involves administering, preferably intravascularly, a therapeutically effective amount of dobutamine and an inhibitor of nitric oxide formation from arginine.

Abstract: A method for prophylaxis or treatment of an animal for systemic hypotension induced by internal nitrogen oxide production. The method involves administering a therapeutically effective amount of certain arginine derivatives to inhibit nitrogen oxide formation from arginine. Preferably N.sup.G -substituted arginine or an N.sup.G,N.sup.G -disubstituted arginine (having at least one hydrogen on a terminal guanidino amino group replaced by another atomic species) is administered to an animal possibly developing or already having such induced systemic hypotension. The arginine derivatives are preferably of the L configuration and include pharmaceutically acceptable addition salts. Prophylaxis or treatment of systemic hypotension in a patient which has been induced by chemotherapeutic treatment with biologic response modifiers such as tumor necrosis factor or interleukin-2 may be accomplished. Treatment of an animal for systemic hypotension induced by endotoxin, i.e.

Abstract: Administration of argininosuccinate synthetase activity reducing agents, e.g., argininosuccinate synthetase induction blocking agents (e.g., antibiotics that bind to DNA sequences present in the upstream regulatory region of the argininosuccinate synthetase gene, such as mithramycin) and argininosuccinate synthetase inhibitors (e.g., L-citrulline antagonists such as methyl citrulline and L-aspartate antagonists such as D-aspartate) is useful to prevent or treat sepsis or cytokine-induced systemic hypotension, is useful in the treatment of sepsis or cytokine-induced systemic hypotension to restore vascular sensitivity to the effects of .alpha..sub.1 -adrenergic agonists, and is useful to suppress an immune response, e.g., in treating inflammation. In one embodiment, certain argininosuccinate synthetase activity reducing agents are used together with arginine antagonists to treat sepsis or cytokine induced hypotension.

Abstract: Administration of argininosuccinate synthetase activity reducing agents, e.g., argininosuccinate synthetase induction blocking agents (e.g., antibiotics that bind to DNA sequences present in the upstream regulatory region of the argininosuccinate synthetase gene, such as mithramycin) and argininosuccinate synthetase inhibitors (e.g., L-citrulline antagonists such as methyl citrulline and L-aspartate antagonists such as D-aspartate) is useful to prevent or treat sepsis or cytokine-induced systemic hypotension, is useful in the treatment of sepsis or cytokine-induced systemic hypotension to restore vascular sensitivity to the effects of .alpha..sub.1 -adrenergic agonists, and is useful to suppress an immune response, e.g., in treating inflammation. In one embodiment, certain argininosuccinate synthetase activity reducing agents are used together with arginine antagonists to treat sepsis or cytokine induced hypotension.

Abstract: An anti-hypotensive formulation comprising an essentially arginine-free or low arginine (less than about 0.1%, most preferably, about 0.01%) containing mixture of amino acids is provided. The invention in particular embodiments of the anti-hypotensive formulation includes ornithine, citrulline or both. A method for prophylaxis and treatment of systemic hypotension in an animal is provided. Most particularly, a method for treating hypotension caused by nitric oxide synthesis through administering a low or essentially arginine-free parenteral formulation to an animal, so as to reduce or eliminate nitric oxide synthesis is described. A method for treating an animal in septic shock is also disclosed, comprising administering to the animal an anti-hypotensive formulation comprising a mixture of amino acids, which is essentially arginine free.

Abstract: Inhibitor of the use of tetrahydrobiopterin as a cofactor for nitric oxide synthase, e.g., substituted 4-phenyl(hydropyridines) such as 1-methyl-4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine or, 4-(3',4'-dihydroxyphenyl)-1,2,3,6-tetrahydropyridine) or tetrahydropterin analog which does not replace tetrahydrobiopterin as a substrate for nitric oxide synthase such as (6R,S)-6,7-dimethyl-tetrahydropterin or (6R,S)-tetrahydrofolic acid or 2,4-diamino-, 2,6-diamino, or 4,6-diamino mono- or disubstituted pyrimidines or the corresponding pyrimidine-3-oxides such as 2,4-diamino-6-(diethylamino)pyrimidine, 2,4-diamino-6-piperidino-pyrimidine-3-oxide, 2,4-diamino-6-hydroxypyrimidine, 4,6-diamino-2-hydroxypyrimidine or 2,5-diamino-4,6-dihydroxypyrimidine is administered to inhibit nitric oxide synthesis from arginine in vascular cells in a subject in need of such inhibition (e.g., for prophylaxis or treatment of cytokine- or endotoxin-induced hypotension (e.g., septic shock).

Abstract: Reducing plasma levels of endogenous arginine by parenteral administration of arginine depleting agent limits nitric oxide formation and results in blood pressure increase. Preferably arginase is administered intravenously to raise blood pressure. The arginine depleting agent can be administered in conjunction with arginine antagonists to potentiate the effect of these. The arginine depleting agent can be used concurrently with .alpha..sub.1 adrenergic agonists in treating systemic hypotension caused by induced production of nitric oxide, to restore vascular contractile sensitivity to the effect of the .alpha..sub.1 adrenergic agonists. Duration of action and avoidance of antigenicity may be obtained by use in conjunction with a carrier or modifier.

Abstract: Methods and compositions for treating and inhibiting hypotension are provided. A therapeutic regimen useful in the present invention includes an arginine-free parenteral formulation administered concurrently with or followed by an arginine analog. The combination therapy provides an augmentation of the anti-hypotensive effect found by the present inventors with arginine analogs, such as N.sup..omega. -methyl-L-arginine, N.sup..omega. -amino-L-arginine or N.sup..omega. -nitro-L-arginine. These arginine analogs, otherwise described as nitric oxide synthase inhibitors, provide for a decrease in nitric oxide concentrations, and are demonstrated to elicit an increase in blood pressure in vivo, particularly in animals with cytokine and/or endotoxin induced hypotension. The parenteral formulation of the therapeutic regimen and methods of the invention are arginine-free and provide a decrease in plasma arginine levels.

Abstract: Methods and compositions for treating and inhibiting hypotension related to both endotoxin and cytokine-induced shock are provided. A therapeutic regimen useful in the present invention includes an arginine-free parenteral formulation administered with or followed by the administration of an anti-endotoxin antibody, an interleukin-1 or interleukin-2 receptor antagonist, an anti-tumor necrosis factor antibody or a combination thereof. Most preferably, the administration of an arginine-free parenteral formulation augments the anti-hypotensive effect of the various antibodies and antagonist described so as to provide an effective treatment for various forms of hypotension. The therapeutic regimens of the invention are proposed to provide for a decrease in nitric oxide synthase, and thereby an increase in blood pressure in vivo, particularly in animals with cytokine- and/or endotoxin-induced hypotension.

Abstract: The present invention involves a method for prophylaxis or treatment of an animal for systemic hypotension induced by endotoxin and/or a biological response modifier such as the cytokines, IFN, TNF, IL-1 or IL-2 and the like. Said method involves administering, preferably intravascularly, a therapeutically effective amount of dobutamine and an inhibitor of nitric oxide formation from arginine. Although preferable administration is intravascular, it is contemplated that other parenteral administration routes such as intraperitoneal, intramuscular or subdermal injection, for example, may prove useful. Enteral or topical administration of arginine analogs may also prove beneficial under certain clinical conditions.