Responses of saphenous and mesenteric veins to administration of dopamine.

Others have observed that dopamine (3,4-dihydroxyphenylethylamine) constricts resistance vessels in skin, but dilates these vessels in the mesentery. We studied the effects of dopamine on cutaneous and mesenteric veins of dogs to see if this agent also produced qualitatively different effects on the tone of capacitance vessels (veins) in these vascular beds. The lateral saphenous or the left colic vein was perfused at constant flow with blood from a femoral artery. Pressures at the tip of the perfusion cannula and at the tip of a catheter 15 cm downstream were recorded continuously. Increases in the pressure gradient between these two points indicated venoconstriction; decreases indicated venodilatation. Dopamine and norepinephrine injected into the perfusion tubing caused constriction of both veins. The constriction was antagonized by blockade of alpha receptors. A dilator action of dopamine was not seen, even after alpha receptor blockade or in the presence of increased venous tone produced by serotonin, norepinephrine, or nerve stimulation. Reserpine and cocaine did not alter responses to dopamine in the saphenous vein; this suggests that the venoconstrictor action of dopamine results mainly from a direct effect on alpha receptors and that uptake into sympathetic nerve endings may not be important in regulating the amount of dopamine available to receptors in the saphenous vein.

Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators.

Di- and triaminopyrimidine 3-oxides (e.g., 2,4-diamino-6-piperidinylpyrimidine 3-oxide and 2,4-diamino-6-(diallylamino)triazine 3-oxide) react with sources of sulfur trioxide, such as sulfur trioxide trimethylamine or chlorosulfuryl chloride, to yield the corresponding heterocyclic O-sulfates. These sulfates are inner salts with unusual physical properties. The structure of the O-sulfate of 2,4-diamino-6-piperidinylpyrimidine 3-oxide was confirmed by X-ray. These O-sulfates are hypotensives. They apparently act by direct vasodilation.

Tetrahydro-2-benzoxepins: a novel family of hypotensives.

A novel series of 1-(alkylamino)-1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepins shows hypotensive activity. A typical example is 1-[2-(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound is an alpha blocker with peripheral and central activities.

Pyrimidinones. 3. N-substituted 6-phenylpyrimidinones and pyrimidinediones with diuretic/hypotensive and antiinflammatory activity.

In an extensive analysis of the antiviral and interferon-induction structure-activity relationship of 6-arylpyrimidinones we found that modifications at positions 1-4 of the pyrimidine ring resulted in a loss of activity. However, we uncovered interesting hypotensive and antiinflammatory activity with a series of N-substituted analogues, the results of which we report herein.

Bronchodilator effects of prostacyclin (PGI2) in dogs and guinea pigs.

prostacyclin (PGI2), a recently discovered unstable product in the biosynthetic conversion of prostaglandin endoperoxides, was examined for bronchopulmonary actions. in anesthetized dogs, PGI2 given i.v. (0.3-30.0 microgram/kg) and by aerosol (0.002-0.2%) inhibited significantly PGF2 alpha-induced increases in pulmonary resistance and decreases in dynamic lung compliance in a dose-related fashion. Intrinsically, PGI2 affected resting bronchopulmonary and cardiac functions minimally, but decreased peripheral and pulmonary vascular pressures. PGI2 (0.1-10 mg/kg, i.p.) afforded protection against histamine-induced asphyxial collapse in normal guinea pigs and ovalbumin-induced anaphylaxis in sensitized animals. Cumulative concentrations of PGI2 (1.0 x 10(-9)--3.0 x 10(-4) M) relaxed contractions of the isolated guine pig trachea produced by carbachol. These bronchodilator and hemodynamic effects could not be ascribed to the stable metabolic product of PGI2, because 6-keto-PGF1 alpha was inactive or markedly less active than PGI2 in these test systems. The results of this investigation suggest that PGI2 possesses considerable bronchodilator and vasodilator activity in experimental animal systems.

Cardiovascular effects of prostaglandin D3 and D2 in anesthetized dogs.

Prostaglandin (PG) D3 has been identified as an inhibitor of human platelet aggregation, but little is known of the hemodynamic activity of this material. In morphine pretreated, chloralose-urethan anesthetized dogs, bolus intravenous injections (1, 3.2 and 10 microgram/kg) of PGD3 and also PGD2 were associated with marked, dose-related increases in pulmonary arterial pressure. Cardiac index and rate increased, while peripheral vascular resistance decreased in response to injections of PGD3. A biphasic (depressor followed by a pressor phase) effect on systemic arterial pressure was observed after PGD2, while PGD3 was associated with dose-related depressor responses. Graded intravenous infusions (0.25, 0.50 and 1.0 microgram/kg/min) of PGD3 and PGd2 were associated with qualitatively similar cardiovascular responses. Quantitatively, PGD3 infusions were associated with greater decreases in peripheral vascular resistance and greater increases in cardiac output, heart rate, and peak left ventricular dp/dt than were infusions of PGD2. In contrast, PGD3 was less potent than PGD2 as a pulmonary pressor material. Systemic arterial pressure responses to infusions of the prostaglandins were variable. In these experiments, PGD3 and PGD2 were associated with qualitatively similar cardiovascular responses characterized by peripheral vasodilatation.

U-54,669F: a novel hypotensive agent.

U-54,669F, a new antihypertensive agent, administered orally was associated with dose-related hypotensive responses in conscious, spontaneously hypertensive, and normotensive rats (0.015-0.5 mg/kg) and in supine conscious monkeys (1-10 mg/kg). No loss of hypotensive efficacy of U-54,669F was observed after 1 wk of daily repetitive treatment. U-54,669F did not alter electrical postganglionic sympathetic nerve activity or postsynaptic sympathetic function. Hypotensive responses to U-54,669F were blunted in spinal cats. U-54,669F was associated with dose-related decreases in norepinephrine (NE) levels in plasma and in cardiac and splenic tissue, whereas brain NE was unaltered. U-54,669F attenuated vascular responses associated with electrical stimulation of sympathetic nerves. However, at hypotensive doses, U-54,669F did not impair the ability of monkeys to withstand orthostatic stress, or contraction of the nictitating membrane secondary to sympathetic stimulation in the cat. U-54,669F appears to alter peripheral sympathetic neurogenic function, but apparently does not enter the central nervous system and does not impair the ability to withstand orthostatic stress at effective hypotensive doses.

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68,215.

U-68,215 [15-Cyclohexyl-9-deoxo-13,14-dihydro-2',9 alpha-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(1', 3'-interphenylene)-PGE1] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED50: 0.8 micrograms/kg) and the intestine (ED50: 22 micrograms/kg), is gastric antisecretory (ED50: 35 micrograms/kg) and antiulcer (aspirin) (ED50: 5 micrograms/kg). The oral antisecretory ED50 in dogs is 50 micrograms/kg. It has a long duration of gastric cytoprotection: 8-10 hours compared to 3 hours for 16,16-dimethyl PGE2. Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induce cellular proliferation of the gastrointestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It inhibits ex vivo platelet aggregation (ED50: 300 micrograms/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at an oral dose corresponding to 1-5 times the antisecretory ED50 in rats and dogs, and to 150 times the cytoprotective ED50 in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.