RESUMO
Series of 3-substituted-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a]isoquinoline-2,4-diones and 2-substituted-9,10-dimethoxy-6,7-dihydro-4H-pyrimido [6,1-a]isoquinolin-4-ones were synthesized and tested for blood pressure lowering properties in anesthetized normotensive cats and conscious spontaneously hypertensive rats. Several compounds in the 2-(arylamino)-9,10-dimethoxy-6,7-dihydro-4H-pyrimido [6,1-a]isoquinolin-4-one series display a high order of activity. The most active compounds are the alkyl derivatives of the 2-mesitylamino/2-mesitylimino tautomeric forms. The 2-(mesitylimino)-3-methyl analogue trequinsin is a potent antihypertensive agent and displays a hemodynamic profile characteristic of an arteriolar dilator. It is also a potent inhibitor of both cAMP phosphodiesterase and platelet aggregation.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Isoquinolinas/síntese química , Tetra-Hidroisoquinolinas , Vasodilatadores/síntese química , Animais , Cães , Relação Dose-Resposta a Droga , Feminino , Cobaias , Isoquinolinas/farmacologia , Masculino , Relaxamento Muscular/efeitos dos fármacos , Fentolamina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Endogâmicos SHR , Vasodilatadores/farmacologiaRESUMO
Four naturally occurring analogues of forskolin were isolated. Forty-nine semisynthetic derivatives were prepared, incorporating structural alterations at the 1-, 6-, 7-, 9-, 11-, and 14/15-positions. Blood pressure lowering properties of 53 compounds were assessed in anesthetized normotensive cats and of 31 compounds in conscious spontaneously hypertensive (SH) rats. The positive inotropic properties of 25 compounds were investigated in an isolated guinea pig atrial preparation. Forskolin was unique among the compounds in its hypotensive activity in cats and in its positive inotropic properties. Although several derivatives displayed oral antihypertensive activity in the SH rats, none was significantly more potent than forskolin. The optimal structural requirements for activity are apparent, since they are found in forskolin itself.
Assuntos
Anti-Hipertensivos , Cardiotônicos , Diterpenos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Gatos , Colforsina , Cães , Cobaias , Contração Miocárdica/efeitos dos fármacos , Ratos , Estimulação Química , Relação Estrutura-AtividadeRESUMO
1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied.2. 5-Hydroxytryptamine (10 mug/ml.) and morphine (20 mug/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine.3. Nicotine (20 mug/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline.4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine.5. 5-Hydroxytryptamine (20 mug/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline.6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines.
Assuntos
Acetilcolina/farmacologia , Coração/efeitos dos fármacos , Morfina/farmacologia , Nicotina/farmacologia , Serotonina/farmacologia , Acetilcolina/metabolismo , Animais , Atropina/farmacologia , Compostos de Bretílio/farmacologia , Colina/farmacologia , Depressão Química , Gânglios/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Isoproterenol/farmacologia , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Fisostigmina/farmacologia , Coelhos , Receptores de Droga , Reserpina/farmacologia , Estimulação QuímicaRESUMO
1 Hypertensive and normotensive rats of the same age group were isolated from an inbred colony of spontaneously hypertensive rats. 2 The perfused hindquarter and mesenteric artery preparations obtained from hypertensive and normotensive rats exhibited an increased reactivity to noradrenaline (NA) and angiotensin II. 3 Dose-response curves to NA obtained from hypertensive and normotensive rats exhibited a steeper slope and higher maximum than those from control rats. 4 These findings suggest that increased vascular reactivity of blood vessels is independent of the development or maintenance of elevated blood pressure.
Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Hipertensão/fisiopatologia , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Membro Posterior/irrigação sanguínea , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos Endogâmicos , VasoconstritoresRESUMO
Apomorphine (10mg/kg, s.c.) does not induce in mice a compulsion to gnaw, but pretreatment with cocaine (10-40 mg/kg, i.p.) caused gnawing activity. This effect of cocaine was inhibited by pretreatment with alpha-methyl-p-tyrosine, haloperidol, and physostigmine, but not with FLA-63, phenoxybenzamine and tetrabenazine. These findings would suggest that dopaminergic mechanism plays a significant role in the potentiation of apomorphine gnawing activity by cocaine and also support the view that inhibition of dopamine uptake is responsible for the stimulatory action of cocaine.
Assuntos
Apomorfina/farmacologia , Comportamento/efeitos dos fármacos , Cocaína/farmacologia , Dopamina/fisiologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Camundongos , Norepinefrina/fisiologia , Fatores de TempoRESUMO
In mice, apomorphine (10 mg/kg s.c.) does not induce a compulsion to gnaw, but pretreatment with antihistamines, viz. pheniramine, chlorpheniramine and mepyramine, in doses ranging from 30 to 60 mg/kg i.p. caused gnawing activity. Mepyramine showed significantly less effect when compared to the other two agents. Antihistamines are known to influence the activity of biogenic amines in central nervous system. The potentiation of apomorphine-induced gnawing by antihistamines might depend upon the reciprocal balance between dopaminergic and cholinergic systems. This was tested by blocking biosynthesis of biogenic amines or by blocking their receptors. The potentiation of gnawing was antagonised by physostigmine (0.25 mg/kg) or blocked by pretreatment with alpha-methyl-p-tyrosine (alpha-MPT) (4 X 150 mg/kg) and bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulphide (FLA) (40 mg/kg), while p-chlorophenyl alanine (p-CPA) (3 X 100 mg/kg) had no effect. Similarly, phenoxybenzamine (30 mg/kg) and haloperidol (1.0 mg/kg) inhibited gnawing activity, but methysergide (10 mg/kg) had no effect. Furthermore, pretreatment with tetrabenazine (20 mg/kg) and L-Dopa (200 mg/kg) did not affect gnawing activity. It is concluded that both pheniramine and chlorpheniramine potentiate apomorphine gnawing by upsetting the cholinergic and dopaminergic balance in favour of dopaminergic dominance.
Assuntos
Apomorfina/farmacologia , Clorfeniramina/farmacologia , Comportamento Compulsivo/efeitos dos fármacos , Feniramina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Compulsivo/fisiologia , Dopamina/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Camundongos , Sistema Nervoso Parassimpático/efeitos dos fármacos , Pirilamina/farmacologiaRESUMO
The H2-receptor antagonist cimetidine (250 micrograms) administered intracerebroventricularly (i.c.v.) 15 and 30 min before clonidine (25 micrograms kg-1 i.v.), significantly antagonized clonidine-induced hypotension in anaesthetized spontaneously hypertensive rats. The hypertensive response of cimetidine was correlated with the inhibition of clonidine-induced hypotension. In addition, cimetidine (250 micrograms i.c.v.) counteracted the hypotensive effects of pentolinium (5.0 mg kg-1 i.v.), guanethidine (5.0 mg kg-1 i.v.) and minoxidil (1.0 mg kg-1 i.v.) These data do not support previous suggestions that the hypotensive action of clonidine is caused by stimulation of the H2-receptor, but suggest that central administration of cimetidine causes peripheral vasoconstriction and this may offer resistance to the hypotensive action of different antihypertensive agents.
Assuntos
Anti-Hipertensivos/farmacologia , Cimetidina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Clonidina/antagonistas & inibidores , Guanetidina/antagonistas & inibidores , Injeções Intraventriculares , Masculino , Minoxidil/antagonistas & inibidores , Tartarato de Pentolínio/antagonistas & inibidores , Ratos , Ratos Endogâmicos SHR , Fatores de TempoRESUMO
The systemic blood pressure effect of cimetidine given intracerebroventricularly (i.c.v.) in anaesthetized spontaneously hypertensive (SH) rats has been investigated. Cimetidine (250 micrograms i.c.v.) caused a gradual long lasting rise in mean arterial blood pressure with maximum of 31.6 +/- 4.5 mm Hg. Chemical degeneration of catecholaminergic neurons with 6-OHDA treatment, central administration of phentolamine and prazosin, and the bilateral adrenalectomy significantly inhibited the pressor response of cimetidine, while propranolol (i.c.v.) had no effect. From these results it appears that the hypertensive response of cimetidine is mediated by central catecholaminergic pathways and is due to an increase in efferent sympathetic outflow and release of catecholamine from the adrenal medulla.