RESUMO
1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.
Assuntos
Benzazepinas/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Benzazepinas/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Fisiológicos Cardiovasculares , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Prazosina/farmacologia , Ioimbina/farmacologiaRESUMO
The acute and chronic effects of a potent selective dopamine beta-hydroxylase inhibitor, SK&F 102698, were assessed in chronically instrumented 1-kidney, 1-clip Goldblatt hypertensive dogs. Blood pressure measured directly from either a carotid loop or from a vascular access port and cardiac output measured by impedence cardiography were monitored following acute (30 and 100 mg/kg, p.o.) and chronic (30 mg/kg/day for 4 days) administration of SK&F 102698. The data indicate that SK&F 102698 failed to alter blood pressure, cardiac output or total peripheral resistance after either acute or chronic administration. It is concluded that dopamine beta-hydroxylase inhibition with SK&F 102698 is not an effective antihypertensive agent in the 1-kidney, 1-clip Goldblatt hypertensive dog model.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dopamina beta-Hidroxilase/antagonistas & inibidores , Hipertensão Renovascular/fisiopatologia , Imidazóis/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Masculino , Volume Sistólico/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
Fenoldopam administration orally or i.v. resulted in significant increases in paraaminohippuric acid (PAH) clearance in both four control dogs and four dogs with chronic renal failure. Oral fenoldopam resulted in significant plasma levels of fenoldopam sulfate metabolites. One metabolite, fenoldopam-8-sulfate, a potential inhibitor of organic anion transport, did not depress renal cortical slice accumulation of PAH. The data therefore indicate that in dogs with chronic renal failure, PAH clearance after fenoldopam administration is a reliable measure of renal plasma flow, and fenoldopam can result in an increase in renal plasma flow.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Falência Renal Crônica/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Administração Oral , Animais , Creatinina/sangue , Cães , Dopaminérgicos/farmacologia , Feminino , Fenoldopam , Humanos , Técnicas In Vitro , Injeções Intravenosas , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Masculino , Ácido p-Aminoipúrico/sangueRESUMO
The pharmacology of SK&F R-105058 and SK&F R-106114, N-ethyl carbamate ester prodrugs of fenoldopam, was evaluated in pentobarbital-anesthetized dogs. The selective dopamine 1 (DA1) antagonist, SCH 23390, significantly attenuated the renal vasodilator effects of SK&F R-82526, the active enantiomer of fenoldopam. This dose of SCH 23390 also significantly attenuated the increase in renal blood flow and decrease in renal vascular resistance induced by the administration of either SK&F R-106114 or SK&F R-105058. The cholinesterase inhibitor, physostigmine, at a dose that significantly enhanced the renal effects of acetylcholine, did not alter the in vivo renal vasodilator effects of SK&F R-105058 or prevent conversion of SK&F R-105058 to fenoldopam. Thus, these data indicate that the renal vasodilator activity of fenoldopam prodrugs involves activation of DA1 receptors and that, unlike other carbamate ester prodrugs, conversion to the parent compound is unlikely to involve cholinesterase.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Benzazepinas/farmacologia , Carbamatos/farmacologia , Pró-Fármacos/farmacologia , Vasodilatadores/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacocinética , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Anestesia , Animais , Benzazepinas/farmacocinética , Biotransformação , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/farmacocinética , Cães , Feminino , Fenoldopam , Pentobarbital , Fisostigmina/farmacologia , Pró-Fármacos/farmacocinética , Circulação Renal/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacocinéticaRESUMO
1. The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D-Tyr(Et)VAVP (SK&F 101926; 25 micrograms kg-1) and the selective V2 antidiuretic agonist, desamino-8-D-arginine vasopressin (dDAVP; 3 micrograms kg-1) was studied in ketamine-anaesthetized rhesus monkeys. 2. The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2-4 weeks). A similar desensitization to dDAVP-associated flushing was observed on repeated administration. 3. Treatment with dDAVP also resulted in reduced SK&F 101926-associated flushing. 4. The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP. 5. The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia. 6. Indomethacin (5 mg kg-1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926. 7. Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia. 8. It was concluded that the flushing response to vasopressin-like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.