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At least 91 records · Page 5Linked to original sources
PubMed1989

Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.

To study the vasodilating effect of insulin after termination of ECC in aortocoronary bypass surgery, 21 patients were randomized to treatment with 7.5 U of fast-acting insulin/kg b.w. as a bolus injection followed by continuous infusion of 15 U/kg b.w. for 1 hour, or to serve as controls. Insulin administration was begun when the last proximal anastomosis had been completed. Cardiac output and central pressures were monitored for 1 hour after termination of ECC. Systemic vascular resistance in both groups was lower at the end of ECC than before surgery (reduction 39% in the controls, 51% in the insulin-treated group). During the following hour the peripheral resistance increased significantly in the controls (from 20 +/- 2 to 29 +/- 2 mmHg X min X m2/l), but no change was found in the insulin group. It is concluded that insulin can maintain a low vascular resistance after aortocoronary bypass surgery.

Adult↗
PubMed1982

[Significance of vasodilator agents in the treatment of heart insufficiency].

Although the use of vasodilators acting on veins and arterioles to treat patients with refractory congestive heart failure has become increasingly widespread, essential problems relating to the clinical efficacy of long-term therapy remain to be solved. The pathophysiological bases of the most common forms of heart failure are discussed and the spectrum of available drugs and their principal mechanism of action are categorized. In addition, a possible conceptual approach to ambulatory oral vasodilator treatment is outlined.

Edema↗
PubMed1994

Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects.

OBJECTIVE: To assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator-cardiotonic agent, 349U85 hydrochloride [6-piperidino-2(1H)-quinolinone hydrochloride], in healthy male subjects. METHODS: This randomized, parallel, double-blind, placebo-controlled, dose escalation trial was conducted at a university-based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24-hour ambulatory electrocardiography, and 12-lead electrocardiography. RESULTS: Doses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration-time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half-life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.

Adult↗
PubMed2002

Influence of the nature of pre-contraction on the responses to commonly employed vasodilator agents in rat-isolated aortic rings.

The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated. Rat-isolated thoracic aortas were exposed to different types of pre-contraction. The following vasoconstrictor agents were used: phenylephrine (PhE), a selective alpha1-adrenoceptor agonist; St 587, a partial alpha1-adrenoceptor stimulant; U46619 (U-46). a thromboxane A2 agonist: and potassium ions causing receptor-independent depolarization of the membrane. After pre-contraction, various differential vasodilator drugs were investigated: methacholine (MCh, endothelium dependent), sodium nitroprusside (SNP, NO donor), forskolin (FSK, adenylyl cyclase stimulant) and nifedipine, a Ca2+-antagonist (selective L-type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (pD2) and efficacy (Emax) obtained from their concentration-response curves. PhE (0.1, 0.3, 3 microM) caused isometric responses of 4.8 +/- 0.3, 6.5 +/- 0.3 and 7.8 +/- 0.5 mN, respectively. An increase of the PhE concentration from 0.1 to 3 microM did not influence the response to FSK while it reduced the pD2 of SNP (8.6 +/- 0.1 to 7.35 +/- 0.1). Under these conditions, only the Emax of MCh was reduced (96.3 +/- 4.3% to 43.3 +/- 6.9%). U46 (0.18, 0.3, 1 microM) increased the contractile force by 7.4 +/- 0.4, 8.8 +/- 0.3 and 10.4 +/- 0.3 mN, respectively. Increasing the concentration of U-46 from 0.18 to 1 microM affected only the efficacy of SNP (84 +/- 4.4% to 17 +/- 8.8%) and MCh (64.5 +/- 12.3% to 0.0 +/- 9.2%) and reduced the potency of FSK (7.91 +/- 0.26 to 7.15 +/- 0.10). The concentration of K+-ions from 25 to 30 and 40 mM increased the contractile force by 4.0 +/- 0.4, 7.0 +/- 0.5 and 10.8 +/- 0.4 mN, respectively. The increase in [K+] caused a potency decrease of FSK (7.1 +/- 0.0 to 5.8 +/- 0.0) whereas both efficacy and potency were reduced for SNP (95.6 +/- 1.8% to 65.8 +/- 1.9% and 8.7 +/- 0.1 to 7.2 +/- 0.1) and MCh (55.4 +/- 3.5% to 24.5 +/- 0.8% and 7.4 +/- 0.3 to 6.1 +/- 0.4). Inhibiting of the endothelial NO production by L-NAME 100 microM resulted after pre-contraction with PhE and potassium in comparable differences in properties for SNP. Pre-contraction with St 587 1, 3, 10 and 30 microM shows comparable results after nifedepine relaxation. The present experiments clearly demonstrate that the characteristics of the applied pre-contraction strongly, but differentially influence both the potency and efficacy of various vasodilator drugs in vitro. Accordingly, in vitro characterization of vasodilator drugs should be performed under a carefully standardized protocol of pre-contraction.

Animals↗
PubMed1985

The metabolism of a new antithrombotic and vasodilating agent, cilostazol, in rat, dog and man.

The metabolism of cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)- qui nolinone, OPC-13013) was studied after the oral administration of cilostazol or 14C-cilostazol in rats, dogs and man. Metabolites of cilostazol identified in the rat, dog and human plasma and urine were monohydroxycilostazol (OPC-13213, OPC-13217, OPC-13366, OPC-13371, OPC-13215 and OPC-13326), monohydroxydehydrocilostazol (OPC-13269 and OPC-13388), 3,4-dihydro-6-hydroxy-2(1H)-quinolinone (6-HQ), their conjugates and dehydrocilostazol (OPC-13015). Major metabolites detected in the rat plasma were OPC-13015, OPC-13217 and OPC-13213, and the plasma concentration of OPC-13015 was 53 to 79% of that of cilostazol. In the dog plasma, major metabolites detected were OPC-13213, OPC-13366 and OPC-13015, and the AUC of OPC-13213 was 79.7% of that of cilostazol. In the human plasma, major metabolites detected were OPC-13015 and OPC-13213, and their AUC were 11.7 and 9.1% of that of cilostazol, respectively. Monohydroxycilostazol and monohydroxydehydrocilostazol were detected at 8.5% of dose in the rat urine and 8.7% in the dog urine, and OPC-13213 showed the highest concentration of these. The conjugates of these and 6-HQ were detected at 0.4 and 24.5%, respectively, in the rat urine and 2.4 and 3.7%, respectively, in the dog urine. These conjugates were mainly sulfate in rats and glucuronide in dogs. In the human urine, OPC-13213 showed the highest concentration, and the conjugates were mainly glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Influence of cerebral vasoconstricting and vasodilating agents on blood flow in regions of focal ischemia.

Regional cerebral blood flow (rCBF) measurements with krypton-85 (100 separate determinations) were compared in squirrel monkeys anesthetized with sodium pentobarbital (a cerebral vasoconstrictor) and halothane (a cerebral vasodilator) before, during, and after middle cerebral artery (MCA) occlusion. Prior to MCA occlusion, a normal physiological response to alterations in arterial carbon dioxide tensions (Paco2) was demonstrated in both groups of monkeys; the cerebral vascular resistance was significantly lower in those anesthetized with halothane. During ischemia, there was loss of autoregulation and a failure to respond to alterations in Paco2 in both groups. Flow in the ischemic region remained uniform in the barbiturate group but decreased progressively in the halothane group, suggesting a "paradoxical response" to the dilating agent. Reactive hyperemia (luxury perfusion) was demonstrated in both groups after restoration of flow. The use of a beta-emitting isotope ensured that measurements in regions of ischemia accurately reflected rCBF and were free of the artifacts ("look through" and Compton scatter) related to use of a gamma-emitting indicator.

Animals↗
PubMed2002

Synthesis and evaluation of some pyrazolo[3,4-d]pyridazinones and analogues as PDE 5 inhibitors potentially useful as peripheral vasodilator agents.

A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC50 values in the range 0.14-1.4 microM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d] pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1981

[Ergometric study of a new vasodilator agent in angina: molsidomine. Value of combination with beta-blockaders].

Molsidomine, a new venous vasodilator, was studied in 40 cases of stable angina by ergometric stress testing. 1. In 10 patients, one hour after 2 mg molsidomine sublingually, the work inducing a 1 mm ST depression (WST 1) increased by 94% (p less than 0,05), the total work by 52% (p less than 0,005) and the maximum ST depression (ST max) fell by 45% (p less than 0,01). Resting heart rate was unchanged. There was a mild fall in systemic blood pressure. 2. Molsidomine had a significant synergic effect in 3 groups of 10 patients on betablocker therapy but with ischaemic changes on exercise: a) Molsidomine 1 mg sublingually increased WST 1 by 36% (p less than 0,05); at a 2 mg dosage, by 55% (p less than 0,001). ST max decreased from 2,4 +/- 0,4 mm to 1,3 +/- 0,3 (p less than 0,005) and 1,2 +/- 0,33 (p less than 0,001) respectively. The maximal effect was obtained with 1 mg in 5 out of 10 patients. b) One and three hours after 2 mg Molsidomine sublingually or orally: WST 1 increased from 97% to 110% (p less than 0,005): ST max decreased in similar proportions (p less than 0,005). c) 2 mg Molsidomine and 230 mg isosorbide dinitrate orally were compared after two hours: WST 1 increased by 130% after Molsidomine (p less than 0,005) and by 112% after isosorbide (p less than 0,005). ST max decreased in similar proportions (p less than 0,005). The blood pressure fell less with molsidomine. Molsidomine appeared to be better tolerated than isosorbide. (5 cases of mild headache in 40 patients compared to 4 cases out of 10 patients). The results of a preliminary clinical trial are reported. The association of molsidomine (2 mg per os three times daily) reduced the number of anginal attacks by over 50% in 16 out of 17 patients inadequately controlled by betablockade alone. 3 patients complained of headache at the onset of therapy. The efficacity was comparable and the tolerance better than in 28 patients with isosorbide dinitrate and betablockade, and in 10 patients with nifedipine and betablockade. In conclusion, molsidomine is a venous vasodilator with useful pharmacokinetic properties. It seems to be effective and well tolerated in the treatment of angina whether used alone or in association with betablockers.

Administration, Oral↗