Journal of cardiovascular pharmacology
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J. Cardiovasc. Pharmacol. · Mar 2001
Acute pressor actions of ouabain do not enhance the actions of phenylephrine or norepinephrine in anesthetized rats.
The inhibition of high-affinity isoforms of the Na+,K+-ATPase by nanomolar levels of ouabain has been proposed to enhance the actions of vasoconstrictor agents that act via a Ca+2-dependent mechanism. The present study tested this hypothesis by evaluating the effects of ouabain (6 and 18 microg/kg, i.v.) on the vasopressor actions of phenylephrine and norepinephrine in anesthetized, reflex-blocked rats. In separate groups of animals, dose-response curves for increases in diastolic pressure produced by phenylephrine were generated after the administration of saline (control), ouabain (18 microg/kg), L-omega-N-nitro arginine methyl ester (L-NAME, 3 micromol/kg) and angiotensin II (15 ng/kg per min). ⋯ In animals in which the pressor actions of norepinephrine were evaluated before and after the administration of ouabain (6 microg/kg), ouabain did not alter the pressor response to norepinephrine. Blockade of alpha-adrenoceptors with phentolamine was found to attenuate as well as partially reverse the increase in diastolic pressure produced by ouabain. These observations suggest that ouabain produces a pressor response by actions on sympathetic nerve endings as well as on vascular smooth muscle and that these actions do not alter the sensitivity to phenylephrine or norepinephrine.
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J. Cardiovasc. Pharmacol. · Feb 2001
Alpha-vascular responses after short-term and long-term inhibition of nitric oxide synthesis.
Apart from the direct actions of nitric oxide (NO) on vascular smooth muscle, this factor may regulate cardiovascular functions through specific actions on alpha-adrenergic constrictor mechanisms. In this study we aim to establish whether the inhibition of the synthesis of this mediator could alter the vasoconstrictor responses mediated by alpha-adrenoceptor stimulation. We have been able to demonstrate that the blockage of the NO synthase really does exist, when both short- and long-term treatments with Nomega-nitro-Larginine methyl ester (L-NAME) are carried out. ⋯ On the other hand, the dose-response curves to both alpha-adrenoceptor agonists were shifted to the right in a non-parallel manner in rats treated long term with L-NAME, the shift being, in the case of B-HT 920, more accentuated when the treatment lasted 21 or 45 days than when it lasted only 7 days. These results indicate that the short-term decrease in NO synthesis does not modify the vascular smooth muscle responses mediated by alpha1-adrenoceptor stimulation, but it does induce a potentiation of sympathetic vasoconstriction mediated by alpha2-adrenoceptors. Nevertheless, the long-term inhibition of NO synthesis causes a compensating decrease in the alpha1- and alpha2-vascular smooth muscle contractile responses.
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J. Cardiovasc. Pharmacol. · Oct 2000
Thiol repletion prevents venous thrombosis in rats by nitric oxide/prostacyclin-dependent mechanism: relation to the antithrombotic action of captopril.
Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. ⋯ Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.
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J. Cardiovasc. Pharmacol. · Apr 2000
Clinical TrialElectrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function.
Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. ⋯ The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.
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J. Cardiovasc. Pharmacol. · Jan 2000
The hemodynamic effects of adenosine infusion after experimental right heart infarct in young swine.
The use of a vasodilator selective to the pulmonary circulation may be beneficial in cases with right-ventricle failure, as it will decrease right-heart afterload without concurrent systemic hypotension. Adenosine has recently been advocated as such a drug, although its clinical efficacy in this respect is still in question. We therefore devised an experimental protocol of right-heart infarct to test the efficacy of adenosine in alleviating symptoms of right-heart failure. ⋯ Discontinuation of the drug resulted in a rapid increase in MAP, SVRI, MPAP, HR, left ventricle stroke work index (LVSWI), and PVRI and in a modest decrease in CI. The continuous infusion of adenosine appears to cause an effective arterial vasodilation, with a consequent unloading of right-heart afterload. Its use may be beneficial in the treatment of increased pulmonary vascular resistance after right-heart failure.