Bracken J. De Witt

An analysis of responses to levosimendan in the pulmonary vascular bed of the cat.

Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K+-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor l-N5-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K+ channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat.

Comparison of responses to novel nitric oxide donors in the feline pulmonary vascular bed.

Pulmonary vascular responses to the novel diazeniumdiolate nitric oxide (NO) donors diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angelis salt, were investigated and compared in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of diethylamine/NO (0.3-10 microg), diethylenetriamine/NO (10-30 microg), spermine/NO (10-30 microg), sulfite/NO (10-30 microg), and angelis salt (10-30 microg) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the compounds that decreased lobar arterial pressure 4 mm Hg (ED(4) mm Hg) was significantly lower for diethylamine/NO compared to S-nitroso-N-acetylpenicillamine which was significantly less than diethylenetriamine/NO, spermine/NO, sulfite/NO, and angelis salt. The half-life of the vasodilator responses, as measured by 50% response recovery time, to diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angelis salt was similar for doses with similar magnitudes of vasodilation, while the half-life to S-nitroso-N-acetylpenicillamine was significantly less than the diazeniumdiolate NO donors. The present data demonstrate that the diazeniumdiolate NO donors diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angelis salt have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed of the cat.

Analysis of vasodilator responses to novel nitric oxide donors in the hindquarters vascular bed of the cat.

&NA; Controlled release of nitric oxide (NO·) may be useful in the treatment of a variety of vascular disorders. NO· donors of the diazeniumdiolate family with different rates of spontaneous NO· release have been synthesized. In the current study responses to seven diazeniumdiolate NO· donors (DEA/NO·, DETA/NO·, OXI/NO·, PIPERAZI/NO·, PROLI/NO·, SPER/NO·, and SULFI/NO·) were investigated in the hindquarters vascular bed of the cat. Intravenous injections of all NO· donors caused dose‐dependent decreases in systemic arterial pressure and the rank order of potency was SNP > DEA/NO· > PIPERAZI/NO· > SPER/NO· > PROLI/NO· > OXI/NO·. Injections of all NO· donors into the hindlimb perfusion circuit caused dose‐related decreases in hindquarters perfusion pressure that were similar to the order of potency in decreasing systemic arterial pressure. The rank order of the time required for the response to return to 50% of the maximal decrease in pressure (T1/2) and total duration of action of the NO· donors was SPER/NO· > PIPERAZI/NO· > DEA/NO· > OXI/NO· > DETA/NO· > PROLI/NO· > SULFI/NO·. After treatment with the NO· synthase inhibitor, N&ohgr;‐nitro‐L‐arginine methyl ester (100 mg/kg, i.v.), hindlimb vasodilator responses to the NO· donors were not significantly different, but vasodilator responses to acetylcholine were significantly reduced. After treatment with zaprinast (2 mg/kg, i.v.), a type V cyclic 3′, 5′‐guanosine monophosphate‐specific phosphodiesterase inhibitor, the duration of vasodilator responses to the NO· donors, as measured by T1/2, was increased significantly, whereas the duration of the response to the &bgr;2‐adrenergic receptor agonist albuterol was unchanged. These data suggest that diazeniumdiolate NO· donors are endothelium‐independent, directly stimulate soluble guanylate cyclase, and decrease vascular resistance by increasing cyclic 3′, 5′‐guanosine monophosphate levels in the hindquarters vascular bed of the cat.