15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and zaprinast

To compare the direct pulmonary vasodilating activity and specificity of phosphodiesterase-5 (zaprinast) and phosphodiesterase-3 (milrinone) inhibitors on the pulmonary vascular (PV) bed of the spontaneously breathing cat with an intact chest.. Prospective, randomized animal study.. Laboratory of university hospital.. Experiments were performed in vivo in intact-chest, spontaneously breathing cats with controlled pulmonary blood flow and constant left atrial pressure.. The responses to intralobar injections of zaprinast and milrinone were investigated at low PV tone. PV tone was then increased by intralobar arterial infusion of a thromboxane A(2) mimic, U46619. Animals received intralobar bolus injections of zaprinast or milrinone, followed by continuous IV infusion of the drug, which was administered in incremental doses titrated to produce a 20% reduction in mean systemic arterial pressure.. At low PV tone, zaprinast, but not milrinone, decreased lobar arterial pressure (LoAP). At elevated PV tone, both drugs caused dose-dependent decreases in LoAP; however, milrinone caused significantly less pulmonary vasodilation. Dose-related decreases in mean systemic arterial pressure were observed with milrinone, but not with zaprinast. When the continuous IV infusion was titrated to produce a 20% reduction in mean systemic arterial pressure, the decreases in lobar arterial pressure with zaprinast infusion were significantly greater than those produced by milrinone.. These data show that zaprinast and milrinone exert a direct in vivo vasodilator effect on the PV bed at low (zaprinast) and elevated (zaprinast and milrinone) PV tone; however, at elevated PV tone, the pulmonary vasodilator effect was greater with zaprinast then with milrinone. This suggests that phosphodiesterase-5 inhibitors may potentially offer a therapeutic alternative in the management of acute pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Analysis of Variance; Animals; Cats; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Intralesional; Male; Milrinone; Phosphoric Diester Hydrolases; Probability; Pulmonary Circulation; Purinones; Random Allocation; Risk Factors; Sensitivity and Specificity; Vascular Resistance

To determine the effect of combining inhaled nitric oxide (NO) with an inhibitor of guanosine 3',5'-cyclic monophosphate-specific phosphodiesterase on total and segmental lung resistances.. A controlled laboratory study in isolated blood-perfused lungs prepared from lambs.. Animal research facility affiliated with a university teaching hospital.. Five newborn lambs at <48 hrs of life.. Isolated blood-perfused lungs were prepared and treated with indomethacin (40 microg/mL) to inhibit prostaglandin synthesis. After a baseline period of normoxia (28% oxygen), pulmonary hypertension was induced with the thromboxane mimetic U46619 (0.1-0.4 microg/kg/min). During pulmonary hypertension, lungs were studied with inhaled NO only, with infusion of zaprinast only (0.25 mg/kg bolus and 0.05 mg/kg/min infusion), and with a combination of the two. For each study condition, the total pressure decrease across the lung was measured, and the inflow-outflow occlusion technique was used to partition the total pressure gradient measured at constant flow (100 mL/kg/min) into gradients across relatively noncompliant large arteries and veins and more compliant small arteries and veins.. U46619 infusion produced significant pulmonary vasoconstriction. The combination of inhaled NO and zaprinast decreased the total pressure decrease across the lung significantly more than NO alone. This effect was primarily attributable to a significantly greater decrease in gradient across the small artery segment after inhaled NO and zaprinast compared with NO alone.. Guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition with zaprinast enhances the effect of inhaled NO, particularly in conditions in which small arteries represent the site of resistance. Phosphodiesterase inhibition may be a promising adjunct to inhaled NO for the treatment of persistent pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Animals, Newborn; Cyclic GMP; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Hypertension, Pulmonary; In Vitro Techniques; Indomethacin; Nitric Oxide; Phosphodiesterase Inhibitors; Purinones; Time Factors; Vascular Resistance; Vasodilator Agents

Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction.. In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6).. Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation.. Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Hypertension, Pulmonary; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Purinones; Sheep; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Wakefulness

Hypoxic pulmonary vasoconstriction (HPV) is essential for matching lung perfusion with ventilation, thus optimizing pulmonary gas exchange. Preceding studies provided evidence for a role of both nitric oxide (NO) and superoxide/ H(2)O(2) formation in this vasoregulatory mechanism. Both agents might be operative via stimulation of guanylate cyclase with formation of the vasodilatory cyclic guanosine monophosphate (cGMP), the loss of which under conditions of hypoxia contributes to HPV. This view is challenged by the recent suggestion of increased rather than decreased superoxide/H(2)O(2) formation in hypoxia. We addressed the role of NO-dependent versus NO-independent guanylate cyclase activity in hypoxic and pharmacologically evoked vasoconstriction in perfused rabbit lungs. Two inhibitors of soluble guanylate cyclase, LY83583 (2 to 16 microM) and methylene blue (20 to 60 microM), increased baseline pulmonary artery pressure under normoxic conditions and markedly amplified the vasoconstrictor response to both hypoxia and the stable thromboxane analogue U46619. Under conditions of preblocked lung NO synthesis (N(G)-mono-methyl-L-arginine), however, additional guanylate cyclase inhibition further enhanced the vasoconstrictor response to U46619 but did not influence the strength of HPV. The selective phosphodiesterase V inhibitor Zaprinast (1 to 10 microM), used for prolongation of the cGMP half-life, reduced the hypoxia-induced pressor response to a larger extent than the pressor response to U46619. This difference was lost under conditions of preblocked NO synthesis. Equilibration of the lung perfusate with molecular NO suppressed the HPV more potently than the U46619-induced vasoconstrictor response. We conclude that NO-dependent guanylate cyclase activity has an important role in attenuating the vasoconstrictor response to alveolar hypoxia in rabbit lungs. In contrast, no evidence was obtained for a role of NO-independent cGMP formation in HPV. In this feature, HPV differs from that elicited by the thromboxane analogue U46619.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aminoquinolines; Animals; Aspirin; Blood Pressure; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Female; Guanylate Cyclase; Hypoxia; In Vitro Techniques; Lung; Male; Methylene Blue; Nitric Oxide; omega-N-Methylarginine; Pulmonary Artery; Purinones; Rabbits; Vasoconstriction; Vasoconstrictor Agents

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenoviridae; Angiotensin II; Animals; Antimetabolites, Antineoplastic; beta-Galactosidase; Bleomycin; Blood Flow Velocity; Blood Pressure; Bradykinin; Cyclic GMP; Endothelin-1; Gene Transfer Techniques; Genes, Reporter; Hypertension, Pulmonary; Hypoxia; Mice; Mice, Inbred Strains; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Norepinephrine; Phosphodiesterase Inhibitors; Pulmonary Alveoli; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Purinones; Sympathomimetics; Vasoconstrictor Agents

Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and c

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Naphthyridines; Phosphodiesterase Inhibitors; Pulmonary Circulation; Purinones; Pyridazines; Rabbits; Rolipram; Vasoconstrictor Agents; Vasodilation

Zaprinast, an inhibitor of guanosine-3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators (including inhaled nitric oxide [NO]). The present study was designed to examine the effects of inhaled nebulized zaprinast, alone, and combined with inhaled NO.. Eight awake lambs with U46619-induced pulmonary hypertension sequentially breathed two concentrations of NO (5 and 20 ppm), followed by inhalation of aerosols generated from solutions containing four concentrations of zaprinast (10, 20, 30, and 50 mg/ml). The delivered doses of nebulized zaprinast at each concentration (mean +/- SD) were 0.23 +/- 0.06, 0.49 +/- 0.14, 0.71 +/- 0.24, and 1.20 +/- 0.98 mg x kg(-1) x min(-1), respectively. Each lamb also breathed NO (5 and 20 ppm) and zaprinast (0.23 +/- 0.06 mg x kg[-1] x min[-1]) in combination after a 2-h recovery period.. Inhaled NO selectively dilated the pulmonary vasculature. Inhaled zaprinast selectively dilated the pulmonary circulation and potentiated and prolonged the pulmonary vasodilating effects of inhaled NO. The net transpulmonary release of cGMP was increased by inhalation of NO, zaprinast, or both. The duration of the vasodilation induced by zaprinast inhalation was greater than that induced by NO inhalation.. Aerosolization of a cGMP-selective phosphodiesterase inhibitor alone or combined with NO may be a useful noninvasive therapeutic method to treat acute or chronic pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Animals; Cyclic GMP; Dose-Response Relationship, Drug; Drug Combinations; Hemodynamics; Hypertension, Pulmonary; Lung; Nitric Oxide; Phosphodiesterase Inhibitors; Pulmonary Circulation; Purinones; Sheep; Vasoconstrictor Agents; Vasodilation

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Triphosphate; Animals; Animals, Newborn; Arginine; Cyclic GMP; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Phosphodiesterase Inhibitors; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Purinones; Sheep; Thromboxane A2; Vasoconstrictor Agents

This study was designed to determine indirectly if the changes in ovine fetal pulmonary vascular tone caused by i.v. injections of nitric oxide-containing solutions are mediated by cGMP. We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions. Injections of nitric oxide solutions as well as zaprinast solutions resulted in dose-dependent decreases in pulmonary arterial pressure that were greater than reductions in systemic arterial pressure. We also evaluated the effects of simultaneous infusions of zaprinast and U46619 (a thromboxane mimetic) on the response to bolus injections of 1.0 micrograms of acetylcholine, 100 ng of endothelin-1, and 10.0 microL of ethanol saturated with nitric oxide. Zaprinast was infused at a rate of 1.5 mg/min, and the concentration of U46619 was titrated to raise mean left pulmonary arterial pressure (LPAP) to the steady state level that was present before infusing zaprinast. All bolus injections reduced left pulmonary arterial pressure more than they reduced mean systemic arterial pressure. However, neither the response magnitudes nor the response durations were affected by simultaneous infusions of zaprinast and U46619. We therefore suggest that modulation of fetal pulmonary vascular tone by endogenously produced nitric oxide may involve mechanisms other than raising smooth muscle cytoplasmic cGMP concentrations.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Dose-Response Relationship, Drug; Fetus; Infusions, Intra-Arterial; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Circulation; Purinones; Sheep; Thromboxane A2; Vasodilator Agents

Inhaled nitric oxide (NO) has been shown to selectively dilate the pulmonary vasculature. Zaprinast, an inhibitor of guanosine 3',5'-cyclic monophosphate-specific phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators. The present study was designed to determine whether intravenous administration of Zaprinast potentiates the vasodilating effects or prolongs the duration of action of intermittent NO inhalation. Eight awake lambs with U-46619-induced pulmonary hypertension breathed three concentrations of NO (5, 10, and 20 ppm) in a random order before and during an intravenous Zaprinast infusion (0.1 mg.kg-1.min-1). Inhaled NO decreased pulmonary arterial pressure (PAP) in a dose-dependent fashion, with mean PAP reduction at 5, 10, and 20 ppm NO inhalation of 6 +/- 1, 7 +/- 1, and 9 +/- 1 (SE) mmHg, respectively. Although the Zaprinast infusion did not change the magnitude of mean PAP reduction, it caused a statistically significant reduction of pulmonary vascular resistance and prolonged the duration of action of inhaled NO (half-times of vasodilator response to 5, 10, and 20 ppm NO inhalation: 1.9 +/- 0.1, 2.1 +/- 0.2, and 2.1 +/- 0.2 min, respectively; half-times of NO inhalation with Zaprinast: 9.7 +/- 1.7, 11.5 +/- 2.2, and 12.3 +/- 2.0, respectively). Plasma concentrations as well as the transpulmonary differences of guanosine 3',5'-cyclic monophosphate were increased by the Zaprinast infusion during NO inhalation. A stable level of pulmonary vasodilation was demonstrated in four additional lambs by combining intermittent NO breathing with an intravenous infusion of Zaprinast.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Cyclic GMP; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Purinones; Sheep; Thromboxane A2; Vascular Resistance; Vasodilation

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Arginine; Blood Pressure; Cardiac Output; Heart Rate; Hypertension, Pulmonary; Isomerism; Methylene Blue; Muscle, Smooth, Vascular; Nitric Oxide; omega-N-Methylarginine; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Purinones; Sheep; Vasodilation

1. The vasorelaxant effects of FK409, a new nitrovasodilator synthesized from a microbial product, were compared with those of nitroglycerin in isolated coronary artery rings of the dog contracted with U46619 (10(-7) M). 2. FK409 (10(-11)-10(-5) M) and nitroglycerin (10(-9)-10(-4) M) each produced a concentration-dependent relaxation. Comparison of EC50 values showed that FK409 was about 25 times more potent than nitroglycerin. 3. Submaximum concentrations of nitroglycerin (10(-6) M) and FK409 (3 x 10(-8) M) elevated guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, effects associated with vasorelaxation. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 4. The concentration-relaxation curves for nitroglycerin and FK409 were shifted to the right by methylene blue (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of soluble guanylate cyclase, and to the left by M&B22,948 (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of cyclic GMP phosphodiesterase. 5. After exposure of coronary arteries to the maximally-effective concentration of nitroglycerin (10(-4) M), the mean EC50 value of FK409 did not change significantly, although that of nitroglycerin increased about 60 fold. After exposure to the maximally-effective concentration of FK409 (10(-5) M), the mean EC50 value of FK409 increased about 6 fold and that of nitroglycerin about 11 fold. 6. These results suggest that the vasorelaxant effect of FK409, like that of nitroglycerin, is due to activation of soluble guanylate cyclase and a resultant increase in intracellular cyclic GMP. However, compared with nitroglycerin, there was less self-tolerance to the relaxant effects of FK409 and relatively little cross-tolerance between the two agents.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Coronary Vessels; Dogs; Female; Guanylate Cyclase; In Vitro Techniques; Male; Methylene Blue; Muscle Relaxation; Nitro Compounds; Nitroglycerin; Prostaglandin Endoperoxides, Synthetic; Purinones; Vasodilator Agents