title: HA1004, an intracellular calcium antagonist, selectively attenuates pulmonary hypertension in newborn lambs.
abstract: HA1004, an isoquinolinesulfonamide and a cyclic nucleotide-dependent protein kinase inhibitor, is an intracellular calcium antagonist that produces vascular smooth muscle (VSM) relaxation in vitro. We studied the hemodynamic effects of intravenous (i.v.) infusions of HA1004 (0.1-2.0 mg/kg) in vivo in 8 newborn lambs, at rest and during pulmonary hypertension induced either by the i.v. infusion of U46619, a thromboxane A2 (TXA2) mimic, or by alveolar hypoxia. For comparison, we also studied the hemodynamic effects of i.v. infusions of nifedipine (15 and 40 micrograms/kg/min), a calcium entry blocker. At rest, HA1004 produced slight but significant changes in pulmonary and systemic arterial pressure (PAP, SAP) and pulmonary and systemic vascular resistances (PVR, SVR) (p < 0.05). During pulmonary hypertension induced by U46619, HA1004 decreased PAP 12-23% and PVR 9-33% (p < 0.05), whereas SAP decreased 7% and SVR decreased 14% at only one dose (p < 0.05). During pulmonary hypertension induced by alveolar hypoxia, HA1004 decreased PAP 6-32% and PVR 11-30% (p < 0.05), whereas SAP decreased 15% only at the highest dose (p < 0.05). Linear regression analysis of the pooled data demonstrated that HA1004 caused selective pulmonary vasodilation during pulmonary hypertension. Nifedipine decreased PAP 6 and 14% and SAP 5 and 17% during pulmonary hypertension. In newborn lambs with pulmonary hypertension, HA1004, an intracellular calcium antagonist, is more selective and potent than nifedipine, a calcium entry blocker, in decreasing PAP and therefore may be useful in treatment of children with pulmonary hypertension.
authors.affiliation: Cardiovascular Research Institute, University of California at San Francisco, 94143.
authors.forename: M R
authors.initials: MR
authors.lastname: Crowley
authors.forename: J R
authors.initials: JR
authors.lastname: Fineman
authors.forename: S J
authors.initials: SJ
authors.lastname: Soifer
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D009126:Muscle Relaxation / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic; D047428:Protein Kinase Inhibitors; D011650:Pulmonary Alveoli; D012044:Regression Analysis; D012756:Sheep; D013449:Sulfonamides; D013928:Thromboxane A2 / Q000031:analogs & derivatives
chemical_list: D002121:Calcium Channel Blockers; D007546:Isoquinolines; D011450:Prostaglandin Endoperoxides, Synthetic; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D009543:Nifedipine