vasoactive-intestinal-peptide and Hypertrophy--Right-Ventricular

Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have pulmonary vasodilatory and positive inotropic effects via receptors VPAC1 and VPAC2, which possess a similar affinity for both peptides, and PAC1, a PACAP-preferring receptor. VIP is a promising option for PH treatment; however, various physiological effects of VIP have limited its clinical use. We investigated the effects of VPAC1 and VPAC2 selective agonists VIP and PACAP to explore more appropriate means of treatment for PH. We examined hemodynamic changes in right ventricular systolic pressure (RVSP), systemic blood pressure (SBP), total pulmonary resistance index (TPRI), total systemic resistance index, and cardiac index (CI) in response to their agonists with monocrotaline (MCT)-induced PH and explored involvement of VIP/PACAP expression and receptors in PH. Sprague-Dawley rats were divided into the MCT group (administered MCT 60 mg/kg) and control group. In MCT-induced PH, decreased VIP and PACAP were associated with upregulation of VPAC1, VPAC2, and PAC1 in lung tissues. Intravenous injection of VPAC2-selective agonist BAY 55-9837 and VIP, but not [Ala(11,22,28)]VIP, improved the CI. The decrease in SBP with VPAC2 agonist was significantly less than that in the control. Although they decreased SBP, these agonists hardly affected RVSP in the control. Activation of VPAC2 receptor with BAY 55-9837 effectively improved RVSP, TPRI, and CI in MCT-induced PH, suggesting a VPAC2 agonist as a possible promising treatment for PH.

Topics: Animals; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Ligands; Male; Monocrotaline; Pituitary Adenylate Cyclase-Activating Polypeptide; Poisons; Rats; Rats, Sprague-Dawley; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide

The pathogenesis of idiopathic pulmonary arterial hypertension (PAH) remains poorly understood. The present authors recently reported that mice with vasoactive intestinal peptide (VIP) gene disruption show a spontaneous phenotype of PAH, with pulmonary vascular remodelling and lung inflammation. To explore the underlying molecular mechanisms in this model, it was examined whether absence of the VIP gene might alter the expression of additional genes involved in the pathogenesis of PAH, as single-gene deletions, in the absence of hypoxia, rarely result in significant pulmonary vascular remodelling. Lung tissue from mice with targeted disruption of the vasoactive intestinal peptide gene (VIP(-/-) mice) and from control mice was subjected to whole-genome gene microarray analysis, and the results validated with quantitative, real-time PCR. Lungs from VIP(-/-) mice showed a wide range of significant gene expression alterations, including overexpression of genes that promote pulmonary vascular smooth muscle cell proliferation, underexpression of antiproliferative genes and upregulation of pro-inflammatory genes. In conclusion, vasoactive intestinal peptide is a pivotal modulator of genes controlling the pulmonary vasculature, its deficiency alone resulting in gene expression alterations that can readily explain both the vascular remodelling and associated inflammatory response in pulmonary arterial hypertension. The present findings shed more light on the molecular mechanisms of pulmonary arterial hypertension, and could lead to better understanding of the pathogenesis of human pulmonary arterial hypertension, and hence to improved therapy.

Topics: Animals; Gene Deletion; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling.. We examined VIP knockout (VIP-/-) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP-/- mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP.. Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing. Although not an exact model of idiopathic PAH, the VIP-/- mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH.

Topics: Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Female; Gene Expression Profiling; Gene Targeting; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Mice; Mice, Knockout; Pulmonary Artery; Survival Rate; Ultrasonography; Vasoactive Intestinal Peptide; Ventricular Remodeling

Vasoactive intestinal peptide (VIP) has regulatory effects on myocardial and vasomotor functions usually demonstrated by in vitro or isolated heart studies. We studied in vivo effects in monocrotaline induced pulmonary hypertensive rabbits immediately after cardiopulmonary bypass (CPB) and tested them versus calcium channel and beta-blockers.. The study consisted of six groups (N=30; five rabbits/group): (1) Control with no pretreatment, monocrotaline injected groups: (solutions were perfused following termination of CPB for 60 min); (2) Control for pulmonary hypertension (PHT); (3) isoproteronol; (4) VIP 10(-6) M; (5) VIP 10(-5) M; (6) nitroglycerine. Normothermic CPB was instituted in thirty rabbits at a flowrate of 100 ml/kg/min for 120 min. Heart rate, mean arterial pressure (MAP), central venous, left atrium (LAP), pulmonary artery (PAP) pressures, pulmonary resistance (Rp), blood gases and ions were measured before and 15, 30, 45 and 60 min after CPB. The VIP 10(-5) M group was subjected to an additional 1.7 x 10(-6) M propranol and 2 mM verapamil infusions for a further 15 min.. LAP, PAP, Qp, and Rp were significantly higher in the PHT control group (P<0.001). VIP 10(-5) M increased MAP and decreased PAP significantly with respect to isoproteronol and VIP 10(-6) M (P<0.05). VIP 10(-5) M also decreased Rp significantly in the early post CPB 15th minute (P<0.05), but did not show any superiority to other agents in the following minutes. Verapamil inhibited VIP 10(-5) M effects but propranol did not.. VIP has dose responsive, positive inotropic and pulmonary vasodilatory effects in whole body CPB model acting via calcium channels.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Calcium Channel Blockers; Cardiopulmonary Bypass; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Isoproterenol; Male; Monocrotaline; Nitroglycerin; Propranolol; Rabbits; Vasoactive Intestinal Peptide; Vasodilator Agents; Verapamil