Mesenteric Arteriopathy in the Rat Induced by Phosphodiesterase III Inhibitors: An Investigation of Morphological, Ultrastructural, and Hemodynamic Changes

Q4 · MEDICINE

Article

Author: Rees, J.A. ; Dayan, A.D. ; Joseph, E.C.

A reproducible model of a phosphodiesterase III (PDE III) inhibitor-induced arteriopathy has been developed in the rat after subcutaneous administration of SK&F 95654. Administration of this potent PDE III inhibitor induced an arteriopathy of mesenteric arteries within 24 hr that was dose-related in intensity and incidence over the range 0.174, 0.348, 0.523, and 0.697 mmol/kg. The arteriopathy was restricted to muscular arteries of external diameter of 100-800 μm and was shown microscopically to be focal or segmental medial necrosis and hemorrhage. A time-course experiment, conducted from 3 to 24 hr postdosing, showed that the first changes observed 6 hr postdosing were on the endothelium followed by focal hemorrhages into the media at 12 hr postdosing, causing compression, degeneration, and necrosis of myocytes. From 16 hr postdosing, there was focal endothelial cell necrosis and loss of confluence. Leukocytes and activated platelets were found adhering to exposed basement lamina and seen to pass through endothelial gaps into the subintima. By 24 hr postdosing, medial necrosis was extensive with large areas of media replaced by erythrocytes, cell debris, and a few leukocytes and platelets. The effect of 3 structurally dissimilar PDE III inhibitors administered subcutaneously at a dose of 0.697 mmol/kg was compared with that of SK&F 95654. The arteriopathy induced by these compounds were identical to that produced by SK&F 95654 with the incidence and severity of lesions ranked in the following order: SK&F 95654 > WIN 62582 > SK&F 94836, with no macroscopic lesions observed for SK&F 94120. Systolic blood pressure was measured for these 4 PDE III inhibitors at regular intervals over the 24-hr period postadministration by a plesthymographic method. The severity of the arterial lesions correlated with the magnitude of hypotension induced by these agents. It is postulated that the arterial damage is a consequence of profound vasodilation resulting in abnormal endothelial permeability and increased wall tension, resulting in progressive medial necrosis and hemorrhage.

01 Sep 1994·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Pharmacologic and Pharmacodynamic Effects of the Selective Low Km Cyclic AMP Phosphodiesterase III Inhibitors WIN 63291 and WIN 62582

Q4 · MEDICINE

Article

Author: Buchholz, R. Allan ; Lesher, George Y. ; Pagani, Edward D. ; Dundore, Ronald L. ; Bacon, Edward R. ; Bode, Donald C. ; Silver, Paul J. ; Singh, Baldev

We describe the biochemical, pharmacologic, and in vivo pharmacodynamic profiles of two novel inhibitors of the cyclic GMP-inhibitable, low Km cyclic AMP phosphodiesterase (PDE) III; WIN 63291, a 6-quinolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhibit PDE III from rat, dog, and human heart and from rat and canine aorta with IC50 values of 5-37 and 55-80 nM, respectively; the IC50 values for milrinone ranged from 300 to 520 nM. WIN 62582 and WIN 63291 are at least 1,000-fold selective for PDE III relative to inhibition of PDE isozymes I, II, IV, and V. We evaluated WIN 62582 and WIN 63291 in conscious rats and dogs after intravenous (i.v.) and oral (p.o.) administration. The dose of WIN 62582 required to reduce mean arterial blood pressure (MAP) by 20% (ED20) in rats was 1.8 mg/kg, with a pharmacodynamic duration of action of approximately 2 h. In comparison, the estimated i.v. ED20 for WIN 63291 in rats was 0.4 mg/kg, with a pharmacodynamic duration of action > 6 h. In conscious dogs, the i.v. doses of WIN 62582 and 63291 required to increase left ventricular (LV)dP/dtmax significantly were 0.1 and 0.01 mg/kg, respectively. In dogs, WIN 63291 0.1 mg/kg p.o. increased LVdP/dtmax by 86% in 30 min; LVdP/dtmax remained increased by 60% for at least 6 h. In comparison, WIN 62582, 0.3 mg/kg p.o., increased LVdP/dt by 56% in 30 min and remained increased by 40% at 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)

100 Deals associated with WIN-62582

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Discovery	GB	Sterling Winthrop Group Ltd	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

WIN-62582

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation