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Reduction of exercise-induced regional contractile dysfunction in dogs using a novel calcium channel blocker (Ro
1Department of Pathophysiology, Universitätsklinikum Essen, Germany.
Insights
Ro 40-5967, a novel calcium channel blocker, improved regional cardiac function during exercise in dogs with coronary artery stenosis. This study demonstrates its potential for treating myocardial ischemia without altering resting hemodynamics.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Physiology
- Ischemic Heart Disease Research
Background:
- Chronic coronary artery stenosis can lead to exercise-induced myocardial ischemia and contractile dysfunction.
- Assessing novel therapeutic agents for managing ischemia is crucial for improving cardiac function.
Purpose of the Study:
- To evaluate the effects of Ro 40-5967, a novel calcium channel blocker, on systemic hemodynamics and regional contractile function.
- To determine if Ro 40-5967 can mitigate exercise-induced myocardial ischemia in a canine model.
Main Methods:
- A canine model of chronic coronary artery stenosis was established using an ameroid constrictor.
- Left ventricular pressure, dP/dt, aortic pressure, and regional wall thickening were measured.
- Hemodynamic and contractile function were assessed at rest and during treadmill exercise before and after Ro 40-5967 administration.
Main Results:
- Exercise induced significant regional contractile dysfunction in the poststenotic myocardium.
- Ro 40-5967 did not alter resting myocardial function.
- Ro 40-5967 significantly improved regional systolic wall thickening during exercise.
Conclusions:
- Ro 40-5967 effectively improved regional contractile function during exercise in the presence of coronary stenosis.
- The drug demonstrated a favorable profile by not affecting resting hemodynamics or distant myocardial regions.
- Ro 40-5967 shows promise as a therapeutic agent for managing exercise-induced myocardial ischemia.
Abstract:
Ro 40-5967 is a calcium channel blocker with a novel chemical structure. The purpose of this study was to evaluate the effects of Ro 40-5967 on systemic hemodynamics and regional contractile function in a canine model of chronic coronary artery stenosis in which no contractile dysfunction is observed at rest, but dynamic exercise elicits regional myocardial ischemia and contractile dysfunction. Thirteen dogs were chronically instrumented with sonomicrometers for the measurement of wall thickness in the anterior and posterior left ventricular walls, a micromanometer for measuring left ventricular pressure (LVP) and its first derivative (dP/dt), and a catheter in the aorta for measuring systemic arterial pressure. An ameroid constrictor on the left circumflex coronary artery produced gradual constriction of the vessel such that treadmill exercise elicited regional contractile dysfunction. Runs were repeated 3 hours later after the administration of Ro 40-5967 (0.3 mg/kg, IV). During the control run, regional systolic wall thickening in the posterior wall fell from 25.5 +/- 6.3% (SD) to 15.9 +/- 5.1% (p less than 0.05). Ro 40-5967 did not change resting function in the poststenotic myocardium (26.9 +/- 8.4%) but improved regional function during the run to 18.2 +/- 6.2% (p less than 0.05). This improvement was associated with a slight decrease in the exercise heart rate (213 +/- 18 vs. 200 +/- 16 bpm, NS), no change in peak ventricular pressure (156 +/- 22 vs. 157 +/- 20 mmHg), mean aortic pressure (123 +/- 19 vs. 118 +/- 20 mmHg), dP/dt (5129 +/- 1143 vs. 5288 +/- 1120 mm Hg/sec), or systolic wall thickening in a distant control region.(ABSTRACT TRUNCATED AT 250 WORDS)