dihydropyridines and Endomyocardial-Fibrosis

To examine the mechanism and significance of tachycardia-induced cardiac damage, using azelnidipine, a relatively new dihydropyridine calcium channel blocker which does not increase heart rate.. Comparing azelnidipine and amlodipine, we examined the cardiac effects and the direct effects on a sinus node/atrial preparation in stroke-prone spontaneously hypertensive rats (spSHRs). By pacing the right atrium, we examined the effect of tachycardia per se on cardiac oxidative stress. Using apocynin, a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, we investigated the role of oxidative stress in cardiac remodelling.. Azelnidipine suppressed cardiac hypertrophy, fibrosis, NADPH oxidase and superoxide in spSHRs more potently than amlodipine, and was associated with lower heart rates than amlodipine. Azelnidipine caused a greater reduction than amlodipine in the beat rate of the sinus node/atrial preparation of spSHRs. A 10 or 20% increase in heart rate, independent of blood pressure or sympathetic nerve activity, significantly enhanced cardiac NADPH oxidase activity, superoxide and activated mitogen-activated protein kinases. Reduction of cardiac oxidative stress by apocynin led to the suppression of cardiac hypertrophy, inflammation and fibrosis in spSHRs, beyond its hypotensive effect.. Our work provided evidence that the increase in heart rate per se, independent of sympathetic nerve activity, enhances cardiac oxidative stress and activates mitogen-activated protein kinases, which seem to be responsible for cardiac remodelling. Azelnidipine, without causing an increase in heart rate, has the potential to be useful for the treatment of cardiac remodelling.

Topics: Amlodipine; Animals; Azetidinecarboxylic Acid; Cardiomegaly; Dihydropyridines; Endomyocardial Fibrosis; Hydralazine; Hypertension; Male; Mitogen-Activated Protein Kinases; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tachycardia; Ventricular Remodeling

ICI 153,110 is an inotropic vasodilator compound intended for the treatment of congestive heart failure. It was administered to rats at dose levels of 5, 10, and 250 mg/kg/day for up to 6 months as part of its preclinical development program. Detailed clinical investigations were conducted during the course of the study and histopathological examination took place after 28 days and 182 days of treatment as well as 42 days following cessation of dosing. Changes were identified in blood vessels in the greater proportion of animals from the high dose group, although some of the changes were also observed at lower dose levels. Vascular tissues from a variety of sites were affected, particularly those of the mesentery, splanchnum, heart, testis, and the pampiniform plexus. Early changes characteristic of acute injury such as arterial medial necrosis and inflammation occurred, which were distinguishable from those following chronic administration of the compound where there was a pronounced arterial and venous wall thickening and accompanying plexiform vasculopathy. The essential components contributing to the thickening were a smooth muscle hypertrophy and hyperplasia of the media. At the end of the period following withdrawal of dosing, vascular thickening was still present and arteritis showed an increased incidence relative to that seen at termination of the main test. Systemic hypertension was not detected during these studies. Vasodilation occurring at or near normal blood pressure, resulting in breakdown of vascular autoregulation and excessive critical wall tension, may have been the cause of the pathological changes. Our findings indicate that medial necrosis is an early component in a sequence of adaptive, destructive, and reparative changes not only following a chemically induced perturbation of the hemodynamic status in arteries and veins but also following a shift back to the "normal state" on withdrawal of compound.

Topics: Animals; Aorta; Arteritis; Blood Pressure; Blood Vessels; Body Temperature; Cardiotonic Agents; Dihydropyridines; Dose-Response Relationship, Drug; Endomyocardial Fibrosis; Female; Heart Rate; Hyperplasia; Hypertrophy; Male; Mesenteric Veins; Mesentery; Muscle, Smooth, Vascular; Myocarditis; Myocardium; Pericarditis; Pyridazines; Random Allocation; Rats; Time Factors; Vasodilator Agents