bq-123 and Hypertrophy--Left-Ventricular

Cardiomyocyte apoptosis and hypertrophy have been studied in the left and right ventricular myocardium of spontaneously hypertensive rats without treatment and after 10-day administration of the ETA-receptor antagonist BQ-123. It is established that BQ-123 prevents the activation of cardiomyocyte apoptosis and significantly decreases the extent of hypertrophy development in the left ventricular myocardium, but does not influence the same mechanisms in the right ventricular myocardium.

Topics: Animals; Antihypertensive Agents; Apoptosis; Endothelin A Receptor Antagonists; Heart Ventricles; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Myocytes, Cardiac; Peptides, Cyclic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ET(A)) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K(+) currents (I(K(+))) in coronary smooth muscle cells. Raising internal Ca(2+) from 200 to 500 nM increased Ca(2+)-sensitive K(+) current in HF-TR and control, but not HF animals. In conclusion, an ET(A)-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca(2+)-sensitive I(K(+)) was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca(2+)-sensitive I(K(+)), illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

Topics: Animals; Blood Pressure; Capillaries; Cardiotonic Agents; Coronary Circulation; Coronary Disease; Coronary Vessels; Dobutamine; Endothelin A Receptor Antagonists; Endothelin-1; Heart Rate; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Peptides, Cyclic; Physical Conditioning, Animal; Potassium Channels, Calcium-Activated; Receptor, Endothelin A; Swine; Swine, Miniature

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Cardiomegaly; Disease Progression; Echocardiography; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Hypertrophy, Left Ventricular; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Organ Size; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Aryl Hydrocarbon; RNA, Messenger

We have recently shown that angiotensin II-induced hypertrophy of cultured rat cardiomyocytes was partially blocked by an endothelin (ET) receptor antagonist (BQ123) selective for the ETA subtype, suggesting the possible involvement of endogenous ET-1 in the mechanism of cardiac hypertrophy in vitro. In the present study, we studied the in vivo blockade effects of BQ123 on cardiac hypertrophy provoked by left ventricular overload with aortic banding in adult rats.. Forty rats were divided into four groups: (1) sham-operated rats without BQ123 administration, (2) rats with aortic banding without BQ123 administration, (3) sham-operated rats with BQ123 administration, and (4) rats with aortic banding with BQ123 administration. BQ123 (250 micrograms/h) was administered continuously by an osmotic pump starting 24 hours before operation. BQ123 blocked increases in the ratio of left ventricular weight to body weight and in the diameter of cardiomyocytes provoked by aortic banding at 1 week, but those blockade actions were no longer observed at 2 weeks. Skeletal alpha-actin and atrial natriuretic peptide (ANP) mRNA in the left ventricle, transcriptional markers for cardiac hypertrophy, significantly increased in the rats with aortic banding at 1 week and 2 weeks. In the rats with BQ123 administration, despite the hemodynamic overload, skeletal alpha-actin and ANP mRNA in the left ventricle remained at the control levels at 1 week; however, those blockade actions were abolished at 2 weeks. Plasma ET-1 levels increased after aortic banding, peaking at 24 hours, then returned to the basal level at 4 days. Prepro-ET-1 mRNA levels in the left ventricle also increased 24 hours after aortic banding, then declined to the basal level at 4 days.. These data suggest that endogenous ET-1 synthesized in the cardiovascular system plays a role in the mechanism of cardiac hypertrophy during the early phase of pressure overload in vivo.

Topics: Actins; Animals; Atrial Natriuretic Factor; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gene Expression; Hypertrophy, Left Ventricular; Male; Peptides, Cyclic; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger