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Research was conducted to examine the involvement of microtubules in early hypertrophic responses of myocardium during pressure overload. The objective is to determine whether the inhibition of microtubule function led to a decreased expression of the immediate early gene c-fos and fetal contractile protein genes. Results revealed another possible physiological function of microtubule cytoskeleton which is the induction of the hypertrophic gene program in reaction to the mechanical load.

The effects of heart failure on the expression of the sarcoplasmic reticulum (SR) calcium-adenosine triphosphatase (Ca2+-ATPase) and the subsequent effect on contractility was investigated in isolated myocyte from dogs with pacing-induced heart failure and normal controls. Results reveal that heart failure depresses the expression of Ca2+-ATPase resulting in a reduction in SR calcium uptake. This leads to a depression in myocardial contractility.

Sarcoplasmic reticulum (SR) Ca2+-adenosine triphosphatase (ATPase) mRNA expression is reduced in the failing human myocardium. However, it is not known whether SR Ca2+-regulatory protein gene expression is altered in human myocardial tissue subjected to pressure overload or volume overload. We sought to determine whether SR Ca2+-regulatory protein gene expression is altered in human atrial tissue subjected to mechanical overload. We obtained right atrial myocardial tissue (about 250mg) at open-heart surgery from three groups of patients: no hemodynamic overload to the right atrium (control group; 12 patients), atrial septal defect (ASD group; 8 patients), and tricuspid regurgitation (TR group; 7 patients). We measured the myocyte size, the area of interstitial fibrosis, SR Ca2+-ATPase, and ryanodine receptor mRNA abundance. The isolated cardiocyte area and the percent area of interstitial fibrosis were in the order TR > ASD > control ( P < 0.05). The SR Ca2+-ATPase mRNA level in TR was significantly decreased ( P = 0.004) compared with the control, whereas in the ASD group it did not differ significantly from control. There were no significant differences in ryanodine receptor mRNA levels among the three groups. SR Ca2+-ATPase gene expression was downregulated in human atrial tissue with TR but not in ASD, which might have resulted from the differences in the degree and/or the type of hemodynamic overload to the myocardium. [ABSTRACT FROM AUTHOR]

Objective: X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs. Methods: In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber. Results: The percent reduction in coronary diameter evoked with 10 μg · kg−1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 μg · kg−1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2 [52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) μm] than at the denuded sites without X-irradiation [group 2, 58(5) μm] (P < 0.05). Conclusions: These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle. [ABSTRACT FROM PUBLISHER]

Objective: The aim was to elucidate the contribution of atheromatous plaque to alterations of smooth muscle contraction to vasoconstrictive agents, by examining vasoreactivity of vascular smooth muscle from the thoracic aorta of 10-13 month old Watanabe heritable hyperlipidaemic rabbits. Methods: From the same vascular ring of the lower thoracic aorta, a pair of small medial smooth muscle strips was prepared from the sites beneath the atheroma (atherosclerotic medial muscle strip) and from those beneath the plaque-free intima (normal medial muscle strip), and isometric tension was measured. Results: Contractions to 118 mM KC1, histamine (30 nM to 10 μM), and noradrenaline (3 nM to 0.3 μM) were similar between atherosclerotic and the normal medial muscle strip. The ED50 to serotonin was 49(SD 28) and 116(66) nM (p<0.05, n = 7) and the maximum tension to serotonin was 125(29)% and 82(29)% of that induced by 118 mM KC1 (p<0.01, n = 7) in atherosclerotic and normal medial muscle strip, respectively. Serotonin specific hyperreactivity of the atherosclerotic strip disappeared in Ca2+−free solution or in the presence of 10 μM H-7, an inhibitor of protein kinase C. After incubation with 0.1 μM phorbol 12,13-dibutyrate, an activator of protein kinase C, the isometric contractions induced by Ca2+ were significantly greater in atherosclerotic than in normal medial muscle strip. Conclusions: These results indicate that medial smooth muscle located beneath the atheroma is specifically hyperreactive to serotonin and that altered protein kinase C activity may explain in part the augmented response to serotonin.Cardiovascular Research 1993;27:2164-2169 [ABSTRACT FROM PUBLISHER]

Determines the functional consequence of a decreased expression of sarcoplasmic reticulum (SR) Ca[sup 2+]-ATPase in tachycardia-induced heart failure. Myocyte contractile function and gene expression of SR Ca[sup 2+]-ATPase; Effects of thapsigargin and cyclopiazonic acid on contractile function and intracellular free Ca[sup 2+] concentration transient in normal myocytes.