Prevention of hypercholesterolemia and atherosclerosis in the hyperlipidemia- and atherosclerosis-prone Japanese (LAP) quail by taurine supplementation.

The effects of taurine supplementation on the serum cholesterol levels and the progression of atherosclerosis were investigated in the hyperlipidemia- and atherosclerosis-prone Japanese (LAP) quail. The ingestion of a high-cholesterol diet containing 1% cholesterol by LAP quails for 60 days resulted in a marked elevation in serum non-HDL cholesterol and triglyceride, as well as severe aortic lesions with lipid droplets. An immunohistochemical study showed that the lesion consisted of mainly lipid-rich macrophages and T cells. Sixty-day taurine supplementation (1% in drinking tap water) to LAP quails fed high-cholesterol diet containing 1% cholesterol significantly reduced serum non-HDL cholesterol from 4,549 to 2,350 mg/dl. The serum triglyceride level also decreased after taurine supplementation from 703 to 392 mg/dl. Although the HDL cholesterol level significantly decreased due to the high-cholesterol diet, it recovered to the control level fed a regular diet in response to taurine. Bile acid production was stimulated and hepatic cholesterol was reduced by taurine supplementation. A quantitative analysis using aortic cross-sections showed that areas of oil-red O positive lipid accumulation significantly decreased by 74% after taurine supplementation. These results demonstrated the lipid-lowering and anti-atherosclerotic effects of taurine in a diet-induced hyperlipidemic LAP quail model. The prevention of atherosclerosis by taurine is mainly attributed to an improvement in the serum cholesterol and triglyceride levels, which may be related to changes in the hepatic cholesterol metabolism.

Alterations in the inotropic responses to forskolin and Ca2+ and reduced gene expressions of Ca2+-signaling proteins induced by chronic volume overload in rabbits.

Volume overload results in eccentric cardiac hypertrophy, but it is still unknown how this mechanical overload modulates the inotropic response to exogenous Ca2+ or adenylyl cyclase stimulation. Inotropic responsiveness in vivo and the levels of gene expression of Ca2+ signaling proteins were studied in rabbit hearts hypertrophied as a result of volume overload at 4 and 12 weeks after arteriovenous shunt formation. In sham-operated control rabbits, left ventricular (LV)+dP/dt was augmented in response to graded doses of CaCl2. Dose-related changes of LV+dP/dt to CaCl2 were attenuated significantly in shunt rabbits with volume overload. Forskolin dose-dependently augmented LV+dP/dt in sham rabbits, which was also attenuated significantly in rabbits with volume overload. The mRNA levels of dihydropyridine receptor, Na+/Ca2+ exchanger, sarcoplasmic reticulum Ca2+-ATPase, and ryanodine receptor decreased significantly at 4 and 12 weeks in the volume-overload rabbits compared with the sham rabbits, but the mRNA levels of phospholamban and calsequestrin remained unchanged. Chronic volume overload alters contractile responsiveness to Ca2+ or adenylyl cyclase stimulation, and downregulation of steady state mRNA levels of Ca2+ signaling proteins might be, at least in part, related to this pathologic process.

Differential alteration of cardiotonic effects of EMD 57033 and beta-adrenoceptor agonists in volume-overload rabbit ventricular myocytes.

BACKGROUND: We investigated the effects of EMD 57033, a prototype Ca2+ sensitizer, and beta-adrenoceptor agonists in ventricular myocytes isolated from the volume-overload (V-O) heart failure model of the rabbit. METHODS AND RESULTS: V-O cardiac hypertrophy was induced in rabbits by the formation of an arterio-venous shunt between the carotid artery and jugular vein 12 to 15 weeks after the operation. Ventricular myocytes were enzymically isolated from normal and V-O rabbit hearts. The myocyte was loaded with a fluorescence Ca2+ dye, indo-1, and Ca2+ transients, and cell lengths were measured simultaneously. V-O myocytes were significantly larger than control myocytes. Duration of Ca2+ transients and cell shortening was significantly longer in the V-O myocytes than in control myocytes. Effects of cardiotonic interventions, including EMD 57033, isoproterenol, and dobutamine, on Ca2+ transients and cell shortening in V-O myocytes were compared with those in control rabbit myocytes. Isoproterenol and dobutamine increased the systolic cell shortening and peak Ca2+ transients and abbreviated the duration of cell shortening and Ca2+ transients. These responses were markedly attenuated in V-O myocytes. By contrast, the response of cell shortening to EMD 57033 was unaltered, and the Ca2+ sensitizing effect of EMD 57033 was rather enhanced in V-O myocytes. CONCLUSION: Our results indicate that the effectiveness of Ca2+ sensitizers is maintained in the V-O rabbit hypertrophy and heart failure model in contrast to the blunted response to beta-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca2+ sensitizers for the treatment of contractile dysfunction in congestive heart failure.

Prostanoids, coronary circulation and coronary artery spasm in open chest dogs and miniature pigs.

Effects of prostanoids on coronary circulation were studied in anesthetized open chest dogs with intact coronary arteries or in closed chest Göttingen miniature pigs with denuded vessels. In the latter model, coronary artery spasm was repeatedly provoked at the previously denuded area by histamine i.c. after pretreatment with cimetidine i.v., H2-blocker. In the canine model, prostacyclin (PGI2) dilated to a greater extent the diameter of the large epicardial coronary artery than did PGE2, and both equally reduced the total coronary resistance. Vasoconstrictive effects of carbocyclic thromboxane A2, a stable analogue of thromboxane A2 (TxA2) on the epicardial coronary artery was augmented from 1.1 +/- 0.3 to 6.5 +/- 1.3% (p less than 0.01) after pretreatment with cyclooxygenase inhibitors. In case of Göttingen miniature pigs 3 months after endothelial denudation and cholesterol freeding, neither PGI2 nor indomethacin prevented histamine-induced coronary artery spasm. Thiothromboxane A2, a stable analogue of TxA2, did not provoke coronary artery spasm in the animals. Therefore, prostanoids may not be crucial to the provocation or prevention of coronary artery spasm from which myocardial ischemia ensues.

Prompt relief of vasospastic angina by calcium antagonists.

A 57-year-old man had recurrent episodes of angina pectoris at rest. An electrocardiogram (ECG) during attack revealed transient ST elevations in leads V1 to V5. His symptoms were not relieved by sublingual nitroglycerin (TNG), but subsided promptly following sublingual or intravenous calcium antagonists. However, there was no difference between the degree of ST elevation on ECG recorded during the treatment of angina with either TNG or with calcium antagonist. Recurrent angina and painless ST elevation on Holter ECG recordings were prevented by a large dose of diltiazem. Coronary arteriography revealed only mild stenosis at the proximal portion of the left anterior descending coronary artery. It is suggested that coronary artery spasm was the cause of angina in this case and that sublingual or intravenous calcium antagonist was more effective in the treatment of acute attack of vasospastic angina than sublingual TNG.