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Objective: This study was designed to compare the effects of prostacyclin synthase (PCS) gene transfer with those of a systemic infusion of beraprost sodium (BPS), a prostacyclin analogue, on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. Methods: PCS gene (3 or 30 μg) was transfected into rat balloon-injured carotid arteries by a non-viral lipotransfection method. BPS (100 or 300 μg/kg/day) was subcutaneously infused with osmotic pumps after the injury. LacZ gene (30 μg) was used as a control. VSMC proliferation was estimated by the bromodeoxyuridine (BrdU) index (BrdU-positive nuclei/total nuclei) at day 7. Neointimal formation was evaluated at day 14. Each treatment group had six rats. Results: PCS gene transfer prevented the increase in intimal/medial area ratio (3 μg: 46.6%, 30 μg: 61.1% reduction; P<0.05, P<0.01, respectively), as did BPS 300 μg/kg/day (49.8% reduction; P<0.05). BPS 100 μg/kg/day, however, had no effects on the ratio. PCS gene transfer and BPS 300 μg/kg/day significantly suppressed the BrdU index. BPS 300 μg/kg/day group had more frequent hematoma and longer bleeding time. There were no significant differences in blood pressure, heart rate, or urinary volume among all groups. Conclusion: Both PCS gene transfer and BPS 300 μg/kg/day reduced neointimal formation after arterial injury by inhibiting VSMC proliferation. PCS gene transfer may be a safer therapeutic modality against neointimal formation than a systemic infusion of BPS because the former method resulted in fewer bleeding complications. [ABSTRACT FROM PUBLISHER]

Objective: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Methods: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar–Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1α, the main metabolite of PGI2, was also measured. Results: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. Conclusions: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR. [ABSTRACT FROM PUBLISHER]

Objective: 1,2-Diacylglycerol may initiate cardiac hypertrophy, probably by activating protein kinase C. To test this hypothesis we determined the 1,2-diacylglycerol content of hypertrophied tissue. Methods: Rats were treated with monocrotaline and developed severe right ventricular hypertrophy followed by congestive heart failure. 1,2-Diacylglycerol content and fatty acid composition, DNA concentrations, and RNA concentrations in the right ventricle from monocrotaline treated rats were compared with values obtained from the left side or from control rats. Results: During the first week, the right ventricle showed no significant change in 1,2-diacylglycerol content and a small increase in RNA concentration. However, the 1,2-diacylglycerol content was significantly increased by 55% at two weeks after monocrotaline injection, when DNA and RNA synthesis was also enhanced to its highest level when compared with control rats (37% and 18%, respectively). At four weeks after monocrotaline injection, conversely, the 1,2-diacylglycerol content was decreased by 25% in the right ventricle from monocrotaline treated rats, most of which had pleural and peritoneal effusions indicating congestive heart failure, although RNA synthesis was sustained at a high level. The fatty acid composition of 1,2-diacylgylcerol did not differ significantly between the right and left ventricles or control rat ventricles. Conclusions: These results suggest that 1,2-diacylglycerol accumulation is associated with development of hypertrophy in monocrotaline treated rats. In contrast, at a stage of congestive heart failure 1,2-diacylglycerol production decreased, suggesting that intracellular transduction mechanisms may be attenuated. [ABSTRACT FROM PUBLISHER]

Leakage of lysosomal enzymes is associated with irreversible cellular damage. To determine the effect of prostaglandin I2 analogue and propranolol on the ischaemic myocardium in relation to changes in lysosomal integrity 26 anaesthetised mongrel dogs were divided into three treatment groups and subjected to 2 h coronary occlusion. In the control group (n = 12) physiological saline was infused throughout the experiment. In the prostaglandin I2 analogue group (n=7) the prostaglandin I2 analogue, OP-41483-α-CD;5(E)-6,9-Deoxa-6,9 α-methylene-15-cyclopentyl-16,17,18,19,20-pentanor-PG I2 α-cyclodextrin clathrate (5 ng·kg−1·min−1) was infused from 25 min before occlusion until the end of the experiment. In the propranolol group (n=7) propranolol (0.3 mg·kg−1) was injected for 10 min 25 min before occlusion. Two hours after occlusion mitochondria were prepared from both ischaemic and non-ischaemic areas in each group and their function measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both non-ischaemic and ischaemic areas was performed and the activities of lysosomal enzymes (N-acetyl-β-glucosaminidase; β-glucuronidase) were measured. In the control group, mitochondrial function in the ischaemic area was reduced compared with that from the non-ischaemic area. The activities of both lysosomal enzymes were increased significantly in the supernatant fraction obtained from the ischaemic area compared with those for the supernatant from the non-ischaemic area. The administration of prostaglandin I2 analogue or propranolol not only prevented the leakage of lysosomal enzymes but also maintained mitochondrial function. These results suggest that mitochondrial dysfunction induced by 2 h occlusion is closely related to the leakage of lysosomal enzymes and that stabilisation of lysosomes by prostaglandin I2 or propranolol favourably alters the extent of ischaemia induced mitochondrial dysfunction. [ABSTRACT FROM PUBLISHER]

To identify the K+ channels responsible for endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation, we studied the effects of various K+ channel blockers on acetylcholine-induced relaxation, which persists even in the presence of both an inhibitor of nitric oxide synthase and that of cyclooxygenase, in canine coronary artery rings. A nonselective K+ channel blocker, tetrabutylammonium (TBA), a large and intermediate conductance Ca2+-activated K+ channel blocker, charybdotoxin (CTX), and a voltage-dependent K+ channel blocker, 4-aminopyridine (4-AP), significantly inhibited this residual relaxation. A combined treatment with CTX and 4-AP almost completely blocked the relaxation. Neither a large (iberiotoxin) nor a small (apamin) conductance Ca2+-activated K+ channel blocker blocked the relaxation. We also investigated effects of K+ channel blockers on basal tone to determine whether or not EDHF is involved in regulating basal tone. TBA and CTX substantially raised basal tone to a greater degree in endothelium-intact preparations than in endothelium-denuded preparations. These results indicate that EDHF may exert its relaxing action through intermediate conductance Ca2+-activated and voltage-dependent K+ channels in canine coronary arteries. In addition, EDHF may play a role in maintaining basal vascular tone. [ABSTRACT FROM AUTHOR]

We investigated the effects of angiotensin II type 2 (AT2) receptor blockade on the antihypertrophic effects of type 1 receptor (AT1) blockade in pressure-overload cardiac hypertrophy in adult rats. Cardiac hypertrophy was induced by banding the abdominal aorta above the renal arteries. The rats were treated with either an AT1 receptor antagonist TCV-116 (TCV, 10 mg/kg/day), an AT2 receptor antagonist PD123319 (PD, 20 mg/kg/day), or both for 4 weeks after the aortic banding. We measured systolic and diastolic blood pressure (BP), body weight (BW), left ventricular weight (LVW), and serum and cardiac angiotensin converting enzyme (ACE) activities. Aortic banding increased BP and LVW/BW, and TCV reversed both these increases. PD affected neither BP nor LVW/BW. TCV+PD reversed the increase in BP but not LVW/BW. Thus, PD was considered to counteract the antihypertrophic effect of TCV without affecting BP. All three treatments reduced cardiac ACE activity without affecting serum ACE activity. Our data demonstrated that AT2 receptor blockade negates the antihypertrophic effects of AT1 receptor blockade in an adult rat model of pressure-overload cardiac hypertrophy. AT2 receptors may mediate the signaling pathways involved in growth inhibition, which could counteract mediation of the cellular growth signaling pathways by AT1 receptors.