The pharmacological differences in antianginal effects of long-lasting calcium channel blockers: azelnidipine and amlodipine.

We examined antianginal effects of azelnidipine and amlodipine in an arginine vasopressin-induced rat anginal model. Oral administration of azelnidipine or amlodipine produced long lasting inhibition of arginine vasopressin-induced ST-segment depression in electrocardiogram. The degrees of inhibition with azelnidipine at doses of 1 and 3 mg/kg were comparable to those with amlodipine at 3 and 10 mg/kg. Both drugs lowered mean blood pressure in a dose-related manner, whereas only azelnidipine decreased heart rate. Azelnidipine at 3 mg/kg and amlodipine at 10 mg/kg produced a similar decrease in the rate pressure product, an index for cardiac oxygen consumption. Their inhibitory effects on calcium-induced vascular contraction were compared in isolated porcine coronary arteries. Both drugs produced a slow-developing inhibition of calcium-induced contraction. Although their inhibitory effects were similar, the way the both drugs inhibited calcium-induced contraction differed with each other. After removing the drug from bathing solution, the inhibitory effects of azelnidipine were not blunted but were sustained for a long time, which indicates that azelnidipine has high vascular affinity. On the other hand, those of amlodipine were rapidly blunted. These results suggest that the mechanisms underlying antianginal effects of azelnidipine differ from those of amlodipine. The antianginal effect with azelnidipine may be accounted for by its high affinity to the coronary blood vessels and the heart rate slowing effect, both of which are not shared with amlodipine.

Spironolactone, but not eplerenone, impairs glucose tolerance in a rat model of metabolic syndrome.

Although some clinical studies have suggested that spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, appears to increase the blood glucose levels, experimental studies have not supported this notion. Here, we investigated the effect of SPL on blood glucose levels in SHR/NDmcr-cp(cp/cp) (ND) rats, an animal model of metabolic syndrome, in comparison with that of eplerenone (EPL), another MR antagonist. At the same dose of 100 mg/kg, SPL and EPL increased the urinary sodium-to-potassium ratio to a comparable extent, indicating that both agents have similar renal MR antagonistic efficacy in ND rats. Interestingly, SPL but not EPL significantly increased the level of blood glucose. The oral glucose tolerance test revealed that treatment with SPL led to glucose intolerance. The levels of serum insulin and adiponectin, regulators of the blood glucose level, were virtually unaffected by treatment with SPL. On the other hand, SPL induced a marked increase in the blood level of aldosterone, known to be a risk factor for insulin resistance. These results demonstrate that in comparison with EPL, SPL characteristically impairs glucose tolerance in an animal model of metabolic syndrome, in association with a higher blood level of aldosterone.

Chronotropic effects of azelnidipine, a slow- and long-acting dihydropyridine-type calcium channel blocker, in anesthetized dogs: a comparison with amlodipine.

Azelnidipine, a dihydropyridine calcium channel blocker unlike other dihydropyridine calcium channel blockers, does not increase but slightly decreases heart rate (HR) in clinical settings. In the present study, the mechanism for the HR-lowering action characteristic of azelnidipine was investigated in anesthetized dogs. In the in situ perfused sinus node preparation, the negative chronotropic action of azelnidipine was almost 5 times more potent than that of amlodipine. When injected intravenously in intact anesthetized dogs, both drugs produced a long-lasting blood pressure reduction, but the action of azelnidipine developed more slowly than that of amlodipine. Azelnidipine hardly affected HR at lower doses and decreased HR at higher doses. On the other hand, amlodipine consistently induced slight tachycardia. The HR-lowering effect of azelnidipine in autonomically blocked dogs was not much different from that in intact dogs, whereas tachycardia induced by amlodipine was eliminated in autonomically blocked dogs. However, neither drug affected the HR gain of baroreceptor reflex induced by changing carotid sinus pressure. These results suggest that compared with amlodipine, azelnidipine has a greater intrinsic negative chronotropic action and induces a lower level of reflex tachycardia most probably due to a slower development of blood pressure-lowering effects and that these characteristics of azelnidipine underlies its HR-lowering effects when administered systemically.

Synthesis and collateral dilator activity of nitroxyalkylamides having direct or latent sulfhydryl moieties.

To develop an orally active, long-acting nitrate that does not induce tolerance, nitroxyalkyl compounds were prepared and their activities evaluated by the use of carotid collaterals in anesthetized dogs. A compound having a favorable pharmacological profile, that is, long-lasting collateral vasodilatation and little hypotension, and lack of nitrate tolerance, was chosen for further evaluation.