Hideaki Kido

Phosphoramidon prevents cerebral vasospasm following subarachnoid hemorrhage in dogs: the relationship to endothelin-1 levels in the cerebrospinal fluid.

There is increasing evidence that the conversion of big endothelin-1 (big ET-1) to endothelin-1 (ET-1) is specifically inhibited by the metalloproteinase inhibitor phosphoramidon. We investigated the effect of phosphoramidon on delayed cerebral vasospasm from subarachnoid hemorrhage (SAH) using a two-hemorrhage canine model. The magnitude of the vasospasm and the drug effect were determined angiographically. On SAH Day 7, diameter of the basilar artery decreased to about 55% of the control value obtained before SAH (on Day 0). Immunoreactive ET (IR-ET) in the cerebrospinal fluid (CSF) significantly increased after SAH (on Day 7). The intracisternal pretreatment of phosphoramidon potently suppressed the decrease in diameter of the basilar artery after SAH, i.e., observed decrease was only about 20%, compared with the value before SAH. In the phosphoramidon group, IR-ET in CSF markedly increased (on SAH Day 2), but the increased levels of IR-ET significantly declined on SAH Day 7. These results clearly indicate that phosphoramidon effectively prevents delayed cerebral vasospasm. Whether the prevention is due to the inhibition of conversion of big ET-1 to ET-1 is now under study.

Anti-aldosteronergic effect of torasemide

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3-3 mg/kg) and furosemide (3-30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.

Phosphoramidon inhibits the conversion of intracisternally administered big endothelin-1 to endothelin-1

It is suggested that endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). We examined the effects of intracisternal administration of big ET-1 on the cerebral arteries in the absence or presence of pretreatment with phosphoramidon, an inhibitor of ET converting enzyme, in anesthetized dogs. After intracisternal administration of big ET-1 (10 micrograms/dog), the caliber of the basilar artery on the angiogram was decreased to about 59% of the control. This was accompanied by a marked increase in immunoreactive ET in the cerebrospinal fluid. Systemic arterial pressure was markedly elevated following big ET-1 injection. All changes induced by big ET-1 were effectively prevented with phosphoramidon. These data suggest that intracisternally administered big ET-1 is converted to ET-1 and that the generated ET-1 produces cerebral vasospasm and hypertension. A phosphoramidon-sensitive metalloproteinase appears to contribute to this conversion.

A novel loop diuretic, torasemide, inhibits thromboxane A2-induced contraction in the isolated canine coronary artery

We examined the effect of a novel antihypertensive diuretic, torasemide, on the vasoconstriction induced by TXA2 in the isolated canine coronary artery. Carbocyclic thromboxane A2 (CTA2), a stable analogue of the potent coronary vasoconstrictor thromboxane A2, exhibited a slow onset and progressive contraction of isolated canine coronary arteries at 2 x 10(-8) M. Torasemide (10(-7) approximately 10(-4) M) elicited a dose-dependent vasodilating action in the isolated canine coronary arteries contracted by CTA2, whereas indapamide or furosemide had little effect on this preparation. The maximum vasodilating response to torasemide was 45 +/- 12% of vasodilating effect induced by 10(-4) M papaverine. These results suggest that torasemide is a promising antihypertensive agent with a coronary protective effect.

Diuretic and Vasodilating Actions of Torasemide

The pharmacological profile of torasemide was examined in experimental animals. In normotensive Wistar rats, torasemide produced less kaliuresis at doses that were equipotent with furosemide in terms of natriuresis. Torasemide but not furosemide exerted a significant diuretic action in rats treated with deoxycorticosterone acetate. Both torasemide and furosemide increased plasma renin activity and aldosterone concentration, but only torasemide significantly inhibited aldosterone-receptor binding in rat kidney. Torasemide also inhibited vasoconstriction induced by thromboxane A2 in isolated canine coronary artery.

Effects of AE0047 on renal haemodynamics and function in anaesthetized dogs

1. The effects of AE0047, a newly developed calcium channel blocker, on renal haemodynamics and function were investigated and compared with those of nicardipine in anaesthetized dogs.

Torasemide, but not frusemide, increases intracellular cAMP and cGMP content in the aorta of the renal hypertensive rat

Abstract— Repeated oral administration of the novel loop diuretic torasemide (3 mg kg−1) and frusemide (30 mg kg−1) for 7 days, elicited a significant fall in the systolic blood pressure in the one‐kidney, one‐clip Goldblatt renal hypertensive rat (RHR). The hypotensive action was greater in the torasemide group than in the frusemide group. Furthermore torasemide increased intracellular cAMP and cGMP content in aorta of RHR. Frusemide caused no effect. It is hypothesized that the increase in adenosine‐ or guanosine‐nucleotides is involved in the antihypertensive action of torasemide, but not in that of frusemide.

PREVENTATIVE AND THERAPEUTIC EFFECTS OF AE0047 ON RENAL INJURY IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. The present study was designed to investigate the preventative and therapeutic effects of AE0047 on renal injury compared with those of nitrendipine in stroke‐prone spontaneously hypertensive rats (SHRSP).

Diuretic Action of the Novel Loop Diuretic Torasemide in the Presence of Angiotensin II or Endothelin-1 in Anaesthetized Dogs

Abstract— The effects of torasemide (0·1 and 1 mg kg−1, i.v.) and furosemide (3 mg kg−1) on renal haemodynamics and excretory responses in the presence of angiotensin II and endothelin‐1 was examined in anaesthetized dogs. Angiotensin II or endothelin‐1 was continuously infused into the renal artery throughout the experiment and a bolus of torasemide or furosemide was injected into the bracheal vein. Continuous intrarenal arterial (i.r.a.) infusion of angiotensin II, at a dose of 5 ng kg−1 min−1, increased renal vascular resistance (RVR) and decreased renal blood flow (RBF) and glomerular filtration rate (GFR), but had no effect on systemic mean arterial pressure (MAP). Urinary excretion of sodium (UNaV) and urine flow (UF) were significantly decreased during angiotensin II infusion. Intravenous injections of torasemide in the presence of angiotensin II caused a dose‐dependent increase in UF, UNaV and urinary excretion of potassium (UKV), while a decrease in RVR was accompanied by an increase in RBF. UKV was greater in the furosemide group than in the torasemide group, despite both groups having the same degree of aquaresis and natriuresis. Continuous i.r.a. infusion of endothelin‐1, 1·5 ng kg−1 min−1, produced effects similar to those of angiotensin II on renal haemodynamics; however, the onset of action was extremely slow compared with the effects produced by angiotensin II. Endothelin‐1 caused a significant decrease in UF, UNaV and UKV only at a later period, despite a relatively early depression of renal haemodynamics. Torasemide and furosemide also produced a sufficient diuretic action in this model. Overall, kaliuresis was greater in the furosemide group than in the torasemide group. The present study demonstrates that torasemide exhibited a significant diuretic action in the angiotensin II‐ or endothelin‐1 ‐induced renal impairment model, with less kaliuresis than furosemide at a concentration which caused the same degree of natriuresis.

Possible mechanism for the anti-atherosclerotic action of the calcium channel blocker AE0047 in cholesterol-fed rabbits.

1. The present study was designed to investigate the anti‐atherosclerotic effect of AE0047, a calcium channel blocker, and to compare it with that of nilvadipine in cholesterol‐fed rabbits. Furthermore, the effects of AE0047 on low‐density lipoprotein (LDL) oxidation were studied in vitro.