Radical scavengers of indapamide in prostacyclin synthesis in rat smooth muscle cell.

Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A2. Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [14C]arachidonate liberation nor prostacyclin synthase of the smooth muscle cells. Indapamide eliminated a stable free radical in a cell-free system, lowered the formation of malondialdehyde from lipid peroxides in rat brain homogenate, and reduced lipid peroxidation by the free radical generating system of xanthine-xanthine oxidase. Indeed, the scavenging action of indapamide significantly attenuated the inhibitory activity of 15-hydroperoxy-arachidonate to prostacyclin synthase activity. These results indicate that indapamide diuretic increases prostacyclin generation in the vascular smooth muscle cells possibly through antioxidant effects and that the enhanced prostacyclin generation is partly responsible for its direct vasodilator action.

Protective effect of the calcium antagonist NKY-722 against renal and arterial injuries in Dahl salt-sensitive rats.

OBJECTIVE: To study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats. DESIGN: Vehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks. METHODS: Systolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out. RESULTS: NKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta. CONCLUSIONS: NKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.

Endothelium-dependent relaxation followed by contraction mediated by NK(1) receptors in precontracted rabbit intrapulmonary arteries.

In the present study, we examined whether substance P (SP) and SP methyl ester (SPME), a selective NK(1) agonist, cause biphasic responses consisting of endothelium-dependent relaxation (EDR) and contraction (EDC) in precontracted rabbit intrapulmonary arteries. In arteries contracted with PGF(2alpha) (2x10(-6) M), SP as well as SPME caused only EDR at low concentration (10(-9) M) and EDR followed by EDC at higher concentrations, indicating the involvement of NK(1) receptors. The SP (10(-8) M)-induced EDR was abolished in arteries moderately contracted by PGF(2alpha) (5x10(-7) M) and the EDC in arteries maximally contracted by PGF(2alpha) (10(-5) M), indicating that EDR and EDC are inversely dependent on preexisting tone. Indomethacin (10(-8) - 10(-6) M), a cyclo-oxygenase inhibitor, and ozagrel (10(-8) - 10(-6) M), a TXA(2) synthetase inhibitor attenuated the EDC in the SPME (10(-7) M)-induced biphasic response and markedly potentiated the EDR. AA-861 (10(-8) - 10(-6) M), a 5-lipoxygenase inhibitor, did not affect the EDR or EDC. L-N(G)-nitro-arginine methyl ester (10(-5) - 10(-4) M), a nitric oxide synthase inhibitor, attenuated the EDR and slightly potentiated the EDC. CP-99994 (10(-10) - 10(-8) M), an NK(1) antagonist, attenuated the EDC and potentiated the EDR in the SPME (10(-7) M)-induced biphasic response, while the NK(2) antagonist SR-48968 (10(-9) - 10(-7) M) had no effect. CP-99994 attenuated the SPME (10(-7) M)-induced EDC under EDR-blockade to a greater extent than the EDR under EDC-blockade, indicating that CP-99994 enhanced the EDR component by preferential inhibition of the EDC component. In conclusion, NK(1) agonists caused a biphasic endothelium-dependent response (EDR and EDC) in submaximally precontracted intrapulmonary arteries. The EDC and EDR mediated by NK(1) receptors may play physiological and/or pathophysiological roles in modulation of vascular tone.

An endothelium-dependent contraction in canine mesenteric artery caused by caffeine.

1. We examined whether or not caffeine caused an endothelium-dependent contraction (EDC) in canine mesenteric artery and whether the endothelium-dependent contracting factors (EDCF) were arachidonic acid metabolites. 2. Caffeine (1, 3 and 10 mM) caused a transient contraction in endothelium-intact arterial strips. Removal of the endothelium significantly attenuated the caffeine (1 and 3 mM)-induced contraction. 3. Caffeine (1 mM)-induced EDC was not affected by quinacrine and manoalide (phospholipase A2 inhibitors), indomethacin and aspirin (cyclo-oxygenase inhibitors), ONO-3078 and S-1452 (thromboxane A2 antagonists) or AA-861 and TMK-777 (lipoxygenase inhibitors). 4. Caffeine (1 mM)-induced EDC was also unaffected by 50-235 (an endothelin A receptor antagonist). In addition, catalase combined treatment with superoxide dismutase, or allopurinol (antioxidant) did not affect the EDC. 5. Gro-PIP and NCDC (phospholipase C inhibitors) did not affect the caffeine-induced EDC. However, wortmannin (a phospholipase D inhibitor) and staurosporine (a protein kinase C inhibitor) attenuated the caffeine-induced EDC. 6. The present experiments demonstrate that caffeine causes an EDC in canine mesenteric artery and suggest that the EDCF mediating this response is probably not arachidonic acid metabolites, endothelin or superoxide. Instead, caffeine-induced EDC may be due to activation of the phospholipase D pathway.

Endothelium-dependent contraction in intrapulmonary arteries: mediation by endothelial NK1 receptors and TXA2.

1. We have examined whether three natural tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) induce an endothelium-dependent contraction (EDC) in the rabbit isolated intrapulmonary artery. 2. Removal of the endothelium almost abolished the contraction induced by SP (10(-8) M) while it did not attenuate the contraction induced by SP (10(-7) M), NKA (10(-9) - 10(-7) M) or NKB (10(-8) and 10(-7) M). 3. The EDC induced by SP (10(-8) M) was abolished by NK1 antagonists (FK-888, CP-96345, CP-99994 and SR-140333) but not by an NK2 antagonist (SR-48968). 4. The EDC induced by SP was attenuated by cyclo-oxygenase inhibitors (aspirin and indomethacin), thromboxane A2 (TXA2) synthetase inhibitors (OKY-046, KY-234 and KY-063) and a TXA2 antagonist (S-1452). 5. The rank order of potency causing endothelium-independent contraction (EIC) was NKA > NKB > SP. The EIC induced by SP (10(-7) M) was attenuated by an NK2 antagonist but not by NK1 antagonists, cyclo-oxygenase inhibitors, TXA2 synthetase inhibitors or a TXA2 antagonist. 6. In conclusion, SP at 10(-8) M induces EDC via endothelial NK1 receptors and TXA2 production, and SP at 10(-7) M induces EIC via NK2 receptors in the rabbit intrapulmonary artery.

The receptor occupation and plasma concentration of NKY-722, a water-soluble dihydropyridine-type calcium antagonist, in spontaneously hypertensive rats.

1. The occupation in vivo by NKY-722 of 1,4-dihydropyridine (DHP) calcium antagonist receptors in myocardium, aorta and cerebral cortex was investigated. At 1 and 3 h after oral administration of NKY-722 (3 mg kg-1) in spontaneously hypertensive rats (SHR), there was a significant (44 and 41%, respectively) decrease in the number of myocardial (+)-[3H]-PN 200-110 binding sites (Bmax) compared to control values. A greater reduction of Bmax values was observed at 1 (86%), 3 (88%), 6 (63%) and 12 (46%) h later by a higher dose (10 mg kg-1) of this drug. The occupation of myocardial 1,4-DHP calcium antagonist receptors after oral administration of NKY-722 correlated significantly with its plasma concentration. There was a significant decrease in cerebral cortical (+)-[3H]-PN 200-110 binding (Bmax) at 1 and 3 h after oral administration of NKY-722 (10 mg kg-1). 2. Oral administration of nicardipine (10 mg kg-1) in SHR caused a significant reduction of Bmax values for (+)-[3H]-PN 200-110 binding in myocardium at 1 and 3 h later and in cerebral cortex at 1 h later. 3. The in vivo specific binding of (+)-[3H]-PN 200-110 in particulate fractions of aorta of SHR was significantly (79 and 83%, respectively) reduced at 1 and 6 h after oral administration of NKY-722 (3 mg kg-1), while myocardial (+)-[3H]-PN 200-110 binding was decreased by 52% only at 1 h later. Also, nicardipine administration reduced in vivo ( + )-[3H]-PN 200-110 binding in aorta at 1 and 6 h later and in myocardium at 1 h later. On the other hand, the administration of both NKY-722 and nicardipine had no significant effect on in vivo (+ )-[3H]-PN 200-110 binding in cerebreal cortex.4 It is concluded that NKY-722 may exert more selective and sustained occupation in vivo of 1,4-DHP calcium antagonist receptors in vascular tissues of SHR than in myocardial and brain tissues.

Preventive effect of iganidipine on renal and cerebral injuries in salt-induced hypertension.

Iganidipine, a new water-soluble calcium antagonist, was administered at a nonhypotensive dose (NHD) of 0.3 mg/kg/day, a moderate-hypotensive dose (MHD) of 1.0 mg/kg/day, and a sustained-hypotensive dose (SHD) of 3.0 mg/kg/day to Dahl salt-sensitive (Dahl-S) rats fed a high-salt diet for 8 weeks. The effects on survival, and on renal and cerebral injuries, were then examined. Iganidipine completely prevented hypertensive death at the SHD and tended to increase the survival at the NHD and MHD. Iganidipine reduced glomerulosclerosis and renal arterial and tubular injuries in a dose-dependent manner. Iganidipine at the SHD, but not NHD or MHD, improved plasma creatinine, serum urea nitrogen, and glomerular filtration rate. Iganidipine at all doses examined increased the urinary prostaglandin (PG) I2 and PGE2, but not PGF2alpha or thromboxane B2, and decreased plasma angiotensin II (AII) level and renin activity. The renal glomerular, tubular, and arterial injuries were significantly correlated with blood pressure (r = 0.56 to 0.80) and plasma AII level (r = 0.50 to 0.71) but not with urinary prostanoids. Iganidipine also reduced the incidence of cerebral infarction. The infarction area was slightly and significantly correlated with urinary PGI2 (r = 0.42) and PGE2 (r = 0.41) but not with blood pressure or plasma AII. In conclusion, iganidipine prevented renal and cerebral injuries in Dahl-S rats. In addition to the reduced blood pressure, the reduction of plasma AII and the increase of vasodilatory prostanoids may also partially contribute to the renal and cerebral protective effects of iganidipine.

Structure-activity relationships for relaxation of smooth muscle by VIP.

Utilizing VIP and five VIP analogues, concentration-response curves for relaxation of rat mesenteric artery and rat gastric longitudinal muscle were determined for comparison with our previously published radioligand binding data on rat smooth muscle and other tissues. The biological potency of the VIP analogues in the present study compared more closely with their potency for VIP receptor binding in smooth muscle tissue (arteries) vs. other tissues (pituitary, brain, liver).

Comparative study of vascular relaxation and receptor binding by PACAP and VIP.

The pharmacological properties of the pituitary adenylate cyclase activating peptides (PACAPs) and vasoactive intestinal peptide (VIP) were compared using: (i) relaxation of vascular and gastric smooth muscle in vitro, and (ii) radioligand binding to membrane preparations of a variety of tissues. Vasoactive intestinal peptide and PACAP-27 were similarly potent in relaxing rat mesenteric arteries, porcine coronary arteries, and rat gastric smooth muscle, whereas PACAP-38 was either more or less potent than the other two peptides depending on the tissue model. Cross-desensitization to relaxation and radioligand binding studies of porcine coronary arteries suggested that VIP and the PACAPs interact with a common receptor in this tissue. A PACAP-preferring receptor with low affinity for VIP was identified in radioligand binding studies of rat brain and anterior pituitary. A second, nonselective, receptor that binds VIP and both PACAPs with high affinity was observed in preparations of rat and porcine arteries and rat lung, liver, brain, and anterior pituitary.

Endothelial cells modulate the vasoinhibitory effect of NKY-722, a Ca2+ channel antagonist, in canine mesenteric arteries.

Modulation of the vasoinhibitory effect of NKY-722 by vascular endothelial cells was studied in canine mesenteric arteries. A high concentration of NKY-722 accumulated in the endothelium-intact arteries and its accumulation in endothelium-removed arteries was significantly less. The vasoinhibitory effect of NKY-722 in endothelium-intact arteries was significantly weaker than that in endothelium-removed arteries. These results suggest that endothelial cells can attenuate the vasoinhibitory effect of NKY-722.

Endothelium-dependent contraction produced by acetylcholine and relaxation produced by histamine in monkey basilar arteries.

The present experiments were carried out to investigate endothelium-dependence of the responses to ACh, arachidonic acid and histamine in monkey basilar arteries. As we reported previously (1), ACh (10(-7) M) and arachidonic acid (5 x 10(-7) M) caused endothelium-dependent contraction (EDC) in both monkey and canine basilar arteries. The endothelium-derived contracting factor (EDCF) is probably TXA2, since the EDC was attenuated by a cyclooxygenase inhibitor (aspirin, 5 x 10(-5) M), thromboxane A2 (TXA2) synthetase inhibitors (OKY-046, 10(-5) M; RS-5186, 10(-6) M) and TXA2 antagonists (ONO-3708, 10(-8) M; S-145, 5 x 10(-9) M). Histamine caused endothelium-dependent relaxation (EDR) in monkey basilar arteries and EDC in canine basilar arteries. The EDR in monkey basilar arteries was attenuated by nitric oxide synthetase inhibitor, NG-monomethyl-L-arginine (L-NMMA) in a concentration-dependent manner and the EDC in canine basilar arteries was attenuated by aspirin, TAX2 synthetase inhibitors and TXA2 antagonists. The EDR and EDC were antagonized by tripelennamine (10(-6) M) but not by cimetidine (10(-5) M), indicating that they are mediated by H1-receptors. From these results, we suggest that in the monkey basilar artery, either there are two types of endothelium, an EDCF type for ACh and arachidonic acid and an EDRF type for histamine, or there is single type of endothelium with two types of signalling processes, one for EDC and one for EDR.

Endothelium-dependent contraction induced by substance P in canine cerebral arteries: involvement of NK1 receptors and thromboxane A2.

We characterized the endothelial responses to substance P (SP) in the isolated canine cerebral artery. SP caused concentration-dependent contraction at 10(-10) - 10(-7) M and relaxation at 10(-10) and 10(-9) M, which were abolished by removal of the endothelium. The SP-induced endothelium-dependent relaxation (EDR) was suppressed, while the endothelium-dependent contraction (EDC) was increased by repeated application. The EDC induced by SP (10(-7) M) was attenuated by SR-140333 (10(-9) - 10(-7) M) and CP-99994 (10(-7) M), both NK1 antagonists, but not by SR-48968 (10(-7) M), an NK2 antagonist, or four antagonistic SP analogues (10(-6) M). The EDC induced by SP (10(-7) M) was attenuated by aspirin (10(-5) M), a cyclooxygenase inhibitor, OKY-046 (10(-5) M), a TXA2 synthetase inhibitor and ONO-3708 (10(-8) M), a TXA2 antagonist. Neurokinin A (10(-7) M) but not neurokinin B (10(-7) M) caused EDC similar to that induced by SP. In conclusion, SP induces EDC via endothelial NK1 receptors and TXA2 production in canine cerebral arteries.

Endothelium-independent and -dependent contractions induced by endothelin-1 in canine basilar arteries.

Endothelium-dependence of contractile responses to endothelin-1 was examined in isolated canine basilar arteries. Within 2 hrs after mounting tissue preparations, endothelin-1 (10(-9) M) caused a monophasic tonic contraction that developed very slowly and was sustained in intact and endothelium-removed arteries. More than 5 hrs after tissue mounting, endothelin-1 (10(-9) M) caused a biphasic contraction consisting of phasic and tonic components in intact arteries, and caused a monophasic tonic contraction in endothelium-removed arteries. This phasic component was significantly decreased by aspirin (5 x 10(-5) M,), OKY-046 (10(-5) M) (a TXA2 synthetase inhibitor) and ONO-3708 (10(-8) M) (a TXA2 antagonist). The present experiments demonstrate that endothelin-1 causes an endothelium-independent tonic contraction and an endothelium-dependent phasic contraction in canine basilar arteries, and suggest that TXA2 plays a role as an endothelium-derived contracting factor.

Endothelium-dependent contraction induced by nicotine in isolated canine basilar artery--possible involvement of a thromboxane A2 (TXA2) like substance.

The present experiments were undertaken to determine whether the response to nicotine in the isolated canine cerebral artery is endothelium-dependent. Changes in the tension of arterial strips were recorded isometrically. Removal of the endothelium was carried out by gentle rubbing, and confirmed by scanning electron microscopy. Rubbing procedure did not affect the contractile response of the strips to serotonin. Treatment of unrubbed strips with nicotine (10(-4)M) caused a transient contraction. This response was abolished by removal of endothelium and attenuated by hexamethonium (5 x 10(-6)M) and atropine (10(-6)M). The nicotine-induced contraction was attenuated also by aspirin (5 x 10(-5)M), a cyclooxygenase inhibitor, OKY-046 (5 x 10(-5)M), a thromboxane A2 (TXA2) synthetase inhibitor and ONO-3708 (5 x 10(-9)M), a TXA2 antagonist. These results indicate that the nicotine-induced contraction in canine cerebral artery is endothelium-dependent, and suggest that the endothelium-derived contracting factor (EDCF) in the nicotine-induced response is a TXA2-like substance.

Somatostatin-induced contraction mediated by endothelial TXA2 production in canine cerebral arteries.

Whether somatostatin causes endothelium-dependent contraction (EDC) in isolated canine basilar arteries was examined. Somatostatin (10(-8)-10(-6) M) caused transient contractions in a dose-dependent manner. These contractions were abolished by removal of the endothelium, while the contractile response to neuropeptide Y occurred even after removal of the endothelium. The EDC induced by somatostatin (10(-7) M) was affected by neither atropine (10(-6) M) nor cyclo-somatostatin (10(-5) M), which suggests that the EDC is not due to release of endogenous acetylcholine and that the endothelial somatostatin receptor is different from hormonal somatostatin receptors. The somatostatin-induced EDC was attenuated by cyclooxygenase inhibitors (aspirin and indomethacin), thromboxane A2 (TXA2) synthetase inhibitors (OKY-064 and RS-5186), and TXA2 antagonists (ONO-3708 and S-145), which suggests that the endothelium-derived contracting factor is TXA2. These findings demonstrate that somatostatin causes EDC via activation of TXA2 synthesis in canine cerebral arteries.

Inhibitory effects of PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 on iNOS induction in rat mesenteric artery.

PGD2 and its metabolites PGJ2 and 15-deoxy-delta12,14-PGJ2 have been reported to inhibit iNOS induction in cultured vascular smooth muscle cells. The present study was undertaken to determine whether these prostanoids inhibit iNOS induction in the isolated rat mesenteric artery. The artery without endothelium was incubated with and without lipopolysaccharide (LPS) at 37 degrees C for 6 hrs, then washed and mounted in an organ bath to measure isometric changes in tension. L-arginine but not D-arginine (10(-6) - 10(-3) M) induced concentration-dependent relaxations only in the artery preincubated with LPS, the relaxations of which were attenuated by L-N(G)-nitroarginine methyl ester (LNAME, 10(-4) M), a non-selective iNOS inhibitor, and 1400W (10(-5) and 10(-4) M), a selective iNOS inhibitor. Co-treatment of cycloheximide (10(-5) M), a protein synthesis inhibitor, or actinomycin D (10(-7) M), an RNA synthesis inhibitor with LPS inhibited the development of relaxing ability in response to L-arginine, indicating iNOS induction by LPS. PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 but not PGE2, PGI2 or PGF2alpha also inhibited the development of relaxing ability in response to L-arginine when added during incubation with LPS. Incubation of the artery with LPS at 37 degrees C for 6 hrs markedly increased production of nitric oxide (NO), which was abolished by 15-deoxy-delta12,14-PGJ2 (10(-5) M). An imunohistochemical study using antibody against murine iNOS showed that 15-deoxy-delta12,14-PGJ2 (10(-5) M) inhibited the expression of iNOS protein in isolated rat mesenteric arteries. These results demonstrated that PGD2 and its metabolites inhibit iNOS induction by LPS in isolated rat mesenteric arteries, resulting in reduced relaxing ability in response to L-arginine.

Pharmacological natures of caffeine-induced endothelium-dependent and -independent contraction in canine mesenteric artery.

The present experiments were carried out to elucidate whether pharmacological nature of caffeine (1 mM)-induced endothelium-dependent contraction (EDC) is different from that of caffeine (10 mM)-induced endothelium-independent contraction (EIC) in canine mesenteric artery. Caffeine (1 mM)-induced EDC was abolished when arterial strips were incubated in Ca(++)-free medium for 20 min, but EIC was not abolished. EGTA and EDTA (0.5 and 1 mM) attenuated the EDC, and at the concentration of 2.5 mM completely abolished the EDC. Nifedipine (10(-6) and 3 x 10(-6) M), diltiazem (10(-6) M) and verapamil (10(-6) M) did not affect the caffeine (1 mM)-induced EDC. Lemakalim (10(-8), 3 x 10(-8) and 10(-7) M) attenuated the caffeine (1 mM)-induced EDC in a concentration-dependent manner. Lemakalim (10(-7) M) nearly abolished the EDC. The inhibitory effect of lemakalim (10(-7) M) on the EDC was antagonized in the presence of glibenclamide (3 x 10(-6) M). In contrast, caffeine (10 mM)-induced EIC was resistant to lemakalim at higher concentration (3 x 10(-7) M). Forskolin (10(-7), 3 x 10(-7) and 10(-6) M) significantly attenuated both the caffeine (1 mM)-induced EDC and caffeine (10 mM)-induced EIC. The inhibitory effect of forskolin on the EDC was augmented in the presence of rolipram (10(-6) M). Nitroglycerin (10(-5) M) attenuated significantly caffeine-induced both EDC and EIC. The inhibitory effect of nitroglycerin on the EDC was augmented in the presence of zaprinast (10(-5) M). The present experiments demonstrate that caffeine-induced EDC is due to nifedipine-resistant and lemakalim-sensitive Ca++ mobilization and the EIC is due to both nifedipine- and lemakalim-resistant Ca++ mobilization in canine mesenteric artery.

AS-924, a novel bifunctional prodrug of ceftizoxime.

To improve the oral absorption of ceftizoxime (CZX), 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-cephem-4- carboxylic acid, we synthesized and evaluated a novel series of bifunctional prodrugs, in which L-alanine was introduced into the aminothiazole-oxime moiety at the C-7 position of the various lipophilic esters of CZX. Among these prodrugs, pivaloyloxymethyl 7beta-[(Z)-2-(2-(S)-alanylaminothiazol-4-yl)-2-methoxyiminoa cetamido]-3-cephem-4-carboxylate hydrochloride (ceftizoxime alapivoxil, AS-924) was well absorbed after oral administration in experimental animals and showed potent therapeutic effects in mice infected with gram-positive and gram-negative bacteria.

Effect of topically applied iganidipine dihydrochloride, a novel calcium antagonist, on optic nerve head circulation in rabbits.

PURPOSE: To study the effect of topically applied iganidipine dihydrochloride (iganidipine), a novel water-soluble calcium channel blocker, on blood flow in the optic nerve head (ONH), intraocular pressure, and systemic blood pressure in rabbits. METHODS: After 0.1% iganidipine (20 microL) was instilled into normal eyes, the change in ONH blood flow was measured using a hydrogen gas clearance flowmeter. Iganidipine (0.0001% to 0.1%) was instilled into eyes with impaired ocular circulation before or after the intravitreal injection of endothelin-1, and the change in ONH blood flow was measured. Changes in intraocular pressure and blood pressure after instillation of 0.1% iganidipine were measured. In all experiments, physiological saline was instilled into the contralateral eye as a control. RESULTS: Iganidipine significantly increased the ONH blood flow in normal eyes with the maximum increment of 31.7% at 45 minutes after instillation. Preinstillation of 0.01% and 0.1% iganidipine significantly inhibited the decrease in ONH blood flow in the eyes with impaired circulation. Moreover, ONH blood flow recovered with postinstillation of 0.1% iganidipine. These effects were persistent. Instillation of 0.1% iganidipine did not change either the intraocular pressure or the blood pressure. CONCLUSION: The instillation of iganidipine persistently increased and maintained the ONH blood flow in rabbit eyes with normal and impaired ocular circulation.

[Effect of topically applied iganidipine dihydrochloride, a novel Ca2+ antagonist, on optic nerve head circulation in rabbits].

PURPOSE: We studied the effect of topically applied iganidipine dihydrochloride, a novel water-soluble calcium channel blocker on the blood flow of optic nerve head (ONH), intraocular pressure, and blood pressure in rabbits. METHODS: 1. 0.1% iganidipine (20 microliters) was instilled into a normal eye. The change in blood flow in the ONH was measured using a hydrogen gas clearance flowmeter. 2. Iganidipine (0.0001%-0.1%) was instilled into a circulation-disordered eye before or after the intravitreal injection of endothelin-1, and change in the blood flow in the ONH was measured. 3. Changes in intraocular pressure and blood pressure after instillation of 0.1% iganidipine were measured. In all experiments, physiological saline was instilled in each contralateral eye as a control. RESULTS: 1. Instillation of iganidipine significantly increased the blood flow in the ONH by 40% at 45 minutes after instillation. 2. Pre-instillation of 0.01 and 0.1% iganidipine almost completely inhibited the decrease of blood flow in the ONH in the circulation-disordered model. The decrease of blood flow in the ONH was corrected with post-instillation of 0.1% iganidipine. These effects were continuous. 3. Instillation of 0.1% iganidipine did not change either intraocular pressure or blood pressure. CONCLUSION: It was shown that instillation of iganidipine continuously increased and maintained the blood flow in the ONH in normal and circulation-disordered rabbit eye models.