Actions of CP-060S on veratridine-induced Ca2+ overload in cardiomyocytes and mechanical activities in vascular strips.

CP-060S, (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one hydrogen fumarate, is a novel cardioprotective drug which is designed to prevent Ca2+ overload and cause vasorelaxation. The effects of this compound were evaluated and compared with those of CP-060R (enantiomer of CP-060S,) and diltiazem (Ca2+ channel antagonist) in a veratridine-induced model of Ca2+ overload and vasorelaxation. After 5-min superfusion of veratridine (74 microM), intracellular free calcium concentrations ([Ca2+]i) of rat single cardiomyocytes, as measured with the fura-2 procedure, were greatly elevated, from 44 +/- 5 nM to 3705 +/- 942 nM, and subsequently generated cell contracture. Pretreatment of cardiomyocytes with more than 300 nM of CP-060S or CP-060R for 30 min provided almost complete protection against the veratridine-induced cell contracture; in CP-060S(1 microM)-treated myocytes, [Ca2+]i were minimal and partially elevated from 42 +/- 5 nM to 72 +/- 14 nM after 5 min of veratridine superfusion. In comparison, diltiazem showed no protection below 1 microM and only partial protection at 10 microM. CP-060S, CP-060R and diltiazem all shifted the concentration-response curve for CaCl2 to the right in a competitive manner in depolarized rat thoracic aorta. The pA2 values of CP-060S, CP-060R and diltiazem were 9.16 +/- 0.18, 8.24 +/- 0.14 and 7.66 +/- 0.09, respectively. Our results indicate that CP-060 behaves stereoselectively as a Ca2+ channel antagonist and non-stereo-selectively to protect against veratridine-induced contracture. The latter effect suggests that Ca2+ entry blockade is not the mechanism by which CP-060S exerts cardioprotection.

Effect of KC399, a newly synthesized K+ channel opener, on acetylcholine-induced electrical and mechanical activities in rabbit tracheal smooth muscle.

1. Effects of KC399, an opener of ATP-sensitive K+ channels were investigated on membrane potential, isometric force and intracellular Ca2+ ([Ca2+]i) mobilization induced by acetylcholine (ACh) in smooth muscle from the rabbit trachea. 2. In these smooth muscle cells, ACh (0.1 and 1 microM) depolarized the membrane in a concentration-dependent manner, KC399 (1-100 nM) hyperpolarized the membrane whether in the presence or absence of ACh. When the concentration of ACh was increased, the absolute values of the membrane potential induced by the maximum concentration of KC399 were less negative. 3. ACh (0.1 to 10 microM) concentration-dependently produced a phasic, followed by a tonic increase in both [Ca2+]i and force. KC399 (above 3 nM) lowered the resting [Ca2+]i and attenuated the ACh-induced phasic and tonic increases in [Ca2+]i and force, in a concentration-dependent manner. The magnitude of the inhibition was greater for the ACh-induced tonic responses than for the phasic ones. Nicardipine (0.3 microM), a blocker of the L-type Ca2+ channel, attenuated the ACh-induced tonic, but not phasic, increases in [Ca2+]i and force. KC399 further attenuated the ACh-induced tonic responses in the presence of nicardipine. 4. In beta-escin-skinned strips, Ca2+ (0.3-10 microM) produced a contraction in a concentration-dependent manner. KC399 (0.1 microM) had no effect on the Ca(2+)-force relationship in the presence or absence of ATP with GTP. However, at a very high concentration (1 microM), this agent slightly shifted the relationship to the right and attenuated the maximum Ca(2+)-induced contraction. 5. We conclude that, in rabbit tracheal smooth muscle, the membrane hyperpolarization induced byKC399 attenuates the ACh-induced tonic increase in [Ca2+], through an inhibition of nicardipinesensitive and -insensitive Ca2+-influxes, thus causing an inhibition of the ACh-induced tonic contraction. The ACh-induced phasic increase in [Ca2+]i and force are also inhibited, but less effectively than the tonic ones, suggesting that the action of such K+ channel openers on agonist-induced responses may be slightly different in tracheal from vascular smooth muscle.

The neuroprotective effect of a potent and selective inhibitor of type I NOS (L-MIN) in a rat model of focal cerebral ischaemia.

Our newly synthesized delta-(S-methylisothioureido)-L-norvaline (L-MIN) was shown to have potent inhibitory effects on Ca(2+)-dependent and constitutively expressed neuronal nitric oxide synthase (type I NOS) when compared to other commonly recognized NOS inhibitors and produced an IC50 value of 5.7 nM. By contrast, this compound exhibited more than 40-fold weaker inhibitory effects on the other NOS isoforms. Administration of L-MIN (0.1, 0.3 and 1 mg kg-1, i.p.) to rats immediately after 2 h middle cerebral artery occlusion and 2 h reperfusion reduced infarct size in a dose-dependent manner. These results suggest that type I NOS activation has a crucial role in the pathogenic cellular mechanisms underlying cerebral ischaemia.

GM-109: a novel, selective motilin receptor antagonist in the smooth muscle of the rabbit small intestine.

The pharmacological properties of the cyclic peptide Phe-cyclo[Lys-Tyr(3-tBu)-beta Ala-].trifluoroacetate (GM-109), a selective motilin antagonist, were investigated in the smooth muscle of the rabbit small intestine. GM-109 (0.1-3 microM) competitively inhibited contractions induced by porcine motilin (pMTL) in rabbit isolated duodenum longitudinal strips, with a pA2 value of 7.37 +/- 0.24. However, the contractile response to acetylcholine, to substance P, to prostaglandin F2 alpha and to KCl was unaffected by 10 microM GM-109 in the same preparation. Both GM-109 and pMTL competitively inhibited 125I-pMTL binding to motilin receptors in a homogenate of the rabbit small intestinal smooth muscle tissue. The pKi value of GM-109 and the pKd value of unlabeled pMTL were 7.99 +/- 0.04 and 9.25 +/- 0.06 (each n = 5), respectively. These results indicate that GM-109 is a selective and competitive motilin receptor antagonist in the smooth muscle of the rabbit small intestine. Thus this compound may be a useful pharmacological tool for examining the functional role(s) of motilin.

Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim.

1. The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol-induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea-pig and human airway smooth muscles. 2. In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration-dependent relaxation of the carbachol-induced contraction. The IC50 values were 0.35 microM (pIC50: 6.46 +/- 0.10, n = 9) and 0.55 microM (pIC50: 6.26 +/- 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 microM (pIC50: 6.73 +/- 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 microM). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03-1 microM) but not by charybdotoxin (100 nM). 3. Levcromakalim (1 microM) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 microM) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4. Levcromakalim (10 microM) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 microM) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 microM) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5. Both KC 128 and levcromakalim relaxed the guinea-pig isolated tracheal smooth muscles precontracted by carbachol (100 nM), histamine (3 micro M) or U46619 (10 nM). KC 128 was approximately 10 times more potent than levcromakalim for each agonist.6. In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentration dependent relaxation of the carbachol-induced contraction.7. It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea-pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles.On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues.These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener- and glyburide-sensitive K+ channels are present in the dog airway smooth muscles.

Sterol mediated regulation of SREBP-1a,1b,1c and SREBP-2 in cultured human cells.

Under conditions of cholesterol depletion and SREBP-1 accumulation, changes in the levels of sterol regulatory element binding protein(s) (SREBPs) and sterol regulated gene mRNA were studied in Hep G2 cells by RNase protection assay. Cholesterol depletion increased the expression of mRNAs for cholesterol biosynthetic enzymes and low density lipoprotein (LDL) receptor. mRNAs levels for SREBP-1c and SREBP-2 were also increased by the cholesterol depletion. In contrast, levels for SREBP-1a and 1b (1a/b) mRNA increased transiently and then decreased. To examine the effect of SREBP-1 accumulation, Hep G2 cells were incubated with a SREBP-1 degradation inhibitor, N-acetyl-leucyl-leucyl-norleucinal (ALLN). The ALLN treatment increased the LDL receptor mRNA significantly, and also increased mRNA levels for HMG-CoA reductase, SREBP-1a/b and SREBP-2. The mRNA level for squalene synthase was not changed, and for SREBP-1c was decreased by the treatment. In conclusion, the regulation of differential expression of SREBP mRNA may be involved in sterol mediated regulation of gene expression. Moreover, the regulation of the SREBP-1 level may be a critical step in the regulation of sterol mediated LDL receptor expression.

In vivo bronchodilator action of a novel K+ channel opener, KC 399, in the guinea pig.

We evaluated the in vivo bronchodilator effects of KC 399, a novel K+ channel opener. In anesthetized guinea pigs, i.v. administration of KC 399 (1-10 micrograms/kg), BRL38227 (lemakalim, 10-100 micrograms/kg) and salbutamol (0.3-3 microgram/kg) evoked a dose-related reduction in the histamine-induced bronchoconstriction. The dose of KC 399 producing a 50% inhibition of the bronchoconstriction induced by histamine was 2.6 (1.9-3.6) microgram/kg. In exerting this action, KC 399 was approximately 13 times more potent than BRL38227, but approximately 4 times less potent than salbutamol. The bronchodilator action of i.v. KC 399 (10 micrograms/kg) lasted for over 30 min, whereas that induced by either BRL38227 (100 micrograms/kg) or salbutamol (3 micrograms/kg) lasted less than 10 min. When given by inhalation, KC 399 (1-30 micrograms/ml) induced a more prolonged effect and was a more potent bronchodilator than BRL38227 (0.3-1 mg/ml) in the histamine-induced bronchoconstriction model. Inhaled KC 399 (30 and 100 micrograms/ml) also prevented the antigen-induced bronchoconstriction in sensitized guinea pigs under anesthetic. When given by the oral route, KC 399, BRL38227 and salbutamol protected conscious guinea pigs from asphyxic collapse in response to inhaled histamine, their effective doses being 0.03, 1 and 3 mg/kg, respectively. From these in vivo experimental results, we conclude that KC 399 is an orally active, potent and long lasting bronchodilator.

Action of KC-399, a newly synthesized potassium channel opener, on mechanical activity and 86Rb efflux in rat aorta.

To clarify the characteristics of KC-399, a newly synthesized potassium channel opener, we investigated the effects of KC-399 and lemakalim on the contractions induced by norepinephrine (NE 1 microM) and K+ (30 and 90 mM) and on 86Rb efflux in rat thoracic aorta. KC-399 (0.01-10 nM) and lemakalim (0.001-10 microM) induced relaxation in aortic rings precontracted with 30 mM K+ or NE, but not with 90 mM K+. The vasorelaxant effect of KC-399 was almost 500 times more potent than that of lemakalim. The vasorelaxation with KC-399 developed more slowly and was more resistant to washout than that induced by lemakalim. Glibenclamide (0.1-1 microM), a blocker of ATP-sensitive K-channels, produced concentration-dependent inhibition of the relaxant action of KC-399 in aorta treated with 30 mM K+. KC-399 (3-100 nM) and lemakalim (0.3-10 microM) stimulated 86Rb efflux in rat aorta; the potency of KC-399 was approximately 100 times greater than that of lemakalim. The effects of KC-399 on 86Rb efflux persisted after an 18-min washout period, but those of lemakalim did not. The stimulatory effects of KC-399 (10 and 30 nM) and lemakalim (1 and 3 microM) on 86Rb efflux were also significantly reduced by glibenclamide (1 microM). These results suggest that KC-399 is a potent and long-lasting vasodilator in vitro and that opening of the ATP-sensitive K+ channel may be involved in its mechanism of action.

Effects of KC 399, a novel ATP-sensitive K+ channel opener, on electrical and mechanical responses in dog tracheal smooth muscle.

The effects were observed of a newly synthesized bronchodilator, KC 339 [N-(2-cyanoethyl)-2,2-bis-fluoromethyl-6-nitro-2H-1-benzopyran-4- carbothioamide], on the electrical and mechanical properties of dog tracheal smooth muscle tissues and on accumulation of second messengers. KC 399 hyperpolarized the membrane in a concentration-dependent manner, the minimum concentration required to produce hyperpolarization being 1 nM and the maximum hyperpolarization occurring with 10 nM. The hyperpolarization was still observed in low K+ solution (< 1.2 mM), but not in high K+ solution (> 20 nM). Similarly, KC 399 inhibited the contraction evoked by less than 30 mM K+, but not by higher concentrations of K+ (> 30 mM). KC 399 (10 nM) suppressed the depolarization and membrane potential oscillation induced by carbachol (< 300 nM). In muscle tissues precontracted with 100 nM carbachol, KC 399 caused a concentration-dependent relaxation. The IC50 value for KC 399 was 4.2 nM (pIC50: 8.38 +/- 0.09, n = 7) and the maximum inhibition induced by 100 nM KC 399 was 96.1 +/- 0.7% (n = 7). KC 399 inhibited more effectively the tonic response of the contraction than the initial phasic response induced by carbachol. The relaxation and hyperpolarization induced by KC 399 were antagonized by glibenclamide and in part by charybdotoxin due to depolarization of the membrane. Carbachol increased the amount of d-myo-inositol-1,4,5-trisphosphate (InsP3), the maximal value occurring 10 sec after application.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a novel benzopyran derivative, KC 399, on the isolated guinea-pig trachealis and human bronchi.

1. In isolated guinea-pig trachealis, KC 399, BRL 38227 and salbutamol suppressed the spontaneously generated tone in a concentration-dependent manner with pD2 values of 8.89 +/- 0.09 (n = 14), 6.18 +/- 0.07 (n = 11) and 7.72 +/- 0.12 (n = 8), respectively. 2. The bronchodilator effects of KC 399 and BRL 38227 were antagonized by glibenclamide but not by charybdotoxin or apamin. The effect of salbutamol was antagonized by charybdotoxin but not by glibenclamide or apamin. 3. KC 399 and BRL 38227 failed to inhibit the tone evoked by 90 mM K+ in guinea-pig trachealis, whereas salbutamol did inhibit it, in a concentration-dependent manner. 4. These bronchodilators also relaxed the tone of isolated guinea-pig trachealis supported by histamine, carbachol, U46619 or leukotriene D4. Their order of potency was always KC 399 > salbutamol > BRL 38227. 5. KC 399 and BRL 38227 relaxed isolated human bronchi contracted with histamine or carbachol. 6. We conclude that KC 399 is a potent relaxant of isolated guinea-pig trachealis and human bronchi in vitro. The relaxant action of KC 399 could be due to the opening of glibenclamide-sensitive K+ channels.

Long term effects of amlodipine on organ damage, stroke and life span in stroke prone spontaneously hypertensive rats.

The long term effects of amlodipine, a new long acting Ca2+ channel antagonist on organ damage, stroke and life span, were examined in stroke prone spontaneously hypertensive rats (SHRSPs). Blood pressure of the SHRSPs increased over the first 16 weeks and reached a stable level of about 250 mmHg in controls and about 200 mmHg in the amlodipine treated group. At 15 weeks after starting amlodipine treatment, all control SHRSPs exhibited varying degrees of myocardial fibrosis, proliferative and/or necrotic vasculitis and glomerular lesions, whereas only a few animals in the amlodipine group showed slight lesions. The average life span of animals was estimated to be 43.3 weeks and 71.1 weeks for control and amlodipine groups, respectively, which suggested a 1.6-fold prolongation of their life span by amlodipine treatment. These results indicate that the long term treatment of amlodipine suppresses the incidence of organ damage and stroke in SHRSPs and prolongs their life span.

Spasmolytic action of nicorandil in canine conductive coronary arteries in vivo is not modified by glibenclamide.

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.

Comparison of cardiovascular effects of SGB-1534 and prazosin, selective alpha 1-adrenoceptor antagonists, in anesthetized dogs.

The cardiovascular effects of a novel antihypertensive agent, SGB-1534, and its alpha 1-adrenoceptor antagonism in the renal vasculature were investigated in anesthetized dogs and compared with those of prazosin. The doses of SGB-1534 (1-100 micrograms/kg) and prazosin (3-300 micrograms/kg) were increased by a factor of about 3 and given i.v. in a cumulative way. SGB-1534 produced dose-dependent decreases in systemic (systolic, mean and diastolic) blood pressure (SBP), left ventricular (LV) systolic and end-diastolic pressure, and femoral vascular resistance, accompanied by no changes in heart rate (HR), LVdP/dt max and pressure-rate product. Femoral blood flow tended to increase, but the change was not significant. Renal blood flow and the vascular resistance remained virtually unchanged. Similar results were obtained with prazosin for the cardiovascular parameters tested except diastolic SBP and femoral vascular resistance, in which no significant changes occurred. SGB-1534 and prazosin dose-dependently attenuated renal vasoconstrictor responses to a relatively selective alpha 1-adrenoceptor agonist, phenylephrine (3 or 10 micrograms) given into the renal artery. When the doses that attenuated the vasoconstrictor response to phenylephrine by 50% were compared on a weight basis, alpha 1-adrenoceptor antagonistic activity of SGB-1534 was approximately 25 times more potent than that of prazosin in the renal vasculature of dogs. Both alpha 1-adrenoceptor antagonists showed a significant positive correlation between the systemic hypotensive effects and the alpha 1-adrenoceptor antagonism in the renal vasculature. Thus, it seems that SGB-1534, like prazosin, has a balanced effect decreasing afterload as well as preload and that the hypotension is mainly due to the alpha 1-adrenoceptor antagonism in the peripheral vasculatures.

Antiplatelet effects of fenflumizole, a new anti-inflammatory drug, in dogs.

Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl) imidazole) was given to dogs in a single oral dose of 3 or 10 mg/kg. The plasma concentrations of fenflumizole and the two metabolites (mono- and di-demethyl forms) attained to the peak level 1-2 hr after dosing of fenflumizole, returning to near the predose levels 8 hr after the dosing. Fenflumizole (10 mg/kg) given orally significantly inhibited collagen- and ADP-induced platelet aggregations ex vivo over 4 hr after the dosing. Fenflumizole effectively inhibited in vitro collagen-induced platelet aggregation, but failed to prevent ADP-induced aggregation. The mono-demethyl form of fenflumizole inhibited in vitro ADP- and collagen-induced aggregations, but the di-demethyl form was ineffective in inhibiting them.

Antithrombotic and ulcerogenic effects of fenflumizole, a new anti-inflammatory imidazole derivative, in rats.

Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl) imidazole) was given to rats in a single oral dose of 30 mg/kg. The plasma concentration of fenflumizole reached a peak 2-3 hr after the dosing in non-fasted as well as fasted rats. Two metabolites (demethylation products) of fenflumizole were also detected in the plasma, but only in traces. Fenflumizole (30 and 100 mg/kg) and aspirin (100 mg/kg), given orally 2 hr prior to i.v. arachidonate (80 mg/kg), were effective in protecting the rats from death. Fenflumizole in single oral doses of 100 to 800 mg/kg dose-dependently developed erosions in the rat gastric mucosa, but was much less ulcerogenic than aspirin (3.12-200 mg/kg). Thus, fenflumizole seems to possess a potent antithrombotic activity and a relatively low gastro-ulcerogenicity in rats.

Effects of nicorandil on the conductive coronary artery of the dog.

The effects of nicorandil (2-nicotinamidoethyl nitrate, SG-75) on the conductive coronary artery were studied and compared with the effects of nitroglycerin and nifedipine. In isolated perfused canine heart preparations with a support dog, nicorandil produced a decrease in the resistance of the conductive coronary artery at reduced perfusion pressures, whereas nitroglycerin had similar effects even at normal perfusion pressures. In anesthetized closed-chest dogs, nicorandil and nitroglycerin produced an increase in the diameter of the conductive coronary artery (nicorandil less than nitroglycerin). Nifedipine failed to produce dilatation of the conductive coronary artery in both preparations. In isolated ring preparations of conductive coronary artery, all three compounds produced relaxation of the potassium-induced contracture, but only nicorandil and nitroglycerin reversed the lanthanum-induced contracture.

Effects of a new anti-inflammatory imidazole derivative, fenflumizole, on platelet aggregation in the rabbit.

The antiplatelet effect of fenflumizole, compared with aspirin or ticlopidine, was examined in in vitro, ex vivo and in vivo situations of the rabbit. Unlike ticlopidine, fenflumizole and aspirin effectively inhibited in vitro the platelet aggregation elicited by arachidonate and collagen. The activity of fenflumizole was 350 times more potent than that of aspirin. Fenflumizole (0.3-3 mg/kg) given p.o. was 4.2 and 8.1 times more potent than aspirin in inhibiting arachidonate- and collagen-induced platelet aggregations, respectively. Ticlopidine (300 mg/kg, p.o.) resulted in only weak effects on the aggregations. Fenflumizole (3 mg/kg) as well as aspirin (10 mg/kg) given p.o., unlike ticlopidine (300 mg/kg), effectively prevented the arachidonate-induced sudden death.

Mechanism of the hypotensive effect of a novel phenylpiperazine derivative, SGB-1534: antagonism at alpha 1-adrenergic and 5-HT2 receptors.

The present in vivo and in vitro experiment was designed to examine the hypotensive mechanisms of 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4 (1H,3H)-quinazolinedione monohydrochloride (SGB-1534). The compound given orally significantly inhibited the pressor response to i.v. noradrenaline in rats and to 5-hydroxytryptamine (5-HT) in guinea-pigs but failed to block the pressor response to i.v. angiotensin II in rats. In pithed rats, SGB-1534 given i.v. had no effects on the prazosin-resistant part of the pressor effect of i.v. adrenaline, whereas it significantly inhibited the yohimbine-resistant part. In isolated guinea-pig aortae, SGB-1534 competitively inhibited the contractile response to noradrenaline with a pA2 value of 8.86, 6 times higher than prazosin. A combination of SGB-1534 with prazosin antagonized the noradrenaline effect as expected for a single class (alpha 1) of receptor. In isolated rabbit femoral arteries, SGB-1534 attenuated the contractile response to 5-HT with a pA2 value of 6.13, 400 times lower than ketanserin. A combination of SGB-1534 with ketanserin antagonized the 5-HT effect as expected for a single class (5-HT2) of receptor. In rat stomach fundus strips, SGB-1534 as well as ketanserin, even in a large dose, unlike methysergide, caused only slight inhibition of contractile response to 5-HT. These results indicate that SGB-1534 is a selective, competitive antagonist of the alpha 1-adrenoceptor and the 5-HT2 receptor, which may help to explain its antihypertensive properties.

Antihypertensive effects of a novel phenylpiperazine derivative, SGB-1534, on several hypertensive models of rats.

The antihypertensive activities of SGB-1534, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4 (1H,3H)-quinazolinedione monohydrochloride, compared with prazosin, were examined in anesthetized or conscious hypertensive rat models. In anesthetized rats, SGB-1534 administered orally (3-10 mg/kg) reduced the blood pressure and significantly inhibited the pressor response to noradrenaline, but did not affect blood pressure responses to angiotensin II, isoproterenol, histamine and acetylcholine. This compound (0.1-3 mg/kg, p.o.) exhibited potent and long-lasting antihypertensive effects in conscious spontaneously hypertensive rats (SHRs), renal hypertensive rats and DOCA-salt rats, but it increased the heart rate only minimally. Repeated p.o. doses of SGB-1534 also reduced the blood pressure in SHRs without noticeable sign of tolerance to antihypertensive effects. In an experimental model for determining blood pressure compensation for postural tilt in anesthetized rats, SGB-1534 was free of postural effects, while prazosin induced orthostatic hypotension. In renal hypertensive rats and SHRs, SGB-1534, unlike prazosin, caused no increase in plasma renin activity. The present results reveal some pharmacological characteristics of SGB-1534 as an orally effective antihypertensive agent.