Quantitative and qualitative changes in adrenoceptors under various conditions were studied by binding experiments. Chronic treatment with reserpine increased the level of α₂-adrenoceptors in rat vas deferens and hypoxia increased the level of α₁-adrenoceptors in rat cardiomyocytes. Adenosine receptor agonists increased the affinity of the α₂-adrenoceptor in rat vas deferens for the agonist with an increase in receptor-mediated responses. Thus two types of changes in receptor binding sites were observed. Next, changes in the GTP-binding (G) protein were studied. Activation of cyclic AMP-dependent protein kinase (PKA) decreased the ADP-ribosylation of Gi (41 K) protein by islet-activating protein (pertussis toxin, IAP). Purified Gi protein was phosphorylated by the enzyme. IAP-sensitive G protein-mediated coupling responses such as phosphatidylinositol turnover in differentiated HL-60 cells were also modified under this condition. These results indicated that phosphorylation of GI by PKA caused a qualitative change of Gi. Lithium ions also decreased the ADP-ribosylation of GI by IAP. Then it determined if the decrease was accompanied with a dissociation of the subunits of Gi. Phosphorylation of Gi by PKA impaired the dissociation of the subunits of GI caused by Mg²⁺ and GTPγS, wheareas lithium ions did not have any effect on their dissociation. Thus some conditions caused a functional change in the so-called “qualitative change” of Gi.

View full abstract

Hypertensive crises require immediate therapy, usually by parenteral drug administration. Sublingual nifedipine has been shown to be highly effective. However, the blood pressure fall following nifedipine is frequently associated with side effects. The use of sublingual captopril has recently been indicated in hypertensive crisis, assuming that by this route, there would be a faster absorption and thus a more rapid effect on blood pressure than with the oral route. To verify this hypothesis, we have compared the hypotensive effects of sublingual nifedipine and sublingual captopril in 52 patients with hypertensive emergencies: 25-mg captopril and 10-mg nifedipine were administered sublingually to 28 and 24 patients, respectively. Blood pressures and heart rates were continuously measured up to 240 min postdose. A significant (P<0.001) hypotensive effect of both sublingual captopril and nifedipine therapy occured at 5 min and persisted for 240 min. Heart rates increased with nifedipine, but decreased with captopril. We observed no sideeffects in the captopril group, but flushing, tachycardia and headache were observed in 6 patients in the nifedipine group. We conclude that sublingual captopril is effective in patients with hypertensive emergencies and that captopril may be an excellent alternative to sublingual nifedipine in the urgent treatment of hypertensive crisis.

View full abstract

The present study was designed to examine the specificity of β-adrenergic antagonists for β₁, β₂-adrenergic and 5HT_1B-serotonergic receptors by the competitive interaction with ¹²⁵I-iodocyanopindolol (¹²⁵I-ICYP) as a radioligand. The β₁-adrenoceptors were preferred by acebutolol, atenolol, betaxolol, practolol, and I-, dl and d-metoprolol, while butoxamine and ICI-118, 551 preferred β₂-adrenoceptors. The selectivities of these β₁ and β₂-antagonists are well-known, but alprenolol which is known as a non-selective antagonist was 7.2-fold more selective for the β₂-adrenoceptors in the present study. All β-antagonists used were more selective towards β-adrenoceptors as compared with 5HT_1B-receptors. Good correlations were observed between the potencies of β-adrenoceptor antagonists for inhibition of ¹²⁵I-ICYP binding to β₁- and β₂-adrenoceptor sites and their potencies for inhibiting the binding of the same radioligand to 5HT_1B-serotonergic receptor sites. These results suggest that β-adrenoceptor antagonists can bind to β-adrenoceptors and 5HT_1B-receptors.

View full abstract

In order to determine the main site of the convulsant action of the neurotropic mycotoxin fumitremorgin A, the role of the brain stem reticular formation was studied. In rabbits lightly anesthetized with urethane and chloralose, electrical stimulation of the reticular formation elicited burst discharges in the common peroneal nerve and in the tibial nerve. This facilitatory effect of electrical stimulation was markedly potentiated by intravenous administration of a small dose of FTA, before onset of actual convulsion. Under the influence of FTA, a remarkable increase in the spontaneous electrical activity of the midbrain reticular formation was observed. The firing pattern of some neurons in the reticular formation corresponded very well with abnormal burst discharges in the common peroneal nerve. These effects of FTA were inhibited by chlorpromazine (0.1-1.0 mg/kg, i.v.), diazepam (0.1-1.0 mg/kg, i.v.), mephenesin (5-10 mg/kg, i.v.) and pentobarbital (5-15 mg/kg, i.v.). It was concluded that FTA might activate some neurons in the midbrain reticular formation and that convulsive burst discharges in peripheral motor nerves resulted from abnormal activation of these neurons, although the role of the medullary reticular formation could not be excluded.

View full abstract

Effect of S-adenosyl-L-methionine disulfate tosylate salt (SAMe-ST) and L-methionine (L-Met) on primary cultured rat hepatocytes were studied. In cultured hepatocytes treated with CCl₄, SAMe-ST and L-Met suppressed the decrease in urea-nitrogen secretion as well as the leakages of GOT and GPT. The membrane-protective action of these two compounds was verified by the histological data. Failure of SAMe-ST to counteract CCl₄-induced reduction of radioactive leucine incorporation into the trichloroacetic acid-insoluble materials in hepatocytes indicates that the observed effects of SAMe-ST or L-Met do not involve acceleration of protein synthesis. The present results indicate that SAMeST remarkably protects hepatocytes from CCl₄-induced hepatotoxicity, probably by either changing the structure or compositions of membrane phospholipids or by modifying the interaction of CCl₄ with the intracellular drug-metabolizing enzyme systems.

View full abstract

E-1020, a newly synthesized imidazopyridinylpyridine or imidazopyridine derivative (structurally closely related to the bipyridine derivative milrinone) increased the force of contraction and cyclic AMP levels in a concentration-dependent manner in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37°C. The concentration-response curve for the increase in force of contraction by E-1020 was biphasic. The maximal positive inotropic effect (PIE) of E-1020 is comparable to that of milrinone, and its potency is 3-fold less than that of milrinone, but 10-fold higher than that of amrinone. The time course of increases in force of contraction induced by E-1020 was coincident with that of cyclic AMP accumulation. The concentration-response curve for the PIE of E-1020 was superimposable to that of cyclic AMP accumulation. Aβ-adrenoceptor antagonist, (±)-bupranolol (3×10^-7 mol/l), did not affect the PIE of E-1020. The increase in the force of contraction and accumulation of cyclic AMP produced by E-1020 were inhibited by a muscarinic receptor agonist, carbachol. The relationship between the force of contraction and cyclic AMP levels in the presence of E-1020 was not modified by addition of carbachoi or isoproterenol. E-1020 shifted the concentration-response curve for isoproterenol to the left. E-1020 shortened the total duration of contraction and relaxation time of isometric contractions. These findings indicate that cyclic AMP is essentially involved in the PIE of E-1020 on the canine ventricular muscle, although the possible involvement of a cyclic AMPindependent mechanism can not be excluded.

View full abstract

We set up a system to measure the luminal pH, potential difference (PD) and bicarbonate output in the anesthetized rat duodenum, and investigated these responses caused by prostaglandins (PGs) and cholinergic agents. When the proximal duodenum (1.7 cm) was perfused at a flow rate of 0.7 ml/min with saline adjusted to pH 4.5, the duodenal pH, PD and HCO₃^- output were 5.5 to 6.0, -4 to -6 mV and 1.2 to 1.6 μEq/10 min, respectively; they were markedly reduced by i.v. injection of saturated KCI. Both natural (PGE₁, PGE₂) and synthetic (PGE₁, PGI₂) PGs, given either s.c. or i.v., significantly elevated all these parameters, while indomethacin (s.c.) decreased the pH as well as the PD. Small but significant increases of the pH were observed after i.v. administration of cholinergic agents (carbachol, hethanechol), a GABAergic agent (baclofen) and an analogue of thyrotropin releasing hormone (YM-14673), with a temporal elevation of the PD; the degree of net HC0₃ ^- output caused by these agents was 20-50% of the values obtained with PGE₂ (100 μg/kg, i.v.), and they were significantly reduced in the presence of atropine. These results suggest that (a) the system using pH deflections can be used to sensitively detect HCO₃^- output in the rat duodenum, and (b) duodenal acid neutralizing capacity may be regulated by central and peripheral cholinergic systems as well as endogenous PGs.

View full abstract

To investigate whether oxygen radicals would be generated by cephaloridine (CER) in the renal cortical microsomes obtained from rats and whether the microsomal lipid peroxidation would be promoted by CER, the microsomes were incubated under a pure oxygen atomosphere in a medium containing the reduced nicotinamide adenine dinucleotide phosphate regenerating system, under various conditions. Generations of superoxide anion and hydrogen peroxide and malondialdehyde formation were all dependent on microsoma! protein concentrations, incubation periods and CER concentrations. Scavengers of the microsomal lipid peroxidation induced by CER, (+)-cyanidanol-3, mannitol, sodium benzoate and N-acetyl tryptophan, which are scavengers of hydroxyl free radicals, inhibited the CER-stimulated lipid peroxidation in the microsomes. Histidine, a scavenger of hydroxyl free radicals and singlet oxygen, and alpha-tocopherol, reduced-glutathione and NN'-diphenyl-p-phenylenediamine, the three of which are non-specific antioxidants, also inhibited the CER-stimulated lipid peroxidation in the microsomes. Accordingly, our findings may strongly support that CER generates not only superoxide anions and hydrogen peroxide but also hydroxyl free radicals in the kidney, and these generated oxygen radicals react with the membrane lipids to induce peroxidation and nephrotoxicity.

View full abstract

Inhibitory effects of the calcium channel blocker nisoldipine on angiotensin II-induced antidiuresis were investigated in anesthetized dogs, and the findings were compared with those of saralasin. Intrarenal arterial infusion of 10 ng/kg/min angiotensin II resulted in marked decreases in renal blood flow (RBF) and urine formation, with a relatively moderate decrease in glomerular filtration rate. There were marked reductions in the fractional excretion of lithium, which is used as an index of the fractional proximal excretion of sodium, and the fractional distal excretion of sodium. Nisoldipine (50 ng/kg/min) administered intrarenally produced a partial inhibition on the decreased response of RBF to angiotensin II. The peptide-induced decreases in urine flow, urinary excretion of electrolytes and fractional excretion of electrolytes were abolished by nisoldipine. In contrast, when saralasin was administered intrarenally at 10 ng/kg/min, a dose which could partially inhibit the angiotensin 11-induced decrease in RBF to the same extent as seen with nisoldipine, the antagonist attenuated, but did not abolish, the antidiuretic action of angiotensin II. Significant decreases in urine formation by angiotensin II were observed, even in the presence of saralasin. These results suggest that nisoldipine, unlike saralasin, preferentially interferes with the stimulatory effect of angiotensin II, as related to the renal tubular reabsorption of sodium and water.

View full abstract

The properties of GABA related compounds on gastric function were studied in standardized perfused rat stomach preparations. Intravenous GABA (400 mg/kg) produced a rapid increase in acid secretion. Acid secretagogue actions of 3-aminobutyric acid and 2-aminobutyric acid were less potent than that of GABA. Intravenous injection of 5-amino-n-valeric acid (400 mg/kg) stimulated gastric acid secretion, but 6-amino-n-caproic acid was inactive. Isoguvacine (40 mg/kg, s.c.) stimulated acid output, whereas guvacine, an isomer of isoguvacine, did not. Systemically administered 3-hydroxy-GABA and β-(p-chlorophenyl)-GABA (PCPGABA) showed significant secretagogue actions. Acid responses to GABA-related compounds were significantly reduced by surgical truncal vagotomy and completely antagonized by atropine. The acid responses to PCPGABA and isoguvacine were partially augmented by yohimbine and propranolol. These results suggest that the secretagogue action of GABA is mimicked by structurally GABA-related compounds, which is mediated through cholinergic receptors, with slight implication of alpha-2 and beta-adrenoceptor mechanisms.

View full abstract

Effects of histamine on the tone and intracellular calcium level (Ca²⁺_i) in porcine coronary arteries were simultaneously investigated by use of the fura-2 microscopic fluorometric method. Histamine (10^-6-10^-4 M) induced concentration-dependent increases in tone and Ca²⁺_i, but these responses were not sustained. Histamine induced a larger contraction than did KCI with a similar increase in Ca²⁺_i. Depletion of the caffeine-sensitive Ca²⁺ store with ryanodine (3×10^-5 M) and repetitive applications of caffeine (2.5×10^-2 M) scarcely affected contractile and Ca²⁺_i responses to histamine. In Ca²⁺-free medium or in the presence of verapamil (10^-6 M), histamine produced a briefer increase in Ca²⁺_i and a smaller contraction than in normal medium. When histamine or caffeine was repetitively applied in Ca²⁺-tree medium, the first application produced an increase in Ca²⁺_i but the second application produced no increase. Although caffeine increased Ca²⁺_i after repetitive histamine applications, histamine failed to increase Ca²⁺_i after repetitive caffeine applications in Ca²⁺_i-free medium. These results indicate that vascular contraction induced by histamine may involve the following mechanisms: an increase in Ca²⁺ influx through Ca²⁺ channels, release of Ca2+ from the intracellular Ca²⁺ store which has an interaction with the caffeinesensitive Ca²⁺ store, and sensitization of contractile proteins to Ca²⁺.

View full abstract

The effects of a calcium antagonist of the dihydropyridine type, felodipine, on the cerebral circulation were studied in comparison with those of nicardipine in pancuronium-bromide immobilized unanesthetized dogs. Felodipine (0.3-10 μg/ kg. i.v.) and nicardipine (0.3-10 μg/kg, i.v.) produced a dose-related decrease in mean blood pressure with almost equal potencies. However, at a dose of 3μg/kg, felodipine produced a more prominent increase in cerebral blood flow (CBF) than nicardipine. Decreases in cerebral vascular resistance were significantly greater in the felodipine group at doses of 0.3 and 3 μg, when compared with the nicardipine group. Cerebral oxygen consumption calculated by multiplying the arterio-venous difference of oxygen content by CBF was increased by these two drugs, but the changes were minimal. These data suggest that the increase in CBF produced by felodipine and nicardipine was primarily due to the direct dilatation of the cerebral blood vessels.

View full abstract

We studied the expression of angiotensinogen and renin genes in rats treated with 3, 3', 5-triiodo-L-thyronine (T₃) at doses of 0.1 and 1 mg/kg of body weight. Liver angiotensinogen mRNA increased by 2 to 3 times 8 to 12 hours after T₃-treatment. This increase was dose-related. Plasma angiotensinogen concentration (PAC) increased 12 hours after T₃-treatment. Brain and renal angiotensinogen mRNA levels and the renal renin mRNA level remained the same throughout the experimental periods. These results suggest that the thyroid hormone initially increases angiotensinogen mRNA and leads to an increase in the production of angiotensinogen in the liver followed by an elevation of PAC.

View full abstract

KW-5805, 5-[2-(diethylamino)ethyl]amino-5, 11-dihydro[1]benzoxepino[3, 4-b]pyridine trihydrochloride, is a new tricyclic compound with antiulcer activities. Its effect on stimulated gastric acid secretion was investigated in the perfused stomach of anesthetized rats. KW-5805 at 0.3-10 mg/kg, i.v., dosedependently inhibited gastric acid secretion stimulated by 2-deoxy-D-glucose (2DG). On the other hand, the compound at 10-20 mg/kg, i.v., exerted a moderate decrease in gastric acid secretion stimulated by bethanechol; and at 10 mg/kg, i.v., it produced no change in gastric acid secretion evoked peripherally by vagal electrical stimulation. When applied intracerebroventricularly at 1-5 μg/rat, this compound dose-relatedly reduced gastric acid secretion stimulated by 2-DG. Three main metabolites (KF-10504, KF-9530 and KF-10847) of KW-5805 at 1 mg/kg, i.v., caused no significant decrease in gastric acid secretion stimulated by 2-DG. Doxepin, a tricyclic compound, definitely depressed the 2-DG stimulated gastric acid secretion at 1 mg/kg, i.v. It is suggested that intravenous administration of KW-5805 inhibits gastric acid secretion stimulated by 2-DG, mainly via centrally mediated mechanisms, and that biotransformation of KW-5805 to the metabolites contributes little to the development of the antisecretory effect.

View full abstract

A (H⁺+K⁺)-ATPase-enriched membrane fraction derived from the fundic portion of hog gastric mucosa was obtained by a combination of differential and repeated 7% Ficoll gradient centrifugation. The microsomal membrane fraction isolated by repeated 7% Ficoll gradient centrifugation was free of ouabain-sensitive (Na⁺+K⁺)-ATPase, 5'-nucleotidase and succinate dehydrogenase; and it was highly enriched in (H⁺+K⁺)-ATPase and K⁺-stimulated p-nitrophenylphosphatase (p-NPPase). The (H⁺+K⁺)-ATPase had a pH optimum of 7.4 and was stimulated by Tl⁺, K⁺, Rb⁺ and NH₄⁺ with Ka values of 0.0667, 0.526, 0.667 and 3.03 mM, respectively, at this pH. On the other hand, monovalent cations such as Na⁺, Li⁺ and (CH₃)₄N⁺ as well as divalent cations such as Cu²⁺, Ca²⁺, Ba²⁺, Sr²⁺ and Cd²⁺ inhibited this enzyme activity concentration-dependently. Ouabain and oligomycin had no effect, whereas omeprazole, a specific (H⁺+K⁺)-ATPase inhibitor, inhibited this enzyme activity in a pH-dependent manner. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis showed a major band (≥=90% of protein) at 97, 400 daltons, which was phosphorylated in the presence of Mg²⁺ and [γ-³²P]-ATP and dephosphorylated in the presence of K⁺. The present method was very simple, and the (H⁺+K⁺)-ATPase activity of the microsomal fraction obtained by this method was much higher compared with those obtained by other methods such as free-flow electrophoresis.

View full abstract

We examined the effect of thromboxane A₂(TXA₂) synthetase inhibitor, OKY-046, on bronchoconstriction induced by antigen and various spasmogenic mediators in guinea pigs in vivo. Further, inhibitory activities of OKY-046 on contractions of isolated tracheae and lung parenchymal strips induced by various contractile agents were also investigated in vitro. OKY-046, but not indomethacin, significantly inhibited antigen-induced bronchoconstriction in a dose-dependent manner. Moreover, OKY-046 attenuated bronchoconstrictions induced by peptide leukotrienes (LTs) and platelet activating factor (PAF), but not those by histamine, prostaglandin D₂ (PGD₂) and STA₂ (a stable TXA₂ mimetic agent). Although contractile responses induced by spasmogens such as peptide LTs, PAF and histamine were not influenced by OKY-046 in isolated tracheae, OKY-046 elicited significant and concentration-dependent inhibitions against contractile responses induced by peptide LTs and PAF in isolated lung parenchymal strips. These results suggest the possible involvement of TXA₂ in the development of anaphylactic bronchoconstriction in sensitized guinea pigs.

View full abstract

The coronary vasodilator effect and negative chronotropic, inotropic and dromotropic effects of mepirodipine, the single stereoisomer of a novel dihydropyridine Ca antagonist, were compared with those of nifedipine and nicardipine using canine isolated, blood-perfused heart preparations. Drugs were injected into each nutrient artery. In the sinoatrial node preparation, the dose producing a 15% decrease in sinoatrial rate was 1.3, 6.5 and 2.5 μg for mepirodipine, nifedipine and nicardipine, respectively. In the papillary muscle preparation, the dose causing a 50% decrease in developed tension was 44, 6.5 and 54 μg for mepirodipine, nifedipine and nicardipine, respectively. The dose causing a 50% increase in blood flow through the anterior septal artery was 0.26, 0.18 and 2.0 /μg for mepirodipine, nifedipine and nicardipine, respectively, while the time required for return to half maximum at the above dose was 13.1, 1.8 and 4.1 min, respectively. In the atrioventricular node preparation, the dose producing a 50% increase in AH interval was 1.6, 2.4 and 3.7 μg for mepirodipine, nifedipine and nicardipine, respectively. These results indicate that mepirodipine is a potent and long-lasting dihydropyridine Ca antagonist, whose vascular selectivity is highest against cardiac contractility, but less selective against sinoatrial node automaticity and atrioventricular nodal conduction, compared with nifedipine.

View full abstract

It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B₄ was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca⁺⁺lonophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A₂ was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.

View full abstract

Changes in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) by activation of α₁ and α₂-adrenoceptors were microfluorometrically measured in rat tail arteries loaded with the Ca²⁺-sensitive fluorescent dye fura-2. Under the normal condition (1.8 mM Ca²⁺), stimulation with the selective α₁-adrenoceptor agonist phenylephrine very rapidly raised [Ca²⁺]_i, to the peak concentration, plateauing at this level, whereas the stimulation with the selective α₂-adrenoceptor agonist UK-14, 304 gradually increased [Ca²⁺]_i. In Ca²⁺-free solution, the stimulation of α₁-adrenoceptors caused a transient increase in [Ca²⁺]_i, whereas the stimulation of α₂-adrenoceptors had no effect. These results directly prove that α-adrenoceptor activation induces both the release of intracellular Ca²⁺ and the influx of extracellular Ca²⁺, whereas activation of α₂-adrenoceptors evokes only the influx of extracellular Ca² 21. Plotting the increase in [Ca²⁺], against the developed contraction revealed that it was always linearly related regardless of the type of α-adrenoceptor stimulated. Therefore, the intracellular mechanisms after the increase in [Ca²⁺]_i are probably common to the vasocontractile responses mediated by α₁- and α₂-adrenoceptors.

View full abstract

The effects of GABA receptor antagonists (bicuculline and phaclofen) and structural GABA-analogues on baclofen stimulated gastric acid secretion were studied in standardized perfused rat stomach preparations. Pretreatment with bicuculline, a GABA_A-receptor antagonist, in the doses of 1 and 3 mg/kg, subcutaneously, had no influence on the gastric acid response to baclofen. In addition, phaclofen, a GABA_B antagonist, in the doses of 3 to 30 mg/kg, intravenously, was found to have no significant effect on the acid response to baclofen. However, GABA-analogues (MOPS and ABA; 10-30 mg/kg, i.v.) and lipophilic GABA derivatives structurally related to beta-amino acids (APPA and APHA; 30 mg/kg, i.v.) significantly counteracted the secretagogue action of baclofen. Further experiments on APPA action showed that the antisecretory effect of APPA could be overcome by higher doses of baclofen. APPA did not affect bethanechol stimulated acid secretion. These results suggest that the secretagogue action of baclofen is independent to GABA_A and GABA_B-receptors and that APPA may interact with baclofen in regulation mechanisms of acid secretion, although further investigations are necessary to define the mode of action of APPA on the GABAergic system.

View full abstract

Changes in coagulative and fibrinolytic activities were studied in rats with hyperlipidemia induced by Triton WR-1339 (T-WR). After intravenous injection of T-WR (150, 200 or 300 mg/kg) into S.D. rats, dose-related increases in plasma lipids (total cholesterol, triglyceride, free cholesterol and phospholipid) were observed. In hyperlipidemic rats that received 300 mg/kg of T-WR, decreases in red blood cell count and Hb value were found. Significant increases in the ma value of the thromboelastogram and the fibrinogen level were observed in these T-WR treated rats. The α₂-plasmin inhibitor activity was found to decrease doserelatedly. These results indicate that T-WR induced hyperlipidemia in rats is accompanied with an increase in coagulative activity and an indirect enhancement of fibrinolytic activity.

View full abstract

Antimuscarinic actions of disopyramide were investigated by measuring the contractile responses of intestinal smooth muscles and ligand binding in cardiac and intestinal membrane preparations. Disopyramide caused a parallel shift of the dose-response curves for acetylcholine, McN-A-343, and carbachol to the right in the guinea pig taenia caeci; pA₂ values were 5.4 for acetylcholine, 5.5 for McN-A343 and 5.9 for carbachol. In the guinea pig ileum, disopyramide competitively antagonized acetylcholine in the contractile responses, having the pA₂ value of 6.1. In microsomal fractions of the guinea pig taenia caecum and heart, disopyramide was capable of replacing ³H-QNB; K_i values were 7×10^-6 M for the taenia and 2×10^-6 M for the heart. These results suggest that disopyramide exerts antimuscarinic action through M₁ and M₂ receptors with a potency approximately 3 times greater for M₂ than M₁.

View full abstract

To examine the effects of nipradilol on ischemic myocardium, experiments were performed on regional myocardial blood flow (MBF) and energy metabolism in anesthetized, open-chest dogs. Nipradilol at a dose of 0.3 mg/kg was i.v.-administered 10 min after coronary ligation. M BFs at various sites, including ischemic and non-ischemic areas, were determined by the hydrogen gas clearance method. The levels of ATP and creatine phosphate (CP) at the site of MBF determination were measured 60 min after ligation, and mitochondrial function (RCI, Q0₂) in the ischemic and non-ischemic areas was determined. Following nipradilol administration, aortic pressure and heart rate were significantly lowered. In ischemic areas with MBF below 40 ml/min/100 g, nipradilol had no influence on MBF. However, the tissue level of ATP in nipradilol treated hearts was significantly higher as compared with untreated hearts. In the area of mild ischemia with MBF of 40-60 ml/min/100 g, nipradilol preserved the tissue ATP and CP levels in spite of a decrease in MBF. Moreover, an inhibition of the decrease in mitochondrial respiratory function was observed in ischemic areas with MBF below 20 ml/min/ 100 g. Thus, nipradilol administered following ischemia preserved ATP content and mitochondrial function in the ischemic myocardium with reduction of heart rate and aortic pressure. This suggests that nipradilol exerts a cardioprotective effect in acute ischemia. It seems that the cardioprotective effect is due to a decrease in myocardial oxygen demand and preservation of mitochondrial function.

View full abstract

Elcatonin is a newly synthetized peptide that prevents experimental ulcer formation. In this study, we examined the influence of elcatonin on endogenous prostaglandin biosynthesis by the gastric mucosa with respect to its antiulcer activity. Control levels of PGE₂ generation for the fundic and antral mucosa were 302±12 and 465±28 ng/g tissue/min, respectively. Pretreatment with elcatonin resulted in a dose-dependent increment in gastric mucosal PGE₂ generation. We conclude that the antiulcer effect of elcatonin is probably due to its ability to enhance endogenous prostaglandin synthesis in the gastric mucosa.

View full abstract

In the liver ischemia-reperfusion model, the lipid peroxide level increased during ischemic periods, while a greater increase was observed during reflow periods. The increase in the cytochrome b₅ content was observed during ischemia and reflow periods. On the contrary, the cytochrome P-450 content remained unchanged during ischemic periods, but decreased during reflow periods. Bifemelane suppressed the elevation of the lipid peroxide level, the cytochrome b₅ content and the decrease in cytochrome P-450 content during the period of reperfusion.

View full abstract