stepholidine and canadine

The antagonistic effect of tetrahydroproberberine (THP) homologues on alpha 1-adrenoceptor was studied by combination of radioligand binding assays and measurements of vasoconstriction responses. The results showed that l-tetrahydropalmatine (l-THP), l-stepholidine (l-SPD), THPB-18 and tetrahydroberberine (THB) competitively inhibited the 125I-BE2254 specific binding in rat cerebral cortex with pK1 values of 5.54 +/- 0.36, 5.56 +/- 0.47, 5.75 +/- 0.56 and 6.01 +/- 0.60, respectively, and the Hill efficiency was not significantly different from unity. They inhibited phenylephrine-induced constrictions with pA2 values of 5.48 +/- 0.58, 5.66 +/- 0.54, 5.64 +/- 0.34 and 5.45 +/- 0.76, respectively, and the slopes of Schild plot were not significantly different from unity. The results indicate that the 4 THP homologues are non-subtype selective competitive antagonists for alpha 1-adrenoceptor with similar affinities.

Topics: Adrenergic alpha-Antagonists; Animals; Berberine; Berberine Alkaloids; Binding, Competitive; Male; Rats; Receptors, Adrenergic, alpha-1; Vasoconstriction

Effect of tetrahydroberberine (THB), l-tetrahydropalmatine (THP) and l-stepholidine (SPD) were supposed to be related to the blocking of calcium influx. In this paper, using Fura-2/AM and AR-CM-MIC cation measurement system, the effects of THB, THP and SPD on cytosolic free calcium ([Ca2+]i) in cultured rat single myocardial cells were examined and compared with verapamil (Ver). THB, THP and SPD (10-100 mumol.L-1) were found to increase resting [Ca2+]i gently, which was not depressed by tetrodotoxin. THB, THP and SPD (1-100 mumol.L-1) were also shown to inhibit the KCl-induced [Ca2+]i elevation, the IC50 values of THB and SPD were 50.9 (95% confidence limits: 18.5-140) mumol.L-1 and 23.5 (95% confidence limits 7.6-73.4) mumol.L-1, respectively. THB, THP and SPD 30 mumol.L-1 were also shown to inhibit the elevation of [Ca2+]i induced by high extracellular calcium and norepinephrine; but the inhibitory effects of these drugs were weaker than those of Ver. The three compounds showed no significant effect on ouabain induced [Ca2+]i increase. These results suggest that the inhibitory effects of THB, THP and SPD on [Ca2+]i in myocite by blocking voltage-dependent calcium channels were similar but inferior to Ver.

Topics: Animals; Animals, Newborn; Berberine; Berberine Alkaloids; Biological Transport, Active; Calcium; Calcium Channel Blockers; Cells, Cultured; Myocardium; Rats; Rats, Sprague-Dawley; Verapamil

The relaxant effects of (-)-stepholidine ((-)-SPD) and tetrahydroberberine (THB) on rat aorta were studied in vitro. (-)-SPD IC50 18.1 (95% confidence limits 11.1-29.5) mumol.L-1 and THB IC50 18.6 (95% confidence limits 9.2-37.9) mumol.L-1 inhibited the contractions caused by KCl (100 mmol.L-1) concentration-dependently. Both (-)-SPD and THB markedly inhibited the 160 mmol.L-1 KCl-stimulated 45Ca influx. The inhibitions by (-)-SPD 10 mumol.L-1 and 100 mumol.L-1 were 18 +/- 13% (P > 0.05) and 47.0 +/- 2.8% (P < 0.01), respectively. The inhibitions by THB 10 mumol.L-1 and 100 mumol.L-1 were 36 +/- 9% (P < 0.01) and 43 +/- 8% (P < 0.05), respectively. The results showed that the effective concentrations of the 2 drugs inhibiting high KCl-induced contraction and 45Ca transmembrane influx in rat thoracic aorta were at a similar level, and that they were nearly 1/100 and 1/10 of those of verapamil respectively, indicating that (-)-SPD and THB had similar calcium channel blocking effect on rat artery, but were weaker than verapamil.

Topics: Animals; Aorta, Thoracic; Berberine; Calcium Channel Blockers; Calcium-Transporting ATPases; Dopamine Antagonists; Female; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Verapamil

The effects of tetrahydroberberine (THB) on ischemic and reperfused myocardium were studied in comparison with verapamil (Ver). In anesthetized rats, THB and its analogues, l-THP and l-SPD, reduced the infarct size after 4 h of left anterior descending coronary artery (LAD) ligation. In Langendorff hearts, in common with Ver, THB 1 and 10 mumol.L-1 markedly decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) in the reperfusion period. The malondialdehyde content and xanthine oxidase activity were also decreased in global ischemic-reperfused hearts pretreated with THB (P < 0.01, or P < 0.05). It suggested that THB could protect the myocardium from ischemic and reperfusion injury.

Topics: Animals; Anti-Arrhythmia Agents; Berberine; Berberine Alkaloids; In Vitro Techniques; Male; Malondialdehyde; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Verapamil; Xanthine Oxidase

Tetrahydroprotoberberines (THPBs), including (-)-stepholidine ((-)-SPD), (-)-tetrahydropalmatine ((-)-THP) and tetrahydroberberine (THB), have been demonstrated to be a new class of DA antagonists in biochemical and neuropharmacological studies. In this paper, the antagonistic action of THPBs was examined by means of single unit recording from nigral DA neuron in chloral hydrate-anesthetized and gallamine-paralyzed rats. Intravenous injection of these compounds could promptly and completely reverse the inhibition of the spontaneous firing induced by DA agonist apomorphine (APO) in a dose-dependent way. Pretreatment with (-)-SPD, (-)-THP or THB could significantly reduce the inhibitory effect of APO and shift the dose-action curve to the right. Besides, the compounds could increase the spontaneous firing of DA neurons. The above results not only strongly support the conclusion that (-)-SPD, (-)-THP and THB are DA antagonists, but also demonstrate that one of their blocking sites is at somatodendritic DA autoreceptors (D-2 receptors). In other words, (-)-SPD did not exhibit any DA agonistic action in this acute electrophysiological study, although its DA agonistic action can be demonstrated in rotational behavior of 6-OHDA-lesioned rats. The dual actions of (-)-SPD, dependent upon different experimental conditions, are discussed.

Topics: Alkaloids; Animals; Apomorphine; Berberine; Berberine Alkaloids; Dopamine Antagonists; Dose-Response Relationship, Drug; Electrophysiology; Neurons; Rats; Rats, Inbred Strains; Substantia Nigra

The protective effects of tetrahydroprotoberberines (THPB), viz., l-tetrahydropalmatine (THP), l-stepholidine (SPD), and tetrahydroberberine (THB) on experimental myocardial infarction by ligating the left coronary artery were estimated in rats. The myocardial infarction size (MIS) was determined by nitro-blue tetrazolium technique. THP, SPD, and THB, as well as propranolol, played a remarkable role in diminishing the MIS within 24 h and decreasing the rise of creatine kinase (CK) and aspartate aminotransferase (AST) in the serum within 4 h after the ligation of the coronary artery. Among these drugs, SPD provided the myocardium with the best protective benefit. Systolic and diastolic blood pressures (SBP and DBP) were rapidly lowered after SPD 2.5 mg.kg-1 iv by 39.5% and 48.5%, respectively. The value of the MBP x HR x LVET was concomitantly decreased by 35.1% in the anaesthetized rats. The myocardial contractility and diastolic compliance were not implicated during the experimental regimen. The prophylactic administration of SPD 2.5 mg.kg-1 improved the cardiac hemodynamic alterations caused by ligating the left coronary artery. SPD depressed the elevation of T and LVEDP, and reduction of +dP/dtmax, Vpm, and Vmax besides complete resistance to the reduction of -dP/dtmax and LVSP, underlying the precautions against the damage of the myocardial contractility and diastolic compliance, especially the latter.

Topics: Alkaloids; Animals; Aspartate Aminotransferases; Berberine; Berberine Alkaloids; Creatine Kinase; Female; Hemodynamics; Male; Myocardial Infarction; Rats; Rats, Inbred Strains

l-Tetrahydropalmatine (l-THP), tetrahydroberberine (THB) and l-stepholidine (l-SPD) are the homologues of tetrahydroproto berberines and have a common antagonistic effect to central dopamine receptors. In the present experiment, the potassium iontophoretic dolorimetry was used to determine the pain threshold of rabbits. Unilateral "Hegu" point (the dorsum of the front paw, between 1st and 2nd metacarpals) and "Waiguan" point (the dorsum of the foreleg, between radius and ulna, 2 cm above the wrist joint) of each rabbit were electrically needled. The effects of iv l-THP 8 mg/kg, THB 16 mg/kg or l-SPD 4 mg/kg on electroacupuncture analgesia were investigated. The experimental results indicated that these 3 agents enhanced the potency of electroacupuncture analgesia and prolonged the duration as well. This investigation gives the evidence that the drug possessing antagonistic effect to central dopamine receptors could be used as a synergist of acupuncture analgesia.

Topics: Acupuncture Analgesia; Alkaloids; Animals; Berberine; Berberine Alkaloids; Electroacupuncture; Female; Male; Pain; Rabbits; Sensory Thresholds

The effects of 12 tetrahydroprotoberberines (THPBs) on D1 and D2 receptors labelled with [3H]DA, [3H]Sch-23390 and [3H]spiperone were evaluated. Their effects on the activity of adenylate cyclase stimulated with DA 40 mumols/L were also assessed. All of the l-THPBs tested behaved as DA receptor antagonists with preferential affinity toward the D1 receptors. Among them, l-stepholidine (l-SPD), a THPB analog with 2 hydroxy groups at the C2 and C10 positions, was the most potent. Its affinity toward D1 receptors was 4-7 times higher than that toward D2 receptors. The results suggest that the hydroxy groups in l-THPBs are very important factors in determining the affinity to DA receptors. Moreover, d-tetrahydropalmatine (d-THP), a dextro-THPB analog, displayed no affinity for the D2 receptor subtype, while its optical isomer, l-THP, was a DA receptor antagonist. This indicates that the levo-optical configuration is necessary for the affinity of THPBs to DA receptors. In addition, l-SPD was 18 times more potent than haloperidol with respect to binding to D1 receptors, but 14 times weaker for D2 receptors. Thus, it is expected that the clinical effects of l-SPD can be distinguished from that of haloperidol.

Topics: Adenylyl Cyclases; Alkaloids; Animals; Berberine; Berberine Alkaloids; Brain; Cattle; Corpus Striatum; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Stereoisomerism

In rats lesioned by unilateral micro-injection of 6-OHDA into substantia nigra, the apomorphine-induced contralateral rotation and the amphetamine-induced ipsilateral rotation were antagonized by THB, l-THP and haloperidol. Scopolamine reversed the antagonistic effect of THB against amphetamine. Thus, THB and l-THP exhibited the DA-receptor antagonistic property which was similar to that of haloperidol. l-SPD (10 mg/kg), however, only antagonized the amphetamine-challenged rotational response, while it could not antagonize, but potentiate, the apomorphine-challenged rotational response. So, l-SPD might be a partial agonistic antagonist of DA-receptors, and its effect was more potent than that of THB and l-THP. l-SPD would be ascertained further in clinic trial. From these results and others, the authors suggest that THPB is a new chemical type of antagonist of brain DA-receptors.

Topics: Alkaloids; Animals; Antipsychotic Agents; Berberine; Berberine Alkaloids; Corpus Striatum; Haloperidol; Rats; Receptors, Dopamine; Scopolamine; Substantia Nigra