1-adrenoceptor Blocking Activity Research Articles

Intravenous Labetalol vs Intravenous Clonidine for Attenuation of Haemodynamic Responses during Laryngoscopy and Intubation in Controlled Hypertensive Patients Undergoing General AnaesthesiaA Randomised Clinical Trial

Introduction: Laryngoscopy and endotracheal intubation during general anaesthesia are associated with haemodynamic surges which can be detrimental, particularly if there is preexisting hypertension or cardiovascular disease. Intravenous (i.v.) labetalol, a β-adrenergic blocker with additional α1- adrenoceptor blocking activity, and clonidine, a centrally acting α2 agonist, are known to attenuate this haemodynamic response. Aim: To compare the effects of i.v. labetalol and clonidine in attenuating haemodynamic changes during laryngoscopy and intubation in controlled hypertensive patients. Materials and Methods: This single centre, parallel-group, double-blind, randomised clinical trial was conducted in the Surgery Operation Theater (OT) of Midnapore Medical College, District Paschim Medinipur, West Bengal, India, from February 2018 to August 2019. The study included 90 adult patients of either sex, who were randomly allocated to receive either clonidine 1 mcg/kg or labetalol 0.15 mg/kg by intravenous route. After recording baseline parameters, patients were preoxygenated with 100% oxygen for 3 min and the study drug was given 5 min prior to induction. Heart Rate (HR), Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) and the rate pressure product were recorded prior to induction, at the time of intubation and 1, 3, 5, and 10 min after intubation. General anaesthesia maintenance was done in a similar manner in both groups. Two-sample t-test was used to assess significance of difference in means between independent samples. Fisher’s exact test was employed for comparing categorical data. Analysis was two-tailed and p-value<0.05 was considered statistically significant. Results: Both the groups were evenly matched at baseline with respect to age and sex as well as standard anthropometric parameters (p-value>0.05). Both drugs were able to attenuate the expected rise in HR following intubation but labetalol was more effective than clonidine throughout the postintubation period. SBP and DBP were comparable between the two groups at baseline but underwent greater attenuation in the labetalol group at intubation and subsequent measurements. The differences were around 10 bpm for HR, 20-30 mmHg for SBP and 10 mmHg for DBP, in favour of labetalol. Adverse events like bradycardia, hypotension, sedation or undesirable ECG changes were not encountered. Conclusion: Intravenous labetalol is more effective than i.v. clonidine in controlling haemodynamic changes during laryngoscopy and intubation in controlled hypertensive patients undergoing general anaesthesia without any complications

Hantzsch-Type dihydropyridines and Biginelli-type tetra-hydropyrimidines: a review of their chemotherapeutic activities.

Years after the first report on 1,4-dihydropyridines (1,4-DHPs) and 1,2,3,4-tetrahydropyrimidines (1,2,3,4-THPMs) appeared, they are revisited as plausible therapeutic agents. This is mainly due to the convenient methods that exist for their synthesis and the diverse pharmacologic properties that these scaffolds present. 1,4-Dihydropyridines and 1,2,3,4-tetrahydropyrimidines are usually regarded as analogous in several aspects. They are both prepared in multi-component reactions using very similar starting materials and synthesis protocols. This leads to common structural features between 1,4-DHPs and 1,2,3,4-THPMs, as well several related biological effects. For example, they share many pharmacological features such as analgesic, anti-tumor, antioxidant, anti-inflammatory, antitubercular, antibacterial, cardiovascular and adrenoceptor blocking activities. Numerous reviews have been devoted to the chemistry and cardiovascular effects of these compounds. However, the lack of a comprehensive literature overview on the chemotherapeutic ability of these scaffolds is behind the present attempt to provide a detailed survey of 1,4-DHPs and 1,2,3,4-THPMs and their structural features as chemotherapeutic agents.

The Nitric Oxide/Soluble Cyclic Guanylase/Cyclic Guanosine Monophosphate Pathway Is Involved in the Cardiovascular Effects of a Novel α1- and β-Adrenoceptor Antagonist

The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α₁- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α₁- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α₁- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α₁-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with N_ω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α₁-adrenoceptors. Our results demonstrated that MH-78 possesses α₁- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α₁-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.

Selectivity and specificity for alpha 1-adrenoceptor blocking activity of R(-)- and S(+)-YM-12617 orally administered to pithed, spontaneously hypertensive rats.

The selectivity and specificity for alpha 1-adrenoceptor blocking activity of the optical isomers of YM-12617 have been examined in pithed, spontaneously hypertensive rats. R(-)-YM-12617 and prazosin (1 mg kg-1 p.o.) produced 360- and 88-fold rightward shifts, respectively, of the dose-response curve of control to phenylephrine, whereas S(+)-YM-12617 (1 mg kg-1 p.o.) failed to cause a shift. Based on dose ratio, R(-)-YM-12617 was 320 times more potent as an alpha 1-adrenoceptor antagonist than S(+)-YM-12617. This potency ratio corresponded to that formed in an in-vitro study. Both R(-)- and S(+)-YM-12617 hardly affected the UK-14304, angiotensin II, vasopressin and isoprenaline dose-response curves. These results suggest that R(-)-YM-12617 exerted selective alpha 1-adrenoceptor blocking activity and its activity was specific for alpha 1-adrenoceptors.

The synthesis of N-phenoxyethyl-1-substituted-1,2,3,4-tetrahydroisoquinolines and their α 1-adrenoceptor blocking activity

A series of phenoxyisoquinolines, N-phenoxyethyl-1-(2-nitrophenyl)-1,2,3,4-THIQs 3a– 3d, N-phenoxyethyl-1-benzyl-1,2,3,4-THIQ 3e, N-phenoxyethyl-1-(2-aminophenyl)-1,2,3,4-THIQs 5f– 5i, N-phenoxyethyl-1-(2-phenoxyethylaminophenyl)-1,2,3,4-THIQs 5f′– 5i′, have been synthesized and tested in isolated rat vas deferens α-adrenoreceptors. Comparison of pA2 values for these compounds in the presence of phenylephrine confirms that α 1-adrenoceptor blocking activity of 3a– 3d (–NO 2 series) is more active than 6a– 6c (–NH 2 series) in the aortic rings isolated from SD rats. On the other hand, the electron-donating group at the 6-position of isoquinoline ring either increases or decreases the α 1-adrenoceptor blocking activity.

N-Allylsecoboldine as a novel agent prevents acute renal failure during endotoxemia

Blockades of cytokine and oxygen radicals release are considered to be beneficial in reducing multiple organ injury and increasing the survival rate in sepsis/septic shock. Thus, we examined the protective efficacy of N-allylsecoboldine, a secoaporphine derivative with antioxidant and α 1-adrenoceptor blocking activities, in rats treated with endotoxin ( E. coli lipopolysaccharide, LPS). Pretreatment of LPS-treated rats with N-allylsecoboldine significantly attenuated the late-phase hypotension, hypoglycemia and incremental plasma tumor necrosis factor (TNF)-α. Overproduction of plasma nitrate in endotoxemia was not changed but the continuous decrease of urinary nitrate appeared to be partially ameliorated by N-allylsecoboldine. However, N-allylsecoboldine inhibited the inducible nitric oxide synthase (iNOS) protein expression in the renal cortex of endotoxemic rats. N-allylsecoboldine also improved the endotoxemia-induced organ injury as demonstrated from the conspicuous recovery of marker enzymes in the LPS-treated rats. Endotoxemia was associated with renal dysfunctions as indicated by decreases in renal blood flow, urinary potassium excretion, and renal nitrate clearance. However, pretreatment with N-allylsecoboldine showed significant alleviation of these renal dysfunctions. In addition, a lower dose of N-allylsecoboldine ameliorated the mortality of LPS-treated mice. This study demonstrates N-allylsecoboldine's ability to avail against acute renal failure and increase survival rate during endotoxemia. These beneficial effects may be attributed to the inhibition of iNOS expression, TNF-α production, and free radical scavenging activities. However, the role of α 1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear.

Discovery of a New Series of Centrally Active Tricyclic Isoxazoles Combining Serotonin (5-HT) Reuptake Inhibition with α2-Adrenoceptor Blocking Activity

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.

(+)-Cyclazosin Derivatives as α1-Adrenoceptor Antagonists

The prazosin-related compound (+)-cyclazosin [(+)-1] is an α 1 -adrenoceptor antagonist with moderate selectivity for the α 1 b -adrenoceptor subtype (selectivity ratio: α 1 b /α 1 a = 90, α 1 b /α 1 d = 24). To improve its pharmacological profile, the novel chiral derivatives (+)-2-(+)-5, bearing a bromo, a methyl, a methoxy or an acetyl group in position 5 of the 2-furoyl moiety, were synthesized and evaluated for their α 1 -adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α 1 b -adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α 1 B /α 1 A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α 1 B / α 1 D selectivity (1513 vs. 138).

In vivo and in vitro pharmacological studies of a new hypotensive compound (QF0301B) in rat: comparison with prazosin, a known α 1-adrenoceptor antagonist

In this work, we studied the in vivo and in vitro pharmacological effects of the novel compound QF0301B (2-[2-( N-4- o-methoxyphenyl- N-1-piperazinyl)ethyl]-1-tetralone) and compared with those of prazosin. In anaesthetized normotensive rats, both QF0301B and prazosin (0.1–0.2 mg/kg iv) caused a pronounced and prolonged fall in mean arterial blood pressure accompanied by bradycardia. Neither QF0301B nor prazosin (0.2 mg/kg iv) significantly modified the cardiovascular effects of either 5-hydroxytryptamine (serotonin, 5-HT, 75 μg/kg iv) or the selective α 2-adrenoceptor agonist B-HT 920 (0.2 mg/kg iv), but both markedly inhibited the hypertensive effect of noradrenaline (5 μg/kg iv), a nonselective α-adrenergic receptor agonist. In isolated rubbed rat aorta rings, QF0301B and prazosin showed marked α 1-adrenoceptor blocking activity, with pA 2 values of 9.00±0.12 and 9.75±0.14, respectively. In addition, QF0301B reversed and competitively antagonized the inhibitory action produced by clonidine in electrically stimulated rat vas deferens and inhibited the force and rate of contraction in rat isolated atria ( pA 2=5.91±0.43), competitively antagonized the contractile effect of 5-HT in rat aorta ( pA 2=6.75±0.06) and in rat stomach fundus ( pA 2=7.13±0.48) and the contractions induced by histamine in isolated guinea pig longitudinal ileal muscle ( pA 2=7.40±0.40). QF0301B showed noncompetitive low action in 5-HT 3, muscarinic and nicotinic receptors, or as Ca 2+ antagonist. These results indicate that a α 1-adrenoceptor blocking lead has been obtained with a new chemical structure and interesting pharmacological properties, which only α 1-adrenoceptor blocking activity seems to be responsible for its cardiovascular effects.

Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo[3,2-c]azepines and related compounds.

A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl- 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak alpha1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.

Effect of chronic antipsychotic drug treatment on preprosomatostatin and preprotachykinin A mRNA levels in the medial prefrontal cortex, the nucleus accumbens and the caudate putamen of the rat.

In situ hybridization histochemistry was used to study the expression of preprosomatostatin (PPSOM) and preprotachykinin A (PPT-A) mRNA in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAC) and the caudate putamen (CP) of the rat after chronic (21 days) treatment with the classical antipsychotic drug haloperidol (1 mg/kg i.p.), the atypical antipsychotic drugs clozapine (15 mg/kg i.p.) and amperozide (5 mg/kg i.p.), and the selective dopamine (DA)-D2/D3 receptor antagonist raclopride (2 mg/kg i.p.). Whereas amperozide markedly elevated the numerical density of PPSOM mRNA expressing neurons in the mPFC (52%), the other drugs did not significantly affect PPSOM mRNA levels in any of the brain regions studied. Amperozide also altered PPT-A mRNA expression in the mPFC, i.e. a decrease (22%) was found. Of the other drugs tested only haloperidol significantly decreased PPT-A mRNA levels in the NAC shell (14%), in the dorso-lateral CP (19%) and in the medial CP (15%). In view of the differences between amperozide and the other drugs studied, as regards both pre-clinical and clinical characteristics, we suggest that the specific effects of amperozide on PPSOM and PPT-A mRNA in the mPFC may be related to its 5-HT releasing action in the frontal cortex, an effect possibly caused by its alpha2-adrenoceptor blocking activity. This effect, in turn, may be related to an antidepressant-like action that this compound exhibits in animal studies. The decrease in PPT-A mRNA levels seen after the haloperidol treatment is probably due to its potent DA-D2 receptor antagonism and may be related to side-effects, rather than therapeutic effects of this drug.

Cardiovascular effects of YM430, a 1,4-dihydropyridine derivative with beta-adrenoceptor blocking activity, in dogs and rats.

We evaluated the cardiovascular effects of YM430, a novel 1,4-dihydropyridine derivative with beta-adrenoceptor blocking activity, in dogs and rats. In anesthetized dogs, YM430 (0.01-0.3 mg/kg, i.v.) dose-dependently decreased mean blood pressure, total peripheral resistance and double product without increasing the heart rate. YM430 (0.01-0.3 mg/kg, i.v.) increased coronary artery as well as vertebral artery blood flow, whereas its effects on carotid, mesenteric, femoral and renal blood flow were small. At the same dose range as that which induced vasodilation effects, YM430 had little effect on the max. dp/dt or PQ-interval. In conscious dogs, YM430 (0.1-1 mg/kg, i.v.) produced dose-dependent hypotension with tachycardia. In conscious rats, oral dosing of YM430 (100 mg/kg p.o.) produced a long-lasting hypotensive effect with slight tachycardia. YM430 also inhibited isoproterenol (0.1 micrograms/kg i.v.)-induced tachycardia. These two effects of YM430 may be attributable to its calcium entry blocking and beta(1)-adrenoceptor blocking activity, respectively. The time course of the hypotensive (calcium entry blocking) effect of YM430 after oral dosing was very similar to that of its inhibition of isoproterenol-induced tachycardia (beta(1)-adrenoceptor blocking effect). These results indicate that the ratio of the two activities (calcium entry blocking and beta(1)-adrenoceptor blocking) of YM430 is constant after oral administration. In conclusion, YM430 could be both an antianginal and antihypertensive agent, because of its dual activities.

Hypotensive effects of YM430, a 1,4-dihydropyridine derivative, in spontaneously hypertensive rats and renal hypertensive dogs.

The hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6-dimethyl-((S)-4-(m-nitrophenyl))-1,4-dihydropyridine-3,5-dicarboxyla te) were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg) produced a dose-dependent decrease in mean blood pressure (MBP) with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the beta 1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10 mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.

Effect of α1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation

Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of alpha-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different alpha 1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these alpha 1-adrenoceptor antagonists in human subjects. In thirteen healthy male subjects (20-42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The alpha 1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative alpha 1-adrenoceptor blocking potency of drugs.

Up-regulation of hepatic LDL receptor gene expression by monatepil, a novel calcium antagonist, in high cholesterol diet-fed Japanese monkeys.

The action of the novel antihypertensive calcium antagonist monatepil on the hepatic LDL receptor was investigated at the gene expression level to clarify the mechanism of its hypolipidemic effect. In cholesterol-fed control monkeys, the LDL receptor mRNA level decreased to approximately 30% of that in the normal diet-fed monkeys. However, the administration of monatepil increased LDL receptor mRNA to normal levels (three- to fourfold stimulation). It is suggested that monatepil raises the number of LDL receptors in liver tissue and that this increase may accelerate the removal of plasma LDL. Treatment with prazosin, an alpha 1-adrenoceptor antagonist, also increased the LDL receptor mRNA level, but this restorative effect was much weaker than that of monatepil, suggesting that mechanisms additional to its alpha 1-adrenoceptor blocking activity are involved in the hypolipidemic effect of monatepil.

Pharmacologic properties of a novel Ca2+ entry blocker, AJ-2615, in vitro.

We studied the in vitro vascular relaxant properties of AJ-2615, (+/-)-N-[6,11-dihydrodibenzo[b,e]-thiepin-11-yl]-4-[4- fluorophenyl]-1-piperazinebutanamide monomaleate, a novel compound with long-lasting antihypertensive activity. AJ-2615 inhibited the high K(+)-induced contractile response in rat aorta with an IC50 of 2.08 x 10(-8) M. It was 13 times less potent than nifedipine and 3, 10, and 15 times more potent than verapamil, diltiazem, and fluanarizine, respectively. AJ-2615 also inhibited the high K(+)-induced 45Ca influx in rat aorta at almost the same concentration as that for inhibition of the contractile response. The inhibition of 45Ca influx was reversed by Bay k 8644, a Ca2+ channel agonist. The effects of AJ-2615 on the contractile response and Ca2+ influx persisted for at least 120 min after AJ-2615 was removed from the medium. These results indicate that AJ-2615 acts directly on the potential-dependent Ca2+ channel in a long-lasting manner. AJ-2615 inhibited [3H]prazosin binding to dog aortic membranes (IC50 = 1.25 x 10(-8) M) and phenylephrine-induced contractile response in superior mesenteric artery (SMA) of rabbits (IC50 = 3.87 x 10(-8) M), indicating that AJ-2615 has potent alpha 1-adrenoceptor blocking activity. AJ-2615 at 10(-6) M did not inhibit the caffeine-induced contractile response in rabbit SMA in Ca(2+)-free medium, nor did it inhibit calmodulin (CAM) activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antianginal effects of YM-16151-4 in various experimental angina models.

The antianginal effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in various experimental angina models and compared with those of nifedipine and propranolol. In anesthetized dogs, YM-16151-4 (0.3 and 1 mg/kg intravenously, i.v.) increased coronary blood flow and reduced myocardial oxygen consumption (MVO2). In isolated dog coronary arteries, YM-16151-4 concentration-dependently inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 91 nM. In anesthetized rats, YM-16151-4 also inhibited the ST-segment depression induced by vasopressin (0.5 U/kg i.v.) with an ED50 value of 29 mg/kg orally, (p.o.). Nifedipine was also effective in these models, but propranolol was not. In addition, YM-16151-4 (0.3 mg/kg i.v.) inhibited the ST-segment elevation in the epicardial ECG induced by coronary artery occlusion in anesthetized dogs. Propranolol (1 mg/kg i.v.) also inhibited this elevation, but nifedipine (0.003 mg/kg i.v.) did not. In anesthetized dogs, furthermore, the prolongation of PQ-interval induced by YM-16151-4 was almost the same as that induced by propranolol. These results demonstrate that YM-16151-4, in contrast to nifedipine and propranolol, is fully effective in these various types of angina models. Thus, YM-16151-4 is expected to prove a valuable antianginal agent in treatment of various types of angina pectoris, with these antianginal effects resulting from the sum of its calcium entry blocking and beta 1-adrenoceptor blocking activities.

Alpha 1-adrenoceptor blocking activities of bevantolol hydrochloride(NC-1400) and labetalol in rat isolated thoracic aorta—Do they distinguish between subtypes?

1. 1. Alpha 1-adrenoceptor blocking activity of bevantolol(NC-1400) was tested in the rat thoracic aorta, comparing with that of labetalol. 2. 2. In alpha 1-adrenoceptor blocking activity, bevantolol(NC-1400) was 1/20th as potent as labetalol. 3. 3. The p A 2 values of bevantolol(NC-1400) and labetalol estimated in the rat thoracic aorta were compared with those in the rabbit thoracic aorta, which were reported by Takayanagi et al. [Takayanagi I., Kizawa Y., Iwasaki S. and Nakagoshi A. (1987) Gen. Pharmac. 18, 87–89]. 4. 4. The p A 2 values of bevantolol(NC-1400) and labetalol were approximately 1 order of magnitude higher in rat aorta than in rabbit aorta, suggesting that both the drugs distinguish between subtypes of alpha 1-adrenoceptors.

Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.

Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.

The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man

Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg.h-1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 micrograms.min-1 before to 685 micrograms.min-1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has alpha 1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.