Β-adrenoceptor Blocking Activity Research Articles

How the Deuteration of Dronedarone Can Modify Its Cardiovascular Profile: In Vivo Characterization of Electropharmacological Effects of Poyendarone, a Deuterated Analogue of Dronedarone.

Since deuterium replacement has a potential to modulate pharmacodynamics, pharmacokinetics and toxicity, we developed deuterated dronedarone; poyendarone, and assessed its cardiovascular effects. Poyendarone hydrochloride in doses of 0.3 and 3mg/kg over 30s was intravenously administered to the halothane-anesthetized dogs (n = 4), which provided peak plasma concentrations of 108 ± 10 and 1120 ± 285ng/mL, respectively. The 0.3mg/kg shortened the ventricular repolarization period. The 3mg/kg transiently increased the heart rate at 5min but decreased at 45min, and elevated the total peripheral vascular resistance and left ventricular preload, whereas it reduced the mean blood pressure at 5min, left ventricular contractility and cardiac output. The transient tachycardic action is considered to be induced by the hypotension-induced, reflex-mediated increase of sympathetic tone. The 3mg/kg delayed both intra-atrial and intra-ventricular conductions, indicating Na+ channel inhibitory action. Moreover, the 3mg/kg transiently shortened the ventricular repolarization period at 5min. No significant change was detected in the late repolarization by poyendarone, indicating it might not hardly significantly alter rapidly activating delayed-rectifier K+ current (IKr). Poyendarone prolonged the atrial effective refractory period greater than the ventricular parameter. When compared with dronedarone, poyendarone showed similar pharmacokinetics of dronedarone, but reduced β-adrenoceptor blocking activity as well as the cardio-suppressive effect. Poyendarone failed to inhibit IKr and showed higher atrial selectivity in prolonging the effective refractory period of atrium versus ventricle. Thus, the deuteration may be an effective way to improve the cardiovascular profile of dronedarone. Poyendarone is a promising anti-atrial fibrillatory drug candidate.

Methods and approaches for determination and enantioseparation of (RS)-propranolol.

Propranolol, a β-adrenergic receptor antagonist, is a chiral compound that is marketed as a racemate, but only the (S)-(-)-enantiomer is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for separation and determination of enantiomers of (RS)-propranolol. In this article a review is presented on different liquid chromatographic methods used for enantioseparation of (RS)-propranolol, using both HPLC and TLC. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned.

Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property.

The design, synthesis, antinociceptive and β-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for β-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

Bioassay, determination and separation of enantiomers of atenolol by direct and indirect approaches using liquid chromatography: A review.

Atenolol, a β-adrenergic receptor antagonist, is a chiral compound used for the treatment of cardiovascular diseases and to treat hypertension, coronary heart disease, arrhythmias, sinus tachycardia and myocardial infarction, where it acts preferentially upon the β-adrenergic receptors in the heart. It is marketed as a racemate, but only the (S)-enantiomer of (RS)-atenolol is responsible for the β-adrenoceptor blocking activity. Different chromatographic methods have been applied for the separation and determination of enantiomers. In this article a review is presented on liquid chromatographic methods for enantioseparation of (RS)-atenolol by both direct and indirect approaches involving practical applications of several chiral stationary phases, chiral derivatization reagents and ligand exchange and impregnation methods. These include methods using both HPLC and TLC for separation, determination and bioassay of enantiomers of atenolol. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned as applicable to (RS)-atenolol. This review provides current available enantioseparation choices not only for (RS)-atenolol but also for other applicable racemic drugs.

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.

The reversal of phenoxybenzamine-produced alpha-adrenoceptor blockade by the isomers of propranolol and INPEA.

Abstract Isomers of propranolol and N-isopropyl-p-nitrophenylethanolamine (INPEA) were used to demonstrate that there are two mechanisms by which the β-adrenoceptor blocking agents will reverse phenoxy-benzamine-produced α-adrenoceptor blockade. In the seminal vesicle preparation, prior administration of either isomer initially protected the receptors from phenoxybenzamine blockade when the contact time for phenoxybenzamine was short. The isomers were equi-effective, suggesting that this action is independent of β-adrenoceptor blocking activity. When the contact time of phenoxybenzamine was prolonged, the ability of the isomers to protect the α-receptors was lost. In the rat blood pressure preparation, after the development of phenoxybenzamine-produced α-adrenoceptor blockade, (-)- and (±)-propranolol or (-)- and (±)-INPEA, in doses that produced marked β-adrenoceptor blocking activity, partially reversed the α-adrenoceptor blockade. Identical doses of (+)-propranolol or (+)-INPEA, which exhibited weak β-adrenoceptor blocking activity did not produce any reversal. The reversal of phenoxybenzamine-produced α-adrenoceptor blockade in this situation appears therefore to be dependent upon the development of β-adrenoceptor blockade.

Effect of some β-adrenoceptor blocking drugs on insulin secretion in the rat

Abstract In pentobarbitone anaesthetized rats (±)-propranolol reduced the stimulatory effect of glucose, sulphonylureas, isoprenaline or phentolamine on insulin secretion. (+)-Propranolol produced similar effects to those produced by the racemate. Sotalol reduced only the insulin secretion stimulated by isoprenaline or phentolamine but not that stimulated by glucose or sulphonylureas. Complete inhibition of isoprenaline-induced hyperinsulinaemia was obtained with practolol, in a dose which was without effect on the plasma insulin elevations produced by glucose or glibenclamide. (±)-Propranolol inhibited glucose or tolbutamide-stimulated insulin secretion from chopped pancreas in vitro indicating a direct action of the drug on the pancreas. It is suggested that propranolol-induced inhibition of insulin secretion may not be entirely due to the β-adrenoceptor blocking activity of the drug.

CaMKII, the Downstream Hypertrophic Signaling Pathway in the Heart: The 2009 Benedict R. Lucchesi Distinguished Lectureship Award

CaMKII, the Downstream Hypertrophic Signaling Pathway in the Heart: The 2009 Benedict R. Lucchesi Distinguished Lectureship Award

ChemInform Abstract: Synthesis and β-Adrenoceptor Blocking Activity of Some Aryloxy- and Benzoyloxy-propanolamines.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

β-adrenoreceptor blocking and antihypertensive activity of PP-24, a newly synthesized aryloxypropanolamine derivative

Abstract PP-24 is a newly synthesized putative β-adrenoceptor antagonist. The objective of the study was to the evaluate β-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg−1) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 μg kg−1) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 μg kg−1). The pA2 of PP-24 to β1-, β2- and β3-adrenoceptors was 7.72 ± 0.082, 7.40 ± 0.082 and 6.39 ± 0.16, respectively. The β1/β2 selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses β-adrenoceptor blockade activity but with non-specific affinity for β1- and β2-adrenoceptor subtypes. The rank order of potency of the antagonists for β1-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of β-adrenoceptors.

Protective effect of labedipinedilol-A, a novel dihydropyridine-type calcium channel blocker, on myocardial apoptosis in ischemia–reperfusion injury

The effects of labedipinedilol-A, a novel dihydropyridine-type calcium channel blocker with α-/β-adrenoceptor blocking activities, on myocardial infarct size, apoptosis and necrosis in the rat after myocardial ischemia/reperfusion (45 min/120 min) were investigated. Ten minutes prior to left coronary artery occlusion, rats were treated with vehicle or labedipinedilol-A (0.25 or 0.5 mg/kg, i.v.). In the vehicle group, myocardial ischemia–reperfusion induced creatine kinase (CK) release and caused cardiomyocyte apoptosis, as evidenced by DNA ladder formation and terminal dUTP deoxynucleotidyltransferase nick end-labeling (TUNEL) staining. Treatment with labedipinedilol-A (0.25 or 0.5 mg/kg) reduced infarct size significantly compared to vehicle group (18.75 ± 0.65% and 8.27 ± 0.29% vs. 41.72 ± 0.73%, P < 0.01). Labedipinedilol-A also reduced the CK, CK-MB, lactate dehydrogenase (LDH) and troponin T levels in blood. In addition, labedipinedilol-A (0.5 mg/kg) significantly decreased TUNEL positive cells from 19.21 ± 0.52% to 9.73 ± 0.81% ( P < 0.01), which is consistent with absence of DNA ladders in the labedipinedilol-A group. Moreover, labedipinedilol-A pretreatment also decreased calcium content in ischemic–reperfused myocardial tissue. In conclusion, these results demonstrate that labedipindielol-A, through reduction of calcium overload and apoptosis, exerts anti-infarct effect during myocardial ischemia–reperfusion and would be useful clinically in the prevention of acute myocardial infarction.

The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display α-/β-Adrenoceptor antagonist and long-Acting antihypertensive activities

A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated α-/β-adrenoceptor blocking activities created a new family of calcium entry and the third generation β-adrenoceptor blockers. Optimizing this research to obtain more potent α-/β-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and α-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac effects of all the compounds 1a– 1j resulted from calcium entry and β-adrenoceptor blocking, which attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 1b as candidate compound for further pharmacological and pre-clinical evaluation studies.

A new aspect of view in synthesizing new type β-adrenoceptor blockers with ancillary antioxidant activities

A series of vanilloid-type β-adrenoceptor blockers derived from antioxidant traditional Chinese herbal medicines were synthesized and tested for their antioxidant and adrenoceptor antagonistic activities. They all possessed significant β-adrenoceptor blocking activities under in vitro experiments and radioligand binding assays. In addition, some compounds were further examined in in vivo tests and produced antagonist effects matching that of propranolol and labetalol by measurements of antagonism toward (−)isoproterenol-induced tachycardia and (−)phenylephrine-induced pressor responses in anesthetized rats. Furthermore, all of the compounds had antioxidant effects inherited from their original structures. In conclusion, compound 11 had the most potent β-adrenoceptors blocking activity, 12 and 13 possessed high cardioselectivity, whereas 14, 15 and 16 possessed additional α-adrenoceptor blocking activity and 15 is the most effective antioxidant of all. The antioxidant activity may be due to their α and β unsaturated side chain at position 1 and ortho-substituted methoxy moiety on 4-phenoxyethylamine.

Eugenolol: An eugenol-derived ?-adrenoceptor blocker with partial ?2-agonist and calcium mobilization inhibition associated vasorelaxant activities

The β-adrenoceptor blocking, vasorelaxant and hypotensive activities of eugenolol (1-(isopropylamino)-3-[(4- allyl-2-methoxy-)phenoxy]-2-propanol) were investigated under in vivo and in vitro conditions. In pentobarbital anesthetized rats, eugenolol (0.1, 0.5, 1.0 mg/kg, i.v.) produced a dose-dependent hypotensive and bradycardia response. Eugenolol also inhibited the tachycardia effects induced by (–)isoproterenol, but did not block arterial pressor responses induced by phenylephrine. In isolated guinea pig tissues, eugenolol competitively antagonized the (–)isoproterenol-induced positive inotropic and chronotropic effects and tracheal relaxation responses. The apparent pA2 values for eugenolol on right atria, left atria and trachea were 8.23 ± 0.04, 8.36 ± 0.13 and 8.18 ± 0.12, respectively. On tracheal strips of reserpinized guinea pig, cumulative doses of eugenolol (10–10–10–7 M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10–8, 10–7, 10–6 M) shifted the eugenolol concentration-relaxation curve significantly to a region of higher concentrations. Binding characteristics of eugenolol and propranolol were evaluated in [3H]dihydroalprenolol binding to pig ventricular membranes. The Ki values of eugenolol and propranolol were 18.1 ± 3.2 and 3.8 ± 0.5 nM, respectively. In guinea pig isolated thoracic aorta, eugenolol relaxed more potently the contractions induced by phenylephrine than those by high K+. The vasorelaxant effect of eugenolol on phenylephrine- or high K+-induced contraction was not attenuated by TEA or Bay K 8644 pretreatment. Furthermore, eugenolol pretreatment had a greater inhibitory effect on phenylephrine induced phasic contraction than on tonic contraction. These results indicate that eugenolol exhibits non-selective β-blocking and vasorelaxant activity by inhibiting Ca2+ channels, receptor-mediated Ca2+ mobilization and by its partial β2-agonist activity. Drug Dev. Res. 40:239–250, 1997. © 1997 Wiley-Liss, Inc.

Membrane stabilizing activity and β-adrenoceptor antagonist-induced bradycardia in conscious dogs

The atrial effective refractory period (AERP) and atrial and ventricular chronotropic effects of the stereoisomers of propanolol, pindolol, metoprolol and penbutolol were studied in conscious atrio-ventricular blocked dogs. Atrial β-adrenoceptor blocking activity was assessed for all the drugs against isoprenaline. All the drugs except dextro-pindolol lengthened AERP and decreased ventricular rate dose relatedly. At comparable levels of atrial β-adrenoceptor blockade, dextro-propanolol, dextro-metoprolol and dextro-penbutolol were more potent to induce AERP lengthening than their respective levo-isomers, whereas dextro-pindolol was less potent than levo-pindolol. In addition, levo-pindolol and levo-metoprolol were more potent to produce ventricular bradycardia than the corresponding dextro-isomers, whereas the levo- and dextro-isomers of propanolol and penbutolol were equipotent. These results confirm that the ventricular bradycardia induced by the different β-adrenoceptor antagonists is partly due to ventricular β-adrenoceptor blockade and to the membrane stabilizing activity of these drugs, and partly to another as yet unknown factor seen especially with the levo-isomers and particularly marked with metroprolol.

P-387 - Anti-anginal effects of YM430, a novel calcium entry blocking agent with β-adrenoceptor blocking activities.

P-387 - Anti-anginal effects of YM430, a novel calcium entry blocking agent with β-adrenoceptor blocking activities.

Synthesis and β-adrenergic blocking activity of 1,4-benzothiazine oxime ethers

Synthesis of 6-, 7-, 8-acetimidoyloxypropanolamines of 3,4-dihydro-3-oxo-2 H-1,4-benzothiazine and 8-iminoxypropanolamines of 3,4,5,6,7,8-hexahydro-3-oxo-2 H-1,4-benzothiazine are reported. All of the synthesized compounds were tested in vitro for their ability to displace [ 3H]dihydroalprenolol from turkey erythrocyte membranes and in vivo for their β-adrenoceptor blocking activity by the inhibition of isoprenaline-induced tachycardia and compared with the corresponding oxypropanolamines which we had previously described as β-blockers.

β-Adrenoceptor Blocking Activity of Diprafenone in Anesthetized Dogs

The effects of diprafenone, a new class Ic antiarrhythmic agent, on canine hemodynamics and cardiac membrane beta-receptor antagonist binding activity, were compared with those of propafenone and propranolol. Mongrel dogs (4-5/group) were anesthetized intravenously (i.v.) with pentobarbital sodium (35 mg/kg) and instrumented for measurement of aortic and coronary blood flows (AF, CBF), blood pressure (BP), and heart rate (HR). Isoproterenol (ISO) was administered as bolus injections before (0.01, 0.03, and 0.1 micrograms/kg, i.v.) and after (0.01-3 micrograms/kg, i.v.) infusions of diprafenone or propafenone (0.3, 1, and 3 mg/kg) or propranolol (0.03, 0.1, and 0.3 mg/kg, i.v.). The ability of the antiarrhythmic agents to displace [3H]dihydroalprenolol (DHA) binding from isolated cardiac ventricular membranes in vitro was also evaluated. Each antiarrhythmic agent blocked the HR and BP responses to ISO in a competitive manner and decreased the specific binding of DHA to cardiac ventricular membranes. Propranolol was 2 to 7 times more potent as a beta-receptor blocking agent than diprafenone, which was 6 times more potent than propafenone. The equilibrium dissociation constants (Ki) for displacement of DHA by propranolol, diprafenone, and propafenone were 2.7, 14.3, and 252 nM, respectively, and have the same rank order of potency for in vivo inhibition of BP and HR responses to ISO. Diprafenone has significant beta-adrenoceptor blocking activity which may contribute to its efficacy as an antiarrhythmic agent and allow its use in treatment of arrhythmias refractory to therapy with class I and class II agents alone.

Simultaneous assessment of membrane-stabilizing and β-adrenoceptor blocking activity of drugs with the rat isolated left atria

Three consecutive challenges of the rat isolated left atria with electrical stimulation and then electrical stimulation and isoprenaline were made. The responses to electrical stimulation decreased and the responses to isoprenaline increased with consecutive challenges such that the maximal combined response to electrical stimulation and isoprenaline remained constant. The sensitivity (pD 2) to isoprenaline decreased with successive challenges. Thus, in studies of the effects of drugs on the responses to electrical stimulation and isoprenaline, it is necessary to perform parallel experiments with untreated atria to monitor changes in the responses unrelated to the addition of drug. Analysis of the effects of procaine, metoprolol, and propranolol on the responses to electrical stimulation and/or isoprenaline demonstrated distinct contractile manifestations of β-adrenoceptor blocking and membrane stabilizing activity. The β-adrenoceptor blocking activity of metroprolol at 10 −7 M and propranolol (3 × 10 −9−10 −6 M) consisted of parallel rightward shifts of the concentration-response curves to isoprenaline alone. There were three components to the membrane-stabilizing action of drugs: first, there was a decrease in the responses to electrical stimulation alone, which was observed with procaine at ⩾ 10 −4 M and propranolol at ⩾ 3 × 10 −9 M, second, there was a small parallel rightward shift of concentration-response curve to isoprenaline alone with metoprolol at 10 −6 M and propranolol at 3 × 10 −6 M (that the inhibitory effects of metoprolol at 10 −6 M or propranolol at 3 × 10 −6 M are greater than can be explained by β-adrenoceptor blockade only may be detected either by determining pA 2 values from the formula pA 2 = pA x + log (x − 1) or by Schild analysis); third, the highest concentrations of procaine (3 × 10 −4 M) and propranolol (10 −5 M) tested decreased the maximal combined response to electrical stimulation and isoprenaline.

Vascular β-adrenoceptor blocking activity of endotoxin and pertussis toxin from Bordetella pertussis in rats

Isolated and purified leucocytosis promoting factor (LPF), alternatively described as pertussis toxin, reduced the hypotension after β 2-adrenoceptor stimulation with salbutamol as well as the negative chronotropic activity induced by the muscarinic receptor stimulant arecoline 4 days after its injection into rats. These inhibitory effects of LPF were accompanied by a reduction in basal blood pressure. No effect on autonomic responsiveness or blood pressure was observed 5 h after injection of LPF. Sublethal doses of purified B. pertussis endotoxin (LPS) elicited neither vascular β 2-adrenergic nor cardiac cholinergic blockade 4 days following injection. Only a distinct vascular β 2-adrenolytic effect was measured 5 h after pretreatment with the same doses of LPS. This gb 2-adrenoceptor hyporesponsiveness was accompanied by neither an anticholinergic nor a hypotensive effect, but rather by a slight but significant but significant elevation of the blood pressure. In conclusion, both components of B. pertussis (LPS and LPF) give rise to vascular β 2-adrenergic hyporesponsiveness irrespective of blood pressure effects. There is an important difference between both components with respect to their various kinetic profiles for this phenomenon: an early occuring and short-lasting β 2-adrenergic blockade for LPS and a late occuring LPF-mediated β 2-adrenergic blockade.