Contractile actions of L-type Ca(2)(+) agonists in human vas deferens and effects of structurally different Ca(2)(+) antagonists.
Journal - European journal of pharmacology
The actions of L-type Ca(2+) agonists, FPL 64176 and Bay K 8644 were investigated in human vas deferens in the presence of structurally different L-type Ca(2+) antagonists. The L-type Ca(2+) agonists (=3microM, ~10min) produced no detectable contractions but higher concentrations evoked intermittent rhythmic contractility of longitudinal and circular muscles. Exposure to the drugs (1microM, >/=20min) evoked only rhythmic contractility even in moderately depolarizing ([K(+)](o), 10mM) medium. These findings suggest low basal activity of L-type Ca(2+) channels (VOCs) in both muscle types. In the presence of L-type Ca(2+) agonists (1microM), high [K(+)](o) (30 or 120mM) evoked contractions with different profiles. Circular muscle had a predominance of rhythmic activity ([K(+)](o) 30mM) and slow time to peak and decline ([K(+)](o) 120mM). Longitudinal muscle was more tonic ([K(+)](o) 30mM) with a rapid time to peak and decline ([K(+)](o) 120mM). The contractions in both muscle types were blocked by nifedipine or methoxyverapamil; indicating the involvement of L-type VOCs and suggests that the distinct contractile profiles originate from differences in mechanisms that regulate contractility. In comparison to the conventional L-type Ca(2+) antagonists, fendiline, prenylamine and thioridazine were more effective against longitudinal than circular muscle contractions. Structurally similar diphenylalkylamines (cinnarizine, flunarizine, and pimozide) and phenothiazines (sulphoridazine, chlorpromazine, and trifluoperazine) inhibited the contractions comparably in both muscle types. These findings are discussed in relation to inhibition of muscle type-specific mechanisms that may contribute more to L-type VOC activation and contractility in longitudinal than in circular muscle.
Attenuation of contractility in rat epididymal vas deferens by Rho kinase inhibitors.
Journal - Autonomic & autacoid pharmacology (England )
The involvement of Ca(2+) sensitization mediated through Rho kinase in the contractility of rat epididymal vas deferens was investigated using Rho kinase inhibitors, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinilcyclohexanecarboxamide dihydrochloride (Y-27632) and 1-(5-isoquinolinesulphonyl)homopiperazine (HA 1077), in comparison with myosin light chain kinase (MLCK) inhibitors, wortmannin and 1-(5-chloronaphthalenesulphonyl)homopiperazine (ML-9) and agents that affect protein kinase C (PKC) and non-receptor tyrosine kinase intracellular signalling. 2 In Ca(2+)-free/ethyleneglycol-bis-(beta-aminoethylether)N,N,N('),N(')-tetraacetic acid (EGTA) (1 mM) medium, noradrenaline evoked sustained contractions. Y-27632 and HA 1077 caused a concentration-dependent inhibition and complete relaxation (IC(50), 1.08 and 1.75 microM respectively). The Ca(2+)-free contraction was reduced by wortmannin (10 microM) or ML-9 (10 microM) but not by inhibitors of diacylglycerol metabolism, 3-[2-[4[bis(4-Fluoropheny)methylene]-1-piperidinyl]-2,3-dihydro-2-thioxi-4(H)-quinazolinone (R59949) (10 microm) or 1,6-bis(cyclohexyloximinocarbonylamino)hexane (RHC-80267) (10 microM) or by the phospholipase A(2) (PLA(2)) inhibitor, quinacrine (up to 100 microM) or tyrosine kinase inhibitor, genistein (30 microM). 3 In the presence of Ca(2+) (2.5 mM), noradrenaline (100 microM) evoked rhythmic activity and biphasic tonic contractions. Y-27632 (1-10 microM) or HA 1077 (1-10 microM) reduced the amplitude of rhythmic activity and tonic contractions. ML-9 (10 microM) attenuated the occurrence of rhythmic activity and modestly reduced the tonic contractions. ML-9 (10 microM) combined with Y-27632 (10 microM) significantly reduced the tonic contractions. ML-9 (30 microM) alone (or combined with Y-27632 10 microM) suppressed the rhythmic activity and substantially reduced (or abolished) the tonic contractions. 4 Contractions evoked by high [K(+)](o) (120 mM) or alpha,beta-methylene ATP (10 microM) were reduced significantly by Y-27632 (1-3 microM) indicating that the Rho kinase signalling pathway is activated by direct tissue depolarization or by stimulation of ligand-gated P(2X) purinoceptors. 5 Collectively, these results indicate that Ca(2+)-sensitization mediated by Rho kinase is involved in agonist- or depolarization-induced contraction of rat epididymal vas deferens. It is the major contractile mechanism underlying noradrenaline-induced Ca(2+)-free responses. It contributes to Ca(2+)-dependent rhythmic contractility and optimizes the development of full contractile tension triggered through calmodulin/MLCK activation by stimulated influx of Ca(2+).
|ISSN : ||1474-8665|
|Mesh Heading : ||1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Adenosine Triphosphate Amides Animals Azepines Calcium Dose-Response Relationship, Drug Egtazic Acid Intracellular Signaling Peptides and Proteins Male Muscle, Smooth Myosin-Light-Chain Kinase Norepinephrine Potassium Protein Kinase Inhibitors Protein-Serine-Threonine Kinases Pyridines Rats Rats, Sprague-Dawley Receptors, Purinergic P2 Vas Deferens rho-Associated Kinases analogs & derivatives pharmacology analogs & derivatives pharmacology pharmacology pharmacology metabolism drug effects physiology antagonists & inhibitors metabolism pharmacology metabolism metabolism pharmacology agonists metabolism physiology|
|Mesh Heading Relevant : ||Muscle Contraction pharmacology antagonists & inhibitors drug effects|
Contractile actions of imidazoline alpha-adrenoceptor agonists and effects of noncompetitive alpha1-adrenoceptor antagonists in human vas deferens.
Journal - European journal of pharmacology (Netherlands )
The contractile actions of imidazoline alpha-adrenoceptor agonists were investigated in human vas deferens longitudinal and circular muscle. The effects of phenoxybenzamine were studied in comparison to dibenamine and SZL-49 (4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-bicyclo[2,2,2]octa-2,5-dienylcarbonyl-2-piperazine), an alkylating prazosin analogue that discriminates between alpha(1H)- and alpha(1L)-adrenoceptor subtypes. The imidazoline alpha-adrenoceptor agonist, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide), was a potent agonist (pD(2); longitudinal muscle 6.9, circular muscle 6.4) and cirazoline a partial agonist (pD(2); longitudinal muscle 6.1, circular muscle 5.1). Oxymetazoline was less effective, indanidine and clonidine were ineffective. SZL-49 produced a differential inhibition of contractions evoked by A-61603 in circular (alpha(1H)) compared to longitudinal (alpha(1L)) muscle and phenoxybenzamine had the opposite effect. Dibenamine inhibited the contractions comparably in both muscle types and analyses of its partial alkylation of receptors yielded identical estimates of equilibrium dissociation constant (pK(d)) for A-61603 in longitudinal (5.82) and circular (5.84) muscle. Receptor occupancy-response relationships revealed that whilst the muscle types are not different in receptor reserves for A-61603, contraction to the potent imidazoline is more efficiently coupled in longitudinal than in circular muscle. This underlies the markedly different responsiveness of the muscle types to cirazoline or oxymetazoline (alpha-adrenoceptor agonists with lower efficacies relative to A-61603).The differential inhibitory actions of phenoxybenzamine and SZL-49 are discussed.
|ISSN : ||0014-2999|
|Mesh Heading : ||Adrenergic alpha-Agonists Adrenergic alpha-Antagonists Dibenzylchlorethamine Dose-Response Relationship, Drug Humans Imidazoles Male Muscle Contraction Norepinephrine Oxymetazoline Phenoxybenzamine Prazosin Receptors, Adrenergic, alpha-1 Tetrahydronaphthalenes Vas Deferens pharmacology pharmacology pharmacology pharmacology pharmacology drug effects physiology|
|Mesh Heading Relevant : ||pharmacology pharmacology pharmacology drug effects analogs & derivatives pharmacology drug effects|
Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens.
Journal - British journal of pharmacology (England )
The effects of irreversible alpha1-adrenoceptor antagonists, SZL-49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive alpha1-adrenoceptor antagonists were also used to further characterize the alpha1-adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. NA evoked concentration-dependent contractions of both muscle types (pD2; 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL-49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half-maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). The competitive alpha1-adrenoceptor antagonists produced dextral shifts of the dose-response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pKB values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pKB, 8.6 and 9.5) or RS-17053 (pKB, 7.1 and 9.0) but not for Rec 15/2739 (pKB, 9.2 and 9.8) or HV 723 (pKB, 8.3 and 8.4). In conclusion, the potency profile of the competitive alpha1-adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL-49 is primarily due to a predominance of the alpha1L-adrenoceptor subtype in longitudinal muscle and alpha1A-subtype in circular muscle.
|ISSN : ||0007-1188|
|Mesh Heading : ||Adrenergic alpha-Antagonists Cystamine Dibenzylchlorethamine Humans Male Muscle Contraction Muscle, Smooth Norepinephrine Prazosin Receptors, Adrenergic, alpha-1 Vas Deferens Vasoconstrictor Agents pharmacology pharmacology pharmacology drug effects anatomy & histology physiology physiology|
|Mesh Heading Relevant : ||analogs & derivatives drug effects pharmacology analogs & derivatives pharmacology drug effects drug effects pharmacology|