1 We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone. 2 Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone. 3 TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC 50 8.3+2.8 nM) and HPRA (EC 50 6.2+2.2 nM), and the contractions produced by prostaglandin F 2a at high concentrations (EC 50 6460+3220 nM in HCCS and 8900+6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 mM). 4 EP-receptors are responsible for prostanoid-induced relaxant e ects in HCCS because only prostaglandin E 1 (PGE 1 ), prostaglandin E 2 and the EP 2 /EP 4 -receptor agonist, butaprost, produced consistent relaxation of this tissue (EC 50 93.8+31.5, 16.3+3.8 and 1820+1284 nM, respectively). In HPRA, both prostacyclin and PGE 1 (EC 50 60.1+18.4 and 109.0+30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC 50 25.2+15.2 and 7050+6020 nM, respectively) caused relaxation, suggesting co-existence of IP-and EP-receptors (EP 2 and/or EP 4 ).
1 This study examined whether pretreatment of rabbits with infusions of prostaglandin El (PGEI) or prostaglandin Eo (PGEO) (which were terminated prior to the onset of ischaemia) reduce myocardial infarct size arising from coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effects of these two prostaglandins were due to the activation of ATP-sensitive potassium (KATP) channels. 2 In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 59 + 4% (n = 10). PGEI or PGEo treatment (1.0 ,yg kg-' min-'), administered as 1 h pretreatments (0.05 ml min-', i.v.), significantly reduced infarct size to 44 + 6% (n = 6) or 42 + 1 % (n = 6), respectively. PGE, or PGEo pretreatment resulted in a significant reduction in mean arterial blood pressure, which returned to baseline within 15 min of discontinuation of the infusion (i.e. prior to LAL ligation). 3 The reduction in infarct size afforded by PGE, was abolished by pretreatment of rabbits with the KATP channel blockers, glibenclamide (60 + 4%; n =8) or 5-hydroxydecanoate (58 + 6%; n = 6). Similarly, glibenclamide also largely attenuated the reduction in infarct size afforded by PGEo (52 + 3%; n = 8).4 We propose that a 1 h pretreatment of PGEI or PGEO reduces infarct size by activating protein kinase C resulting in the opening of KATP channels.
OBJECTIVE To investigate the primary pharmacology of fesoterodine (a novel antimuscarinic drug developed for treating overactive bladder) and SPM 7605 (its active metabolite, considered to be the main pharmacologically active principle of fesoterodine in man) against human muscarinic receptor subtypes, and to investigate in vitro and in vivo functional activity of these agents on the rat bladder compared with existing standard agents. MATERIALS AND METHODS The displacement of radioligand binding by fesoterodine, SPM 7605 and standard agents in membrane preparations of Chinese hamster ovary (CHO) cells expressing the different human muscarinic receptors (M1–M5) was characterized. Agonistic and antagonistic activities were studied using different CHO cell lines stably expressing the human recombinant muscarinic receptor subtypes. The effects of fesoterodine and SPM 7605 on isolated bladder strips contracted by carbachol or electrical field stimulation (EFS) were investigated. In vivo the effects of fesoterodine and SPM 7605 on micturition variables were assessed using continuous cystometry in conscious female Sprague‐Dawley rats, and compared to those of oxybutynin and atropine. RESULTS In vitro SPM 7605 potently inhibited radioligand binding at all five human muscarinic receptor subtypes with equal affinity across all five. Fesoterodine had a similar balanced selectivity profile but was less potent than SPM 7605. Both substances were competitive antagonists of cholinergic agonist‐stimulated responses in human M1‐M5 cell lines and had a similar potency and selectivity profile to the radioligand‐binding studies. In rat bladder strips, fesoterodine and SPM 7605 caused a rightward shift of the concentration‐response curve for carbachol with no depression of the maximum, and concentration‐dependently reduced contractions induced by EFS. The potency of both drugs was similar to that of atropine and oxybutynin. In the presence of the esterase inhibitor neostigmine, the concentration‐response curve of fesoterodine was shifted to the right, suggesting that part of the activity was caused by metabolism to SPM 7605 by tissue enzymes. In vivo, low doses (0.01 mg/kg) of fesoterodine and SPM 7605 reduced micturition pressure and increased intercontraction intervals and bladder capacity, but did not affect residual volume. CONCLUSIONS Fesoterodine and its active metabolite, SPM 7605, are nonsubtype selective, competitive antagonists of human muscarinic receptors, but SPM 7605 has greater potency than the parent compound. Pharmacodynamic studies in the rat bladder in vitro confirm the competitive muscarinic antagonist profile of these agents in a native tissue preparation, and in vivo studies in the rat showed effects on bladder function consistent with a muscarinic antagonist profile.
The large conductance calcium-sensitive potassium channel (K Ca or maxi-K) is an important modulator of human corporal smooth muscle tone, and therefore, erectile capacity. The goal of this investigation was to evaluate the actions of prostaglandin E 1 (PGE 1 ), the most widely used and effective drug for the treatment of impotence, on the activity of the K Ca channel, a prominent K current present in human corporal smooth muscle. Whole-cell patch clamp studies conducted on short-term cultured and enzymatically dissociated human corporal smooth muscle cells, revealed mean resting potentials of 7 50.8 AE 2.1 mV (n 8) and 7 34 AE 4 mV (n 8), respectively. In the attached-patch con®guration, the corresponding single-channel slope conductance values for the K Ca channel subtype were 173 AE 4 pS (n 8) in cultured cells, and 190 AE 13 pS (n 3) in freshly isolated myocytes. Furthermore, voltage clamp experiments revealed that relative to control values, the application of PGE 1 to cultured cells (3.3 or 33 mM) elicited an apparent increase in both the open probability (P o ; ranging from 1.2 ± 23 fold), and the mean open time (5 ± 6 fold) of the K Ca channel at membrane potentials of 90 mV and 110 mV. PGE 1 -induced alterations in K Ca channel activity were also observed in freshly isolated corporal myocytes. In the whole cellrecording mode, statistically signi®cant, Charybdotoxin-sensitive (100 nM) 2 ± 3 fold increases in the outward K currents were observed in both cultured and freshly isolated corporal myocytes. The presence of a PKA inhibitor (fragment 6 ± 22 amide; 10 mM) in the pipette tip was also associated with a nearly complete ablation of the observed PGE 1 -induced whole cell K currents. Taken together, these data con®rm and extend our previous observations, and indicate that PGE 1 -induced relaxation of human corporal smooth muscle is related, at least in part, to activation of the K Ca channel subtype resulting in cellular hyperpolarization.
The action of PGE1, PGE2, PGI2 and iloprost on superoxide anion generation, lysosomal enzyme release, and changes of Ca2+ fluxes in human polymorphonuclear leukocytes (PMN) was studied in vitro. Both PGE-type compounds were equipotent inhibitors of FMLP-and PAF-stimulated superoxide anion generation, beta-glucuronidase release (IC50 3-5 mumol/l) and Ca2+ influx while PGI2 and iloprost were ineffective at concentrations up to 10 mumol/l. These inhibitory actions of PGE1 and PGE2 were paralleled by an increase in cAMP level of the PMN while no change occurred with PGI2 and iloprost. None of the prostaglandins affected the initial intracellular Ca2+ liberation after challenge with FMLP or PAF. Preincubation of PMN with PGE1 and PGE2 but not with iloprost resulted in subsequent desensitization against a second administration of these compounds. None of the compounds affected PMN activation produced by arachidonic acid or calcimycin (A 23187). These data demonstrate that PGE-type compounds are effective inhibitors of receptor-mediated (PAF, FMLP) activation of human PMN while prostacyclins are considerably less potent. This suggests that the inhibitory prostaglandin receptor on human PMN belongs to the E-type being functionally different from the inhibitory prostaglandin receptor on human platelets. These results suggest that compounds, such as PGE1 and PGE2 might be superior to prostacyclins to prevent PMN-associated generation of reactive oxygen species and lysosomal enzyme release in situations with endogenous PMN activation, i.e. inflammatory reactions.
Uneven numbered 1‐alkenes, such as 1‐pentadecene, 1‐heptadecene, 1,8‐heptadecadiene, 1,8,11‐heptadecatriene and 1,8,11,14‐heptadecatetraene are the predominant hydrocarbons in germinating safflower (Carthamus tinctorius L.). According to their chain length and positions of double bonds they are derived from palmitic, stearic, oleic, linoleic or linolenic acid, respectively. This has been proved by administration of synthetic α‐, β‐, or γ‐deuterated 12‐phenyldodecanoic acids to germinating safflower. Mass spectrometric analysis of the resulting deuterium‐labelled 11‐phenyl‐1‐undecenes shows that only a single hydrogen from C‐3 and carbon dioxide from C‐1 of the precursor fatty acid is lost during vinyl group formation. A strong isotope effect (kH/kD≥ 10) during the conversion of racemic 12‐phenyl[3‐2H]dodecanoic acid to 11‐phenyl‐1‐[2‐2H]undecene is consistent with an initial enzymatic attack on a non‐activated hydrogen at C‐3 accompanied by simultaneous fragmentation into the respective 1‐alkene and carbon dioxide. Mechanisms, based on ionic or radical abstraction of a hydrogen from C‐3 of the fatty acid, followed by decarboxylation are discussed. The results are applicable to the formation of various vinylic substituents in natural products such as porphyrins, acetylenic hydrocarbons, pheromones from marine brown algae and terpenoids.
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