ALBERT

Notes: 1 We have investigated the actions of the α1D-adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at α1- and α2-adrenoceptors. 2 In rat aorta (α1D-adrenoceptor), BMY 7378 (pA2 of 8.67) was about 100 times more potent than yohimbine (pA2 of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein (α2C-adrenoceptor), BMY 7378 (pA2 of 6.48) was approximately 10 times less potent than yohimbine (pA2 of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 μm) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional α2D-adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for α2C-adrenoceptors (pKi of 6.54) over other α2-adrenoceptors. 6 It is concluded that BMY 7378, in addition to α1D-adrenoceptor selectivity in terms of α1-adrenoceptors, shows selectivity for α2C-adrenoceptors in terms of α2-adrenoceptors.

Notes: 1 The purpose of this study was to examine the effect of inhibition of the formation of cytochrome P450 metabolites of arachidonic acid with 1-aminobenzotriazole (ABT) on the development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with nitric oxide synthesis inhibitor l-NAME (SHR-l-NAME). 2 Administration of l-NAME in drinking water (80 mg l−1) to SHR for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 ± 4 mmHg) as compared to SHR controls drinking regular water (165 ± 3 mmHg). The administration of ABT (50 mg kg−1 i.p. alt diem) for 6 days significantly attenuated elevation of blood pressure in SHR-l-NAME (204 ± 4 mmHg). 3 l-NAME-induced increase in urine volume and protein was significantly lower in ABT-treated animals. 4 The impaired vascular responsiveness to noradrenaline and isoprenaline in the perfused mesenteric vascular bed of SHR-l-NAME-treated animals was significantly improved by ABT treatment. 5 Morphological studies of the kidneys and hearts showed that treatment with ABT minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, significant narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-l-NAME. 6 In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischaemia was significantly better in ABT-treated SHR-l-NAME. 7 These results suggest that in hypertensive individuals with endothelial dysfunction and chronic NO deficiency, inhibitors of 20-HETE synthesis may be able to attenuate development of high blood pressure and end-organ damage.

Notes: 1  The aim of the current study was to investigate the existence of P2Y4 purinergic receptors in the HT-29 human colon cancer cell line. 2  We utilized Western blots and immunocytochemistry for the analysis. 3  Western blotting demonstrated two bands that could not be found after the antibody had been preabsorbed with the control peptide, suggesting that both bands are related to the P2Y4 purinergic receptor. 4  Immunocytochemistry showed immunoreactivity for the P2Y4 purinergic receptor localized in the cytoplasm of the HT-29 cells. 5  This is the first demonstration of the protein expression of P2Y4 purinergic receptors in a human colon cancer cell line.

Notes: 1 The effect of WAY 405 ((R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide), a putative 5-HT1A receptor antagonist, on cardiovascular function was studied. 2 In anaesthetized rats, the i.v. injection of WAY 405 did not significantly modify basal heart rate nor blood pressure at doses of 1, 3, 10 and 30 μg kg−1; while the antagonist dose dependently antagonized the 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin)-induced hypotension and bradycardia. 3 WAY 405 antagonized noradrenaline-induced contraction in isolated arteries, with pKB values of 6.6 ± 0.1, 6.5 ± 0.1 and 6.5 ± 0.1, for rat tail artery (α1A-adrenoceptors), rabbit aorta (α1B-adrenoceptors), and rat aorta (α1D-adrenoceptors) respectively. 4 The results show that in the control of blood pressure the new compound, WAY 405, behaves as a silent 5-HT1A receptor antagonist in the anaesthetized rat, also having low affinity for vascular α1-adrenoceptors.

Notes: 1 The objective was to investigate a possible contribution of a nerve-derived hyperpolarizing factor to the differences between non-adrenergic non-cholinergic (NANC) nerve-mediated relaxations in different states of active tone in the rat gastric fundus. 2 NANC relaxations induced by electrical field stimulation (ES: 0.1, 0.5 and 1 Hz; 25 V; 1 ms; 10 s) in 40% contracted strips (S40) were greater when compared with those in 80% contracted strips (S80). 3 ES-induced relaxations were effectively attenuated by Nω-nitro-l-arginine (l-NNA; 100 μm) in S40 and S80. Percentage reduction of the responses obtained in the presence of l-NNA in S40 group was less than that of S80. 4 In S40 group, nifedipine (0.5–1 μm) and verapamil (0.5–1 μm) inhibited the responses to 0.1 and 0.5 Hz. Nifedipine (1 μm) and verapamil (0.5 μm) caused no change in the responses to ES in S80. 5 In S40, when l-NNA (100 μm) and nifedipine or verapamil, either in 1 μm concentration, were administered together, the inhibition on the electrical relaxations were more than that of each drug alone. 6 In conclusion, NANC nerve-mediated relaxations are increased when studied in an active state of 40%, and a factor, sensitive to nifedipine seems to be responsible for this distinction.

Notes: 1 The aim of the present study was to examine the modulator influence of muscarinic M2 receptors on responses of rat urinary bladder detrusor muscle evoked by endogenous stimuli, i.e. by stimulation of the bladder innervation. 2 Responses were evoked by electrical field stimulation (EFS; 2–20 Hz, 0.8 ms, 60 V) of isolated strip preparations mounted in organ baths. The tension of the muscle strips was recorded digitally. EFS was performed by applying stimulation with either a short duration (5 s) or a longer duration (to reach peak response; approximately 20 s). 3 Effects of muscarinic receptor antagonists (muscarinic M1/M3 receptor selective: 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP); muscarinic M2 receptor selective: methoctramine), a β-adrenergic antagonist (propranolol) and an adenosine receptor antagonist (8-p-sulfophenyltheophylline) were assessed on contractile activity and on poststimulatory relaxations. 4 Low concentrations of methoctramine (10−8 m) reduced or tended to reduce the EFS-induced contraction, e.g. at 2 Hz by 12% while methoctramine at 10−7 m had no significant effect. In addition, in the presence of 4-DAMP (10−9 m), which tended to inhibit contractions at all frequencies (2–20 Hz; −17 to −25%), methoctramine at 10−8 and 10−7 m induced a further reduction of the contractile responses (−5 to −10%; 2–20 Hz). 5 The β-adrenergic receptor antagonist propranolol (10−6 m) and the adenosine receptor antagonist 8-p-sulfophenyltheophylline (10−6 m) both increased contractile responses by 9–21% (2–10 Hz, long duration; P 〈 0.05–0.001) as a consequence of antagonizing relaxatory stimuli. Neither antagonist affected the contractile responses to EFS with the short duration stimulation. Poststimulatory relaxations were reduced by 30–60% (P 〈 0.05) by propranolol and by 40–60% (P 〈 0.001) by 8-p-sulfophenyltheophylline, but for 8-p-sulfophenyltheophylline only after stimulation with the short duration. 6 In the presence of methoctramine (10−7 m), the 8-p-sulfophenyltheophylline-induced increases of the contractile response to long duration EFS were significantly enhanced at 10 Hz (+12 ± 4%; P 〈 0.05), whereas no such enhancement of the propranolol inhibitory effect occurred in the presence of methoctramine. However, poststimulatory β-adrenoceptor-evoked relaxations after short duration EFS were increased by about 35% in the presence of methoctramine, but not those after long duration. 7 Thus, muscarinic M2 receptor activation inhibits adenosine receptor- and β-adrenoceptor-evoked relaxations of the rat detrusor muscle. The inhibition occurs via a transient postjunctional mechanism that mainly affects responses with a short latency.

Notes: 1 β-Adrenoceptor (AR) ligands have been the mainstay of cardiovascular therapy for decades, with β-AR antagonist being used for hypertension, angina and myocardial infarction and adrenaline in use for cardiopulmonary resuscitation for nearly 100 years. 2 Ischaemia of the heart through coronary artery occlusion causes cell injury and death through necrosis and apoptosis. Reperfusion of the ischaemic myocardium results in cardiac dysfunction and infarction. 3 Stimulation of α- and β-ARs in the ischaemic heart have variable and inconsistent effects depending on when the agonist is applied. This review describes the different effects of stimulation of the three established β-AR subtypes (β1-, β2- and β3-ARs) either before ischaemia (preconditioning) or during ischaemia and reperfusion of the heart (postconditioning). 4 Brief periods of ischaemia preceding a major ischaemic episode can have a protective effect against post-ischaemia–reperfusion damage, known as ischaemic preconditioning. This review considers the role of endogenous catecholamines released during preconditioning and the nature of the adrenoceptor subtypes that mediate these effects. The clinical significance of this to the use of β-AR antagonists is considered. 5 The transduction pathways and effects on apoptosis of the cardioprotective and deleterious effects of AR activation are considered. 6 This commentary reviews the literature and attempts to bring together a unified synopsis of the effects of adrenoceptor stimulation in myocardial ischaemia and the potential clinical relevance.

Notes: 1 This double-blind, cross-over, placebo-controlled study on six healthy male volunteers was designed to evaluate the effects of α2-adrenoceptor antagonism on cardiac parasympathetic regulation. 2 The subjects received atipamezole intravenously as a three-step infusion, which aimed at steady-state serum concentrations of 10, 30 and 90 ng ml−1 at 50-min intervals. 3 Drug effects were assessed with repeated recordings of blood pressure and electrocardiogram, in which the high-frequency (0.15–0.40 Hz) R-R interval variation is supposed to reflect cardiac parasympathetic efferent neuronal activity. 4 At the end of the three steps of the infusion, the mean (±SD) concentrations of atipamezole were 10.5 (3.9), 26.8 (5.6) and 81.3 (21.1) ng ml−1. 5 Within this concentration range, atipamezole appeared to reduce slightly the high-frequency R-R interval fluctuations, indicating a minor vagolytic effect in the heart. 6 Atipamezole increased systolic and diastolic arterial pressure, on average by 20 and 14 mmHg (maxima at the second step of the infusion), which evidently reflects an overall sympathetic augmentation.

Notes: 1 A fructose (Fru)-enriched diet induces a mild increase in blood pressure associated with hyperglycaemia, hypertriglyceridaemia, and insulin resistance, resembling the human ‘syndrome X’, being an useful model to study hypertension and type 2 diabetes. 2 A sustained elevation of blood pressure is associated with cardiovascular structural modifications such as left ventricular hypertrophy and increased wall thickness:lumen diameter ratio in blood vessels. 3 Prostanoids (PR), metabolites of arachidonic acid through the cyclooxygenase pathway, include vasoactive substances synthesized and released by the vessel walls. 4 The aim of the present study was to analyse, in Fru-treated rats: (i) the morphology of mesenteric vessels and; (ii) the PR production in aorta and mesenteric vessels, in order to assess whether these parameters are related with the haemodynamic alterations observed in this experimental model. 5 Blood pressure, glycaemia and triglyceridaemia, were significantly elevated in both (4 and 22 weeks) Fru-treated groups. Meanwhile body and heart weight as well as insulinaemia were similar between experimental animals and controls. 6 The mesenteric vessels of Fru-treated rats (22 weeks) showed an increased thickness and area of the media when compared with the controls; meanwhile, the lumen diameter was similar in both groups. 7 The Fru treatment for 4 weeks did not modify PR production in aorta, whereas in the mesenteric bed it diminished prostaglandin (PG) E2 release significantly compared with the controls. However, in the group treated for 22 weeks, Fru reduced PGI2 production in the aorta, as assessed by 6-keto-PGF1α measurements. Meanwhile, in the mesenteric bed, the chronic Fru treatment decreased PGE2 release but, rather surprisingly, increased the output of PGI2 when compared with its corresponding controls. 8 In conclusion, the present study shows the existence of an alteration in the morphology of mesenteric vessels in Fru-treated rats, which could be related to an increase in peripheral resistance and the consequent mild hypertension observed in this model. However, a diminished release of vasodilator PRs, such as PGE2 in mesenteric vessels at 4 and 22 weeks and PGI2 in aorta at 22 weeks could further impair the vessel response. The increase in PGI2 observed in the chronic group in mesenteric vessels could be attributed to a compensatory mechanism.

Notes: 1 The characteristics of semicarbazide-sensitive amine oxidase (SSAO) are reviewed and the unknown physiological or pathological role of this enzyme emphasized. 2 The various mechanisms of action proposed for the vasodilator drug hydralazine are considered. In particular, the inhibitory action on various enzymes, related or not to cardiovascular function, are discussed. 3 Studies linking inhibition of SSAO to hydralazine hypotension are reviewed and a general hypothesis relating both actions is presented. The hypothesis postulates that (a) vascular SSAO is involved in the regulation of vascular tone, and (b) hydralazine vasodilation is the consequence of vascular SSAO inhibition. 4 Evidence supporting these postulates is presented and vascular SSAO inhibition is proposed as a novel mechanism of vasodilation.