Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries.
(25/2042)
OBJECTIVES: The study aimed to evaluate the role of alpha-adrenergic mechanisms during dynamic exercise in both normal and stenotic coronary arteries. BACKGROUND: Paradoxical vasoconstriction of stenotic coronary arteries has been reported during dynamic exercise and may be due to several factors such as alpha-adrenergic drive, a decreased release of nitric oxide, platelet aggregation with release of serotonin, or a passive collapse of the vessel wall. METHODS: Twenty-six patients were studied at rest, during two levels of supine bicycle exercise and after 1.6 mg sublingual nitroglycerin. The alpha-blocker phentolamine was given to 16 patients before exercise, five of whom had also taken a beta-adrenergic-blocker the same morning. Ten patients served as controls. The cross-sectional areas of a normal and a stenotic coronary vessel were determined by biplane quantitative coronary arteriography. RESULTS: In the normal vessel segments, coronary cross-sectional area did not change after phentolamine injection, but increased in all patient groups similarly during exercise. Although coronary vasoconstriction existed in stenotic vessel segments in control patients, phentolamine-treated patients showed exercise-induced vasodilation without difference in patients with and without chronic beta-blockade. CONCLUSIONS: Exercise-induced vasoconstriction of stenotic coronary arteries is prevented by intracoronary administration of phentolamine. There was no difference in coronary vasomotion between patients receiving phentolamine alone and patients receiving phentolamine in addition to a beta-blocker. This finding suggests that exercise-induced vasoconstriction is mediated not only by endothelial dysfunction but also by alpha-adrenergic mechanisms. (+info)
alpha2C adrenoceptors inhibit adenylyl cyclase in mouse striatum: potential activation by dopamine.
(26/2042)
alpha2C adrenoceptors occur in high density in the striatum, but the functional role of these receptors is uncertain. Mice with targeted inactivation of the alpha2C adrenoceptor gene (Adra2c-/-) and genetically related control mice expressing the wild-type alpha2C adrenoceptor (Adra2c+/+) were used to determine whether striatal alpha2C adrenoceptors modulate adenylyl cyclase activation. In striatal slices from Adra2c+/+ mice, the alpha2 adrenoceptor antagonist RX821002 facilitated forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner. In contrast, RX821002 had no effect on forskolin-stimulated cAMP accumulation in striatal slices from Adra2c-/- mice or in striatal slices from Adra2c+/+ mice treated with reserpine and alpha-methyl-rho-tyrosine to deplete monoamine neurotransmitters. Given the sparse innervation of the striatum by noradrenergic neurons, the possibility that dopamine can activate the mouse alpha2C adrenoceptor at physiologically relevant concentrations was investigated using normal rat kidney (NRK) cells transfected with the mouse alpha2A or alpha2C adrenoceptor cDNA (NRK-alpha2A or NRK-alpha2C cells). Inhibition of [3H]RX821002 binding by agonists in homogenates of transfected cells revealed an affinity of dopamine for alpha2C adrenoceptors that was higher than the affinity of norepinephrine for its cognate receptor, the alpha2A adrenoceptor. Both norepinephrine and dopamine inhibited forskolin-stimulated cAMP accumulation in intact NRK-alpha2C cells. In NRK-alpha2A cells, norepinephrine facilitated forskolin-stimulated cAMP accumulation, an effect not observed for dopamine. Together, these data demonstrate that the alpha2C adrenoceptor is negatively coupled to adenylyl cyclase and is tonically activated in mouse striatal slices. The endogenous activator of the striatal alpha2C adrenoceptor may be dopamine, as well as norepinephrine. (+info)
In vivo measurement by [3H]Tamsulosin of alpha1 adrenoceptors in rat tissues in relation to the pharmacokinetics.
(27/2042)
The present study was undertaken to simultaneously measure alpha1 adrenoceptors in rat tissues by [3H]tamsulosin in vivo. In vivo specific [3H]tamsulosin binding was observed in the prostate, vas deferens, aorta, submaxillary gland, spleen, heart, lung, and kidney after i.v. injection of the ligand but not in the cerebral cortex and liver. Specific [3H]tamsulosin binding in the kidney, lung, heart, and spleen was greatest at 3 min after i.v. injection and declined rapidly with the disappearance of [3H]tamsulosin from the plasma. On the other hand, [3H]tamsulosin binding in the prostate and aorta peaked at 10 to 60 min after i.v. injection, and a considerable level of specific binding in both tissues persisted up to 240 min. The most sustained binding of [3H]tamsulosin occurred in the submaxillary gland. In vivo specific [3H]tamsulosin binding in rat tissues was effectively inhibited by the coinjection of low doses of unlabeled tamsulosin, prazosin, and terazosin with the radioligand but not by relatively high doses of yohimbine and propranolol. Based on estimated ID50 values, in vivo inhibitory effect of tamsulosin compared with prazosin was 5 to 14 times greater in rat tissues except the spleen, which showed 1.6 times less potent than prazosin. From ratios of ID50 (spleen) to ID50 (submaxillary gland) or ID50 (prostate), tamsulosin was 9 and 19 times, respectively, greater than prazosin in selectivity of alpha1 adrenoceptors in the submaxillary gland and prostate versus the spleen, respectively, suggesting that tamsulosin binds to alpha1A subtype with higher affinity than alpha1B subtype in vivo. The present study suggests that [3H]tamsulosin is a useful radioligand for in vivo measurement of alpha1 adrenoceptors in rat tissues. (+info)
Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors.
(28/2042)
The pharmacological profiles of the alpha1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrine-induced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human alpha1-adrenoceptor subtypes, naftopidil was selective for the alpha1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha1a- and alpha1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for alpha1a- and alpha1d-adrenoceptor subtypes. (+info)
Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between beta- and alpha1-adrenoceptors.
(29/2042)
Extensive evidence indicates that norepinephrine modulates memory storage through an activation of beta-adrenoceptors in the basolateral nucleus of the amygdala (BLA). Recent findings suggest that the effects of beta-adrenergic activation on memory storage are influenced by alpha1-adrenoceptor stimulation. Pharmacological findings indicate that activation of postsynaptic alpha1-adrenoceptors potentiates beta-adrenoceptor-mediated activation of cAMP formation. The present study examined whether inactivation of alpha1-adrenoceptors in the BLA would alter the dose-response effects on memory storage of intra-BLA infusions of a beta-adrenoceptor agonist, as well as that of a synthetic cAMP analog. Male Sprague Dawley rats received bilateral microinfusions into the BLA of either the beta-adrenoceptor agonist clenbuterol (3-3000 pmol in 0.2 microliter) or 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo-cAMP) (0.2-7 nmol in 0.2 microliter) alone or together with the alpha1-adrenoceptor antagonist prazosin (0.2 nmol) immediately after training in an inhibitory avoidance task. Retention was tested 48 hr later. Clenbuterol induced a dose-dependent enhancement of retention, and prazosin attenuated the dose-response effects of clenbuterol. Posttraining intra-BLA infusions of 8-bromo-cAMP also induced a dose-dependent enhancement of retention latencies. However, concurrent infusion of prazosin did not alter the dose-response effects of 8-bromo-cAMP. These findings are consistent with the view that alpha1-adrenoceptors affect memory storage by modulating beta-adrenoceptor activation in the BLA. Moreover, these findings are consistent with those of pharmacological studies indicating that beta-adrenoceptors modulate memory storage by a direct coupling to adenylate cyclase, whereas alpha1-receptors act indirectly by influencing the beta-adrenoceptor-mediated influence on cAMP formation. (+info)
Pharmacological analysis of the novel, selective alpha1-adrenoceptor antagonist, KMD-3213, and its suitability as a tritiated radioligand.
(30/2042)
Pharmacological profiles of tritiated KMD-3213, a new antagonist of alpha1-adrenoceptor (AR), were examined in recombinant and native alpha1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10-2000 pM) showed high affinity for alpha1a-AR (pK(D) = 10.5). However, no significant binding to alpha1b-AR and insufficient/unsaturated binding to alpha1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pK(D)>9). In competition experiments, KMD-3213 also had higher affinity for alpha1a-AR than for other two subtypes; pKi = 10.4, 8.1 and 8.6 for alpha1a-, alpha1b- and alpha1d-AR, respectively. [3H]-KMD also bound to the native alpha1A-AR (rat submaxillary gland) with high affinity, but not to alpha1B-AR (rat liver). In rat kidney which expresses alpha1A- and alpha1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pK(D) = 10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax = 159 and 267 fmol mg(-1) protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi = 7.6 and 10.7, respectively), for WB4101 (pK = 8.1 and 10.0) and for YM-617 (pKi = 8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional alpha1A- (rat caudal artery, pA2= 10.0 against NS-49) and alpha1L-AR (dog mesenteric artery, pA2 = 9.9 against NA) than in alpha1B- (dog carotid artery, pA2 = 7.7 against NA) and alpha1D-AR (rat thoracic aorta, pA2 = 8.3 against NA). These results confirm the alpha1A-AR selectivity and high affinity of KMD-3213, and indicate that [3H]-KMD can label selectively alpha1A-AR. (+info)
Effects of GABA on noradrenaline release and vasoconstriction induced by renal nerve stimulation in isolated perfused rat kidney.
(31/2042)
We examined effects of gamma-aminobutyric acid (GABA) on vasoconstriction and noradrenaline (NA) release induced by electrical renal nerve stimulation (RNS) in the isolated pump-perfused rat kidney. RNS (1 and 2 Hz for 2.5 min each, 0.5-ms duration, supramaximal voltage) increased renal perfusion pressure (PP) and renal NA efflux. GABA (3, 10 and 100 microM) attenuated the RNS-induced increases in PP by 10-40% (P<0.01) and NA efflux by 10-30% (P<0.01). GABA did not affect exogenous NA (40 and 60 nM)-induced increases in PP. The selective GABA(B) agonist baclofen (3, 10 and 100 microM) also attenuated the RNS-induced increases in PP and NA efflux, whereas the RNS-induced responses were relatively resistant to the selective GABA(A) agonist muscimol (3, 10 and 100 microM). The selective GABA(B) antagonist 2-hydroxysaclofen (50 microM), but not the selective GABA(A) antagonist bicuculline (50 microM), abolished the inhibitory effects of GABA (10 microM) on the RNS-induced responses. The selective alpha2-adrenoceptor antagonist rauwolscine (10 nM) enhanced the RNS-induced responses. GABA (3, 10 and 100 microM) potently attenuated the RNS-induced increases in PP by 40-60% (P<0.01) and NA efflux by 20-50% (P<0.01) in the presence of rauwolscine. Prazosin (10 and 30 nM) suppressed the RNS-induced increases in PP by about 70-80%. Neither rauwolscine (10 nM) nor GABA (10 microM) suppressed the residual prazosin-resistant PP response. These results suggest that GABA suppresses sympathetic neurotransmitter release via presynaptic GABA(B) receptors, and thereby attenuates adrenergically induced vasoconstriction in the rat kidney. (+info)
In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.
(32/2042)
It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. (+info)