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Humans↗
Biomedical subjects
N O'Hara
Publications and source records attributed to N O'Hara.
Direct evidence for the interaction between papaverine and alpha 2-adrenergic receptors in canine platelets.
The effects of papaverine on specific [3H]-yohimbine binding to canine platelet alpha 2-adrenergic receptors and on the platelet aggregation were assessed and compared with those of verapamil. Both compounds concentration-dependently inhibited [3H]-yohimbine binding with KI values for respective compounds of 0.39 +/- 0.05 microM (n = 3) and 15 +/- 0.19 microM (n = 3). In the presence of either compound KD values in Scatchard analysis of the equilibrium ligand binding increased in concentration-dependent manner, whereas Bmax did not change, indicating competitive inhibition of the ligand binding by these compounds. (-)-Epinephrine (3 microM) potentiation of adenosine diphosphate (ADP, 0.1 microM) aggregation was inhibited by papaverine with IC50 of 11 +/- 3.6 microM (n = 4). In the same experiments verapamil inhibited the platelet aggregation with lower IC50 (3.1 +/- 0.87 microM, n = 4) in comparison with that for papaverine. These results suggest that papaverine, like verapamil, inhibits physiological response of canine platelets through alpha-adrenergic receptor stimulation by direct interaction with the receptors.
Animals↗
Effect of propranolol, alprenolol, pindolol, and bopindolol on beta 2-adrenoceptor density in human lymphocytes.
Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound effects." To investigate the position of the new nonselective beta-adrenoceptor antagonist bopindolol [with moderate intrinsic sympathomimetic activity (ISA)], this drug was compared with propranolol (no ISA), alprenolol (weak ISA), and pindolol (marked ISA). The effects on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]iodocyanopindolol (ICYP) binding--were investigated in healthy volunteers aged 23-35 years. None of the test drugs changed the affinity of ICYP for beta 2 adrenoceptors. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; during treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol, beta 2-adrenoceptor density declined slowly, being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h, though heart rate was significantly increased. Alprenolol treatment (4 X 100 mg/day) did not significantly affect beta 2-adrenoceptor density. Pindolol treatment (2 X 5 mg/day) caused a 50% decrease of beta 2-adrenoceptor density after 2 days, which remained reduced during treatment. After withdrawal, beta 2-adrenoceptor density was still significantly diminished after 4 days. During and after treatment heart rate was not affected. Bopindolol treatment (2 mg/day) caused a 40% decrease of beta 2-adrenoceptor density after 2 days, which remained reduced during treatment. After withdrawal, beta 2-adrenoceptor density was still significantly diminished after 4 days. During and after treatment heart rate was not affected. It is concluded that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Alpha 2-adrenergic receptors on canine platelet membranes characterized by [3H]-yohimbine binding.
Alpha 2-adrenoceptors on canine platelet membranes were characterized by [3H]-yohimbine binding. Binding of [3H]-yohimbine to the membranes was rapidly saturated, stable and reversible with high affinity. Dissociation constant (KD) calculated from Scatchard analysis of the equilibrium experiments was 1.89 +/- 0.20 nM which was in good agreement with KD (1.97 +/- 0.60 nM) obtained in the kinetic experiments. Maximal binding sites of the ligand (Bmax) was 249 +/- 20 fmoles/mg protein. Adrenergic antagonists inhibited the ligand binding in following rank order of potency; yohimbine greater than phentolamine greater than phenoxybenzamine greater than corynanthine greater than prazosin. This order was in good correlation with that for these drugs in the inhibition of platelet aggregation. Hill coefficients for the displacement curves of the ligand binding by adrenergic agonists were less than 1.0 which were converted into near unity in the presence of 5'-guanylyl-imidodiphosphate (100 microM). These results demonstrate that canine platelet membranes have alpha 2-adrenoceptors and suggest that the binding of these receptors to adrenergic agonists is regulated by guanine nucleotides.
Animals↗
Papaverine inhibits binding of [3H]-prazosin and [3H]-yohimbine to rat renal cortical membranes.
We examined the effects of papaverine on specific [3H]-prazosin and [3H]-yohimbine bindings to rat renal cortical membranes and compared these effects with those of verapamil. Papaverine inhibited both ligand bindings with KI values of 4.2 +/- 1.7 microM and 48.4 +/- 8.7 microM (N = 5) in the inhibition of [3H]-prazosin and [3H]-yohimbine bindings, respectively. In contrast with verapamil, which competitively inhibited both ligand bindings, papaverine inhibited them in a different manner. Although the affinities of these ligand binding sites for papaverine are low, alpha-receptor blockade is a possible mechanism of action of this compound.
Animals↗
Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity".
Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Properties of alpha- and beta-adrenoceptors in circulating blood cells of patients with essential hypertension.
The properties of platelet alpha 2-adrenoceptors and of lymphocyte beta 2-adrenoceptors were determined in 40 male patients with established essential hypertension and compared with those in 40 male normotensives. The densities of platelet alpha 2-adrenoceptors (assessed by 3H-yohimbine binding) and of lymphocyte beta 2-adrenoceptors [determined by (+/-)-125iodocyanopindolol binding] were in patients with essential hypertension significantly higher than in controls; there were significant positive correlations between the mean arterial blood pressure of the subjects and alpha 2- and beta 2-adrenoceptor density, respectively. Concomitantly with receptor densities, functional responses to adrenergic stimulation were exaggerated in essential hypertension: in platelets, the aggregatory response to (-)-adrenaline (via alpha 2-adrenoceptor stimulation) was enhanced; in lymphocytes, the cyclic AMP response to (-)-isoprenaline (via beta 2-adrenoceptor stimulation) was elevated. It is concluded that the increased adrenoceptor density and responsiveness in circulating blood cells of patients with essential hypertension may reflect increased sympathetic activity, which might contribute to the elevation of blood pressure.
Adult↗
Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.
We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.
Adult↗
Acute regulation of lymphocyte beta 2-adrenoceptors is altered in patients with essential hypertension.
The effects of acute stimulation of the sympathetic activity by dynamic exercise on lymphocyte beta 2-adrenoceptor density [assessed by (-)-125iodocyanopindolol (ICYP) binding] and responsiveness [10 mumol/l isoprenaline-induced cyclic adenosine monophosphate (cAMP) increases] were studied in 10 normotensive (Pdiast < 90 mmHg) volunteers and in 10 patients with established essential hypertension (Pdiast > 95 mmHg). In normotensives, dynamic exercise on a bicycle (80% of maximum heart rate) for 15 min led to an increase in lymphocyte beta 2-adrenoceptor density from 1080 +/- 77 to 2033 +/- 152 ICYP binding sites/cell; concomitantly isoprenaline-induced increase in lymphocyte cAMP was enhanced. This effect appears to be mediated by beta 2-adrenoceptor stimulation, since the exercise-induced increase in beta 2-adrenoceptor density was markedly attenuated by pretreatment of the volunteers with propranolol (5 mg intravenously 45 min before exercise), but not by pretreatment with the beta 1-selective antagonist bisoprolol (2.5 mg intravenously 30 min before exercise). In patients with essential hypertension, lymphocyte beta 2-adrenoceptor density (1512 +/- 101 ICYP binding sites/cell) was significantly higher than in controls (P < 0.05); the same held true for isoprenaline-induced cAMP increases. In these patients, however, dynamic exercise caused only a slight increase in lymphocyte beta 2-adrenoceptor density (to 1859 +/- 154 ICYP binding sites/cell) and in isoprenaline-induced cAMP increases. From these results it is concluded that in essential hypertension acute regulation of the beta-adrenoceptor/adenylate cyclase system is impaired.
Adult↗
Beta-adrenoceptor changes in human lymphocytes, induced by dynamic exercise.
In 10 healthy volunteers the effects of acute increases in concentrations of catecholamines in plasma induced by dynamic exercise (on a bicycle for 15 min at 80% of maximum heart rate) on lymphocyte beta 2-adrenoceptor density (determined by (+/-)-125iodocyanopindolol binding) and -responsiveness (determined by cyclic AMP responses to 10 mumol/l isoprenaline) were investigated. Immediately after exercise plasma catecholamines were increased about 4-fold; concomitantly receptor density and cyclic AMP production increased 55% and 65%, respectively. One hour after exercise beta-adrenoceptor density and plasma catecholamines had reached values, which were not significantly different from pre-exercise values, while cyclic AMP production was significantly diminished. It is concluded, that acute increases in concentrations of catecholamines in plasma may increase beta-adrenoceptor density and - responsiveness in human lymphocytes.
Adult↗
A study on the cardiodepressant action of a beta-blocking agent carteolol in heart-lung preparation of the dog.
Direct cardiodepressant activities of three beta-blockers, carteolol, pindolol and propranolol, were estimated using heart-lung preparation of the dog. Beta-blocking doses of these drugs to inhibit the positive chronotropic effect of isoproterenol by 50% were 2.2 micrograms for carteolol, 4.0 micrograms for pindolol and 21 micrograms for propranolol. Cardiac performance of the preparation was not influenced by up to 1 mg of these three beta-blockers. After 10 mg of these drugs, the cardiac function curves were shifted rightward and downward indicating the heart failure. It was doubtful, however, that this result indicated the cardiodepressant action of beta-blockers, for the preparation showed spontaneous deterioration without beta-blocker treatment. The influences of these beta-blockers on the compromised heart-lung preparations showed essentially similar results. In conclusion, direct cardiodepressant activity of the beta-blocker, if any, was exerted with far more large doses than their beta-blocking doses. The implication of the results in clinical use of beta-blockers, especially in relation to heart failure, was discussed.
Animals↗
Estimation of cardiodepressant potency of nadolol, alprenolol, propranolol and pindolol, beta-blocking agents, in heart-lung preparation and blood-perfused excised papillary muscle preparation of the dog.
Direct cardiodepressant potency of nadolol was determined by comparing its effect with those of alprenolol, propranolol and pindolol, in both heart-lung preparation and blood-perfused papillary muscle preparation of the dog. In the heart-lung preparation, mean 50% beta-blocking doses of the beta-blockers to inhibit the positive chronotropic action of isoproterenol were 3.75 micrograms for nadolol, 12.5 micrograms for alprenolol, 9.6 micrograms for propranolol and 1.6 micrograms for pindolol. Alprenolol and propranolol in a dose of 10 mg shifted the cardiac function curves rightward and downward, while nadolol and pindolol in the dose of 10 mg did not shift the cardiac function curves. In the blood-perfused papillary muscle preparation, mean 50% beta-blocking doses of the beta-blockers, administered i.v. to the donor dog, to inhibit the positive inotropic action of isoproterenol were 9.1 micrograms/kg for nadolol, 56.6 micrograms/kg for alprenolol, 68.3 micrograms/kg for propranolol and 8.1 micrograms/kg for pindolol. Nadolol did not depress the contractile force in doses up to 1 mg/kg given i.v. or doses up to 10 mg given intra-arterially (i.a.) close to the preparation. Alprenolol and propranolol exerted the dose-related negative inotropic effects, when larger doses (30-300 micrograms) were injected i.a. Thus, it is confirmed that nadolol virtually possesses no direct cardiodepressant activity and also that the depressant activity is exerted only by large doses of the other beta-blockers.
Adrenergic beta-Antagonists↗
Identical binding properties of (+/-)- and (-)-125Iodocyanopindolol to beta 2-adrenoceptors in intact human lymphocytes.
In intact human lymphocytes the properties of (+/-)- and (-)-125iodocyanopindolol (ICYP) binding to beta 2-adrenoceptors were investigated. Binding of both ligands was in concentrations ranging from 10-200 pM saturable resulting in identical Bmax-values (about 550-650 specific ICYP binding sites/cell); the KD-value of (-)-ICYP (14.8 +/- 0.1 pM, N = 3), however, was about two times lower than that of (+/-)-ICYP (26.5 +/- 2.5 pM, N = 3). Irrespective of the ligand used alprenolol, betaxolol, ICI 118,551 and isoprenaline inhibited binding with identical KI-values. Binding was stereospecific, since the (+)-isomers of alprenolol and isoprenaline were about 50 times less potent in inhibiting binding than their respective (-)-isomers. In concentrations greater than 250 pM both ligands labeled a second class of binding sites in a non-saturable manner. These low affinity sites showed no stereospecificity; they may be related to unspecific uptake of the ligands into the cell. In kinetic experiments biphasic dissociation reactions were obtained for (+/-)- as well as (-)-ICYP; for both ligands the ratio fast/slow dissociating component was 40/60. It is concluded, that at low receptor concentrations (2.5-5 pmoles/l in the present study) the contribution of the (+)-isomer of ICYP to binding of the racemic ligand can be neglected. Thus, at low receptor concentrations both (+/-) and (-)-ICYP exhibit identical binding properties to beta 2-adrenoceptors in intact human lymphocytes.
Alprenolol↗
Increased density and responsiveness of alpha 2 and beta-adrenoceptors in circulating blood cells of essential hypertensive patients.
In 40 male patients with established essential hypertension (P diastolic greater than mmHg) the density and responsiveness of platelet alpha 2-adrenoceptors and lymphocyte beta 2-adrenoceptors were measured and compared with those in 40 male age-matched normotensive subjects (P diastolic less than 90 mmHg). The mean densities of platelet alpha 2-adrenoceptors (assessed by 3H-yohimbine binding) and of lymphocyte beta 2-adrenoceptors (assessed by (+/-) 125 iodocyanopindolol binding) were significantly increased in essential hypertensive patients (P less than 0.01). If data from all 80 subjects were combined there were significant positive correlations between mean arterial blood pressure of the subjects and alpha 2-adrenoceptor density (r = 0.591, P less than 0.001) and beta 2-adrenoceptor density (r = 0.648, P less than 0.001), respectively. The increases in and beta-adrenoceptor densities in essential hypertension were accompanied by enhanced responsiveness alpha- of platelets to 10 microM adrenaline to adrenergic stimulation: the aggregatory response via alpha 2-adrenoceptor stimulation) was increased, and in lymphocytes isoprenaline (0.01 - 100 microM) produced (via adrenoceptor stimulation) greater increases in cyclic AMP at each concentration than in control. Furthermore, activation of platelet adenylate cyclase by prostaglandin E1 was exaggerated in essential hypertensive patients. It is concluded that the increased density and responsiveness of alpha- and beta-adrenoceptors in essential hypertension may reflect enhanced sympathetic activity, and may contribute to the elevation of blood pressure.
Adolescent↗
Participation of kinins or prostaglandins in SQ 14,551-induced immediate decrease of blood pressure in anesthetized dogs.
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Animals↗
Potentiation of bradykinin-induced decrease of blood pressure in dogs by SO 14,551, the disulfide metabolite of captopril.
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Angiotensins↗
Effects of perhexiline on hemodynamics in anesthetized open-chest dogs.
Cardiohemodynamic effects of perhexiline were investigated in anesthetized open-chest dogs, measuring blood flow rates of the pulmonary artery (PAF), superior and inferior venae cavae (SVCF and IVCF), right atrial pressure (RAP), systemic blood pressure (SBP), and heart rate (HR). Sum of SVCF and IVCF was interpreted as venous return (VR). Perhexiline, 0.3-3 mg/Kg, injected intravenously over 2 min caused dose-dependent increases in PAF, VR, and RAP, followed by decreases in PAF and VR at higher doses. SBP and HR were depressed with perhexiline dose-dependently. Verapamil, 0.03-0.3 mg/Kg, also increased PAF, VR, and RAP to the lesser extent than perhexiline. Verapamil decreased these variables except RAP more markedly than perhexiline. Treatment with propranolol (1 mg/Kg) and phentolamine (1 mg/Kg) which completely blocked cardiohemodynamic effect of 1 microgram/Kg of norepinephrine, markedly attenuated the effects of perhexiline on VR and PAF but not completely. It is concluded that the effect of perhexiline to increase VR and PAF is in most part mediated through the cardiovascular reflex control for blood pressure reduction by the drug, though a direct effect on capacitance vessels may be included.
Anesthesia↗
Different mechanisms underlying reduced beta 2-adrenoceptor responsiveness in lymphocytes from neonates and old subjects.
To investigate the mechanism underlying age-dependent changes in beta-adrenoceptor function we have determined beta 2-adrenoceptor density (by (+/-)-125iodocyanopindolol (ICYP) binding) and beta 2-responsiveness (cyclic AMP responses to isoprenaline stimulation) in lymphocytes derived from 20 neonates, 54 young adults (19-30 years) and 15 old subjects (60-86 years). In young adults the mean number of lymphocyte beta 2-adrenoceptors amounted to 862 +/- 36 (range 500-1560) ICYP binding sites/cell (N = 54); it was slightly higher in old subjects with 1230 +/- 94 (698-1980) ICYP binding sites/cell (N = 15). In contrast, lymphocytes derived from neonatal blood had a significantly lower mean beta 2-adrenoceptor number (385 +/- 35 (130-608) ICYP binding sites/cell, N = 20, P less than 0.01). (-)-Isoprenaline (0.01-100 microM)-induced increases in lymphocyte cyclic AMP content were significantly lower in neonates and old subjects than in young adults. While for neonates and young adults significant positive correlations between beta 2-adrenoceptor density and 10 microM (-)-isoprenaline-induced cyclic AMP increases exist, in old subjects cyclic AMP increases were much lower than could be expected from the beta 2-adrenoceptor number. It is concluded that the mechanism underlying reduced beta 2-adrenoceptor responsiveness in neonates and old subjects is different: while in neonates it seems to be due to the reduced beta-adrenoceptor number, in old subjects it is caused by a post-receptor defect--presumably by a decreased activity of the adenylate cyclase.
Adenylyl Cyclases↗