The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms.

The presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol > CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

CGP 12177A modulates brown fat adenylate cyclase activity by interacting with two distinct receptor sites.

The interaction of [(-)-4-(3-t-butylamino-2-hydroxy-propoxy)benzimidazol-2-one] (CGP 12177) (CGP) with receptors that couple to adenylate cyclase was examined in membrane homogenates from rat interscapular brown adipose tissue (IBAT). Although typically regarded as a beta adrenoceptor antagonist, CGP stimulated adenylate cyclase activity with an activation constant of about 3 microM. Consistent with its classification as an antagonist, CGP inhibited norepinephrine-stimulated cyclase activity and did so at concentrations that had little or no stimulatory effect. CGP also inhibited activity stimulated by the atypical agonist [(R*,R*)-4-[2-[[2[(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]phenyl]phenoxyacetic acid (BRL 37344), but only at CGP concentrations that stimulated activity when tested alone. The beta-1-selective antagonist ICI 89,406 blocked norepinephrine-stimulated adenylate cyclase activity, but did not inhibit the activity stimulated by CGP. Together, these results indicate that CGP modulates IBAT adenylate cyclase by interacting with two receptors. One is the beta-1 receptor of which CGP is a high-affinity antagonist. The second appears to be an atypical receptor of which CGP is a partial agonist.     

Changes in plasma glucose and lactate evoked by α and β2-adrenoceptor stimulation in conscious fasted rabbits

In conscious fasted rabbits, the iv infusion of salbutamol (3 micrograms/kg per min) and clonidine (2 micrograms/kg per min) induced a blood glucose increase amenable to blockade, respectively by ICI 118551 (1 micrograms/kg per min) and idazoxan (20 micrograms/kg per min). Amidephrine (10 micrograms/kg per min) and salbutamol mediated an increase in plasma lactate which was attenuated by prazosin (50 micrograms/kg, sc) and ICI 118551 respectively. Clonidine did not alter basal plasma lactate. The iv infusion of adrenaline (0.3 micrograms/kg per min) evoked an increase in plasma lactate more sensitive to blockade by ICI 118551 than by prazosin. ICI 118551 also shortened the hyperglycaemic response to adrenaline, 3-Mercaptopicolinic acid (25 mg/kg) reduced salbutamol- and adrenaline-mediated hyperglycaemia and increased at the same time the lactate/glucose ratio. Our data show that plasma lactate levels may be regulated by alpha 1- and beta 2-excitatory adrenoceptor stimulation. However, only the increase in blood lactate derived from beta 2-adrenergic stimulation seems to contribute to the overall catecholamine-mediated hyperglycaemia.     

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans

The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non-selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross-over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test. During smoking, plasma concentrations of adrenaline increased markedly and evenly by approximately 0.3 ng/ml in all three experimental sessions. Plasma concentrations of noradrenaline remained unchanged. Propranolol, a non-selective beta blocker, caused a marked rise in diastolic and mean blood pressure and forearm vascular resistance during smoking. This response was not seen in the control series or after selective beta-1 blockage with atenolol. This difference is attributable to propranolol's blockade of adrenaline's vasodilating effect mediated by beta-2 receptors in the resistance vessels. Furthermore, atenolol attenuated the systolic blood pressure and tachycardiac responses induced by cigarette smoking by comparison with placebo. This study suggests that selective beta-1 blockers are preferable in the management of patients who are habitual smokers.     

In vivo interactions between beta-1 and beta-2 adrenoceptors regulate catecholamine tachyphylaxia in human adipose tissue.

Catecholamine tachyphylaxia was investigated in human s.c. adipose tissue in situ by using microdialysis. The tissue was dialyzed with adrenergic agents (10(-8) mol/l) and the glycerol concentration (lipolysis index) was determined. Perfusion with adrenaline caused a 3-fold rise in the glycerol concentration, which peaked at 30 min and then (within 1 hr) declined to a level 75% higher than base line; the latter elevation was constant for at least 2 hr. Noradrenaline or isoprenaline in the absence and presence of a selective beta-2 receptor antagonist, or the selective beta-1 adrenergic agonist dobutamine, caused a 2- to 2.5-fold transient lipolytic response which also peaked at 30 min but then (within 3 hr) declined to the base-line level. On the other hand, isoprenaline plus a selective beta-1 receptor antagonist or the beta-2 selective adrenergic agonist terbutaline caused a constant lipolytic effect for at least 3 hr. Noradrenaline or adrenaline plus a nonselective beta adrenergic antagonist as well as the alpha-2 selective adrenergic antagonist clonidine caused a sustained antilipolytic action for at least 3 hr. In conclusion, the adrenoceptor subtypes involved in lipolysis regulation in humans have different in vivo sensitivities to homologous desensitization. Beta-2 and alpha-2 adrenoceptors are resistant in this respect whereas activation of beta-1 adrenoceptors leads to rapid desensitization. However, simultaneous beta-1 and beta-2 receptor activation is accompanied by different degrees of tachyphylaxia, indicating regulatory in vivo interactions within this receptor family in human adipose tissue.     

A beta adrenoceptor with atypical characteristics is involved in the relaxation of the rat small intestine

In several studies in guinea pig ileum or rat colon a beta adrenoceptor with characteristics distinct from beta-1 or beta-2 receptors has been observed and has been denoted as "atypical" beta adrenoceptor. In this study the relaxation of the rat small intestine was investigated, using isolated segments of the rat jejunum. Several beta-1 or beta-2 agonists and antagonists were tested on the rat jejunum preparation, and it was found that nonselective and selective antagonists for beta-1 or beta-2 receptors showed a relatively low affinity, compared to their affinity for beta-1 or beta-2 receptors. BRL 37344, an agonist which has been reported to be selective for the atypical beta adrenoceptor, was more potent although a partial agonist compared to isoprenaline, whereas it is clearly less active than isoprenaline on beta-1 or beta-2 receptors. These findings indicate that beta adrenergic relaxation of the rat small intestine is mediated via atypical beta adrenoceptors. Efforts were made to confirm these findings with binding studies on small intestinal 45,000-g membranes. Competition radioligand binding experiments were performed with the radiolabeled ligand [125I]iodocyanopindolol and the various antagonists which were also tested in the intact rat jejunum preparations. Receptor binding experiments only revealed beta adrenoceptors of the beta-2-subtype, which does not correspond with the results obtained in the jejunum relaxation. Probably the beta-2 receptors found in the binding studies are located on circular smooth muscle cells or on epithelial cells, whereas longitudinal smooth relaxation is mediated by atypical beta adrenoceptors. Atypical beta adrenoceptors were not measured in binding studies probably because [125I]iodocyanopindolol is an unsuitable ligand to label atypical intestinal beta adrenoceptors.     

Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-plots

In the present study we investigated whether the beta adrenoceptor subtype binding activity in plasma samples can predict selective and nonselective beta blockade in humans. From the right shifts of isoprenaline dose-response curves 0 to 84 hr after administration of propranolol and the beta-1 selective bisoprolol, in vivo beta blockade was assessed. In an in vitro radioreceptor assay with membrane preparations of beta-1 or beta-2 adrenoceptors, plasma samples were assayed for subtype selective blocking activity. After propranolol administration, in vitro beta-1 and beta-2 adrenoceptor occupancy declined from initially 97% to less than 10% within 48 hr. An isoprenaline dose ratio (DR)-1 of 1 coincided with a 50% occupancy of the beta-1 or the beta-2 subtype in vitro. In Schild-plots using plasma concentrations (radioreceptor assay) and the isoprenaline DR-1 for heart rate, diastolic blood pressure and inotropy (QS2C), slopes of unity were observed. After bisoprolol administration, in vitro beta-1 occupancy shifted from initially 95% to less than 10% within 72 hr. For the beta-2 subtype, an occupancy of greater than 10% was detectable only within the first 12 hr. An isoprenaline DR-1 of 1 coincided with a 50% occupancy of beta-1 adrenoceptors. The bisoprolol Schild-plots yielded a slope of unity for inotropy, but less than unity for the heart rate and diastolic blood pressure. From an extended analysis of subtype selective antagonism in Schild-plots, the fractions of the beta-2 adrenoceptor subtype participating in the isoprenaline response were calculated: heart rate 0.45 +/- 0.12 and diastolic blood pressure 0.23 +/- 0.13. It is concluded that in vitro receptor occupancy can predict beta blockade in humans for propranolol. Beta adrenoceptor subtype-mediated effects in humans can be evaluated with a selective antagonist and a refined analysis of Schild-plot data.     

Multiple beta adrenergic receptor subclasses mediate the l-isoproterenol-induced lipolytic response in rat adipocytes.

l-Isoproterenol has been proposed to stimulate lipolysis in rat epididymal adipocytes via atypical beta adrenergic receptors, whereas radioligand binding studies only revealed the presence of beta 1 adrenergic receptors on adipocyte membranes. We have made use of the unique properties of CGP12177 to evidence that both the beta 1 and the atypical beta adrenergic receptor subtypes are mediating the lipolytic response of rat epididymal adipocytes to l-isoproterenol. CGP12177, an antagonist with high affinity for beta 1 receptors, triggers lipolysis by specifically stimulating the atypical receptors. For this response, CGP12177 displays low potency (EC50 = 68 nM), but high intrinsic activity (94% relative to l-isoproterenol). At low concentrations (3 nM), CGP12177 inhibits the lipolytic response to 10 nM l-isoproterenol by 43%, indicating that at least this fraction of the response is beta 1 receptor-mediated. The response to BRL37344, which is a selective agonist for the atypical receptors, is not inhibited by CGP12177. The pA2 values of the beta adrenergic antagonists propranolol, metoprolol and atenolol were calculated from the rightward shifts that they impose on dose-response curves of both l-isoproterenol and CGP12177. With l-isoproterenol, these values (6.54, 5.83 and 5.07, respectively) are lower than those expected for beta 1 and beta 2 receptors, indicating that atypical receptors are also involved in the lipolytic response to this agonist. With CGP12177, the pA2 values of propranolol, metoprolol and atenolol are even lower (5.80, 5.03 and 4.06, respectively), and are likely to be a more accurate reflection of their affinities for the atypical receptors.     

Characterization of the beta adrenoceptor subtype(s) mediating the positive inotropic effects of epinine, dopamine, dobutamine, denopamine and xamoterol in isolated human right atrium.

In patients with chronic heart failure cardiac beta-1 adrenoceptors are reduced, whereas beta-2 adrenoceptor changes vary depending on the etiology of the disease. Beta Adrenoceptor agonists can be used for short-term inotropic support in chronic heart failure; their clinical efficacy might depend on which beta adrenoceptor subtype(s) mediates their positive inotropic effect. Thus, the beta adrenoceptor subtype(s) involved in the positive inotropic effects of clinically used beta adrenoceptor agonists was characterized on isolated electrically driven human right atria by the use of the selective beta-1 adrenoceptor antagonist CGP 20712 A (300 nmol/l) and/or the selective beta-2 adrenoceptor antagonist ICI 118,551 (30 nmol/l). Epinine evoked positive inotropic effects through stimulation of beta-1 and beta-2 adrenoceptors to about the same degree, whereas dobutamine acted mainly at beta-1 adrenoceptors but had a significant beta-2 adrenoceptor component. Both agonists were full agonists causing the same maximum increase in contractile force (Emax) as did isoprenaline or Ca++ (Emax = 1.0). In contrast, denopamine was a partial selective beta-1 adrenoceptor agonist (Emax = 0.75-0.85). Dopamine was in the presence of uptake1-blockade (by 5 mumol/l phenoxybenzamine) a partial agonist (Emax = 0.60-0.70) acting selectively at beta-1 adrenoceptors; in the absence of uptake1-blockade, however, dopamine was a full agonist, indicating that part of its positive inotropic effect is indirect via the release of endogenous noradrenaline. Xamoterol did not exert positive inotropic effects, but concentration-dependently slightly decreased basal force of contraction.     

Effects of selective (beta-1 and beta-2) and nonselective beta adrenoceptor antagonists on the cardiovascular and metabolic responses to isoproterenol: comparison with ICI 141,292

Six groups of four dogs were studied under pentobarbital anesthesia. Plasma levels of free fatty acids (FFA), glucose, insulin and lactate were measured after four challenges with isoproterenol (0.125 micrograms/kg/min i.v. for 10 min). In control animals, infusion of isoproterenol elevated plasma FFA, glucose, insulin and lactate, raised heart rate and lowered diastolic blood pressure. Propranolol lowered resting heart rate and blocked all the isoproterenol-induced responses. Atenolol (beta-1-selective antagonist) slowed resting heart rate and blocked FFA and heart rate responses. ICI 118,551 (beta-2-selective antagonist) blocked the glucose, insulin and lactate responses and the fall in diastolic blood pressure. Selectivity was lost at higher doses. ICI 141,292 (potent beta-1-selective antagonist and modest partial agonist) exhibited beta-1-selective blockade against both cardiovascular (heart rate) and metabolic (FFA) receptors. Partial agonist activity was also beta-1-selective, but there was no evidence of agonist activity at the metabolic receptors.     

Role of alpha-adrenergic receptors in the effect of the beta-adrenergic receptor ligands, CGP 12177, bupranolol, and SR 59230A, on the contraction of rat intrapulmonary artery

This study investigates the effect of the aryloxypropanolamines 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177), bupranolol, and 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A) [commonly used as beta(3)- and/or atypical beta-adrenergic receptors (beta-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of beta-AR ligands for alpha(1)-adrenergic receptors (alpha(1)-AR) were also evaluated using [(3)H]prazosin binding competition experiments performed in rat cortical membranes. In intralobar pulmonary artery, CGP 12177 did not modify the basal tone, but antagonized the contraction induced by the alpha(1)-AR agonist phenylephrine (PHE). In arteries precontracted with PHE, CGP 12177 elicited relaxation, whereas in those precontracted with prostaglandin F(2alpha) (PGF(2alpha)), it further enhanced contraction. CGP 12177 induced an increase in intracellular calcium concentration in pressurized arteries loaded with Fura PE-3 and precontracted with PGF(2alpha). In PGF(2alpha) precontracted arteries, phentolamine (an alpha-AR antagonist) and phenoxybenzamine (an irreversible alpha-AR antagonist) antagonized the contractile responses to PHE and CGP 12177. Both responses were also decreased by bupranolol and SR 59230A. Specific [(3)H]prazosin binding was displaced by CGP 12177, bupranolol, and SR 59230A with pK(i) values of 5.2, 5.7, and 6.6, respectively. In contrast, (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium (BRL 37344) and disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243) (nonaryloxypropanolamines beta(3)-AR agonists) displayed very low affinity for [(3)H]prazosin binding sites (pK(i) values below 4). These data suggest that CGP 12177 exhibits partial agonist properties for alpha(1)-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an alpha(1)-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of beta(3)- and atypical beta-AR in the regulation of vascular tone.     

Recruitment of functionally active heart beta2-adrenoceptors in the initial phase of endotoxic shock in pithed rats

A supersensitivity of the beta-adrenoceptor-mediated chronotropic response has been demonstrated in atria isolated from rats subjected to septic shock. Our study was undertaken to investigate whether bacterial endotoxin/LPS affects the increase in heart rate induced by beta-adrenoceptor agonists in the rat also in vivo. In pithed and vagotomized rats, the nonselective beta-adrenoceptor agonist isoprenaline (0.05-0.15 nmol/kg) and agonists at the high- and low-affinity state of beta1-adrenoceptors, that is, prenalterol (0.3-3 nmol/kg) and (+/-)-4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazole-2-one (CGP 12177; 3-6 nmol/kg), respectively, and at beta2-adrenoceptors, that is, fenoterol (1-5 nmol/kg), increased heart rate by 50 to 60 beats/min. Administration of LPS (0.4, 1, and 1.5 mg/kg), under continuous infusion of vasopressin, dose-dependently amplified the chronotropic response to isoprenaline, prenalterol, and fenoterol (by 80%, 50%, and 100%, respectively) but not to CGP 12177. The beta2-adrenoceptor antagonist erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118551 0.1 mumol/kg) did not affect the chronotropic responses of isoprenaline, fenoterol, and prenalterol under non-endotoxic conditions, but abolished the potentiation of tachycardia produced by LPS (1.5 mg/kg). The beta1-adrenoceptor antagonist (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]propyl]-amino]ethoxy]-benzamide CGP 20712A; 0.1 mumol/kg almost completely reduced the chronotropic effects of isoprenaline, fenoterol, and prenalterol both in control rats and in animals exposed to LPS (1.5 mg/kg). We conclude that LPS sensitizes cardiac beta-adrenoceptors by recruiting functionally active beta2-adrenoceptors, but the amplification of tachycardia occurs only when both beta1- and beta2-adrenoceptors are concomitantly activated. The pithed rat may serve as a model to examine the beta-adrenoceptor supersensitivity in vivo.     

Regional differences of responses to adrenoceptor agonists in isolated and perfused canine coronary arteries

Regional differences of the responses to adrenoceptor agonists were investigated in isolated canine coronary arteries by use of a cannula inserting method. Acetylcholine induced a dose-dependent vasodilation. Norepinephrine and epinephrine produced a vasoconstriction followed by a strong vasodilation in large coronary arteries and only a weak vasodilation in small coronary arteries. Phenylephrine (a selective alpha-1 agonist) induced a strong vasoconstriction in both arteries. The threshold dose and ED50 value for phenylephrine in small coronary arteries were much larger than those in large coronary arteries, although the vasoconstrictions by KCl and prostaglandin F2 alpha were not different between in large and small coronary arteries. Clonidine and xylazine (selective alpha-2 agonists) produced a slight vasoconstriction but not dose-dependently and a vasodilation with extremely large doses. ED50 value of vasodilation for salbutamol (a selective beta-2 agonist) was approximately 80 times greater than that for isoproterenol (a non-selective beta-agonist) in large coronary arteries, but was approximately 20 times in small coronary arteries. The maximal dilator response to salbutamol was about the same as that to isoproterenol in small coronary arteries, whereas it was much smaller than that to isoproterenol in large coronary arteries. These results suggest that adrenoceptors are heterogeneous according to the distance from the coronary orifice in canine epicardial coronary arteries.     

beta3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current

beta3-adrenergic receptor (beta3-AR) activation produces a negative inotropic effect in human ventricles. Here we explored the role of beta3-AR in the human atrium. Unexpectedly, beta3-AR activation increased human atrial tissue contractility and stimulated the L-type Ca2+ channel current (I Ca,L) in isolated human atrial myocytes (HAMs). Right atrial tissue specimens were obtained from 57 patients undergoing heart surgery for congenital defects, coronary artery diseases, valve replacement, or heart transplantation. The I(Ca,L) and isometric contraction were recorded using a whole-cell patch-clamp technique and a mechanoelectrical force transducer. Two selective beta3-AR agonists, SR58611 and BRL37344, and a beta3-AR partial agonist, CGP12177, stimulated I(Ca,L) in HAMs with nanomolar potency and a 60%-90% efficacy compared with isoprenaline. The beta3-AR agonists also increased contractility but with a much lower efficacy (approximately 10%) than isoprenaline. The beta3-AR antagonist L-748,337, beta1-/beta2-AR antagonist nadolol, and beta1-/beta2-/beta3-AR antagonist bupranolol were used to confirm the involvement of beta3-ARs (and not beta1-/beta2-ARs) in these effects. The beta3-AR effects involved the cAMP/PKA pathway, since the PKA inhibitor H89 blocked I(Ca,L) stimulation and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) strongly increased the positive inotropic effect. Therefore, unlike in ventricular tissue, beta3-ARs are positively coupled to L-type Ca2+ channels and contractility in human atrial tissues through a cAMP-dependent pathway.     

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.     

Effects of 1-(4-nitrophenyl)-2-isopropylaminoethanol (INPEA) and propranolol and their dextro-isomers on hemodynamic and metabolic responses to isoproterenol in dogs

The effects of dl-propranolol, D-(-)-(4-nitrophenyl)-2-isopropylaminoethanol (INPEA) and L-(+)-INPEA on the hemodynamic and metabolic responses to isoproterenol were investigated in dogs anesthetized with pentobarbital. Isoproterenol (200 micrograms/kg i.p.) was injected 15 min after an i.v. injection of propranolol or INPEA, or their dextro-isomers. Isoproterenol increased heart rate, myocardial contractile force (determined by a strain gauge arch), blood glucose, blood lactate and plasma free fatty acids, and decreased diastolic blood pressure. dl-Propranolol (1 or 3 mg/kg) or D-(-)-INPEA (5 or 15 mg/kg) inhibited all the responses to isoproterenol. d-Propranolol (1 or 3 mg/kg) did not inhibit the isoproterenol-induced responses of heart rate, myocardial contractile force and plasma free fatty acids, but it inhibited the isoproterenol-induced responses of diastolic blood pressure, blood glucose and blood lactate, although the inhibition was small. Similar results were obtained by L-(+)-INPEA; L-(+)-INPEA (5 or 15 mg/kg) did not inhibit the isoproterenol-induced responses of heart rate, myocardial contractile force and plasma free fatty acids, but it inhibited the isoproterenol-induced responses of diastolic blood pressure, blood glucose and blood lactate, although the degree of inhibition was small. These results indicate that dextro-isomers of propranolol and INPEA may have a weak beta-2 adrenoceptor antagonistic action.     

Nifedipine attenuates both alpha-1 and alpha-2 adrenoceptor-mediated pressor and vasoconstrictor responses in conscious dogs and primates

Effects of the calcium channel blocker, nifedipine, were examined on the pressor and vasoconstrictor responses to stimulation of alpha-1 and alpha-2-adrenoceptors in chronically instrumented conscious dogs and Rhesus monkeys. Norepinephrine (NE), a mixed alpha-1 and alpha-2 adrenoceptor agonist, phenylephrine (PE) and methoxamine (M), selective alpha-1 adrenoceptor agonists, and B-HT 920, a selective alpha-2 adrenoceptor agonist, were injected i.v. after ganglionic (hexamethonium), beta adrenoceptor (propranolol) and muscarinic receptor (atropine methyl bromide) blockade. In the dog, NE (0.1 microgram/kg i.v.), PE (1 microgram/kg i.v.), M (20 micrograms/kg i.v.) and B-HT 920 (1 microgram/kg i.v.) produced similar increases in mean arterial pressure (NE, 52 +/- 4 mmHg; PE, 42 +/- 4 mm Hg; M, 43 +/- 7 mm Hg; B-HT 920, 45 +/- 6 mm Hg) and total peripheral resistance (NE, 20.8 +/- 5.8 mm Hg/l/min; PE, 23.1 +/- 4.2 mm Hg/l/min; M, 18.2 +/- 2.1 mm Hg/l/min; B-HT 920, 24.8 +/- 7.1 mm Hg/l/min). Nifedipine (0.5 microgram/kg/min i.v.) caused a similar attenuation of the pressor (NE, -54 +/- 8%; PE, -43 +/- 8%; M, -49 +/- 6%; B-HT 920, -56 +/- 8%) and vasoconstrictor (NE, -66 +/- 11%; PE, -52 +/- 9%; M, -60 +/- 13%; B-HT 920, -57 +/- 10%) responses to each of the alpha-adrenoceptor agonists. Nifedipine also attenuated pressor responses to alpha-1 and alpha-2 adrenoceptor agonists similarly in conscious monkeys. Thus, in conscious dogs and monkeys, calcium channel blockade attenuates similarly both alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction.