Reversing dobutamine-induced tachycardia using ivabradine increases stroke volume with neutral effect on cardiac energetics in left ventricular post-ischaemia dysfunction.

AIM: Compensatory tachycardia can potentially be deleterious in acute heart failure. In this study, we tested a therapeutic strategy of combined inotropic support (dobutamine) and selective heart rate (HR) reduction through administration of ivabradine. METHODS: In an open-chest pig model (n = 12) with left ventricular (LV) post-ischaemia dysfunction, cardiac function was assessed by LV pressure catheter and sonometric crystals. Coronary flow and blood samples from the coronary sinus were used to measure myocardial oxygen consumption (MVO2 ). LV energetics was assessed by comparing MVO2 with cardiac work at a wide range of workloads. RESULTS: In the post-ischaemia heart, dobutamine (5 µg kg(-1)  min(-1) ) increased cardiac output (CO) by increasing HR from 102 ± 21 to 131 ± 16 bpm (beats per min; P < 0.05). Adding ivabradine (0.5 mg kg(-1) ) slowed HR back to 100 ± 9 bpm and increased stroke volume from 30 ± 5 to 36 ± 5 mL (P < 0.05) by prolonging diastolic filling time and increasing end-diastolic dimensions. Adding ivabradine had no adverse effects on CO, mean arterial pressure and cardiac efficiency. Similar findings on efficiency and LV function were also seen using an ex vivo working mouse heart protocol. CONCLUSIONS: A combined infusion of dobutamine and ivabradine had a neutral effect on post-ischaemia LV efficiency and increased left ventricular output without an increase in HR.

Ivabradine treatment prevents dobutamine-induced increase in heart rate in patients with acute decompensated heart failure.

BACKGROUND: Ivabradine is a heart rate (HR)-lowering agent acting by inhibiting the If-channel. Dobutamine does increase the HR and has some deleterious effects on myocardium. So, we aimed to evaluate whether ivabradine treatment blunts a dobutamine-induced increase in HR. METHODS: The main study population consisted of 58 acute decompensated heart failure patients requiring inotropic support with left-ventricular ejection fraction below 35%, who were randomized to ivabradine (n = 29) or control (n = 29). All patients underwent Holter recording for 6 h and then dobutamine was administered at incremental doses of 5, 10 and 15 µg/kg/min, with 6-h steps. Holter recording was continued during dobutamine infusion. Ivabradine 7.5 mg was given at the initiation of dobutamine and readministered at 12 h of infusion. Also, a nonrandomized beta-blocker group with 15 patients receiving beta-blocker was included in the analysis. Control and beta-blocker groups did not receive ivabradine. RESULTS: In the control group, mean HR gradually and significantly increased at each step of dobutamine infusion (81 ±â€Š11, 90 ±â€Š16, 97 ±â€Š14 and 101 ±â€Š16 b.p.m., respectively; P = 0.001), whereas no significant increase in HR was observed in the ivabradine group (82 ±â€Š17, 82 ±â€Š15, 85 ±â€Š14 and 83 ±â€Š12 b.p.m., respectively; P = 0.439). Mean HR was also found to significantly increase during dobutamine infusion in the beta-blocker group (75 ±â€Š13, 82 ±â€Š13, 86 ±â€Š14 and 88 ±â€Š13 b.p.m., respectively; P = 0.001). The median increase in HR from baseline was significantly higher in the control group compared to those in the ivabradine group (5 vs. 2 b.p.m.; P = 0.007 at first step, 13 vs. 5 b.p.m.; P = 0.001 at second step and 18 vs. 6 b.p.m.; P = 0.0001 at third step of dobutamine, respectively). CONCLUSIONS: Ivabradine treatment prevents dobutamine-induced increase in HR and may be useful in reducing HR-related adverse effects of dobutamine.

Peroxynitrite and myocardial contractility: in vivo versus in vitro effects.

Generation of peroxynitrite (ONOO-) as a result of altered redox balance has been shown to affect cardiac function; however, inconsistencies in the data exist, particularly for myocardial contractility. The hypothesis that the cardiac impact of ONOO- formation depends on its site of generation, intravascular or intramyocardial, was examined. Cardiac contractility was assessed by pressure-volume analysis to delineate vascular versus cardiac changes on direct infusion of ONOO- into the right atria of conscious dogs both with normal cardiac function and in heart failure. Additionally, ONOO- was administered to isolated murine cardiomyocytes to mimic in situ cardiac generation. When infused in vivo, ONOO- had little impact on inotropy but led to systemic arterial dilation, likely as a result of rapid decomposition to NO2- and NO3-. In contrast, infused ONOO- was long lived enough to abolish beta-adrenergic (dobutamine)-stimulated contractility/relaxation, most likely through catecholamine oxidation to aminochrome. When administered to isolated murine cardiomyocytes, ONOO- induced a rapid reduction in sarcomere shortening and whole cell calcium transients, although neither decomposed ONOO- or NaNO2 had any effect. Thus, systemic generation of ONOO- is unlikely to have primary cardiac effects, but may modulate cardiac contractile reserve, via blunted beta-adrenergic stimulation, and vascular tone, as a result of generation of NO2- and NO3-. However, myocyte generation of ONOO- may impair contractile function by directly altering Ca2+ handling. These data demonstrate that the site of generation within the cardiovascular system largely dictates the ability of ONOO- to directly or indirectly modulate cardiac pump function.

Effect of Larrea divaricata Cav. extract and nordihydroguaiaretic acid upon peroxidase secretion in rat submandibulary glands.

Free radicals are involved in several diseases, including cancer, central nervous system alterations and inflammatory pathologies. Peroxidase is an oral enzyme implicated in the defence of oral cavity. It has been determined that flavonoids and lignans possess antioxidant and free radical scavenging either directly or indirectly, usually by means of increasing the secretion of free radicals scavenger enzymes. Larrea divaricata Cav. is a plant used in folk Argentine medicine for the treatment of cancer and inflammatory ailments. In this study, we have determined the effect and mechanism of action of an aqueous extract of the leaves of L. divaricata and NDGA on peroxidase secretion in female rat submandibular glands. The extract significantly increased the secretion and total peroxidase. % of secreted peroxidase (X +/- S.E.M.): extract maximum response: 150 +/- 10; % of total peroxidase (X +/- S.E.M.): extract maximum response: 1000 +/- 90. The effect of the extract on peroxidase secretion was mediated by beta1 adrenoceptors (% of secreted peroxidase: extract + atenol maximum response: 50 +/- 4 ). Meanwhile, NDGA produced a decrease in peroxidase secretion (peroxidase secreted: basal: 0.44 +/- 0.03; NDGA 2.5 x 10(-6) M: 0.20 +/- 0.02; prostaglandins E2 (PGE2) 10(-7)M: 1.32 +/- 0.5; NDGA + PGE2: 0.46 +/- 0.035), an effect that was exerted by the inhibition on prostaglandins synthesis.

Role of endothelium and K+ channels in dobutamine-induced relaxation in rat mesenteric artery.

1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a beta 1-adrenoceptor agonist, in rat isolated mesenteric arteries, the effects of inhibitors of nitric oxide (NO) activity, blockers of K+ channels and high extracellular K+ were studied by measuring isometric tension in both endothelium-intact and -denuded arteries. 2. Dobutamine inhibited the phenylephrine (PE)-induced sustained tension with a pEC50 of 7.40 +/- 0.08 in endothelium-intact arteries. Removal of functional endothelium attenuated the effect of dobutamine. The relaxation induced by dobutamine was inhibited by the beta 1-adrenoceptor antagonist CGP 20712A (3 mumol/L) but not by the beta 2-adrenoceptor antagonist ICI 118,551 (3 mumol/L) in endothelium-denuded arteries. 3. Pretreatment with NG-nitro-L-arginine (L-NNA; 100 mumol/L) or methylene blue (3 mumol/L) induced a similar degree of inhibition of the dobutamine-induced relaxation in endothelium-intact arteries, while NG-nitro-D-arginine (100 mumol/L) and indomethacin (10 mumol/L) had no effect. In contrast, pretreatment with L-NNA (100 mumol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3 mumol/L) inhibited the relaxant response to SNP. 4. Charybdotoxin (CTX; 100 nmol/L), iberiotoxin (IBX; 100 nmol/L) and tetraethylammonium ions (TEA+; 3 mmol/L) significantly reduced the dobutamine-induced relaxation. Tetrapentylammonium ions (TPA+; 5 mumol/L) markedly inhibited the relaxant effect of dobutamine. The pEC50 values for control and in the presence of TPA+ in endothelium-intact arteries were 7.35 +/- 0.11 and 6.14 +/- 0.17, respectively, and 6.35 +/- 0.09 and 5.87 +/- 0.17 for control and in the presence of TPA+ in endothelium-denuded arteries, respectively. In contrast, glibenclamide (3 mumol/L) was ineffective. At 5 mumol/L, TPA+ also inhibited the relaxation induced by forskolin. 5. The maximal relaxation of PE-contracted arteries induced by 3 mumol/L dobutamine was completely abolished in the 60 mmol/L K(+)-contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 mumol/L induced inhibition of the high-K+ response. 6. The present results indicate that endothelium, probably NO but not prostacyclin, was involved in the dobutamine-induced relaxation in rat mesenteric arteries. Activation of CTX-, IBX- and TPA(+)-sensitive K+ channels contributed towards the observed relaxation. Loss of the ability to relax the 60 mmol/L K(+)-contracted arteries suggests that endothelium-derived vasoactive factors affected by concentrations of dobutamine less than 3 mumol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium-independent relaxant effect.

Do beta-blockers affect the diagnostic sensitivity of dobutamine stress thallium-201 single photon emission computed tomographic imaging?

BACKGROUND: The effects of beta-blockers on dobutamine stress 201Tl tomographic imaging are not known. This study was undertaken to examine whether beta-blockers affect the sensitivity of dobutamine stress 201Tl imaging. METHODS AND RESULTS: One hundred ten patients without previous myocardial infarction underwent dobutamine stress 201Tl single photon emission computed tomography (SPECT) and coronary arteriography, both studies within a 1-week period. Dobutamine was infused at rates of 5, 10, 20, 30, and 40 microg/kg/min in 3-minute stages. Atropine (as much as 1 mg) was injected intravenously when the patient's heart rate was <100 beats/min. Patients in group 1 (n = 72) were receiving beta-blockers and patients in group 2 (n = 38) were not. The SPECT images in group 1 showed perfusion abnormalities in 62%, 87%, and 94% of patients with one-, two-, and three-vessel coronary artery disease (> or = 50% diameter stenosis), respectively, compared with 75%, 71% and 100% in group 2 (p not significant). The overall sensitivities were 82% (37 of 45) in group 1 and 80% (16 of 20) in group 2 (p not significant). The specificities were 81% (22 of 27) in group 1 and 83% (15 of 18) in group 2 (p not significant). The overall accuracies were the same for both groups (82%). Atropine was added more often in group 1 than in group 2 (37/72 vs 5/38, p < 0.001). CONCLUSIONS: Our results suggest that beta-blockers do not affect the sensitivity, specificity, and accuracy of dobutamine stress 201Tl SPECT imaging for detecting coronary artery disease if atropine is given when the chronotropic response is inadequate. In patients receiving beta-blockers, however, the addition of atropine to dobutamine stress is more frequently required.

Dobutamine increases alveolar liquid clearance in ventilated rats by beta-2 receptor stimulation.

Although it is well known that beta-adrenergic agonist stimulation increases alveolar epithelial sodium and fluid transport, it is not known whether the beta-1 or the beta-2 receptor mediates this effect. Two clinically relevant beta-adrenergic agonists, dopamine (beta-1 agonist) and dobutamine (beta-1 and beta-2 agonist) were used to define the contribution of these two beta-receptors to beta-adrenergic stimulated fluid clearance from the air spaces of the lungs. Alveolar fluid clearance was measured in anesthetized, ventilated rats over one hour after instilling an isosmolar 5% albumin solution in Ringer's lactate with 3 microCi 125I-albumin. The concentrations of the labeled and unlabeled albumin were used to quantify alveolar liquid clearance. Dopamine, whether given intra-alveolar (10(-4) M) or intravenously (5-10 micrograms/kg/min), had no effect. However, both intra-alveolar (10(-4) M) and intravenous (5 micrograms/kg/min) dobutamine increased alveolar liquid clearance by approximately 50% over one hour compared to controls. ICI 118,551, a potent and specific beta-2 antagonist, blocked the effect of dobutamine. The dobutamine effect was blocked by amiloride (10(-3) M), an inhibitor of sodium uptake. In summary, the beta-2 receptor mediates beta-adrenergic stimulation of alveolar epithelial sodium and fluid transport.

Effect of beta-blockade on dobutamine stress echocardiography.

Dobutamine is an effective pharmacologic stress used in conjunction with echocardiography because of its beta-agonist properties. Concurrent beta-blockade might alter this effectiveness; however, current clinical experience has been variable. The purpose of this study is to determine whether concurrent beta-blockade alters the ability of a dobutamine stress echocardiogram to detect a fixed coronary stenosis by preventing the onset of a wall motion abnormality or by altering the dose at which the wall motion abnormality appears. Paired dobutamine stress tests with and without beta-blockade (esmolol 500 microgram/kg initial bolus, 100 microg/kg/min infusion) were performed in a canine model (n = 8) with a fixed single-vessel coronary stenosis. Heart rate, systolic pressure, proximal left anterior descending coronary flow, myocardial thickening (by sonomicrometry), and left ventricular area change (by epicardial echocardiography) were monitored. Simultaneous beta-blockade resulted in (1) a delayed and diminished increase in hemodynamic parameters (peak heart rate 164.1 +/- 22.3 without beta-blockade vs 110.1 +/- 28.9 beats/min with beta-blockade, p < 0.001, and peak systolic blood pressure 137.9 +/- 26.8 mm Hg without beta-blockade vs 107.3 +/- 15.3 mm Hg with beta-blockade, p = 0.01), (2) an elimination of the physiologic effects of low-dose (5 and 10 microg/kg/min) dobutamine (-0.7 percent +/- 16.7 percent change in myocardial thickening from baseline with beta-blockade, p = NS), and (3) an elimination or alteration in timing of inducible wall motion abnormalities caused by severe coronary artery stenoses (mean termination dose 28.8 +/- 9.9 with beta-blockade vs 15.6 +/- 6.1 microg/kg/min without beta-blocker, p < 0.01). The findings in this canine model suggest that the competitive antagonist markedly attenuates the ability of dobutamine stress echocardiography to detect a significant coronary lesion and may alter its ability to detect viable myocardium at low-dose testing. Further clinical studies to determine the sensitivity of dobutamine stress echocardiography in the presence of beta-blockers and to establish protocol standards are necessary.

Cholera toxin accentuates the antagonism by acetylcholine of higenamine-induced positive chronotropy is isolated right atria of mice.

+/- -Higenamine (demethylcoclaurine), a cardiotonic principle from aconite root, chronotropic and inotropic actions mediated through beta 1-adrenergic receptors. We have investigated the influence of cholera toxin (CTX), a Gs-protein activator, and pertussis toxin (PTX), a Gi-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice. CTX (100nm, 1h) pretreatment accentuated the inhibitory responses to cumulative applications of ACh (30nM--30 microns for the positive chronotropic effects induced by higenamine (100nM), isoproterenol (3 and 10 nM) or dobutamine (100nM). In normal atria (CTX-untreated), ACh physiologically antagonized the positive chronotropic effects of these beta-adrenergic agonists. Pretreatment with PTX (150 microgram/kg, i.p., 3d) abolished the CTX (100nm, 1 h)-induced accentuation in the inhibitory effect of ACh against higenamine. PTX pretreatment also attenuated the physiological antagonism by ACh against higenamine in normal atria. The negative chronotropic effect of ACh was not affected by a submaximal concentration of forskolin (1 micron). The These results suggest an accentuated antagonism between higenamine and ACH in CTX-treated, but not in untreated, isolated right atria of mice, which may occur through a functional interaction between the beta1-adrenergic-Gs and muscarinic-Gi systems.

The beta-adrenoceptor subtype(s) mediating adrenaline- and dobutamine-induced blood pressure and heart rate changes in healthy volunteers.

In order to characterize the beta-adrenoceptor subtype(s) mediating blood pressure and heart rate changes induced by adrenaline and dobutamine, we compared the effects in healthy male volunteers of propranolol (5 mg i.v.) and of the beta 1-adrenoceptor selective antagonist bisoprolol (15 mg p.o.) on adrenaline- and dobutamine-infusion induced changes in systolic (P(syst)) and diastolic blood pressure (P(diast)) and heart rate with those on blood pressure and heart rate (HR) changes induced by "pure" alpha- or beta-adrenoceptor agonists (phenylephrine, selective alpha, terbutaline, selective beta 2, isoprenaline, non-selective beta 1 and beta 2). Both beta-adrenoceptor antagonists did not affect phenylephrine (0.25 -1.0 microgram/kg/min for 10 min) infusion induced P(syst)- and P(diast)-increases and HR-decreases. On the other hand, propranolol completely suppressed terbutaline (25-150 ng/kg/min for 15 min) and isoprenaline (3.5-35 ng/kg/min for 8 min) infusion induced P(syst)- and HR-increases and P(diast)-decreases while bisoprolol significantly attenuated only isoprenaline-effects but had nearly no effect on terbutaline effects. Thus, in these doses bisoprolol antagonized only beta 1-adrenoceptor mediated effects, propranolol both beta 1- and beta 2-adrenoceptor mediated effects, but both antagonists had no alpha-adrenoceptor antagonistic effects. Dobutamine (1.0-6.0 micrograms/kg/min for 15 min) infusion significantly increased P(syst), but did not significantly affect P(diast) and HR; bisoprolol markedly reduced dobutamine-induced P(syst)-increase. In the presence of propranolol, however, dobutamine caused P(syst)- and P(diast)-increases and HR-decreases. Adrenaline (20-120 ng/kg/min for 15 min) infusion increased P(syst) and HR and decreased P(diast). Bisoprolol did not affect P(syst)- and HR-increases, but significantly attenuated P(diast)-decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Preconditioning with dobutamine in the isolated rat heart.

The ability of dobutamine to precondition the isolated rat heart against postischemic contractile dysfunction was assessed. Hearts were perfused with varying concentrations of dobutamine for 5 min followed by a 5 min "washout" period and 30 min of global ischemia. The hearts were reperfused for 30 min to assess postischemic function. Dobutamine improved postischemic developed pressure, +dp/dt, heart rate x developed pressure, end diastolic pressure, and coronary flow in a concentration-dependent manner. The concentration of dobutamine showing the maximum protective effect was 10(-6)M. Propranolol administered with dobutamine significantly attenuated the protective effect. The results indicate that transient treatment with dobutamine can precondition the rat heart against ischemia/reperfusion injury. The mechanism of protection appears to involve beta-adrenergic stimulation.

Atropine increases the accuracy of dobutamine stress echocardiography in patients taking beta-blockers.

Dobutamine-atropine stress echocardiography is used for the non-invasive diagnosis of coronary artery disease, but stress test results may be influenced by beta-blockers. The aim of this study was to assess if the addition of atropine can compensate for the presence of beta-blockers in dobutamine stress echocardiography. Twenty-six patients referred for evaluation of chest pain were studied twice, on and off metoprolol 100 mg b.i.d. (in random order sequence) with a wash-out period of at least 48 h. Dobutamine stress echocardiography was performed using up to 40 micrograms.kg-1.min-1, followed, if necessary, by the addition of atropine to achieve 85% of the age-predicted maximal heart rate, unless symptoms or markers of ischaemia appeared. Atropine was given to patients on beta-blockers more often [(22/26) vs (6/26)] than to those off beta-blockers (P < 0.001). Heart rate at every stage of the test was lower on beta-blockers. Chest pain occurred in patients on beta-blockers significantly less than in those off beta-blockers (8% vs 46%), and the addition of atropine made no significant difference (31% vs 46%). During dobutamine stress, new wall motion abnormalities occurred in three patients on beta-blockers (12%); this number increased to 15 after the addition of atropine (57%). New or worsened wall motion abnormalities occurred in 12 patients (46%) off beta-blockers with dobutamine alone and in 14 patients after adding atropine (53%).(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related subsensitivity of cerebellar Purkinje neurons to locally applied beta 1-selective adrenergic agonist.

Previous electrophysiological studies in aged rats have revealed a number of deficits in noradrenergic neurotransmission in the central nervous system. Such deficits include subsensitivity to the depressant effects of norepinephrine on cerebellar Purkinje neurons, which has been attributed specifically to altered beta adrenergic receptor-mediated processes. The objective of this study was to determine which beta adrenergic receptor subtype, beta 1 or beta 2, is responsible for this age-related subsensitivity. The effects of beta 1 and beta 2 agonists on spontaneous activity of Purkinje neurons was first examined in young rats and the selectivity of these agents was validated using selective beta 1 and beta 2 antagonists. The effects of the selective beta 1 and beta 2 agonists were then compared in young (3-month-old) and aged (18- and 26-month-old) Fischer 344 rats. These agents were applied to Purkinje neurons by pressure microejection from multibarreled micropipettes and the change in neuronal action potential discharge rate was recorded. Both dobutamine, a beta 1-selective agonist, and zinterol, a beta 2-selective agonist, induced dose-dependent inhibitions of Purkinje cell firing rate. Dobutamine-induced inhibitions were blocked by the selective beta 1 antagonist, ICI 89406 and not by the beta 2-selective antagonist, ICI 118551; conversely, zinterol-induced inhibitions were not blocked by ICI 89406 but were blocked by the presence of ICI 118551. Purkinje neurons of both groups of aged rats were significantly less sensitive to locally applied dobutamine than Purkinje cells of young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine inhibits the positive chronotropic and inotropic responses to norepinephrine and Bay k 8644 in the isolated, blood-perfused dog atrium.

We investigated the effects of adenosine on the positive chronotropic and inotropic responses to an endogenous catecholamine (norepinephrine), a beta 1-adrenoceptor agonist (dobutamine), an adenylate cyclase activator (forskolin), a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, IBMX) and a calcium channel agonist (Bay k 8644) in the isolated, blood-perfused dog atrium. Each drug was injected into the sinus node artery of the isolated atrium. Adenosine infusions at low (45 or 90 nmol/min) and high (184 or 450 nmol/min) doses induced a dose-dependent decrease of sinus rate and atrial contractile force. The positive chronotropic and inotropic responses to norepinephrine, dobutamine and forskolin were dose-dependently depressed by adenosine. IBMX- and Bay k 8644-induced positive cardiac responses were also inhibited by adenosine at high doses but not at low doses. These results suggest that adenosine attenuates calcium channel-dependent as well as cyclic AMP-dependent positive chronotropic and inotropic responses to cardiostimulants in the isolated dog atrium.

8-Bromo cyclic GMP mimics the actions of nitroglycerin in modulating responses produced by full and partial alpha-adrenoceptor agonists in canine saphenous vein.

The purpose of the present study was to determine whether 8-bromo cyclic GMP (8-Br cGMP) mimics the actions of nitroglycerin (GTN) in inhibiting alpha-1 versus alpha-2 adrenoceptor-mediated constrictor responses in canine saphenous vein. Phenylephrine (PE) and L-dobutamine were used as full and partial alpha-1 adrenoceptor agonists, respectively, and B-HT 920 was employed as a selective alpha-2 adrenoceptor agonist. The ability of 8-Br cGMP and GTN to inhibit vasoconstrictor responses to a standard agonist concentration of PE, L-dobutamine and B-HT 920 was determined. 8-Br cGMP like GTN produced a selective antagonism of alpha-2-mediated responses of B-HT 920 and had minimal effects on alpha-1-induced constrictor responses of phenylephrine. However, when a portion of the alpha-1-adrenoceptor pool was inactivated by phenoxybenzamine (POB) (5 x 10(-8) M, 1 x 10(-7) M) 8-Br cGMP like GTN produced a significant depression of responses to PE. In addition, contractions produced by L-dobutamine, a selective partial alpha-1 adrenoceptor agonist (no alpha receptor reserve), were highly sensitive to inhibition by 8-Br cGMP and GTN. These results suggest that the presence of a large alpha-1-adrenoceptor reserve to PE concealed an underlying functional antagonism to alpha-1-adrenoceptor-mediated responses by GTN and 8-Br cGMP. The similarity in the efficacy and potency of these two agents (8-Br cGMP and GTN) suggests that the effects of GTN in canine saphenous vein may be the result of an increase in the intracellular concentration of cGMP.

Modification of dobutamine- and terbutaline-induced calcium and fluid secretion from rat salivary glands by atenolol and butoxamine.

Saliva was elicited from rat salivary glands by terbutaline at i.p. doses of 1, 5, 10 and 25 mg/kg b.wt. but not by doses of 0.1 or 0.5 mg/kg b.wt. Dobutamine elicited no secretion at 1 or 2 mg/kg but did at 5, 10 and 25 mg/kg b.wt. At 5 mg/kg terbutaline evoked nearly maximal volumes but with dobutamine, volumes were small at this dosage. At dosages of 10 and 25 mg/kg volumes with the two agonists were similar for parotid, but with submandibular, the volumes evoked by dobutamine were nearly two times as high as those elicited by terbutaline. Mean [Ca] of parotid saliva was also similar at all dosages of dobutamine (approximately 12 mEq/liter) and generally similar at all dosages of terbutaline (11-15 mEq/liter). Mean [Ca] of dobutamine-elicited submandibular saliva was approximately 6, 7 and 8 mEq/liter at 5, 10 and 25 mg/kg b.wt, respectively. With parotid, [Ca] was approximately 10 mEq/liter at 1, 5 and 10 mg/kg b.wt. but increased to 16-18 mEq/liter at 25 mg/kg. The time course of calcium secretion is described for both agonists at each dosage. [Ca] of both glands was decreased 60 min after i.p. injection of 10 or 25 mg/kg doses of dobutamine or terbutaline but was not changed by 5 mg/kg doses. Administration of 10 mg/kg of atenolol, the selective beta 1 antagonist, 20 min prior to injection of a 10 mg/kg dose of either terbutaline (beta 2 agonist) or dobutamine (beta 1 agonist) blocked secretion from both glands, and prevented the usual agonist-induced reduction in glandular concentration of calcium. Butoxamine, on the other hand, did not modify effects of terbutaline on fluid secretion or depletion of glandular calcium; it did partially inhibit dobutamine-induced fluid and calcium secretion but not depletion of glandular calcium. The present data suggest that beta adrenoceptors of salivary glands are predominantly of the beta 1 subtype and that it is these that regulate calcium and fluid secretion. On the basis of the data with the antagonists, it is concluded that terbutaline activates beta 1 rather than beta 2 receptors since the beta 1 antagonist but not the beta 2 antagonist blocked secretory responses to terbutaline.

[Comparison of the effects of dobutamine with dopamine and isoproterenol on inotropism and chronotropism in the mammalian heart (author's transl)].

The effects of dobutamine on inotropism and chronotropism of the heart were studied in vivo and in vitro and were compared with those of dopamine and isoproterenol. These compounds increased epicardial contractile force and the heart rate of the open-chest, bilaterally vagotomized dog under pentobarbital anesthesia. The dose-ratio for the contraction was [dobutamine: dopamine: isoproterenol = 1:0.8:40] and for the heart rate, [= 1:1:300]. Both drugs augmented the twitch contraction of the isolated dog ventricular papillary muscle with the dose-ratio of [dobutamine: dopamine: isoproterenol = 1:0.7:11]. This mechanical response was associated with an elevation of the plateu voltage and an increase in repolarization of the action potential, but with no alteration of the maximum rate of rise of the action potential, the resting potential and the input membrane resistance. The discharge frequency of the rabbit S-A node pacemaker potential was accelerated chiefly due to an increase in the slope of the diastolic slow depolarization. With concentration of these catecholamines for the equivalent positive inotropic potency on the papillary muscle, this effect of isoproterenol was more potent than the effects of dobutamine and dopamine. These positive inotropic and chronotropic actions of the catecholamines were abolished by a beta-receptor antagonist. Those actions of dopamine were markedly reduced by reserpine pretreatment. In addition, dobutamine had little vascular effect. These results indicatte that dobutamine has a positive inotropic effect and a less positive chronotropic effect and that such is due to the direct action on the ventricular myocardium and the S-A node through beta 1-adrenergic receptors.