Cardiac responses after norepinephrine-induced ventricular hypertrophy in rats.

The increase in norepinephrine (NE) blood levels in human heart failure correlates with prognosis. In this study, we determined whether continuous NE infusion alters the positive inotropic and chronotropic responses of isolated rat cardiac muscles. Osmotic minipumps were implanted subcutaneously (s.c.) in 43 adult male rats to deliver NE (160 micrograms/kg/h for 14 days); 42 rats were sham-operated. Isolated left and right atria and left and right ventricular (LV, RV) papillary muscles were prepared to measure positive inotropic or chronotropic responses to NE, phenylephrine, forskolin, dibutyryl cyclicAMP (dbcyclicAMP), and calcium chloride. NE infusion caused (a) a 22% increase in LV wet weight without altering atrial or RV wet weights; (b) an 18% decrease in maximal inotropic response to calcium chloride in LV papillary muscles only; (c) a significantly decreased peak response to NE [72 +/- 5 vs. 93 +/- 5% (sham rats) of calcium chloride] but not to forskolin or dbcyclicAMP in RV papillary muscles; (d) an increased incidence of ectopy at low concentrations of NE, forskolin, and dbcyclicAMP in LV papillary muscles; (e) no alteration in papillary muscle responses to phenylephrine but significantly increased left atrial inotropic responses [51 +/- 5 vs. 33 +/- 2% (sham rats) of calcium chloride] and right atrial chronotropic responses [30 +/- 2 vs. 18 +/- 4 (sham rats) beats/min]; and (f) a selective decrease in beta 1-adrenoceptor density in both ventricles. Thus, NE infusion causes selective LV hypertrophy; responses of compounds that increase intracellular cyclicAMP are affected to a greater extent in papillary muscles from the hypertrophied ventricle than in tissues from the other chambers of the heart.     

Cardiovascular effects of the toxin(s) of the Australian paralysis tick, Ixodes holocyclus, in the rat.

An extract of toxin(s) from the Australian paralysis tick, Ixodes holocyclus, produced positive inotropic responses in rat left ventricular papillary muscles and positive contractile responses in rat thoracic aortic rings. There was no measurable chronotropic response in rat right atria, but positive inotropic concentrations in papillary muscles produced arrhythmias in right atria. Positive inotropic responses were attenuated by verapamil, but unaffected by metoprolol, cimetidine, pyrilamine, tetrodotoxin and pinacidil. Microelectrode studies on isolated left ventricular papillary muscles demonstrated that the extract prolonged action potential duration at 20, 50 and 90% of repolarisation and delayed ventricular papillary muscle relaxation. Cardiovascular tissues isolated from rats with experimentally induced tick paralysis showed no myocardial damage as identified by histological and ultrastructural examination. The basal rate and force of contraction of isolated cardiac tissues were lower from tick-paralysed than normal rats. Concentration-response curves to dobutamine and calcium chloride were similar between tissues from tick-paralysed and normal rats. Thus, the Australian paralysis tick, I. holocyclus, produces one or more toxins with direct cardiovascular effects which mimic the effects produced by direct blockade of cardiac and vascular K+ channels.     

Selective alpha 1- and alpha 2-adrenoceptor agonist-induced contractions and 45Ca fluxes in the rat isolated aorta.

1 Contractile responses produced by the alpha 1-adrenoceptor selective agonist, phenylephrine, and the alpha 2-adrenoceptor selective agonists, oxymetazoline and clonidine, have been compared to those produced by noradrenaline (non selective) in the rat aorta. 2 The relative order of potency of the agonists was noradrenaline greater than phenylephrine greater than clonidine greater than oxymetazoline. Noradrenaline and phenylephrine produced similar maximal responses. The maximal responses produced by oxymetazoline and clonidine were about 59% and 24% respectively of those produced by noradrenaline. 3 Concentrations of agonists producing maximal contractions exhibited different response-time relationships. Responses to noradrenaline and phenylephrine were biphasic while responses induced by oxymetazoline and clonidine were monophasic. 4 In calcium-free solution, contractions stimulated by oxymetazoline and clonidine were almost abolished while those stimulated by noradrenaline and phenylephrine were reduced by about 60-70%. The calcium entry blocker, cinnarizine, almost completely inhibited responses to oxymetazoline and clonidine and reduced noradrenaline- and phenylephrine-stimulated responses by about 60%. 5 All the agonists stimulated the uptake of 45Ca into the La3+-resistant Ca2+ fraction of the artery but only noradrenaline and phenylephrine stimulated the efflux of 45Ca into calcium-free solution. The 45Ca uptake stimulated by oxymetazoline and clonidine was abolished by cinnarizine and that stimulated by noradrenaline and phenylephrine was reduced by about 85%. 6 It is concluded that clonidine and oxymetazoline stimulate contractions that are totally dependent on extracellular calcium. Noradrenaline and phenylephrine stimulate contractions that are partly dependent on extracellular calcium and partly dependent on intracellular calcium stores.     

Myocardial chronotropic and inotropic responsiveness in vitro after chronic α-adrenoreceptor blockade in the rat

1 Positive chronotropic and inotropic myocardial responses to different adrenoreceptor agonists were studied using isolated right atria and left ventricular papillary muscles from rats treated orally for 5 weeks with prazosin, an α₁-antagonist, or vehicle (distilled water). 2 Chronotropic responses to the α-adrenoreceptor agonists isoprenaline and salbutamol were similar in atria from both groups of rats, with no differences in their basal rates, maximum rate increases or pD₂ values for either agonist. 3 Basal contractile force of field-stimulated papillary muscles was similar in both prazosin-treated (0.089 ± 0.014 g mg^-1) and control groups (0.104 ± 0.035 g mg^-1). In response to noradrenaline, force increased maximally by 145 ± 30% and 131 ± 30% above resting levels respectively, and pD₂ values for this β- and α-agonist showed no changes after chronic prazosin treatment. Inotropic responses to isoprenaline were also not different with maximum increases in force of 94.5 ± 20.2% for prazosin-treated and 84.5 ± 18.5% for controls, and similar pD₂ values. 4 However, in response to the α-agonist phenylephrine (in the presence of propranolol), maximum increases in force were greater in relation to the noradrenaline maxima after prazosin treatment (48.8 ± 4.2%) than in controls (32.0 ± 4.3%, P<0.02). pD₂ values for phenylephrine were also significantly higher after long-term α-blockade (5.71 ± 0.10 vs 5.30 ± 0.19 for controls, P<0.05). 5 Long-term α-blockade in the rat therefore led to supersensitivity of α-mediated inotropism in the heart, but both β-mediated inotropic and chronotropic responses were unaffected. These results show selectivity of action of chronic prazosin treatment on α-receptors in the rat heart.     

Thyroid hormone-dependent interconversion of myocardial alpha- and beta-adrenoceptors in the rat.

1 The effects of thyroid state on the properties of adrenoceptors mediating inotropic and chronotropic responses of the rat heart were assessed on the basis of the relative potencies of alpha- and beta-adrenoceptor agonists, the effects of alpha- and beta-adrenoceptor antagonists and the tissue uptake of [3H]-phenoxybenzamine ([3H]-PB). 2 In isolated, electrically driven left atria the ratio of the inotropic potencies of isoprenaline and phenylephrine and the inhibitory potency of propranolol (40nM-4 muM) were significantly reduced after thyroidectomy and were moderately increased after thyroxine treatment of control rats. 3 Block of inotropic responses to noradrenaline and to phenylephrine by PB (7.3 nM-7.3 muM) and the tissue uptake of [3H]-PB were significantly greater in preparations from thyroidectomized than in those from control or from thyroxine treated rats. alpha-Adrenoceptor inhibition by phentolamine (0.26-2.6 muM) also increased after thyroidectomy, and phentolamine effectively protected alpha-adrenoceptors from block by and binding of [3H]-PB. 4 The beta1-receptor antagonist H 93/26 (0.1 muM) significantly potentiated alpha-adrenoceptor blockade by PB in hypothyroid but not in control preparations. 5 In spontaneously beating right atria the chronotropic potency of agonists and the effects of antagonists were altered in the same way as were inotropic responses and the slope of the agonist concentration-response curves were significantly reduced after thyroidectomy. Effects of agonists and antagonists were not significantly influenced by thyroxine treatment. 6 Changes in the effects and tissue uptake of sympathomimetic drugs observed after thyroidectomy were reversed to or beyond control levels by thyroid hormone treatment of thyroidectomized animals. 7 The results presented are interpreted as indicating a thyroid hormone-dependent interconversion of myocardial alpha- and beta-adrenoceptors. It is suggested that this interconversion is similar to that observed earlier in frog hearts at different temperatures, and that both effects may reflect an allosteric transition between two forms of a single basic structure.     

DISEASE-INDUCED CHANGES IN α-ADRENOCEPTOR-MEDIATED CARDIAC AND VASCULAR RESPONSES IN RATS

1. The physiological relevance of cardiac and vascular α-adrenoceptors may increase in disease states in which β-adrenoceptors are altered. To test this, positive inotropic and vasoconstrictor responses to phenylephrine were measured in isolated tissues from rats with experimentally-induced hyperthyroidism, hypothyroidism and diabetes as well as in genetically spontaneous hypertensive rats (SHR). 2. In left atria, positive inotropic responses to phenylephrine were increased in hypothyroid and diabetic rats and abolished in hyperthyroid and SHR. 3. In contrast, phenylephrine produced increased positive inotropy in left ventricular papillary muscles from hyperthyroid rats, increased potency in diabetic rats and negative inotropic responses in hypothyroid rats. 4. The potency of phenylephrine as a vasoconstrictor in thoracic aortic rings was increased in hyperthyroid and SHR and decreased in hypothyroid rats. 5. Thus, disease states which alter β-adrenoceptor responsiveness can independently regulate atrial, ventricular and vascular responses to the α₁-adrenoceptor agonist, phenylephrine. Therefore, these disease states may alter the physiological control of the cardiovascular system by noradrenaline and adrenaline as well as the responsiveness in disease states to therapeutic agents acting via α-adrenoceptors.     

A COMPARISON OF THE CARDIAC ACTIONS OF DOPAMINE AND NORADRENALINE IN ANAESTHETIZED DOGS AND GUINEA-PIG ATRIA

1. The positive chronotropic and inotropic actions of dopamine and noradrena-line have been compared in anaesthetized dogs and isolated guinea-pig atria. 2. Inotropic activity was measured with a strain-gauge arch in vagotomized dogs or estimated from max (dp/dt) in dogs with denervated hearts. 3. The effects of propranolol and haloperidol on the concentration-response curves to both amines were studied in isolated atria. 4. In anaesthetized vagotomized dogs noradrenaline was more potent than dopamine but dopamine appeared to have a selective inotropic action, less apparent with noradrenaline. In denervated hearts, doses of noradrenaline and dopamine which caused similar increases in max (dp/dt) also caused similar increases in heart rate. 5. In isolated atrial preparations, concentrations of dopamine and noradrenaline which produced similar increases in force of contraction also had similar chronotropic effects. 6. Propranolol produced a shift to the right of the concentration-response curves to both dopamine and noradrenaline but the antagonism of noradrenaline was quantitatively greater. Haloperidol had no effect in concentrations below those found to cause general tissue depression. 7. It is concluded that neither dopamine nor noradrenaline show any real difference in their relative inotropic and chronotropic activities in the absence of autonomic innervation.     

Evidence for a prostacyclin-mediated chronotropic effect of angiotensin II in the isolated cat right atria

The positive chronotropic effect of angiotensin II was studied on the isolated spontaneously beating cat right atria. Angiotensin II and prostacyclin produced similar positive chronotropic and inotropic effects which were not affected by beta-adrenoceptor and histamine H2-receptor blockers. [Sar1,Ile8] angiotensin II, however, inhibited the positive chronotropic and inotropic responses to angiotensin II without altering that to prostacyclin, noradrenaline and histamine. Nicotine completely abolished the positive chronotropic action of angiontensin II without altering its positive inotropic effect. Nicotine failed to abolish the effects of prostacyclin, noradrenaline and histamine on the rate and contractility. These results were taken as evidence that the angiotensin II-induced increase in heart rate is probably mediated through the increase of prostacyclin biosynthesis in the isolated cat right atria.     

Altered alpha 1-adrenoceptor-mediated responses in atria of rats with chronic left ventricular infarction.

Phosphoinositide (PI) turnover, chronotropic and inotropic responses to alpha 1-adrenoceptor activation, and alpha 1-adrenoceptor density were studied in atria from rats with left ventricular myocardial infarction (LVMI) and noninfarcted rats. LVMI was produced after surgical ligation of the left coronary artery in 8-week-old Wistar rats. Rats were killed 4 weeks after this operation when rats with LVMI had developed significant hypertrophy of both ventricles and atria. Phenylephrine 0.1 mM to 1 mM, with propranolol 0.3 mM, produced a concentration-dependent increase in heart rate (HR) in right atria from noninfarcted rat hearts, and this response was significantly reduced in rats with LVMI. In electrically driven left atria, the concentration-dependent, phenylephrine-induced positive inotropic responses observed with propranolol added were also significantly impaired in rats with LVMI as compared with those of noninfarcted rats. In contrast, neither PI turnover in response to phenylephrine in the presence of propranolol nor alpha 1-adrenoceptor density was reduced in rats with LVMI. These results suggest that the impaired alpha 1-adrenoceptor-induced chronotropic and inotropic responses in atria from rats with LVMI are not due to downregulation of alpha 1-adrenoceptors or to impaired activation of PI turnover after alpha 1-adrenoceptor stimulation, but to impairment of one or more biochemical responses distal to PI hydrolysis or changes in coupling mechanisms other than hydrolysis of PIs.     

COMPARATIVE STUDY OF CHRONOTROPIC AND INOTROPIC RESPONSES TO 5-(1-HYDROXY-2-ISOPROPYLAMINOBUTYL)-8- HYDROXYCARBOSTYRIL HYDROCHLORIDE HEMIHYDRADE (PROCATEROL), SALBUTAMOL, NORADRENALINE AND ISOPRENALINE IN THE DOG HEART

1. The cardiac chronotropic and inotropic responses to 5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrade (procaterol) and salbutamol have been compared to noradrenaline and isoprenaline in isolated blood-perfused canine atrial and ventricular preparations. 2. All four compounds induced dose-related positive chronotropic and inotropic effects, but different individual response patterns were observed. 3. Procaterol and salbutamol were partial agonists compared to noradrenaline and isoprenaline for causing chronotropic and inotropic responses. The order of efficacy for the adrenoceptors mediating both chronotropic and inotropic responses was isoprenaline, noradrenaline, salbutamol and procaterol. The slopes of the salbutamol dose-response curves were flatter than those for isoprenaline and noradrenaline; the slopes of the procaterol dose-response curves were flatter than those for salbutamol. 4. Because of these differences, the order of activity depended upon the level of response chosen for the comparison. When doses producing small chronotropic and inotropic responses were compared, the order of activity was isoprenaline, noradrenaline, procaterol and salbutamol; whereas with doses producing large responses the order was isoprenaline, noradrenaline, salbutamol and procaterol. 5. Procaterol was longer acting than salbutamol, and salbutamol was longer acting than noradrenaline.     

Increased sensitivity of neonatal mouse myocardia to autonomic transmitters

1 Chronotropic and inotropic responses to noradrenaline and acetylcholine were examined in isolated right atrial and ventricular preparations from neonatal and adult mice. 2 Noradrenaline and acetylcholine produced positive and negative chronotropic responses, respectively, in the atria from both ages. Noradrenaline produced positive inotropic responses in ventricular preparations from both ages. In all cases, the sensitivity, expressed in terms of pD₂ values, was higher in neonatal preparations. 3 In the ventricle, desipramine produced a leftward shift of the concentration–response curve for noradrenaline in the adult, but no such shift was observed in the neonate. The sensitivity to isoprenaline of ventricular preparations was higher in the neonate than in the adult. 4 Our results demonstrated developmental decreases in sensitivities to autonomic transmitters in mouse myocardia. As for the inotropic response to noradrenaline of ventricular muscle, both pre- and postjunctional mechanisms were responsible for the developmental decrease in sensitivity.     

A comparison between the adenosine receptors mediating adenylate cyclase inhibition and cardiac depression in the guinea pig heart

Stable analogues of adenosine were used to investigate the specificity of the receptors mediating its negative chronotropic and inotropic responses in isolated guinea-pig atria. The order of potencies for both responses was NECA = L-PIA = CHA = 2-chloroadenosine much greater than D-PIA. These analogues also inhibited adenylate cyclase in atrial and ventricular membranes, the order of potency being L-PIA = CHA = NECA much greater than D-PIA. The methylxanthines 8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine and isobutylmethylxanthine antagonized both the pharmacologic responses of these agonists and their effect on adenylate cyclase. Antagonism produced by the methylxanthines was competitive as indicated by linear Schild plots for all three antagonists. The affinity constants obtained for the chronotropic and inotropic responses were similar to those obtained for adenylate cyclase inhibition. These results suggest that the negative inotropic and chronotropic effects of adenosine are mediated by RI adenosine receptors coupled to inhibition of adenylate cyclase.     

The postnatal development of adrenoceptor responses to agonists and electrical stimulation in rat isolated atria.

1. Isolated right and left atria from rats of ages ranging from newborn to adult were used to measure chronotropic and inotropic responses to noradrenaline, isoprenaline, tyramine, and electrical stimulation of intramural nerves. 2. Right atria from newborn animals showed increases in rate with noradrenaline, isoprenaline, and tyramine which did not differ significantly from those of atria from adults. The ED50 values for the chronotropic actions of noradrenaline and isoprenaline were not significantly different at any age from the values in adult preparations. 3. Paced left atria from newborn rats showed well developed positive inotropic responses to noradrenaline and isoprenaline. Newborn left atria (and those from 1 and 2 week old animals) were supersensitive to noradrenaline but not to isoprenaline. 4. Left atria from newborn animals showed very small inotropic responses to both tyramine and field stimulation of intramural nerves. These responses developed progressively with age over the first three weeks of life. The results are discussed with respect to the development of cardiac beta-adrenoceptors and of cardiac sympathetic innervation.     

Chronotropic responses in rats implanted with an acrylic orthopaedic cement

The chronotropic and inotropic responses were studied in isolated atria and papillary muscles from rats who had carried a pellet of methyl methacrylate polymer for one week and from sham operated control rats. Right atria isolated from implanted rats were hyporesponsive to the positive chronotropic effects of isoproterenol and glucagon but not to dibutyryl cAMP or to CaC12. Inotropic response of left atria and papillary muscles to isoproterenol was unaltered. No change in the beta-receptor density or affinity was associated with these phenomena. The results indicate that methyl methacrylate exposure leads to a disruption in the signal transduction of chronotropic stimuli mediated by the adenylate cyclase system. The alteration occurs at some point after receptor binding and before cAMP action.     

Effects of tetramethylpyrazine on isolated atria of the Guinea-pig.

The chronotropic and inotropic effects of tetramethylpyrazine (TMPZ) obtained from the stem of JATROPHA PODAGRICA H OOK (Euphorbiaceae) have been investigated on guinea-pig isolated atria. TMPZ caused negative chronotropic and inotropic responses on the isolated atria of guinea-pigs. These TMPZ - induced negative chronotropic and inotropic responses were resistant to the action of atropine. Prior administration to the bath fluid of TMPZ also antagonized the positive chronotropic and inotropic effects of isoprenaline, noradrenaline and calcium on the tissue preparations. It is concluded that TMPZ probably exerts a non-specific inhibitory effect on the isolated cardiac muscles examined, and that this non-specific depressant action on the myocardium might have contributed, at least in part, to the observed IN VIVO depressor (blood pressure lowering) effects of the amide alkaloid reported earlier.     

Positive chronotropic and inotropic effects of angiotensin II in the dog heart

The effects of angiotensin II on sinus rate and atrial contractility were investigated in 17 isolated canine atria and 5 isolated paced ventricular preparations perfused with arterial blood conducted from a heparinized donor dog. When angiotensin II was injected into the cannulated sinus node artery, positive chronotropic responses were dose-dependently produced starting from the 0.01 microgram dose although inotropic responses to angiotensin II were not consistently induced. Angiotensin II produced a similar inotropic response pattern in the paced ventricular preparation. Moreover, when angiotensin II was given into the jugular vein of the donor dog, similar positive chronotropic and inotropic responses were also shown in the isolated atrium. Angiotensin II-induced positive chronotropic and slight inotropic effects were not influenced by treatment with the beta-adrenoceptor blocking agents, propranolol and carteolol, but significantly suppressed by saralasin which has been reported to be a competitive antagonist of angiotensin II. From these results, it is suggested that angiotensin II induced a positive chronotropic and slight positive inotropic effect via angiotensin II receptors in the dog heart.     

Cardiac and vascular responses in deoxycorticosterone acetate-salt hypertensive rats

1. Hypertension leads to ventricular hypertrophy and, eventually, to heart failure. The present study has investigated the functional consequences of deoxycorticosterone acetate (DOCA)-salt hypertension in rats by defining the inotropic, chronotropic and vascular responses to noradrenaline (NA; beta1-adrenoceptor agonist), forskolin (adenylate cyclase activator) and theophylline (phosphodiesterase inhibitor). 2. Administration of DOCA (25 mg, s.c., every 4th day) and excess salt (1% NaCl in drinking water) to uninephrectomized rats increased left ventricular wet weight by 35 and 71% after 4 and 8 weeks, respectively. Addition of KCl (0.4%) or CaCl2 (1%) in the drinking water for 4 weeks attenuated blood pressure increases, but not ventricular weight increases (46 and 28%, respectively). 3. Positive inotropic responses in papillary muscles from uninephrectomized rats to NA (-log EC50 6.73+/-0.38; n = 7), forskolin (-log EC50 6.15+/-0.31; n = 7) and CaCl2 (-log EC50 2.40+/-0.02; n = 14) were unchanged in hypertrophied left ventricles of DOCA and DOCA-CaCl2 rats, although maximal responses to NA were decreased in DOCA-KCI rats (1.2+/-0.6 mN, n = 8; DOCA-salt 2.9+/-0.5 mN, n = 6); theophylline was less potent in DOCA-salt rats. Positive chronotropic responses to NA, forskolin and theophylline in right atria and negative inotropic responses to carbachol in papillary muscles were unchanged. 4. Maximal vasoconstrictor responses to NA in thoracic aortic rings were reduced in DOCA-KCI rats to 2.4+/-0.9 mN (n = 5), but were increased in DOCA-CaCl2 rats to 26.6+/-2.2 mN (n = 7; DOCA-salt 7.8+/-2.2 mN, n = 9). Vasorelaxant responses to forskolin and theophylline were unchanged. 5. These results show that cardiac responses are only minimally affected during the development of DOCA-salt hypertension-induced hypertrophy, despite the reported decreases in adenylate cyclase activity, in these rats. This is in contrast with the decreased responses reported in other rat models of cardiac hypertrophy and in the failing human heart. Thus, hypertrophy in hearts of DOCA-salt hypertensive rats does not produce similar changes to the failing human heart.     

Comparison between spontaneously beating atria from control and streptozocin-diabetic rats.

Isolated spontaneously beating atria from streptozocin diabetic rats were compared with those from controls. Diabetic atria were found to have reduced rates, increased forces of contraction and reduced sensitivity to the inotropic effects of noradrenaline, isoprenaline, tyramine and calcium. Positive chronotropic responses to tyramine were also reduced but those to noradrenaline and isoprenaline were increased suggesting that tyramine releasable stores of noradrenaline were reduced. Elevation of glucose concentration in the medium from 5.6 to 27 mM resulted in decrease of inotropic sensitivity to the agents used in both control and diabetic rat atria. Resting contractile force of control rat atria was reduced by the inclusion of either 22 mM 2-deoxyglucose, 10(-3) i.u. insulin ml-1 or 5 mM acetate in the medium. The rate was also reduced by medium containing 2-deoxyglucose but increased by insulin. 2-Deoxyglucose also reduced inotropic but increased chronotropic sensitivity to isoprenaline. Possible mechanisms responsible for the changes observed are discussed.     

Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin

Relaxin produces powerful inotropic and chronotropic responses in isolated atria. The effect of relaxin has been examined in a rat model of cardiac failure, induced by myocardial infarction (MI). Maximum inotropic responses to isoprenaline (sham 5.4+/-0.3 mN; MI 2.6+/-0.3 mN; P<0.001) and relaxin (sham 5.1+/-0.6 mN; MI 2.8+/-0.5 mN; P=0.013) were reduced in left atria following MI. No change in chronotropic responsiveness was observed in right atria. Pertussis toxin (PTX) treatment restored inotropic responses to isoprenaline (sham 5.5+/-1.3 mN; MI 5.8+/-1.0 mN; P=0.850) but not to relaxin. Instead, PTX reduced inotropic responses to relaxin in sham animals to the same level seen in the MI group (sham 3.2+/-1.7 mN; MI 2.8+/-0.6 mN; P=0.847). In right atria, PTX treatment did not affect the maximum chronotropic response to isoprenaline, but reduced responses to relaxin in both sham and MI animals. R3 relaxin and relaxin receptor (LGR7) mRNA was present in atria and left ventricle (LV) from sham and MI animals. R3 relaxin mRNA expression was increased in atria but not LV from MI animals. LGR7 mRNA expression was reduced in atria and LV from MI animals. PTX treatment in unoperated rats increased chronotropic responses (vehicle 184.3+/-5.3 beats min(-1); PTX 211.3+/-9.5 beats min(-1); P=0.029) and produced a rightward shift in the concentration-response curve to isoprenaline in left atria. PTX reduced inotropic (vehicle 3.3+/-0.7 mN; PTX 0.8+/-0.2 mN; P=0.005) and chronotropic (vehicle 130.2+/-8.1 beats min(-1); PTX 90.6+/-11.1 beats min(-1); P=0.012) responses to relaxin. 6 In left atria, relaxin produced a small increase in cAMP compared to those produced by isoprenaline and forskolin. However, PTX treatment significantly reduced relaxin-, isoprenaline- and forskolin-stimulated cAMP accumulation. Cardiac failure in MI animals caused a reduced inotropic response to both relaxin and (-)-isoprenaline. In non-MI animals, PTX treatment also reduced inotropic responses to relaxin. Differences between responses to (-)-isoprenaline and relaxin can be explained by changes in coupling efficiency occurring at the level of adenylate cyclase.     

The influence of drugs on the overflow of noradrenaline and the identification of receptors in guinea-pig atria.

1 Salbutamol (1.0 microM) and isoprenaline (1.2 nM) significantly increased the fractional release of tritiated noradrenaline from driven left atria but phentolamine (10 microM) failed to do so. Butoxamine (4.0 microM) blocked the increase in overflow produced by isoprenaline. Isoprenaline (1.2 nM), phentolamine (10.0 microM) and salbutamol (1.0 microM) failed to increase the overflow of tritiated noradrenaline from spontaneously beating atria. 2 Spontaneously beating atria were therefore used to identify the receptors mediating chronotropism and inotropism. 3 There was no clear relationship between inotropism and chronotropism. 4 The inotropic effects of both dobutamine (0.04-4.0 microM) and isoprenaline (0.11-9.0 nM) were inhibited by practolol (4.0 microM) and by butoxamine (4.0 microM). The chronotropic effects were inhibited only by practolol (4.0 microM). 5 Both inotropic and chronotropic effects of noradrenaline (3.0-200 nM) were antagonized by practolol (4.0 microM), but not by butoxamine (4.0 microM). Thus both functions appeared to be mediated by beta 1-adrenoceptors when noradrenaline was the agonist. 6 Inotropic responses to salbutamol (0.45-7.5 microM) were inhibited by both practolol (4.0 microM) and by butoxamine (4.0 microM), but chronotropic responses were antagonized only by butoxamine (4.0 microM), Thus salbutamol acts on both beta 1-and beta 2-adrenoceptors to produce an inotropic response but only on beta 2-adrenoceptors to produce its chronotropic response. 7 It is concluded that both beta 1- and beta 2-adrenoceptors can mediate chronotropism and inotropism in guinea-pig isolated atria. Determination of the postsynaptic effects of drugs should be carried out on spontaneously beating rather than driven atria to obviate modification of the responses by noradrenaline release from sympathetic neurons.