Haemodynamic actions of a novel sino-atrial node function modulator, ZENECA ZD7288, in the anaesthetized dog: a comparison with zatebradine, atenolol and nitrendipine.

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows sinus node rate. Its effects on haemodynamic function have been studied in pentobarbitone anaesthetized dogs, in comparison with zatebradine, atenolol and nitrendipine. 2. ZD7288 lowered heart rate in the dose-range 0.02 to 1.0 mg kg-1 i.v. from 152 to 77 beats min-1. Myocardial contractile function (measured as both dPLV/dtmax and right ventricular free wall developed force) decreased along with rate. Stroke volume increased as rate decreased. Cardiac output decreased at doses in excess of 0.2 mg kg-1, i.v. 3. These haemodynamic changes were reversed when heart rate reduction was reversed by atrial pacing and are, therefore, considered to be indirect consequences of heart rate changes induced by ZD7288. 4. The effects of zatebradine paralleled those of ZD7288 (heart rate reduced from 149 to 60.5 beats min-1 over the dose-range 0.02 to 1.0 mg kg-1, i.v.), except that dPLV/dtmax did not decrease with heart rate and increased during arial pacing. 5. Neither ZD7288 nor zatebradine had significant effects on atrio-ventricular conduction at intrinsic heart rates, but both significantly and dose-dependently prolonged the atrio-ventricular conduction interval during atrial pacing at 180 beats min-1. 6. The observed effects of atenolol were commensurate with removal of beta-sympathetic cardiac drive. Atrial pacing was found not to restore the pre-atenolol heamodynamic state completely.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of prenalterol (H133/22) in normal man.

1 Prenalterol, (S-(-)-1-(4 hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride) a cardio-selective beta-adrenergic receptor agonist, was infused intravenously into six normal male volunteers to determine the cardiovascular effects of this drug. 2 On different occasions, each volunteer received a placebo infusion, an infusion of 0.5 mg prenalterol and an infusion of 1 mg prenalterol. Cardiac output (impedance cardiography), arterial pressure (sphygmomanometry), heart rate and ECG were measured throughout. 3 Prenalterol produced a statistically significant increase in cardiac output and at the end of the infusion this increase was 24% with 0.5 mg and 29% with 1 mg, mainly due to an increase in stroke volume (18% and 17%) with a lesser change in heart rate (+2 and +7 beats/min). Pulse pressure increased but mean arterial pressure showed little change. Peripheral resistance fell by 18% and 20%. As indicated by systolic time indices myocardial contractility increased. 4 Prenalterol at plasma concentrations in excess of 20 nmol l-1 produced significant inotropic effects but did not markedly increase heart rate at concentrations of 60 nmol l-1.     

Effects of prenalterol,a partial beta adrenoceptor agonist,on the left ventricular function in anesthetized cardiac denervated beagle dogs

Cardiovascular effects of prenalterol, a partial beta adrenoceptor agonist, were investigated in pentobartial anesthetized dogs. In these preparations, in which the heart was acutely denervated, intravenous administration of prenalterol significantly enhanced contractility (left ventricular max dP/dt) as well as heart rate, and reduced left atrial pressure. Hence the data confirmed that this agent is an effective inotropic as well as a chronotropic agent. Ventricular function curves were determined in these studies to establish the efficacy of the myocardium in handling volume loads at various filling pressures. In order to relate the increased output directly to increases in inotropy, heart rate was kept constant by electrical pacing. Prenalterol significantly shifted these curves upward and to the left, indicating enhanced contractility. In a separate series, it was demonstrated that the inotropic effect of prenalterol persists for longer durations as indicated by the significant shift that occurred in left ventricular function curves 70 min after administration of a single dose of the drug. The data collectively suggest that prenalterol, an orally effective inotropic agent, possesses prolonged duration of action; hence, this drug may be more preferable than dopamine or dobutamine in the treatment of heart failure since the effects of these two agents are transient and are subjected to tolerance during continuous intravenous infusions.     

Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model.

Clentiazem, 8-chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 micrograms kg-1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min-1) for 3-5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post-dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0-infinity) was significantly increased in congestive heart failure dogs (8.8 +/- 1.6 vs 21.8 +/- 1.4 micrograms min ml-1) (mean +/- SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0.9 +/- 0.1 vs 0.2 +/- 0.11 kg-1) and total body clearance (1.9 +/- 0.4 vs 0.7 +/- 0.21 h-1 kg-1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.     

Effect of prenalterol, a beta-1-adrenoceptor agonist, on renin secretion rate in the anaesthetized dog

The effects of the beta-1-adrenoceptor agonist, prenalterol, 20 microgram/kg intravenously on renin secretion rate (RSR), renal haemodynamics and sodium excretion were examined in anaesthetized dogs with innervated or denervated kidneys. In dogs with innervated kidneys, prenalterol increased RSR from 1.1 +/- 0.2 to 7.9 +/- 0.1 units X min.-1 X g-1 (P less than 0.01). Prenalterol did not affect mean arterial pressure, renal blood flow, glomerular filtration rate or sodium excretion. Heart rate was increased by 53 +/- 17 beats/min. (P less than 0.01). The increase in RSR produced by prenalterol was independent of intact renal innervation as RSR increased to the same extent in dogs with denervated kidneys. Pretreatment with the beta-1-adrenoceptor antagonist, metoprolol 0.5 mg/kg intravenously, abolished the increase in RSR produced by prenalterol. These findings suggest that prenalterol directly activates renal beta-1-adrenoceptors to increase RSR.     

An antiarrhythmic effect of adenosine during myocardial ischaemia and reperfusion

Adenosine (10 micrograms kg-1 min-1, infused into the lumen of the left ventricle) and dipyridamole (0.25 mg kg-1 intravenously, a dose that potentiated markedly the fall in arterial pressure in response to bolus doses of adenosine) each reduced the number of extrasystoles which occurred during the first 30 minutes following coronary artery occlusion in anaesthetised greyhound dogs (from 786 +/- 115 in control dogs to 156 +/- 44 in those treated with adenosine and to 388 +/- 167 with dipyridamole). Intracoronary adenosine (1 microgram kg-1 min-1, infused into the ischaemic area) however appeared to increase the number of extrasystoles to 1230 +/- 214. Left ventricular infusion of adenosine reduced the incidence of ventricular fibrillation (from 88 to 43%) when the ischaemic myocardium was perfused at the end of a 40 min occlusion period. In the dose used in this study (10 micrograms kg-1 min-1) adenosine caused a sustained fall in blood pressure but did not alter blood gases. In control dogs the levels of purine derivatives in blood draining the myocardium rendered ischaemic by coronary artery occlusion (local coronary venous samples) increased gradually during the ischaemic period (from 9 +/- 3 microM pre-occlusion to 25 +/- 7 microM post-occlusion). Dipyridamole increased the resting plasma concentration of purines prior to occlusion by approximately 90%; these remained raised for the occlusion period. These results support the suggestion that adenosine may act as a locally produced endogenous antiarrhythmic agent.     

Effect of Prenalterol,a β-1-Adrenoceptor Agonist,on Renin Secretion Rate in the Anaesthetized Dog

Abstract: The effects of the β-1-adrenoceptor agonist, prenalterol, 20 μg/kg intravenously on renin secretion rate (RSR), renal haemodynamics and sodium excretion were examined in anaesthetized dogs with innervated or denervated kidneys. In dogs with innervated kidneys, prenalterol increased RSR from 1.1±0.2 to 7.9±0.1 unitsXmin.^?1Xg^?1 (P<0.01). Prenalterol did not affect mean arterial pressure, renal blood blow, glomerular filtration rate or sodium excretion. Heart rate was increased by 53±17 beats/min. (P<0.01). The increase in RSR produced by prenalterol was independent of intact renal innervation as RSR increased to the same extent in dogs with denervated kidneys. Pretreatment with the β-1-adrenoceptor antagonist, metoprolol 0.5 mg/kg intravenously, abolished the increase in RSR produced by prenalterol. These findings suggest that prenalterol directly activates renal β-1-adrenoceptors to increase RSR.     

Effects of a beta 1-adrenoceptor agonist, prenalterol, on renal function and renin secretion rate in anesthetized dogs

Experiments were conducted to examine the effects of prenalterol on renal function and renin secretion in anesthetized dogs. Specifically, we tested whether prenalterol alters renal function directly, or only indirectly as a consequence of a systemic action of the drug. Accordingly, prenalterol was infused into one renal artery for five consecutive 15-min periods, at incremental rates of 0.1, 0.3, 0.9, 2.7, and 8.1 micrograms X kg-1 X min-1. Heart rate and mean arterial blood pressure were recorded, and renal functions and renin secretion rates were measured bilaterally. Direct intrarenal prenalterol infusion caused a 60 bpm increase in heart rate and resulted in marked increases in renin secretion rates from both kidneys. Intrarenal prenalterol infusion also reduced urinary sodium and potassium excretions bilaterally and equally. There were no consistent changes in mean arterial blood pressure, or in glomerular filtration rate or renal blood flow, during prenalterol infusion. We conclude that although prenalterol increases renin secretion rate markedly and may alter renal electrolyte excretion, these effects are not mediated by a direct intrarenal action of the drug.     

Effects of the calcium channel blockers, diltiazem and Ro 40-5967, on systemic haemodynamics and plasma noradrenaline levels in conscious dogs with pacing-induced heart failure.

1. Calcium channel blockers increase cardiovascular morbidity and mortality in patients with left ventricular dysfunction. These adverse effects are probably related to the negative inotropic effect of calcium channel blockers and/or a neurohormonal activation. 2. The present study was designed to examine, in conscious dogs, the acute haemodynamic and sympathetic effects of diltiazem and Ro 40-5967 (a novel calcium channel blocker) in the control state and in heart failure. 3. Thirteen dogs were instrumented with a micromanometer and an aortic catheter. After completion of experiments in the control state, heart failure was induced by right ventricular pacing (250 beats min-1, 3 weeks). Diltiazem and Ro 40-5967 were given intravenously (0.8 mg kg-1 and 1.0 mg kg-1 respectively). Cardiac output was measured by a thermodilution technique. 4. In the control state, both agents decreased similarly mean aortic pressure with significant increases in heart rate, cardiac output (both +1.0 l min-1 and P < 0.001) and plasma noradrenaline (both +55%) without changes in left ventricular dP/dtmax. In heart failure, for matched decreases in mean aortic pressure, neither diltiazem nor Ro 40-5967 changed heart rate significantly; diltiazem decreased cardiac output (-0.3 l min-1, P < 0.02) and dP/dtmax (-14%, P < 0.001) while Ro 40-5967 still increased cardiac output (+0.3 l min-1, P < 0.02) although the increased amount was smaller than in the control state. Plasma noradrenaline level was increased more during diltiazem infusion (+120%) than during Ro 40-5967 infusion (+38%, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propranolol on regional myocardial blood flow and function during severe coronary stenosis in dogs

The effects of propranolol alone or associated with atrial pacing were studied on regional myocardial blood flows (RMBF) and regional contractility (sonocardiometry) in non-ischemic, moderately and severely ischemic areas of the canine myocardium. In non-ischemic areas, propranolol reduced both epicardial and endocardial flows, increased the endo/epi ratio and decreased regional contractility. The reductions in subendocardial flow and function were correlated. In moderately and severely ischemic areas, propranolol increased subendocardial flow, reduced subepicardial flow, increased the endo/epi ratio and preserved or even slightly improved regional contractility. There was a good correlation between the propranolol-induced protective effects on regional contractility and the drug-induced increase in subendocardial flow since under atrial pacing subendocardial flow no longer increased and regional function dropped dramatically.     

重组人脑钠肽对慢性心衰犬血流动力学和肾功能的影响

目的研究国产重组人脑钠肽(rhBNP)对慢性心衰犬血流动力学及肾功能的影响。方法用右心室快速起搏(RVP)或狭窄下腔静脉(TIVCC)形成犬的心衰模型。结果RVP心衰犬iv rhBNP后,平均动脉压(MAP)、左室内压(LVSP)、LVdp/dt、肺动脉压(PAP)、左室舒张末期压(LVEDP)、总外周阻力(TPR)及肾血管阻力(RVR)呈剂量依赖性下降,LVdp/dt/P、左室做功(LVW)、心输出量(CO)和心率(HR)无明显改变;TIVCC心衰犬在iv同剂量rhBNP后,MAP,LVEDP和CO下降,其他心功能指标无明显改变。两种心衰犬给药后尿量和尿钠排出量均增加。结论rhBNP有舒张血管和利尿作用,能明显降低心衰犬的心脏前后负荷,不影响心脏收缩功能。     

The effects of timolol on arrhythmias and prostanoid release during canine myocardial ischaemia and reperfusion

Timolol (50 micrograms kg-1), administered intravenously to chloralose-anaesthetized open-chest greyhounds 30 min prior to occlusion of the left anterior descending coronary artery, reduced heart rate and mean arterial blood pressure. This dose caused a 20 fold increase in the dose of isoprenaline required to increase heart rate by 25 beats min-1. During the first 30 min of myocardial ischaemia the number of extrasystoles in the timolol-treated dogs (327 +/- 179) was less than in the control group (888 +/- 168) and none of the dogs that received timolol fibrillated. The haemodynamic changes induced by coronary artery occlusion (decreased cardiac output and stroke volume, increased peripheral vascular resistance) were similar in both control and timolol-treated dogs as were the increases in PCO2 and decreases in PO2 and pH in blood draining from the ischaemic myocardium. Timolol did not alter the release during myocardial ischaemia, of either thromboxane B2 or prostacyclin (measured as 6-keto PGF1 alpha). Reperfusion-induced ventricular fibrillation occurred in 7 out of 8 control dogs and in 5 out of 10 timolol-treated dogs. The overall survival following occlusion and reperfusion was improved by 10% to 50% by timolol.     

Cardiovascular actions of dopexamine in anaesthetized and conscious dogs.

1. Arterial blood pressure, heart rate and cardiac contractility were measured in pentobarbitone-anaesthetized mongrel dogs and in conscious, instrumented dogs. 2. In anaesthetized dogs (n = 5), dose-response curves were obtained by intravenous infusion of increasing doses of dopexamine (5-20 micrograms kg-1 min-1). Infusions were administered three times to each animal to determine whether the responses were reproducible. Dopexamine increased heart rate and myocardial contractility and decreased blood pressure. The dose-response curves for dopexamine did not differ significantly over time. 3. In a second group of dogs (n = 6), dose-response curves (5-20 mg kg-1 min-1) were obtained as above and repeated after the administration of amitriptyline (2 mg kg-1, i.v.). Amitriptyline caused a non-significant reduction in the inotropic and chronotropic responses to dopexamine. 4. Control dose-response curves for dopexamine (5-50 micrograms kg-1 min-1) were similarly obtained in a third group of dogs (n = 6), and repeated after bilateral vagotomy and sympathetic denervation of the heart. In these animals, a third dose-response curve for dopexamine was obtained after the administration of ICI 118551 (0.2 mg kg-1, followed by 0.2 mg kg-1 h-1). The chronotropic response to dopexamine was significantly reduced after cardiac denervation. There was a small, non-significant reduction in the inotropic and depressor responses after denervation. Administration of ICI 115881 significantly reduced both the inotropic and chronotropic response to dopexamine and caused a non-significant reduction in the depressor response. 5. The effect of raclopride (0.2 mumol kg-1, p.o.) was investigated by comparison of the dose-response curves for dopexamine in a control group of dogs (n = 6) to those obtained in dogs which had been pretreated with raclopride (n = 5). Raclopride had no significant effect on the cardiovascular responses to dopexamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetized dogs.

Bradykinin in a dose (25 ng kg-1 min-1) which did not alter coronary flow, or saline, were infused into a small branch of the left anterior descending coronary artery in dogs anaesthetized with chloralose and urethane, for 10 min prior to coronary artery occlusion and throughout the 25 min occlusion period. The degree of inhomogeneity of conduction and epicardial ST-segment changes were measured in the ischaemic zone with a composite electrode. In control dogs, coronary artery occlusion led to severe arrhythmias with an incidence of ventricular fibrillation of 47% and tachycardia of 80% and with a mean of 528 +/- 140 ventricular premature beats. In marked contrast, those dogs administered bradykinin had no ventricular fibrillation or tachycardia and the number of premature beats was significantly less (53 +/- 19). ST-segment changes were also much less in these dogs. These results raise the possibility that bradykinin might contribute to the protective effects of preconditioning and acts as an 'endogenous myocardial protective substance'.     

Prevention by dexamethasone of the marked antiarrhythmic effects of preconditioning induced 20 h after rapid cardiac pacing.

Dogs were paced, via a pacing electrode in the right ventricle, for four 5 min periods at a rate of 220 beats min-1. On the following day they were reanaesthetized, thoracotomized and the left anterior descending coronary artery occluded for 25 min. Pacing markedly reduced the severity of ischaemia-induced arrhythmias (e.g. reduction in VF from 45% in unpaced dogs to 10% in paced dogs; P < 0.05), an effect reversed by dexamethasone (4 mg kg-1 i.v., 45 min prior to pacing). This protection may be due to the induction of nitric oxide synthase or cyclo-oxygenase.     

The influence of diltiazem and nifedipine on renal function in the rat.

The effect of intravenous administration of the calcium-entry blocking drugs, diltiazem and nifedipine, on renal haemodynamic and tubular function was examined in denervated kidneys of pentobarbitone-anaesthetized rats. Infusion of vehicle for the compounds had no effect on renal function which was stable for the duration of the experiments. Diltiazem was infused at 5, 10 and 20 micrograms kg-1 min-1. Blood pressure did not change following 5 micrograms kg-1 min-1 diltiazem but was significantly reduced, by 12 mmHg, after 10 micrograms kg-1 min-1 and by 17 mmHg after 20 micrograms kg-1 min-1. Renal blood flow was not affected by any dose of diltiazem while at the lowest dose of drug, glomerular filtration rate (g.f.r.) was significantly increased, by 24%. Absolute and fractional sodium excretion were increased significantly, 154% and 77% respectively, by 5 micrograms kg-1 min-1 diltiazem, 20% and 24% respectively, by 10 micrograms kg-1 min-1 diltiazem, but were unchanged by 20 micrograms kg-1 min-1. Infusion of nifedipine at 0.5, 1.0 and 2.0 micrograms kg-1 min-1 decreased systemic blood pressure by 9, 9 and 20 mmHg, respectively. Renal blood flow was increased (7%) by 1.0 microgram kg-1 min-1 only, while g.f.r. did not change at any dose. Urine flow, absolute and fractional sodium excretions were increased, 127%, 96% and 90% respectively, by 0.5 microgram kg-1 min-1 nifedipine, 127%, 197% and 194% respectively, by 1.0 microgram kg-1 min-1, while these variables remained unchanged by a dose of 2.0 micrograms kg-1 min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor.

Intravenous bolus injections of 5-hydroxytryptamine (5-HT; 3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (5-MeO-T; 3, 10 and 30 micrograms kg-1), renzapride (BRL 24924; 3, 10, 30 and 100 micrograms kg-1) and isoprenaline (0.03, 0.1 and 0.3 micrograms kg-1) to anaesthetized pigs increased heart rate by, respectively, 22 +/- 3, 44 +/- 3 and 65 +/- 4 beats min-1 (5-HT; n = 17); 12 +/- 1, 26 +/- 2 and 44 +/- 4 beats min-1 (5-MeO-T; n = 15), 5 +/- 2, 11 +/- 2, 18 +/- 4 and 37 +/- 5 beats min-1 (renzapride; n = 8) and 17 +/- 2, 46 +/- 3 and 75 +/- 3 beats min-1 (isoprenaline; n = 13). The responses to 5-HT, 5-MeO-T and renzapride were antagonized by ICS 205-930 (1 and 3 mg kg-1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5-HT. These findings indicate that 5-HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5-HT4 receptor identified in mouse brain colliculi.     

Cardiovascular effects of two new calcium antagonists, PY 108-068 and PN 200-110, in conscious spontaneously hypertensive rats.

1. The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computerized analysis of the intra-aortic blood pressure (BP) recorded continuously for 26 h in conscious unrestrained spontaneously hypertensive rats. Both compounds were studied at three doses (50, 100 and 200 micrograms kg-1) and each dose was administered intravenously 5 times (09 h 00 min, 14 h 00 min, 19 h 00 min, 24 h 00 min and 09 h 00 min). Baroreflex sensitivity was measured 1 h following the last injection. 2. The two compounds were found to induce rapid (3 min) and dose-dependent falls in BP. After the first administration, these decreases reached -20% and -35% for systolic BP (SBP) and diastolic BP (DBP) respectively with PY 108-068 (200 micrograms kg-1) and -25% and -45% for SBP and DBP respectively with PN 200-110 (200 micrograms kg-1). 3. The duration of the reduction in BP increased with the dose and was much longer for PN 200-110 (180 min for SBP) than for PY 108-068 (20 min for SBP). 4. A tachycardia was associated with the decrease in BP which did not differ at 200 micrograms kg-1 between PY 108-068 (+ 108 beats min-1) and PN 200-110 (+ 103 beats min-1). Baroreflex sensitivity was not significantly increased by either drug. 5. The 5 repeated injections of PY 108-068 and PN 200-110 evoked similar responses. 6. In conclusion, both compounds exhibited marked hypotensive properties.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reserpine induces vascular alpha 2-adrenergic supersensitivity and platelet alpha 2-adrenoceptor up-regulation in dog.

1. The aim of the present study was to investigate the influence of catecholamine levels on the regulation of alpha 2-adrenoceptor sensitivity in dogs. 2. Blood pressure and heart rate values at rest, plasma catecholamine levels, platelet and adipocyte alpha 2-adrenoceptors as well as the alpha 2-mediated cardiovascular responses to clonidine (10 micrograms kg-1 i.v., after alpha 1-, beta-adrenoceptor plus muscarinic blockade) or noradrenaline (0.5, 1, 2 and 4 micrograms kg-1 i.v. after alpha 1- and beta-adrenoceptor blockade) were measured before and after reserpine treatment (0.1 mg kg-1 day-1 s.c. over 15 days). 3. Reserpine induced a significant decrease in resting systolic and diastolic blood pressures (213 +/- 2/87 +/- 6 mmHg before vs 158 +/- 5/59 +/- 3 mmHg after treatment) as well as in heart rate (91 +/- 2 beats min-1 before vs 76 +/- 3 beats min-1 after treatment). 4. A 5 min tilt test performed under chloralose anesthesia, failed to modify blood pressure before treatment whereas it induced a significant fall in the same animals after the 15 day treatment. Plasma levels of noradrenaline significantly decreased (262 +/- 58 vs 66 +/- 31 pg ml-1) whereas plasma adrenaline levels were unchanged. 5. The alpha 2-mediated pressor responses to noradrenaline were significantly increased after reserpine. Clonidine induced a marked pressor effect (+72 and +45% in systolic and diastolic blood pressures respectively) after reserpine treatment. This effect was suppressed by administration of RX-821002, a new specific alpha 2-adrenoceptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the myocardial-selective alpha 1-adrenoceptor antagonist UK-52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs.

1. Adrenaline-induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK-52046, 3.8 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 0.01) by UK-52046 but not by atenolol or the combination of both drugs. 2. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK-52046, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-1) had any effect upon ouabain-induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-1 respectively 190 (4-674), 246 (9-1204) and 12 (1-154)]. Both doses of UK-52046 were associated with significant falls in blood pressure. 6. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7-30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK-52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29).(ABSTRACT TRUNCATED AT 400 WORDS)