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.     

Effects of verapamil on regional myocardial blood flow and ST segment. Role of the induced bradycardia

The effects of verapamil on regional myocardial blood flow and on the $\text{ST}$ segment were studied in both normal and ischemic regions in dogs with and without cardiac pacing.In the absence of cardiac pacing, verapamil (0.05 mg/kg/min/10 min) induced marked bradycardia, a drop in blood pressure and an increase in epicardial and endocardial flows both in normal and ischemic regions of the heart. However, in ischemic regions, redistribution was favorable since the endo/epi ratio increased from 0.46 to 0.61 (p<0.01) whereas this ratio did not vary in normal regions (0.94 vs. 0.92). This increase is accompanied by less marked $\text{ST}$ segment elevation during coronary occlusion in dogs treated with verapamil.In dogs with cardiac pacing, administration of verapamil under the same conditions again induced a drop in blood pressure and, in normal regions only, a homogeneous but less marked increase in epicardial and endocardial flows, the endo/epi ratio varying from 0.94 to 0.98. In contrast, in ischemic regions, blood flow was not modified by verapamil, but the endo/epi ratio dropped from 0.46 to 0.31 (p<0.01), while the $\text{ST}$ segment elevation observed did not differ from that recorded during the control occlusion.These results demonstrate the major role of verapamil-induced bradycardia in the anti-anginal effects of this drug.     

Expression of beta 2-adrenoceptors mediating cyclic AMP accumulation in astroglial and neuronal cell lines derived from the rat CNS

The effect of isoprenaline on cyclic AMP accumulation has been investigated in the rat neuronal cell line B50 and the rat astrocytoma cell line C6. Noradrenaline and isoprenaline stimulated cyclic AMP accumulation in both cell lines. Isoprenaline (0.5 microM; EC50 = 0.1 microM) produced a rapid (T1/2 = 1.3 min) increase in [3H]cyclic AMP accumulation in B50 cells while the response to isoprenaline (0.1 microM; EC50 = 0.01 microM) in C6 cells was somewhat slower (T1/2 = 7.5 min). The response to 0.5 microM isoprenaline was antagonized by both propranolol (IC50 = 8.4 +/- 1.6 nM; N = 3) and the beta 2-selective antagonist ICI 118551 (IC50 = 2.1 +/- 0.2 nM; N = 6). However, no attenuation of the response to isoprenaline (0.5 microM) was observed at concentrations of the beta 1-adrenoceptor antagonist atenolol up to 10 microM (N = 3). In contrast, in C6 cells, which have previously been shown to possess beta 1-adrenoceptors, atenolol inhibited isoprenaline-induced (0.1 microM) cyclic AMP accumulation (IC50 = 2.0 +/- 0.5 microM; N = 6). Furthermore, the beta 2-selective antagonist ICI 118551 was much less potent in the C6 cell line (IC50 = 0.2 +/- 0.05 microM; N = 3) than in the B50 cells. In conclusion, the present data suggest that isoprenaline mediates cyclic AMP accumulation in the neuronal cell line via activation of beta 2-adrenoceptors, while in the astrocytoma cell line the cyclic AMP response is mediated by beta 1-adrenoceptors.     

Electrophysiologic and blood-flow responses in the endocardium and epicardium to disopyramide and MS-551 during myocardial ischemia in the dog.

The aim of this study was to determine whether a quantitative relation exists between changes in regional myocardial blood flow (RMBF) and those in electrophysiologic determinants recorded via left ventricular endocardial and epicardial bipolar electrograms after administration of disopyramide (DP) and a class III antiarrhythmic drug, MS-551 (MS), during myocardial ischemia in the dog. Dogs were given DP (1 mg/kg, i.v., n = 14), MS (1 mg/kg, i.v., and 0.1 mg/kg/min, d.i.v., n = 13), or saline (n = 12). The effective refractory period (ERP) was determined by an S1-S2 extrastimulus method, and RMBF by a nonradioactive microsphere technique. The duration of regional electrograms (DRE) was measured as an indicator of conduction time in the myocardium. DP blunted ischemia-induced shortening of ERPs and lengthened DREs at the endocardial and epicardial sites, with a greater effect seen epicardially (p < 0.01 each). DP reduced RMBF, especially at the endocardial surfaces of the ischemic zone (p < 0.05). MS prolonged ERPs at the endocardial and epicardial sites in the ischemic and normal zones (p < 0.05-0.01), but there were no significant differences between the two sites. MS prolonged DREs (p < 0.05), but the magnitude of the prolongation of the DREs was similar to the values in the control group. MS had no effects on RMBF. DP treatment prolonged DREs at both sites in the ischemic zone more markedly than MS or saline treatment (p < 0.01 each). DP reduced RMBF at the endocardial site of the ischemic zone more markedly than MS or saline (p < 0.05 in each). Accordingly, MS prolonged ERPs, but did not increase disparities between endocardial and epicardial sites in the ischemic myocardium, whereas DP had a greater ERP-prolonging effect at the epicardial site than at the endocardial site. DP reduced endocardial RMBF more markedly than epicardial RMBF. These observations suggest that differences in ERPs between endocardial and epicardial ischemic myocardium caused by DP treatment are not due to the difference in RMBF reduction between the two tissue layers, and that DP and MS do not affect the same population of ion channel(s) when ERPs are prolonged.     

Adrenoceptor blocking hemodynamic and coronary effects of YM-09538, a new combined alpha- and beta-adrenoceptor blocking drug, in anesthetized dogs

In anesthetized dogs. YM-09538, a new sulfonamide-substituted phenylethylamine, competitively antagonised the phenylephrine-induced vasopressor response with a DR10 of 0.50 mg/kg i.v. and the isoproterenol-induced positive chronotropic response with a DR10 of 0.66 mg/kg i.v., indicating that YM-09538 blocks both alpha 1- and beta 1-adrenoceptors and almost to the same extent. YM-09538 was 4 times more potent than phentolamine in blocking alpha 1-adrenoceptors and 3 times less potent than propranolol in blocking beta 1-adrenoceptors. YM-09538 non-selectively blocked cardiac beta 1- and vascular beta 2-receptors and was devoid of intrinsic beta-sympathomimetic and local anesthetic activities. In anesthetized closed-chest dogs, YM-09538 resembled propranolol in reducing heart rate, cardiac output, max. dLVP/dt and left ventricular cardiac work but differed from propranolol in decreasing total peripheral resistance, in increasing femoral blood flow, in causing larger falls in arterial blood pressure and in decreasing pulmonary arterial pressure. In anesthetized open-chest dogs, YM-09538 reduced heart rate, myocardial contractile force and arterial blood pressure. In non-ischemic myocardium, transmural flow and coronary vascular resistance were respectively strongly increased and decreased and the endo/epi flow ratio was slightly but not significantly reduced. In ischemic myocardium, YM-09538 also increased transmural flow and since endocardial and epicardial flows were augmented to the same extent, the endo/epi flow ratio remained unchanged. All these hemodynamic and coronary effects of YM-09538 can be accounted for the drug's combined alpha- and beta-adrenoceptors blocking properties.     

An investigation into the type of β-adrenoceptor mediating sympathetically activated renin release in the cat

1 Stimulation of the renal nerves in the cat was previously shown to cause renin release which could be blocked by propranolol. An attempt was made in this study to determine the type of beta-adrenoceptor mediating this response.2 In anaesthetized, unilaterally nephrectomized cats, a comparison was made of the ability of two selective beta-adrenoceptor antagonists to block the tachycardia and hypotension caused by isoprenaline (mediated respectively by beta(1)- and beta(2)-adrenoceptors) and the release of renin caused by renal nerve stimulation.3 Isoprenaline (mean dose of 0.224 +/- 0.022 nmol/kg), increased heart rate by approximately 43 beats/min and decreased mean blood pressure by 47 mmHg. Stimulation of the distal cut ends of the renal nerves, at a rate sufficient to reduce renal blood flow by 30%, resulted in an approximately 150% increase in plasma renin activity.4 Administration of the selective beta(1)-adrenoceptor antagonist, atenolol (0.38 to 11.28 mumol/kg), caused a dose-related inhibition of nerve stimulated renin release and of isoprenaline-induced tachycardia, with no diminution of the vasodepressor response to isoprenaline; in contrast, the selective beta(2)-adrenoceptor antagonist, erythro-DL-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol (ICI 118, 551, 0.03 to 2.86 mumol/kg), caused a dose-related inhibition of the isoprenaline-induced vasodepression without altering the increase in plasma renin activity caused by renal nerve stimulation. Only at the highest dose of ICI 118, 551 was there a reduction of isoprenaline-induced tachycardia, by about 40%.5 The selective inhibition of neurally activated renin release by atenolol but not by ICI, 118, 551 is consistent with the suggestion that the beta-adrenoceptors mediating renin release resemble those in the heart more closely than those in peripheral blood vessels.     

The relative importance of the time-course of receptor occupancy and response decay on apparent antagonist potency in dynamic assays

1. The potency of the beta1-adrenoceptor antagonist atenolol was measured as an inhibitor of responses to isoprenaline in guinea-pig left atria. Measurements were made in two ways, firstly, by pre-incubating the atria with a given concentration of atenolol followed by an isoprenaline dose-response curve and, secondly, by measuring the response to isoprenaline followed by addition of atenolol. 2. It was found that the estimation of atenolol potency as an antagonist of beta1-adrenoceptors by these two methods gave divergent results. Specifically, it was found that the isoprenaline-induced increased rate of myocardial relaxation was resistant to receptor blockade. Thus, the rate-limiting step in the relaxation response was dissociated from receptor activation and therefore, could not be used for the measurement of receptor occupancy. 3. In contrast, the positive inotropic response was very responsive to receptor occupancy. However, when atenolol was used to block a steady-state isoprenaline response, there was a complicating depression of basal inotropy after receptor blockade that obfuscated measurement of receptor blockade. 4. In general, these data indicated that the blockade of a steady-state agonist response to measure the potency of an antagonist might in some cases yield erroneous results. These studies indicate some caution in the interpretation of blockade responses in pre-contracted or pre-stimulated pharmacological preparations.     

Local modulation of noradrenaline release in vivo: presynaptic beta 2-adrenoceptors and endogenous adrenaline

Isoprenaline bitartrate (0.5 microgram/kg/min i.v.) increased the rate of noradrenaline release into the circulation of pentobarbitone-anesthetized rabbits. This increase was much greater than that produced by an equi-hypotensive dose of the vasodilator hydralazine (0.2 mg/kg i.v.), suggesting that it was only partly due to baro-reflex activation of sympathetic nerves. This facilitatory effect of isoprenaline was also observed in the nephrectomized, pithed rabbit, with electrically stimulated sympathetic outflow, ruling out central nervous system and renin-angiotensin effects. ICI 118,551 HCl (0.3 mg/kg + 0.1 mg/kg/h i.v.) blocked the isoprenaline-induced hypotension, but did not affect the isoprenaline-induced tachycardia, suggesting that it selectively blocked beta 2-adrenoceptors. ICI 118,551 totally abolished the isoprenaline-induced increase in noradrenaline release, suggesting a beta 2-effect. Atenolol (0.3 mg/kg + 0.1 mg/kg/h) blocked the isoprenaline-induced tachycardia, a beta 1-effect, but only slightly attenuated the isoprenaline-induced increase in noradrenaline release. Atenolol by itself decreased heart rate and arterial pressure, but there was no reflex rise in the noradrenaline release rate, which suggests that atenolol impairs baroreceptor activation of sympathetic nerves. In another series of experiments, also in the pentobarbitone-anesthetized rabbit, adrenaline was released into the circulation by splanchnic nerve stimulation. This resulted in prolonged increases of adrenaline levels in heart tissue. After the plasma adrenaline levels had returned to prestimulation values, the rate of noradrenaline release into the plasma was enhanced. This increase was not observed in rabbits treated with either desipramine HCl (1 mg/kg i.v.) or propranolol HCl (2 mg/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-adrenoceptor blockade by atenolol, metoprolol and propranolol in the anaesthetized cat.

The inhibitory effects of atenolol, metoprolol and propranolol on isoprenaline-induced tachycardia, broncho-relaxation and vasodilatation were investigated in the reserpinized and anaesthetized cat. In low doses all three antagonists inhibited the heart rate response to isoprenaline, the order of potency being propranolol greater than metoprolol greater than atenolol. While propranolol inhibited the bronchodilation and vasodilation responses to isoprenaline in the same dose range as it blocked the heart rate response, atenolol and metoprolol had to be given in considerably higher doses to block these effects. The results indicate that both metoprolol and atenolol, in contrast to propranolol, are selective beta1-adrenoceptor antagonist. No statistically significant difference in the degree of selectivity was found between metoprolol and atenolol. The three compounds were devoid of intrinsic beta-mimetic activity.     

The inhibitory effects of iberiotoxin and 4-aminopyridine on the relaxation induced by beta 1- and beta 2-adrenoceptor activation in rat aortic rings.

1. In rat aortic rings contracted by phenylephrine, the relaxation induced by isoprenaline was partly inhibited by iberiotoxin, (ibTX), tetraethylammonium, 4-aminopyridine (4-AP) and 1,9-dideoxyforskolin, but not by glibenclamide. 2. In the presence of 4-AP, 1,9-dideoxyforskolin failed to inhibit further the relaxant response to isoprenaline. Cromakalim-induced relaxation was inhibited by glibenclamide. 3. In the absence of endothelium, ibTX and 4-AP still inhibited the relaxant response to isoprenaline. 4. The inhibitory effect of ibTX on the relaxant response to isoprenaline was eliminated by pretreatment with ICI-118,551, a beta 2-adrenoceptor antagonist, but not by atenolol, a beta 1-adrenoceptor antagonist. 5. The inhibitory effect of 4-AP on the relaxation induced by isoprenaline was abolished by atenolol, but not by ICI-118,551. 6. The inhibitory effect of ibTX on the isoprenaline-induced relaxation in the presence of atenolol was completely abolished by MDL 12,330A, an adenylate cyclase inhibitor. Further, the inhibitory effect of 4-AP on the isoprenaline-induced relaxation in the presence of ICI-118,551 was markedly reduced by MDL 12,330A. 7. The relaxation induced by dibutyryl cyclic AMP was partly inhibited by 4-AP but not by ibTX. However, in the presence of KT5720, an inhibitor of cyclic AMP-dependent protein kinase, ibTX failed to inhibit further the relaxation induced by isoprenaline. 8. These results suggest that, in rat aortic rings, KCa channels are involved in the relaxation induced by isoprenaline. In addition, KCa channels are mainly activated by beta 2-adrenoceptors through cyclic AMP-dependent pathways. Further, the inhibition of isoprenaline-relaxation by 4-AP may be related to the activation of beta 1-adrenoceptors and cyclic AMP formation.     

Beta1- and beta3-adrenoceptors mediate relaxation in ovine trachealis smooth muscle

Isoprenaline (non-selective) and noradrenaline (beta1-selective) concentration-dependently relaxed ovine tracheal strips precontracted with carbachol. The pD2 values were 7.07 +/- 0.08 and 6.13 +/- 0.10 for isoprenaline and noradrenaline, respectively. In the same preparation, salbutamol either produced weak relaxation or in some cases, contractile responses indicating the presence of very little or no beta2-adrenoceptors in this preparation. Isoprenaline-and noradrenaline-induced relaxations were antagonized by propranolol and atenolol with pA2 values in the range reported in the literature for an action on beta1-adrenoceptors. ICI 118551 also antagonized isoprenaline- and noradrenaline-induced relaxation but at concentrations much higher than are required to block beta2-adrenoceptors, confirming that beta2-adrenoceptors do not contribute significantly to these responses. The selective beta3-adrenoceptor agonist, BRL 37344A produced concentration-dependent relaxation of tracheal strips. BRL 37344A was a full agonist producing 100% relaxation of carbachol-induced tone. BRL 37344A-induced relaxation was weakly antagonized by propranolol confirming an action, mainly, on beta3-adrenoceptors. Cyanopindolol antagonized isoprenaline-induced relaxation (in the presence of propranolol, 10(-7) M) with a pA2 value of 8.06 +/- 0.24. It was therefore concluded that beta1- and beta3-adrenoceptors mediated agonist-induced relaxation in sheep tracheal strips.     

A comparison of the cardioselectivity of five beta-adrenoceptor blocking drugs

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.     

Comparative effects of nicorandil, a nicotinamide nitrate derivative, and nifedipine on myocardial reperfusion injury in dogs

The effects of the nicotinamide nitrate compound nicorandil (SG-75) and the slow channel calcium entry blocker nifedipine on the recovery of subendocardial segment shortening (% SS) were compared with a vehicle-treated group following 30 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion. Sonomicrometry was used to determine % SS in ischemic and nonischemic myocardium, and radioactive microspheres were used to determine regional myocardial blood flow. Nicorandil (100-micrograms/kg bolus followed by 25 micrograms/kg/min i.v.), nifedipine (10-micrograms/kg bolus followed by 3 micrograms/kg/min i.v.), or vehicle (saline) was administered 15 min prior to and throughout the occlusion period. Both drugs produced equivalent decreases in the heart rate X systolic pressure product before and during LAD occlusion. In addition, total left ventricular weights, the area at risk, the percent of the left ventricle at risk, and collateral blood flow were similar in all three groups. During coronary occlusion, % SS in the ischemic region was equally depressed in each series and passive systolic lengthening resulted. However, following reperfusion, only the nicorandil-treated animals showed an improvement in myocardial segment function through 3 h of reperfusion as compared with the control group. Transmural myocardial blood flow within the ischemic region during reperfusion returned to control values in all three groups; however, the endocardial/epicardial blood flow ratio (endo/epi) was significantly decreased in the control and nicorandil-treated dogs. In contrast, the endo/epi was greater than the preocclusion control in the nifedipine series during reperfusion. Thus, although the mechanism of action of nicorandil in this model is unknown, the improvement in % SS in the nicorandil-treated group was not related to changes in peripheral hemodynamics or improved regional blood flow, since nifedipine produced similar changes in hemodynamics and resulted in a better recovery of perfusion.     

Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow, myocardial oxygen tension, and electrical abnormalities during acute coronary artery occlusion in dogs

Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow (RMBF), myocardial oxygen tension (PO2), and excitation and conduction abnormalities during the occlusion of the left anterior descending coronary artery (LAD) were examined in anesthetized dogs, and compared with those of nifedipine and dipyridamole. RMBF was calculated from the H2 gas clearance curves, and PO2 was measured using a membrane-coated Pt wire. Excitation and conduction abnormalities during the LAD occlusion were represented in terms of the degree of ST-T alternans (STTA), TQ depression, and conduction delay, which appeared in epicardial electrograms. Nicardipine and nifedipine in a dose of 10 micrograms/kg increased RMBF and PO2 levels in nonischemic and mildly ischemic tissues, but not in severely ischemic tissues. Nicardipine in a dose of 100 micrograms/kg and nifedipine in a dose of 10 micrograms/kg attenuated the degree of STTA, TQ depression, and conduction delay observed in severely ischemic tissues. In mildly ischemic tissues where only TQ depression was observed without STTA, nicardipine in a dose of 30 micrograms/kg attenuated TQ depression. Dipyridamole in a dose of 1 mg/kg produced only a slight attenuation of STTA and conduction delay. These results suggest that the beneficial effects of nicardipine as well as of nifedipine on myocardial ischemia are due to the increase in the myocardial PO2 levels caused by the increased RMBF and also to direct protecting effects on ischemic myocardial cells. In the severely ischemic tissues, the latter is a main effect of the drugs. In increasing the PO2 level, nicardipine was similarly potent as nifedipine, but in the direct effect, nicardipine was less potent, and dipyridamole was almost ineffective.     

Antagonistic effects of bisoprolol on several beta-adrenoceptor-mediated actions in anaesthetized cats

The beta-adrenoceptor antagonistic activity of i.v. administered bisoprolol ((+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy] -3-isopropylamino-2-propanol, hemifumarate) was studied under two different sets of experimental conditions in anaesthetized cats and compared to the activity of atenolol and propranolol. The responses of several target organs to beta 2-adrenoceptor stimulation were used: inhibition of isoprenaline effects on diastolic blood pressure, hindlimb perfusion pressure, soleus muscle contractility and histamine aerosol-induced bronchoconstriction. The inhibition of isoprenaline-induced tachycardia served as indicator of beta 1-antagonism. The slopes of agonist dose ratio vs. antagonist dose effect were close to unity for propranolol but deviated from unity for atenolol and even more so for bisoprolol. In spite of the ensuing difficulty of comparisons, bisoprolol showed the most pronounced selectivity indices (10-20), followed by atenolol (1-7.5) and propranolol (0.3-1.6). Thus, bisoprolol exhibited a higher degree of beta 1-selectivity in the cat than did atenolol, regardless of the parameter used for measurement of beta 2-antagonism. Propranolol proved to be non-selective or even had a somewhat higher affinity for beta 2- than for beta 1-adrenoceptors.     

甘草酸二铵对大鼠心肌损伤的保护

目的：观察甘草酸二铵对大鼠急性心肌的缺血的保护作用。方法：利用异丙肾上腺素造成大鼠急性心肌缺血模型,观察甘草酸二铵对模型的心电图、心肌脂质过氧化物丙二醛（MDA）、超氧化物歧化酶（SOD）、血清磷酸肌酸激酶（CPK）减少,减少MDA的生成,增加心肌组织SOD的活力,抑制CPK和LDH的释放。结论：甘草酸二铵对大鼠心肌缺血有保护作用,机制可能与抗脂质对过氧化提高SOD活力有关。     

Alpha-adrenoceptor control of norepinephrine release from acutely ischaemic myocardium: effects of blood flow, arrhythmias, and regional conduction delay

We studied the effects of yohimbine, and alpha-adrenoceptor blocker with selectivity for the alpha 2-subtype, on myocardial norepinephrine (NE) overflow, regional myocardial blood flow (RMBF), and patterns of epicardial conduction abnormalities during occlusion of the proximal left anterior coronary artery in an open-chest anaesthetised dog model. With a 12-min period of coronary occlusion (n = 9), spontaneous overflow of NE into ischaemic venous effluent was not observed either before or after yohimbine (1 mg/kg i.v.), but the drug significantly potentiated the enhanced NE overflow during supramaximal stimulation of the left stellate ganglion at low (1 Hz) and high (10 Hz) frequency [peak NE 4.3 +/- 0.4 pmol/ml control; 11.8 +/- 5.4 pmol/ml yohimbine (p less than 0.005)] with a delayed return towards prestimulation levels. Myocardial NE overflow on coronary reperfusion was also enhanced. Yohimbine increased arterial epinephrine two- to threefold but did not substantially alter myocardial lactate overflow during coronary occlusion. RMBF was reduced 24 and 36% to ischaemic endocardium and epicardium, respectively (p less than 0.01, compared with control occlusion). This contrasted with a 9 and 6% decrease in flow to the respective nonischaemic areas (p = NS, compared with control occlusion. Spontaneous ventricular fibrillation and the area and magnitude of epicardial conduction abnormalities in the ischaemic myocardium were both increased compared with the control occlusion. Thus, alpha-blockers with selectivity for the alpha 2-adrenoceptor may be detrimental to acutely ischaemic myocardium, presumably through increased local catecholamine release at the nerve terminal.     

Failure of an angiotensin II antagonist to influence isoprenaline-induced antidiuresis in rats

Summary The purpose of this study was to elucidate the role of angiotensin II in isoprenaline-induced antidiuresis by use of the competitive angiotensin II antagonist saralasin. Isoprenaline is known to enhance the formation of angiotensin II. Since angiotensin II has been shown to increase proximal tubular salt and volume reabsorption and to decrease renal fluid and salt excretion the renal effects of isoprenaline might, at least partly, be mediated by angiotensin II.Isoprenaline, infused at 0.1 g/kg·min i. v. into anaesthetized rats, led to a marked decrease of urine flow, sodium and potassium excretion and to an increase in urinary osmolality, confirming previous data. Effective renal plasma flow increased significantly. Immediately after onset of the isoprenaline infusion a transient small fall in GFR was observed. On continuation of the infusion, GFR recovered, but marked antidiuresis persisted. Changes in renal hemodynamics, therefore, can be excluded as being responsible of the antidiuretic effect. Saralasin, infused at 6 g/kg· min i.v., did not affect isoprenaline-induced antidiuresis, antinatriuresis, antikaliuresis, and the increase in urinary osmolality, but prevented the rise in renal plasma flow observed during isoprenaline infusion, probably as a consequence of a weak angiotensin II-like effect of saralasin on renal vessels.It is concluded that angiotensin II does not play a role in isoprenaline-induced antidiuresis. The results are compatible with the view that -adrenoceptor stimulation may directly affect the tubular handling of water and salt.     

Blockers of sulfonylureas receptor 1 subunits may lead to cardiac protection against isoprenaline-induced injury in obese rats

Recent studies have found that blockers of sulfonylureas receptor 1(SUR1) might have cardiac ischemic protective effects. We evaluated the effects of a selective SUR1 blocker gliclazide on cardiac function and arrhythmia after isoprenaline-induced myocardial injury in obese rats. Diet-induced obese rats received isoprenaline or saline shots subcutaneously. Gliclazide or saline was given q12h for 48h to rats received isoprenaline. We measured ECG and hemodynamic parameters and collected blood samples for CK-MB, glucose and lipid profile determination, and then harvested hearts for water content, histological and immunohistochemical analysis and infarct size measurements. The obese rats' hearts receiving isoprenaline-induced myocardial injury showed up-regulated SUR-1 expression in the peri-microvascular area. Obese rats receiving gliclazide lavage had less severe arrhythmia (ASI: 4.00±0.61 vs. 2.14±0.39, P<0.05) and myocardial edema (water percentage: 85.16±0.46% vs. 81.56±0.57%, P<0.05). Less infarct size (47.6±12.8% vs. 32.7±9.1%, P<0.05) and improved diastolic function (LVEDP: 6.86±0.85% vs. 2.51±1.09%, P<0.05;-(dp/dt)(max): -1663.6±387.91mmHg/s vs. -2834.8±290.76mmHg/s, P<0.05) were also observed in rats receiving gliclazide lavage. Blocking of the SUR1 thus exerts a protective effect on the isoprenaline-induced myocardial injury in obese rats. That SUR1 blocker leads to ischemic protection suggesting a critical biological role of SUR1 in regulating the function of the cardiovascular system than previously recognized under pathophysiological conditions.     

Betaxolol, a cardioselective beta-adrenoceptor antagonist, attenuates ischemic myocardial acidosis in dogs

The effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial acidosis were studied in dog hearts, in which the left anterior descending coronary artery was partially occluded for 90 min, and were compared with those of atenolol and propranolol. Myocardial ischemia produced a decrease in myocardial pH (measured by a micro glass pH electrode) and an elevation of the ST segment of epicardial ECG (assessed by a surface electrode). Betaxolol (0.01, 0.03 or 0.1 mg/kg), atenolol (0.03 or 0.1 mg/kg) or propranolol (0.03 or 0.1 mg/kg), when injected i.v. 30 min after ischemia, restored myocardial pH and the ST segment of ECG that had been altered by partial occlusion. However, the effect of betaxolol on myocardial acidosis was more potent than that of atenolol or propranolol. The decrease in (+)dp/dt by betaxolol (0.03 mg/kg) was less potent than that by atenolol (0.1 mg/kg) and equivalent to that by propranolol (0.1 mg/kg), although the restorations of myocardial acidosis by the drugs were almost equivalent. These results have confirmed that beta-adrenoceptor antagonists attenuate the ischemia-induced myocardial acidosis and have shown that among three beta-adrenoceptor antagonists, betaxolol is the most effective in improving myocardial acidosis with a relatively weak effect on myocardial contractile function.