Blood flow regulation during acute regional ischemia in feline hearts: importance of postjunctional alpha 1- and alpha 2-adrenoceptors.

Influence of postjunctional alpha 1- and subsequent alpha 2-adrenergic antagonism on myocardial blood flow was measured in a group of anesthetized cats with acute occlusion of the left anterior descending coronary artery (LAD) and a control group (n = 10 for both). The relatively selective postjunctional alpha 1-(doxazosin) and alpha 2-adrenergic (SK&F 104078) antagonists were applied after beta-adrenergic blockade (propranolol). Regional myocardial blood flow was obtained with radiolabeled microspheres. Major hemodynamic determinants for perfusion were kept constant both within and between groups by right atrial pacing and aortic obstruction. Mean coronary resistance in nonischemic myocardium was permanently lower in the occlusion group as compared with controls (p less than 0.01). Subsequent alpha 2-adrenergic antagonism reduced mean coronary resistance in controls only (p less than 0.05). Cardiac output (CO) and dP/dt was reduced in LAD-occluded hearts after alpha 2-adrenergic blockade (p less than 0.01, p less than 0.05). The study demonstrates the significance of postjunctional alpha 2-adrenergic-mediated vasoconstriction in well-perfused myocardium of control hearts, whereas such vasoconstriction was deteriorated in LAD-occluded hearts. A role for myocardial alpha 2-adrenoceptors for maintenance of global cardiac function in acute regional ischemia was also indicated.     

Evidence for heterogeneity of prejunctional alpha-2-adrenoceptors.

The interactions between SK&F 104078 and several selective alpha 2-adrenoceptor agonists at pre- and postjunctional alpha 2-adrenoceptors were investigated in order to assess the previously reported selectivity of SK&F 104078 for postjunctional alpha 2-adrenoceptors and to determine whether or not SK&F 104078 could uncover subtypes of alpha 2-adrenoceptors located prejunctionally as has also been suggested. The alpha 2-adrenoceptor agonists, UK 14,304, xylazine, B-HT 933, B-HT 920, clonidine and M-7, produced concentration-dependent prejunctional alpha 2-adrenoceptor-mediated inhibition of neurogenic responses in the guinea pig atrium and rat vas deferens and produced postjunctional alpha 2-adrenoceptor-mediated contraction of the canine saphenous vein. The alpha 2-adrenoceptor antagonist, rauwolscine, blocked all the agonists at both pre- and postjunctional alpha 2-adrenoceptors without demonstrating preference for any agonist or any synaptic location of alpha 2-adrenoceptors. In marked contrast, SK&F 104078 produced equivalent antagonism of all agonists in the canine saphenous vein but had no significant effect against the same agonists in the guinea pig atrium, suggesting a high degree of selectivity for postjunctional alpha 2-adrenoceptors in these test systems, consistent with our previous observations. In the rat vas deferens, however, SK&F 104078 significantly antagonized the prejunctional alpha 2-adrenoceptor-mediated effects of clonidine and M-7 but did not block the responses to UK 14,304, xylazine, B-HT 933 and B-HT 920. These results indicate that the prejunctional alpha 2-adrenoceptor antagonist effects of SK&F 104078 are tissue and agonist dependent, and that there may be at least two subtypes of prejunctional alpha 2-adrenoceptors that can be discriminated with SK&F 104078 but not with rauwolscine. Both subtypes of prejunctional alpha 2-adrenoceptors may be present in the rat vas deferens, while only the SK&F-104078-insensitive subtype is present in the guinea pig atrium.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Cardiovascular effects of SK&F 104078, a novel alpha-adrenoceptor antagonist, in normotensive and hypertensive rats.

SK&F 104078 is a novel alpha-adrenoceptor antagonist derived from the 3-benzazepine alpha 2-adrenoceptor antagonist SK&F 86466. SK&F 104078 will block both alpha 1- and vascular postjunctional alpha 2-adrenoceptors but does not block most prejunctional alpha 2-adrenoceptors. Intravenous (i.v.) administration of SK&F 104078 decreased blood pressure (BP) in both spontaneously hypertensive and DOCA-salt hypertensive rats. SK&F 104078 potentiated the hypotensive response to tilt in anesthetized spontaneously hypertensive rats (SHR). Although SK&F 104078 had no effect on BP in normotensive rats, the tilt-induced decrease in BP in these animals was also potentiated. In this regard, SK&F 104078 resembled the selective alpha 1-adrenoceptor antagonist prazosin, rather than the alpha 2-adrenoceptor antagonists rauwolscine or SK&F 86466. Oral administration of SK&F 104078 had no significant effect on BP in SHR unless extremely high doses were administered. This was consistent with low plasma concentrations of SK&F 104078 observed after oral administration. After i.v. administration, the clearance of SK&F 104078 from plasma was 123 ml/min/kg, the steady-state volume of distribution was 17 L/kg, and the fraction excreted unchanged in urine was less than 1%. The low oral bioavailability of SK&F 104078 did not appear to be due to high first-pass oxidative metabolism, since pretreatment of SHR with the suicide substrate inhibitor of cytochrome P-450, 1-aminobenzotriazole (ABT), did not result in increased oral efficacy. SK&F 101253, a close structural analogue of SK&F 104078, was an effective antihypertensive when administered orally. Comparison of the stability of SK&F 101253 and SK&F 104078 in acid media showed SK&F 104078, but not SK&F 101253, to be rapidly degraded.(ABSTRACT TRUNCATED AT 250 WORDS)     

The alpha 2-adrenoceptor antagonist SK&F 104078 has high affinity for 5-HT1A and 5-HT2 receptors

The affinity of SK&F 104078, a putative selective postjunctional alpha 2-adrenoceptor antagonist, was determined at 5-HT1A and 5-HT2 receptors in rat brain. SK&F 104078 had moderate affinity towards alpha 2-adrenoceptors (pKi 6.7) but displayed higher affinity at 5-HT1A (pKi 8.1) and 5-HT2 (pKi 7.6) receptors. If SK&F 104078 is used in functional studies to define heterogeneity within of alpha 2-adrenoceptors, care must be taken to define the role of 5-HT1A and 5-HT2 receptors in the response being measured.     

Effects of intracoronary nifedipine on blood flow and segment shortening in normal and ischemic myocardium: potentiation by ischemia of the negative inotropic effect

The effects of intracoronary nifedipine on myocardial blood flow (flow probe or microspheres) and regional function (ultrasonic crystals in subendocardium) were examined both in the normal myocardium and in myocardium made ischemic by a partial coronary occlusion in the open-chest anesthetized dog. In a first group of experiments (n = 7), without ischemia, nifedipine infused into the left anterior descending coronary artery (LAD) during a 1-min period (doses 0.75-8 nmol/kg body weight) decreased coronary vascular resistance with a maximal effect at 4 nmol/kg. Systolic segment shortening was decreased from 10.7 to 7.4% (p less than 0.05) by 6 nmol/kg, whereas lower doses had no effect. In a second experimental group (n = 7), a partial LAD occlusion was applied to decrease subendocardial segment shortening by about 50%. Nifedipine (2 nmol/kg) injected into the partially occluded LAD induced a marked segmental bulging during early systole and systolic segment shortening was eliminated (from 4.2 to -3.1%, p less than 0.02) in the LAD-dependent myocardium. Concomitant with the decreased regional function, nifedipine caused a transmural redistribution of myocardial blood flow in the ischemic area, the endocardial/epicardial blood flow ratio increasing from 0.49 to 0.61 (p less than 0.02). It is concluded that ischemia potentiates the direct depressant effect of nifedipine on myocardial regional function.     

Transient drug-induced myocardial dysfunction is not ameliorated by PGI2 in dogs

Prostacyclin (PGI2), a potent vasodilatory substance that effectively inhibits platelet aggregation is under clinical investigation for the treatment of angina pectoris. We studied the effects of PGI2 on transient drug-induced myocardial dysfunction in anesthetized, thoracotomized dogs. Regional myocardial function was assessed using two pairs of piezoelectric transducers and a multidimensional measuring gauge; one pair was implanted in the distribution area of the left circumflex branch (LCX) and the other in the distribution area of the descending branch (LAD) of the left coronary artery. After intravenous injection of isoproterenol (ISO), which led to an increase in systolic shortening in the LCX and LAD areas, a critical stenosis was performed on the LCX and maintained at this level. Intravenous ISO injection now induced regional dysfunction in the LCX-dependent segment with the occurrence of systolic bulging. Infusion of PGI2 at a dosage of 100 ng/kg/min caused a decrease in arterial blood pressure and an increase in heart rate, but had no effect on regional myocardial function. ISO-induced myocardial dysfunction in the critically stenosed LCX segment, which was observed before PGI2 administration, was not ameliorated, but rather aggravated, by PGI2. It may be concluded that PGI2 does not improve normal or ISO-stimulated myocardial function in pressure-dependent perfused areas of the heart.     

Characteristic dysfunction of stunned myocardium induced by 2,3-butanedione monoxime without ischaemia

1. In the present study, we tested the hypothesis that, even in the absence of prior ischaemia, 2,3-butanedione monoxime (BDM), an inhibitor of contraction at the actin-myosin level, could produce the postischaemic dysfunction characteristic of stunned myocardium. 2,3-Butanedione monoxime was injected directly into the left anterior descending coronary artery (LAD) before and again after myocardial stunning produced by 15 min occlusion of the LAD followed by 30 min reperfusion. 2. Regional myocardial force, segment shortening and regional work were measured in both the LAD-perfused area and the area perfused by the circumflex coronary artery, which served as a control area. Regional dysfunction produced by BDM injection or ischaemia-reperfusion was assessed quantitatively by five parameters: end-diastolic length (EDL), shortening onset delay (delay), systolic bulge (bulge), end-shortening time delay (EST) and tail work ratio (TWR). 3. It was found that injection of BDM into the LAD caused dyskinesis similar to that caused by occlusion-reperfusion. Both displayed elevated EDL and marked increases in delay, bulge, EST and TWR; these parameters were significantly higher in the dyskinesis caused by BDM injection. Despite dysfunctional fibre shortening, intracoronary BDM injection did not reduce regional force. 4. Thus, BDM can elicit changes similar to those characteristic of postischaemic dysfunction. Because contractility was not impaired, dysfunction was apparently caused by disrupting the association between contractile force and muscle motion.     

Alpha 2-adrenoceptor blocking profile of SK&F 104078: further evidence for receptor subtypes.

1. The ability of the putative, selective post-junctional alpha 2-adrenoceptor antagonist, SK&F 104078 to antagonize the effects of structurally-diverse agonists at pre-junctional alpha 2-adrenoceptors in the guinea-pig ileum and rat vas deferens in vitro and in the rat heart in vivo, and at post-junctional alpha 2-adrenoceptors in the rabbit ear vein in vitro, was examined. Results obtained with SK&F 104078 were compared with those obtained with yohimbine. 2. Xylazine and B-HT933 each caused a concentration-dependent inhibition of the field-stimulation-evoked twitch responses of the guinea-pig ileum and rat vas deferens. SK&F 104078 did not antagonize either agonist in the guinea-pig ileum and exerted only minimal blocking activity against xylazine in the rat vas deferens. In contrast, SK&F 104078 competitively antagonized B-HT933 in the rat vas deferens (pA2 = 6.45). Yohimbine competitively antagonized both agonists in each tissue (pA2 values ranged between 7.46 and 7.88). 3. In the pithed rat xylazine and B-HT933, injected intravenously, caused a dose-dependent reduction in the tachycardia elicited by stimulation of the cardiac preganglionic sympathetic nerves. SK&F 104078 (10 mg kg-1, i.v.) caused a 20-30 fold rightward displacement of the dose-response curve to xylazine, but did not affect responses to B-HT933. Yohimbine (1 mg kg-1, i.v.) antagonized both agonists to a similar degree. 4. In the rabbit ear vein xylazine, B-HT933, noradrenaline and UK 14304 elicted vasoconstrictor responses. Prazosin was without effect, but in contrast, SK&F 104078 was a competitive antagonist of each of the agonists (pA2 values ranged between 6.63 and 6.72).(ABSTRACT TRUNCATED AT 250 WORDS)     

SCH 23390 and SK&F 83566 are antagonists at vascular dopamine and serotonin receptors

SCH 23390 and SK&F 83566 have been utilized as selective antagonists at postjunctional dopamine receptors. However, in the isolated rabbit thoracic aorta evidence for competitive antagonism of serotonin was obtained. The KB values were 11 and 34 nM for SK&F R-83566 and SCH 23390, respectively. The S-enantiomer of SK&F 83566 was a weaker antagonist at the vascular serotonin receptor (KB = 1.5 microM). Thus, these results indicate that SCH 23390 and SK&F 83566 are not totally specific for the dopamine DA-1 receptor because they can also be potent antagonists at the vascular serotonin receptor.     

Actions of two new bradycardic agents, AQ-AH 208 and UL-FS 49, on ischemic myocardial perfusion and function

The effects of continuous infusions (30 min) of two new bradycardic agents, AQ-AH 208 (3,4-dihydro-6,7-dimethoxy-2-(3-((2-(3,4 dimethoxyphenyl) ethyl)-amino methyl) propyl)-1(2H)-isochinolinon) (10 and 25 micrograms/kg/min) and UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3(3((2-(3,4-dimethoxyphenyl) ethyl) methylimino) propyl)-2H-3-benzazepin-2 on) (1.0 and 2.5 micrograms/kg/min) on ischemic myocardial perfusion and function were studied in anesthetized open chest dogs. Coronary stenosis was induced by narrowing an extracorporeal shunt between the carotid and left anterior descending coronary artery. Regional perfusion was measured by use of radioactive microspheres and regional myocardial function (% segment shortening) was assessed by sonomicrometry. AQ-AH 208 and UL-FS 49 produced dose-dependent reductions in heart rate of 13 to 55 beats/min without prominent effects on left ventricular dP/dt, aortic blood pressure, and % segment shortening of the normally perfused area. In nonischemic myocardium, AQ-AH 208 did not change transmural blood flow in spite of the bradycardia, whereas UL-FS 49 decreased flow. At the high infusion rate, ischemic subendocardial perfusion increased from 0.43 to 0.58 ml/min/g following UL-FS 49 and from 0.57 to 0.84 ml/min/g after treatment with AQ-AH 208. Consequently, endo/epi rose from 0.52 to 0.80 and 0.62 to 0.96, respectively. Atrial pacing abolished the effects of UL-FS 49 on ischemic myocardium whereas the effects of AQ-AH 208 were only partially reduced. Ischemic myocardial function deteriorated less during treatment with UL-FS 49 and was significantly improved following AQ-AH 208 as compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of a specific leukotriene receptor antagonist in splanchnic artery occlusion shock

The purpose of this study was to examine the effects of a new potent peptidoleukotriene receptor antagonist, SK&F 104353, in splanchnic artery occlusion shock. SK&F 104353 was administered as a 1 mg/kg initial bolus followed by an infusion of 3 mg/kg per h for the entire 2 h post-reperfusion observation period. In a group of conscious rats, this dose of SK&F 104353 shifted the LTD4 dose response curve rightward 10-fold, indicating effective antagonism of peptidoleukotriene responses in the rat. Anesthetized rats subjected to splanchnic artery occlusion shock survived an average of only 98 +/- 8 min whereas all animals receiving SK&F 104353 survived the 2 h reperfusion period (P less than 0.02 from vehicle). Therefore, the survival rate of the splanchnic artery occlusion shock group of rats receiving SK&F 104353 was improved to 100% compared with 50% survival for the vehicle-treated splanchnic artery occlusion shock group (P less than 0.025). In the splanchnic artery occlusion shock + SK&F 104353 group the increase in the plasma activities of the lysosomal hydrolase, cathepsin D, and the cardiotoxic peptide, myocardial depressant factor, were significantly attenuated in comparison to the splanchnic artery occlusion shock + vehicle group (P less than 0.025). These data indicate that the peptidoleukotriene receptor antagonist, SK&F 104353 is beneficial in splanchnic artery occlusion shock, and furthermore suggests that it may be a therapeutically useful agent in bowel ischemic shock.     

Neuroinhibitory effects of SK&F 85174, a novel dopamine receptor agonist

SK&F 85174 (3-allyl-6-chloro-2,3,4,5-tetra-hydro-1-(4-hydroxy-phenyl)-1-H-3-benzaze pine-7, 8-diol methanesulfonate) the N-allyl derivative of SK&F 82526, a selective postjunctional dopaminergic agonist, retains the potent agonist activity of the parent molecule at the postjunctional dopamine receptor, as evidenced by activation of the dopamine-sensitive adenylate cyclase in rat caudate homogenates (EC50 = 11 nM). However, unlike SK&F 82526, SK&F 85174 is a potent inhibitor of adrenergic neurotransmission. This neuroinhibitory effect can be demonstrated both in isolated vascular preparations, and in in situ preparations in the anesthetized dog measuring both cardiac and vascular neurotransmission. In each of these preparations, the effect of SK&F 85174 can be blocked by the dopamine receptor antagonists, metoclopramide, or 1-sulpiride, showing that its action occurs via activation of prejunctional dopamine receptors. Inhibition of the responses to sympathetic nervous system activation, when combined with the ability to increase renal blood flow by stimulation of postjunctional dopamine receptors, could make SK&F 85174 an effective therapeutic agent for a variety of cardiovascular disorders, including angina pectoris, hypertension, and congestive heart failure.     

Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.     

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.     

Improved recovery of myocardial segment function following a short coronary occlusion in dogs by nicorandil, a potential new antianginal agent, and nifedipine

The effects of nicorandil [SG-75, 2-nicotinamidoethyl nitrate (ester)] and nifedipine on the recovery of myocardial segment shortening were compared to a vehicle-treated group following a short occlusion (15 min) of the left anterior descending coronary artery (LAD) and reperfusion (5 h). The relationship between myocardial blood flow and myocardial segment shortening was examined by means of the radioactive microsphere technique and sonomicrometry. Nicorandil (100 micrograms/kg followed by 25 micrograms/kg/min, i.v.) or nifedipine (3 micrograms/kg followed by 1 microgram/kg/min, i.v.) was administered 10 min prior to and throughout the occlusion period. Both drugs produced similar decreases in mean arterial pressure (approximately 25 mm Hg) during LAD occlusion. Similar degrees of ischemia (flow deprivation) were produced in the vehicle, nicorandil, and nifedipine groups; however, nicorandil produced a significantly greater decrease in the heart rate-left ventricular systolic pressure product during coronary occlusion. During reperfusion of the LAD there was no difference in the hemodynamics of the vehicle, nicorandil, or nifedipine groups. Neither drug altered myocardial blood flow to the ischemic region during the occlusion or reperfusion period when compared to the vehicle-treated group; however, both nicorandil and nifedipine pretreatment significantly improved recovery of percentage of segment shortening of the ischemic region. Nicorandil improved the recovery of function (percentage of segment shortening) to a greater extent than did nifedipine throughout the reperfusion period, most likely because of the greater decrease in afterload produced by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacologic differentiation between pre- and postjunctional α2-adrenoceptors by SK & F 104078

Summary Most ₂-adrenoceptor antagonists do not discriminate between pre- and postjunctional ₂-adrenoceptors, and this has led to the commonly held belief that pre- and postjunctional ₂-adrenoceptors may represent one homogeneous population of receptors. SK&F 104078 has been shown to be a potent antagonist at postjunctional ₂-adrenoceptors at concentrations that do not block prejunctional ₂-adrenoceptors. Thus, SK & F 104078 is a competitive postjunctional ₂-adrenoceptor antagonist in canine and rabbit saphenous veins, canine saphenous artery and human platelet with a dissociation constant of approximately 100 nmol/l. Conversely, SK & F 104078 is inactive as a prejunctional ₂-adrenoceptor antagonist in atria from dog, guinea pig, rabbit and rat, and in guinea-pig ileum at concentrations up to 10,000 nmol/l. Likewise, SK & F 104078 has the ability to block postjunctional arterial ₂-adrenoceptors in vivo in the pithed rat at doses that do not inhibit prejunctional ₂-adrenoceptors in the same model. The results suggest that pre- and postjunctional ₂-adrenoceptors may not represent one homogeneous class, but rather are discrete subtypes of the ₂-adrenoceptor that may be differentiated by SK & F 104078. Send offprint requests to R. R. Ruffolo, Jr.     

Evidence that SK & F 104078 does not differentiate between pre- and postjunctional α2-adrenoceptors

Summary We have investigated the proposed postjunctional selectivity of the a2-adrenoceptor antagonist SK & F 104078 employing the pithed rat, rat isolated atrium and human saphenous vein preparations. In the pithed rat, SK & F 104078 (5 mg kg^–1) produced a 20-fold shift in the prejunctional ID₅₀ (concentration of agonist producing 50% inhibition of the cardioacceleration to a single stimulus) and a 3-fold shift in the postjunctional ED₅₀ (concentration producing 50% of maximum rise in diastolic blood pressure) of the ₂-adrenoceptor agonist xylazine. However, the ₂-adrenoceptor antagonist yohimbine also showed apparent selectivity for prejunctional receptors in the pithed rat. In the rat isolated atrium, yohimbine was approximately 10 times more potent than SK & F 104078 at enhancing the stimulation-evoked release of tritium in tissues preincubated with (³H)-noradrenaline. In the human saphenous vein, yohimbine and SK & F 104078 had pA₂ values of 7.40 and 6.33, respectively, against contractions to noradrenaline, so that yohimbine was again approximately ten times more potent than SK & F 104078. In conclusion, SK & F 104078 behaved like yohimbine in its relative potencies at pre- and postjunctional ₂-adrenoceptors both in vivo and in vitro, so that we fail to find any selectivity of SK & F 104078 for postjunctional ₂-adrenoceptors.Send offprint requests to J. R. Docherty at the above address     

超声二维斑点追踪显像评价冠心病患者心室肌局部收缩功能

目的:探讨超声二维斑点追踪显像(STI)技术诊断局部心室肌运动异常的临床价值。方法:根据冠状动脉造影(CAG)结果将入选患者分组。对照组为CAG示冠状动脉正常者25例,缺血组为CAG示冠状动脉左前降支(LAD)狭窄≥75%者28例。分别记录心尖位四腔、长轴及两腔切面高帧频图像,应用STI技术测量重度冠状动脉狭窄患者的LAD供血区域各个节段心肌的收缩期纵向峰值应变及应变率。结果:对照组与缺血组成功获得二维应变及应变率的节段数分别为94.0%和93.3%。纵向峰值应变后间隔中间段,前间隔及前壁中间段、心尖段缺血组较对照组均明显减低,差异有统计学意义(P<0.05);纵向峰值应变率前间隔及前壁中间段、心尖段缺血组较对照组均明显减低,差异有统计学意义(P<0.05)。结论:当冠状动脉出现严重狭窄时,STI技术能较好定位冠状动脉粥样硬化性心脏病患者的异常心肌节段,并显示无明显室壁运动异常的冠心病患者局部心肌收缩功能降低。     

Effects of the acylcarnitine-transferase blocking agent sodium 2[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) on metabolism and regional function in the underperfused canine myocardium

We investigated the effects of sodium 2[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) on regional myocardial function and metabolism in anesthetized, thoracotomized dogs subjected to a 53.5% reduction in flow through the circumflex branch of the left coronary artery (LCX). Regional function in the area supplied by the LCX and the left anterior descending coronary artery (LAD) was assessed by means of two pairs of subendocardially inserted ultrasonic transducers. Hemoglobin content, oxygen saturation, pH, PCO2, PO2, lactate, glucose, and free fatty acids were determined in arterial and local venous blood obtained from the area supplied by the LCX. POCA (20 mg/kg/20 min i.v.) induced a transient decrease in left ventricular power and cardiac output. Arterial free fatty acid (FFA) levels increased continuously throughout the experiment, whilst arterial glucose levels showed a continuous decrease. FFA uptake, lactate release, and oxygen uptake were reduced in the underperfused area by POCA. At the same time, POCA induced a transient increase in end-diastolic segment length and a sustained decrease in systolic shortening during the ejection phase in the underperfused area. No changes in regional function were observed in the area perfused by the nonconstricted LAD.