Cetamolol: a new cardioselective beta-adrenoceptor blocking agent without membrane-stabilizing activity

Cetamolol, a new beta-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery litigation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.     

A comparative study of the acute effects of cetamolol (AI-27,303), atenolol, propranolol, and dexpropranolol on blood pressure, sympathetic nerve and ganglion activity of cats

The effects of cetamolol (AI-27,303, Betacor), atenolol, propranolol, and dexpropranolol were evaluated in 36 chloralose-urethane anesthetized cats. Blood pressure, sympathetic nerve discharge, and ganglionic activity (from the superior cervical ganglion) were recorded after the intravenous administration of 2.5, 5.0, and 10 mg/kg doses of the compounds. The results indicate that cetamolol and atenolol decreased blood pressure and discharge in the postganglionic sympathetic nerve and impaired transmission at the level of sympathetic ganglia. Propranolol and dexpropranolol given at the same doses produced a larger decrease in blood pressure, but increased the sympathetic discharge and had no effect on ganglionic spike amplitude.     

In vitro studies on cetamolol, a new potent cardioselective beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity

In vitro studies on the new beta-adrenoceptor antagonist, cetamolol (Betacor), have demonstrated that the compound is a potent antagonist of the chronotropic effects of isoproterenol on guinea pig atria. The pA2 value (8.05) of cetamolol was slightly lower than that of propranolol (8.44). The compound was shown to possess a moderate degree of cardioselectivity as indicated by a lower pA2 value for the antagonism of isoproterenol-induced relaxation of the isolated guinea pig trachea (pA2 = 7.67) compared with that derived from atrial experiments (pA2 = 8.05). Up to concentrations of 10(-4) M, cetamolol displayed negligible negative inotropic activity relative to propranolol in the electrically stimulated guinea pig left atrial preparation. When applied to isolated right atria from reserpinized rats, cetamolol had a positive chronotropic effect (approximately 75% of that displayed by practolol) which was antagonized by pretreatment with propranolol, thus indicating intrinsic sympathomimetic activity. Specificity experiments in a number of isolated tissues indicated that cetamolol had very little antihistaminic, anticholinergic, alpha 1-adrenergic blocking, or calcium antagonistic properties. Biochemical receptor binding studies are in general agreement with the observations from the isolated tissue experiments.     

Effect of beta adrenergic receptor agonists and blockaders on the action of bradykinin

A study was made of the effect of beta-adrenomimetics (isoprenaline, orciprenaline, inoline) and beta-adrenoblockers (propranolol, pindolol, oxprenolol, atenolol and practolol) on changes in the tone of smooth muscles of an isolate ileum of guinea-pigs, increase in microvascular permeability and depressor reaction in rats induced by bradykinin. beta-Adrenomimetics decreased spasmogenic and microcirculatory effects of bradykinin. Depending on the selectivity and presence of partial agonistic activity, beta-adrenoblockers exerted different influence on changes in the tone of extravasal muscles and permeability induced by bradykinin. In doses of 0.1, 0.5 and 1 mg/kg (intravenously) beta-adrenoblockers potentiated and prolonged the depressor effect of bradykinin.     

Effect of partial agonist activity in beta blockers in severe angina pectoris: a double blind comparison of pindolol and atenolol.

The use of beta adrenoceptor blockade in the treatment of rest angina is controversial, and the effects on severe angina of partial agonist activity in beta blockers are unknown. Eight patients with effort angina and seven with effort and nocturnal angina and severe coronary artery disease were studied initially when they were not taking any antianginal drugs. Pindolol 5 mg thrice daily (with partial agonist activity) and atenolol 100 mg daily (without partial agonist activity) were given for five days each in a double blind randomised manner. Diaries of angina were kept and treadmill exercise testing and ambulatory ST monitoring performed during the last 48 hours of each period of treatment. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared with pindolol (p less than 0.01). The duration of exercise was significantly increased and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory monitoring were reduced by atenolol. Reduction in resting heart rate is important in the treatment of both effort and nocturnal angina. Partial agonist activity in beta adrenoceptor antagonists may be deleterious in patients with severe angina pectoris.     

Cardiovascular and renin responses to vanadate in the conscious dog: attenuation after calcium channel blockade

The effects of vanadate on cardiovascular function and on the secretion of renin and vasopressin were investigated by infusing sodium orthovanadate (0.32 mu mole/kg X min) intravenously into five conscious dogs. Vanadate caused significant increases in mean arterial pressure, total peripheral resistance, pulmonary arterial pressure, and cardiac output. These data illustrate that the hemodynamic effects of vanadate in the conscious dog are similar to those of the anesthetized dog but that minor differences do exist. Vanadate significantly suppressed plasma renin activity, but plasma vasopressin was unchanged. The effects of vanadate also were investigated in the same dogs on another day after administration of the calcium channel blocker, verapamil (0.3 mg/kg bolus + 0.01 mg/kg X min). After calcium channel blockade, the increases in arterial pressure and pulmonary arterial pressure induced by vanadate were attenuated, and cardiac output did not increase. Calcium channel blockade also prevented the vanadate-induced decrease in plasma renin activity. These data suggest that the cardiovascular and humoral alterations produced by vanadate in the conscious dog are at least partially mediated by changes in intracellular calcium.     

Beta-blockade with intrinsic sympathetic activity modifies favorably exercise-induced changes in plasma lipoproteins

The effects of beta-blockade on acute exercise-induced changes in plasma lipoprotein levels were investigated in 12 healthy normotensive subjects by use of beta-blockers of three types: a nonselective agent, a beta 1-selective agent, and a nonselective agent with intrinsic sympathomimetic activity (ISA) or partial agonist activity. Each subject received each drug and a placebo for 1 wk each according to a randomized double-blind crossover design. After placebo, exercise caused 10-20% increases in total plasma cholesterol and the high-density lipoprotein (HDL)-cholesterol fraction. The total-to-HDL cholesterol ratio fell, particularly during the 30-min recovery phase. Pindolol treatment increased resting values of HDL cholesterol (from 43 +/- 4 to 48 +/- 4 mg/dl) and potentiated the response to exercise (to 59 +/- 5 vs. 51 +/- 4 mg/dl after placebo). The total-to-HDL cholesterol ratio was significantly lower after pindolol treatment than after placebo. In contrast, neither atenolol nor timolol affected exercise-induced changes in plasma lipoprotein levels. The effects of pindolol on other study parameters (exercise endurance and exercise-induced increases in systolic blood pressure, heart rate, and potassium) were similar to the effects of the nonselective agent, timolol. We conclude that the effects of pindolol on the plasma lipid profile are due to its ISA and that the process activated (possibly plasma lecithin-cholesterol acyltransferase activity) is under minimal sympathetic control and, therefore, sensitive to the expression of ISA both at rest and in response to exercise.     

The bronchodilator acitivity of an 11-deoxyprostaglandin (AY 23 578).

The bronchodilator activity of AY-23 578 was studied in vivo and in vitro techniques. In the conscious guinea pig, aerosols of AY-23 578, prostaglandin (PGE2) E2, and isoproterenol afforded significant protection against histamine-induced convulsions. In the anesthetized guinea pig, where changes in tracheal pressure were taken as an index of bronchoconstriction, AY-23 578, PGE2, and isoproterenol were equipotent in inhibiting the bronchoconstriction induced by histamine. AY-23 578, PGE2, and isoproterenol reduced or prevented neostigmine-, prostaglandin F2alpha- or carbachol-induced increases in pulmonary resistance, and decreases in dynamic compliance in the anesthetized cat. The activities of the former two compounds were qualitatively similar but less potent than isoproterenol. In both the guinea pig and the cat, the aerosol administration of effective bronchodilator doses of AY-23 578 did not exhibit any significant cardiovascular effects. Both AY-23 578 and PGE2 caused relaxation of the isolated guinea pig tracheal strip; PGE2 was about six times more potent than AY-23 578. It is concluded that AY-23 578 is an effective bronchodilator in both the guinea pig and cat.     

Synthesis of 4-(1-oxo-isoindoline) and 4-(5,6-dimethoxy-1-oxo-isoindoline)-substituted phenoxypropanolamines and their beta1-, beta2-adrenergic receptor binding studies

Phenoxypropanolamines with 1-oxo-isoindoline and 5,6-dimethoxy-1-oxo-isoindoline groups at the para position were synthesized. beta1, beta2-Adrenergic receptor binding affinities for the synthesized compounds were tested and compared with propranolol and atenolol. It was found that the incorporation of para-amidic functionality within the 1-oxo-isoindoline ring and 5,6-dimethoxy-1-oxo-isoindoline ring system led to a high degree of cardioselectivity in the phenoxypropanolamines. Two of the compounds and possessed beta1-adrenergic receptor affinity comparable with that of atenolol and both showed a better cardioselectivity than atenolol. Both and are undergoing further pharmacological evaluation.     

Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue

The platelet anti-aggregating, cardiovascular and gastro-intestinal actions of a hydantoin prostaglandin analogue, BW245C have been compared with prostacyclin and PGD2 in several species. In human plasma in vitro, BW245C was 0.2 times as active as prostacyclin and 8 times as active as PGD2 in inhibiting platelet aggregation. In rat and rabbit plasma, BW245C was only weakly active but was more potent in sheep and horse plasma. Since the activity of PGD2 varied in a parallel fashion, BW245C may interact with PGD2 binding sites on platelets. The potency of BW245C as a vasodepressor also varied between species, being 0.5, 0.1, 0.06 and less than 0.02 times as active as prostacyclin in the anaesthetised dog, monkey, rat and rabbit respectively. The relative activity of BW245C as an inhibitor of platelet aggregation ex vivo was more comparable, being 0.08, 0.04 and 0.05 times as active as prostacyclin following intravenous infusion in the rabbit dog and monkey respectively. In the rabbit, BW245C was a highly selective platelet inhibitor with minimal cardiovascular actions, whereas in the dog and monkey, BW245C lowered BP in anti-aggregating doses. The potent platelet anti-aggregating actions of BW245C following parenteral or oral administration makes this hydantoin a potentially-useful anti-thrombotic prostaglandin analogue.     

Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.     

The bronchodilator activity of 20-isopropylidene prostaglandin E2 (CS-412)

The bronchodilator activity of 20-isopropylidene prostaglandin E₂ (CS-412) was studied . In the conscious guinea pig, aerosols of CS-412, prostaglandin E₂ (PGE₂), or salbutamol afforded similar protection against histamine-induced convulsions. In the anesthetized guinea pig, where increase in intratracheal pressure was taken as an index of bronchoconstriction, CS-412, PGE₂, and salbutamol were equipotent in inhibiting the bronchoconstriction induced by histamine. CS-412, PGE₂ and salbutamol were equally effective in reducing the serotonin-induced increase in pulmonary resistance in the anesthetized cat. CS-412 was different from PGE₂ in bronchoconstrictor activity in anesthetized cats with normal bronchotonus. PGE₂ caused bronchoconstriction in the cats. CS-412 showed 30 times less constrictor activity than PGE₂. It was concluded that CS-412 is an effective bronchodilator without unfavorable side effects.     

Randomised controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics.

OBJECTIVE--To compare the effects of uteroplacental circulation of two beta adrenoceptor blockers, atenolol (cardioselective) and pindolol (non-selective with intrinsic sympathomimetic activity). DESIGN--Controlled double blind double dummy study. SETTING--Departments of obstetrics and gynaecology in two Swedish university hospitals. SUBJECTS--29 women with pregnancy induced hypertension in the third trimester, 13 randomised to atenolol and 16 to pindolol. MAIN OUTCOME MEASURES--Pulsatility index in fetal aorta, umbilical artery, and maternal arcuate artery. Volumetric blood flow in fetal aorta and umbilical vein. RESULTS--Mean arterial blood pressure decreased by 9.0 (95% confidence interval -13.0 to -5.0) mm Hg in the atenolol group and by 7.8 (-11.4 to -4.2) mm Hg in the pindolol group. During atenolol treatment the pulsatility index increased significantly from 1.82 (SD 0.20) to 2.07 (0.32) in the fetal thoracic descending aorta, from 1.44 (0.28) to 1.79 (0.27) in the abdominal aorta, and from 0.93 (0.17) to 1.05 (0.19) in the umbilical artery; the volumetric blood flow in the umbilical vein decreased from 106 (28.8) to 84 (22.6) ml/min/kg. No such changes were seen after treatment with pindolol. Birth weight was similar in the two groups but placental weight was significantly different (529 (122) g in atenolol group v 653 (136) g in pindolol group; p = 0.03). CONCLUSION--The hypotensive effect was similar with both drugs, but only the beta 1 blocker atenolol had significant effects on fetal haemodynamics, although within normal ranges. The implications of these findings can be only speculative, but negative fetal consequences of beta 1 adrenoceptor blockade cannot be excluded.     

Prodepin: A new product of the adrenomedullin (ADM) gene has systemic vasodilator activity

The purpose of the present study was to investigate the effects of products of the ADM gene other than ADM on systemic hemodynamics in the anesthetized rat, rabbit, piglet, cat and dog. Bolus intravenous (i.v.) injections of rat proADM_22–41 (3–30μg) significantly decreased systemic arterial pressure (SAP) and systemic vascular resistance in the anesthetized rat. Unlike ADM, rat proADM_22–41 markedly increased cardiac output in the rat. Bolus i.v. injections of human proADM_22–41 up to 500μm had not effect in all species studied and rat proADM_22–41 had no effect in species other than the rat. The present data suggest that rat proADM_22–41 is a novel product of the ADM gene other than ADM and possesses marked systemic vasodilator activity. The present data also suggest that the hemodynamic activity of this peptide is species specific.     

Time-course effects of two barbiturates on cardiovascular activity and temperature in the squirrel monkey

Heart rate (HR), mean arterial blood pressure (BP) and core temperature (TEMP) were recorded from conscious, chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous injections of methohexital and secobarbital. Methohexital (0.3–17.0 mg/kg) and secobarbital (1.0–30.0 mg/kg) decreased HR, BP and TEMP in a dose-dependent manner. Methohexital resulted in a greater decrease in blood pressure than secobarbital, but the latter caused greater decreases in heart rate and temperature. The duration of all effects of methohexital was substantially briefer than the effects of secobarbital at the higher doses studied. The data show that these two barbiturates differ not only in duration of action but also in the magnitude of effect on cardiovascular activity in the squirrel monkey.     

Antioxidant activity of β-blockers: An effect mediated by scavenging reactive oxygen and nitrogen species?

The therapeutic effects of beta-blockers are normally explained by their capacity to block the beta-adrenoceptors, however, some of the beneficial cardiovascular effects shown by this group of compounds have already been associated with the antioxidant properties that some of them seem to possess. The beta-blockers atenolol, labetalol, metoprolol, pindolol, propranolol, sotalol, timolol, and carvedilol were tested for their putative scavenging activity for ROS (O(2)(-), H(2)O(2), HO(.), HOCl, and ROO(.)) and RNS ((.)NO and ONOO(-)). Some of the studied compounds are effective ROS and/or RNS scavengers, these effects being possibly useful in preventing oxidative damage verified in hypertension as well as in other cardiovascular diseases that frequently emerge in association with oxidative stress.     

Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice

We have previously shown that some features of the defense response, such as increases in arterial blood pressure (AP), heart rate (HR), and ventilation were attenuated in prepro-orexin knockout (ORX-KO) mice. Here, we examined whether the same was true in orexin neuron-ablated [orexin/ataxin-3 transgenic mice (ORX/ATX-Tg)] mice. In addition, we examined other features of the defense response: skeletal muscular vasodilation and shift of baroreceptor reflex. In both anesthetized and conscious conditions, basal AP in ORX/ATX-Tg mice was significantly lower by approximately 20 mmHg than in wild-type (WT) controls, as was the case in ORX-KO mice. The difference in AP disappeared after treatment with an alpha-blocker but not with a beta-blocker, indicating lower sympathetic vasoconstrictor outflow. Stimulation of the perifornical area (PFA) in urethane-anesthetized ORX/ATX-Tg mice elicited smaller and shorter-lasting increases in AP, HR, and ventilation, and skeletal muscle vasodilation than in WT controls. In addition, air jet stress-induced elevations of AP and HR were attenuated in conscious ORX/ATX-Tg mice. After pretreatment with a beta-blocker, atenolol, stimulation of PFA suppressed phenylephrine (50 microg/kg iv)-induced bradycardia (DeltaHR=-360+/-29 beats/min without PFA stimulation vs. -166+/-26 during stimulation) in WT. This demonstrated the resetting of the baroreflex. In ORX/ATX-Tg mice, however, no significant suppression was observed (-355+/-16 without stimulation vs. -300+/-30 during stimulation). The present study provided further support for our hypothesis that orexin-containing neurons in PFA play a role as a master switch to activate multiple efferent pathways of the defense response and also operate as a regulator of basal AP.     

Central nervous system actions of corticotropin-releasing factor on cardiovascular function in the absence of locomotor activity

Studies were performed in conscious and anesthetized Sprague-Dawley rats to examine whether the cardiovascular responses to intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) required concomitant locomotor activation. I.c.v. administration of CRF to conscious animals elicited significant increases in arterial pressure, heart rate, mesenteric resistance, and iliac blood flow, as well as intermittent locomotor, grooming and chewing activity. Intravenous infusion of the anesthetic agent, Saffan, at the minimal dose required to abolish locomotor activity caused slight but significant elevations of heart rate and mesenteric vascular resistance. I.c.v. administration of CRF to anesthetized animals produced delayed, yet significant and sustained increases in the heart rate and arterial pressure, without altering regional blood flow. These results demonstrate that locomotor activation is not requisite for the expression of CRF-induced pressor and tachycardic responses. It is concluded that CRF acts within the central nervous system to influence cardiovascular function in the absence of locomotor activity.     

Effects of Anesthetics on the Renal Sympathetic Response to Anaphylactic Hypotension in Rats

The autonomic nervous system plays an important role in rat anaphylactic hypotension. It is well known that sympathetic nerve activity and cardiovascular function are affected by anesthetics. However, the effects of different types of anesthesia on the efferent renal sympathetic nerve activity (RSNA) during anaphylactic hypotension remain unknown. Therefore, we determined the renal sympathetic responses to anaphylactic hypotension in anesthetized and conscious rats and the roles of baroreceptors in these responses. Sprague-Dawley rats were randomly allocated to anesthetic groups that were given pentobarbital, urethane, or ketamine-xylazine and to a conscious group. The rats were sensitized using subcutaneously injected ovalbumin. The systemic arterial pressure (SAP), RSNA and heart rate (HR) were measured. The effects of sinoaortic baroreceptor denervation on RSNA during anaphylaxis were determined in pentobarbital-anesthetized and conscious rats. In all of the sensitized rats, the RSNA increased and SAP decreased after antigen injection. At the early phase within 35 min of the antigen injection, the antigen-induced sympathoexcitation in the conscious rats was significantly greater than that in the anesthetized rats. Anaphylactic hypotension was attenuated in the conscious rats compared to the anesthetized rats. The anesthetic-induced suppression of SAP and RSNA was greater in the order ketamine-xylazine >urethane = pentobarbital. Indeed, in the rats treated with ketamine-xylazine, RSNA did not increase until 40 min, and SAP remained at low levels after the antigen injection. The baroreceptor reflex, as evaluated by increases in RSNA and HR in response to the decrease in SAP induced by sodium nitroprusside (SNP), was suppressed in the anesthetized rats compared with the conscious rats. Consistent with this finding, baroreceptor denervation attenuated the excitatory responses of RSNA to anaphylaxis in the conscious rats but not in the pentobarbital-anesthetized rats. RSNA was increased markedly in conscious rats during anaphylactic hypotension. Anesthetics attenuated this antigen-induced renal sympathoexcitation through the suppression of baroreceptor function.