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Background: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values., Objective: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings., Study Design: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm 2 ]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm 2 ]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy., Results: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02)., Conclusion: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To test whether labetalol improved cardiovascular function in anaesthetized dogs injected with dexmedetomidine., Study Design: Prospective, randomized, blinded, clinical trial., Animals: A group of 20 healthy client-owned dogs undergoing ovariohysterectomy., Methods: Each dog received dexmedetomidine (5 μg kg -1 ) and methadone (0.2 mg kg -1 ) intramuscularly. General anaesthesia was induced with propofol and maintained with isoflurane in oxygen. All dogs were mechanically ventilated, and epidural anaesthesia with lidocaine was performed. Standard anaesthetic monitoring, invasive blood pressure, oesophageal Doppler and near-infrared tissue perfusion/oxygenation were applied. Peak velocity (PV), mean acceleration and stroke distance (SD) from the oesophageal Doppler were recorded. Arterial elastance (Ea) was calculated. Tissue oxygenation (rStO 2 ) was also recorded. Prior to surgery, animals received either 0.1 mg kg -1 of labetalol intravenously (IV) over 60 seconds or the equivalent volume of saline. Data were recorded for 20 minutes. Age, weight and propofol dose were compared with a Wilcoxon rank-sum test. The effects of time, treatment and their interaction with haemodynamic and perfusion variables were analysed with mixed-effect models and Tukey's post hoc tests., Results: Significant effects of the interaction between treatment and time were observed whereby heart rate (HR) was higher in dogs given labetalol (p = 0.01), whereas arterial blood pressure and Ea were lower (p < 0.01). Similarly, PV, SD and rStO 2 were higher in the labetalol group, and significant effects were detected for the interaction between treatment and time (p < 0.01)., Conclusions and Clinical Relevance: Labetalol at a dose of 0.1 mg kg -1 IV in dogs under general anaesthesia and administered a pre-anaesthetic medication of dexmedetomidine produced mild vasodilation (reduction of Ea), resulting in an increase in HR and left ventricular outflow. Although labetalol could be an effective option to achieve haemodynamic optimization after dexmedetomidine-induced vasoconstriction, future studies are needed to assess long-term effects., (Copyright © 2023 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the effectiveness of labetalol vs dexmedetomidine for attenuation of hemodynamic stress response to laryngoscopy and endotracheal intubation., Design: Prospective, randomized, controlled, observer-blinded study., Setting: This study was carried out in Tanta University Hospital., Patients: Ninety patients of both sexes; American Society of Anesthesiologists physical status I and II; age range from 20 to 60 years; scheduled for elective surgery under general anesthesia., Interventions: Patients were divided into 3 groups (30 each). Group A received 1 μg/kg of dexmedetomidine as intravenous (IV) infusion, group B received labetalol 0.25mg/kg IV, and group C received 10mL saline IV., Measurements: The groups were compared for heart rate (HR), mean arterial pressure (MAP), and rate pressure product (RPP). Hemodynamic parameters were recorded during the preinduction; after induction; at intubation; and at 1, 3, 5, 10, and 15minutes. The primary outcomes were hemodynamic changes (HR, MBP, and RPP), and the secondary outcome was propofol dose requirement for induction of general anaesthesia., Results: Significant decrease (P < .05) in HR, MBP, and RPP in groups A and B in comparison with group C and in group A in comparison with group B. Just before intubation, there was a significant decrease (P < .05) in HR, MBP, and RPP in groups A and B in comparison with group C. In group C, there was a significant increase in HR, MBP, and RPP at all points when compared with the baseline. In group A, the mean propofol induction dose (mg) was statistically significantly low as compared with that in groups B and C., Conclusion: Dexmedetomidine attenuates the hemodynamic stress response to laryngoscopy and intubation more effectively compared with labetalol without any deleterious effects. Furthermore, dexmedetomidine decreases dose of propofol for induction of anesthesia as guided by bispectral index., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We investigated the effects of labetalol and pindolol on uterine, placental, and fetal hemodynamics following norepinephrine-induced maternal hypertension in a sheep model of increased placental vascular resistance. Also, we examined fetal and placental hemodynamic responses to acute hypoxemia after antihypertensive medication. Norepinephrine increased maternal heart rate (HR), mean arterial pressure (MAP) and uterine vascular resistance (R(UtA)), and decreased uterine volume blood flow (Q(UtA)). Both labetalol and pindolol decreased maternal HR, MAP, and R(UtA), but did not restore Q(UtA). Fetal MAP was unaffected while fetal HR and placental volume blood flow (Q(UA)) decreased and placental vascular resistance increased. During hypoxemia, which was induced by decreasing maternal inspiratory oxygen fraction, all these parameters remained unchanged in the labetalol group while fetal HR increased and Q(UA) further decreased in the pindolol group. We conclude that labetalol and pindolol may compromise uterine and placental hemodynamics. Hypoxemic stress provokes divergent hemodynamic responses in fetuses exposed to these differently acting adrenoceptor antagonists.

Although well established in treating hypertension and cardiovascular (CV) disease, clinical trial data suggest that beta-blockers (eg, atenolol) may be less effective than other antihypertensive classes in reducing stroke and CV mortality despite similar blood pressure (BP) reductions. One possible explanation is that atenolol is less effective in reducing central aortic pressure. Newer vasodilating beta-blockers may prove more effective in reducing central pressure and cardiovascular events. Carvedilol and labetalol appear to cause vasodilation through alpha(1)-receptor blockade; nebivolol induces endothelium-dependent vasodilation by stimulating nitric oxide bioactivity. Their favorable hemodynamic profile includes reduction of peripheral vascular resistance (PVR) while maintaining or improving cardiac output (CO), stroke volume, and left ventricular function, whereas nonvasodilating beta-blockers tend to raise PVR and reduce CO and left ventricular function. Compared with conventional beta-blockers, vasodilating beta-blockers have beneficial hemodynamic effects including decreased pressure wave reflection from the periphery, leading to decreases in central aortic blood pressure. Larger trials are needed to determine whether reduced central pressure will translate into improved CV outcomes compared with nonvasodilating beta-blockers.

Objective: Assessment of the preventive effect on cardiovascular changes following experimental brain death (BD) in the pig by pretreatment with labetalol, an alpha and beta adrenoreceptor blocking agent., Study Design: Experimental study., Animals: Ten 25-35 kg domestic pigs allocated either in the control group (n = 5) or the labetalol group (n = 5)., Methods: BD was achieved in anaesthetized animals by the rapid inflation of a Foley catheter inserted into the sub-dural space. In the labetalol group, the agent (total: 10 +/- 3 mg.kg-1) was administered immediately before BD and thereafter over a 20-min period, in order to maintain haemodynamic parameters at control values. The following haemodynamic data were recorded over a 3 hour period after BD: heart rate (HR), dP/dtmax, mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and left anterior descending coronary artery blood flow (CBF). Afterwards, a dynamic loading test with 500 mL of dextran over 20 min was performed., Results: In the control group, BD elicited a significant increase in HR (from de 96 +/- 9 to 176 +/- 11 b.min-1), dP/dtmax (from 1,960 +/- 123 to 4,904 +/- 930 mmHg.s-1), MAP (from 88 +/- 5 to 119 +/- 11 mmHg), CO (from 2.4 +/- 0.2 to 3.6 +/- 0.7 L.min-1) and CBF (from 45 +/- 6 to 73 +/- 7 mL.min-1) respectively. Apart from a slight increase in HR and a significant increase in CBF (from 34 +/- 4 to 55 +/- 6 mL.min-1), no other modifications occurred in the labetalol group. Following volume expansion, the labetalol group animals experienced a significant increase in CO (from 2.3 +/- 0.3 to 3.7 +/- 0.2 L.min-1), dP/dtmax (from 1,400 +/- 91 to 2,100 +/- 212 mmHg.s-1) and MAP (from 55 +/- 5 to 70 +/- 5 mmHg). In the opposite, a significant decrease in dP/dtmax (from 1,645 +/- 450 to 628 +/- 152 mmHg.s-1) occurred in the control group., Conclusion: The protective effect of labetalol confirms the role played by the activation of the cardiac sympathetic nervous system in the cardiocirculatory changes following BD.

This study was designed to compare the effects of nicardipine (0.02 mg/kg) and labetalol (0.5 mg/kg) on the uterine blood flow and fetal circulation after intravenous administration in unanesthetized, chronically instrumented pregnant goats. Significant decreases in maternal blood pressure and uterine blood flow were observed in both groups. The maternal heart rate increased significantly after the injection of nicardipine, whereas this change was not observed after the labetalol injection. The fetal heart rate, blood pressure and acid-base status did not change after the injection of either nicardipine or labetalol. These observations in pregnant goats suggest that both nicardipine and labetalol might be useful drugs for the treatment of acutely hypertensive crises in pregnant patients.

The effect of the new hybrid (beta-, alpha-) adrenoceptor blocking drug proxodolol on cardiac output and its distribution between 16 vascular regions, by using the microsphere method on anesthesized normotensive rats and rats with persistent renovascular hypertension. Proxodolol given in beta-adreno-blocking doses similar to those of labetalol was shown to exert vasodilating effects in normotensive rats. Renal, adrenal, splenic, and skeletal muscle vessels were most sensitive to labetalol, whereas cardiac and pulmonary vessels were responsive to proxodolol. In rats with persistent renovascular hypertension, proxodolol had a vasodilating effect only when it was used in doses inducing alpha-adrenoceptor blockade.

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (-27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (-7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (-20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the beta 2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the beta-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the beta-adrenoceptor antagonist activity of dilevalol was apparent.

Objective: The purpose of this study was to investigate the effects of labetalol on uterine blood flow and cardiovascular parameters in acutely instrumented, hypertensive gravid baboons., Study Design: During the latter half of pregnancy six gravid baboons were acutely instrumented, with ultrasonic flow probes placed on ipsilateral, external iliac, and uterine arteries and a flow-directed pulmonary artery catheter in the pulmonary artery. After a stable arterial pressure baseline was obtained, norepinephrine was infused to increase mean arterial pressure by at least 20%. A 20-minute hypertensive steady state was obtained. Labetalol at 0.5 and 1.0 mg/kg was randomly infused, followed by a 2.0 mg/kg dose, each over 1 minute. A 20-minute recovery period followed every labetalol infusion, allowing the hypertensive steady state to reestablish. External iliac and uterine blood flow measurements were continuously recorded during the baseline and experimental trials. Mean arterial blood pressure, heart rate, pulmonary artery and capillary wedge pressure, central venous pressure, and cardiac output were obtained at 5, 10, and 15 minutes during each steady state and after each labetalol infusion., Results: Labetalol at all dosages significantly reduced the mean arterial pressure and the systemic vascular resistance at 1.0 and 2.0 mg/kg. External iliac blood flow was not consistently significantly reduced; however, uterine blood flow was significantly reduced after the 1.0 and 2.0 mg/kg labetalol dosages (p < 0.05). Although uterine vascular resistance tended to increase after the 1.0 and 2.0 mg/kg doses, statistical significance was not achieved., Conclusion: Low-dose labetalol (0.5 mg/kg) significantly reduces the pharmacologic hypertensive gravid baboon's mean arterial blood pressure without adversely affecting uterine blood flow.

The interaction of cocaine with myocardial and vascular adrenoceptors is incompletely understood. The systemic and coronary hemodynamic effects of intravenous cocaine (1.5 mg/kg) were examined in dogs with and without pretreatment with propranolol (2 mg/kg i.v.) or labetalol (5 mg/kg i.v.) on different days. A total of 24 experiments was completed (three sets of experiments) using eight dogs chronically instrumented for measurement of aortic and left-ventricular pressure, left-ventricular dP/dt, subendocardial segment length, coronary blood flow, and cardiac output. Myocardial oxygen consumption was estimated from the pressure work index (PWI). Cocaine significantly (p < 0.05) increased heart rate (+51 +/- 17 bpm), mean arterial pressure (+72 +/- 10 mm Hg), left-ventricular systolic and end-diastolic pressures (+56 +/- 9 and +14 +/- 6 mm Hg, respectively), coronary blood flow (+32 +/- 10 ml/min) and the PWI (+10.0 +/- 2.3 ml O2/min/100 g). Significant reductions in stroke volume (-9 +/- 5 ml) and percent segment shortening (-7.1 +/- 1.7) were observed. These changes returned to control after 30 min. After pretreatment with propranolol, the cocaine-mediated increases in mean arterial pressure, left-ventricular systolic pressure, rate-pressure product, and the pressure work index (4.4 +/- 0.7 ml O2/min/100 g) were significantly (p < 0.05) less than those observed with cocaine alone. Cocaine also reduced contractility [dP/dt50 (-341 +/- 80 mm Hg/s)] and increased systemic vascular resistance (+2703 +/- 339 dyn.s.cm-5) in the presence of propranolol. Labetalol abolished the cocaine-mediated increases in heart rate and coronary blood flow and significantly attenuated the increases in mean arterial pressure, left-ventricular systolic pressure, cardiac output, rate-pressure product, and calculated myocardial oxygen consumption when compared to results obtained with cocaine alone. The results demonstrate that a portion of the basic dynamic effects of cocaine is mediated by stimulation of alpha and beta adrenoceptors. Combined alpha and beta adrenergic blockade reduces the hemodynamic effects of cocaine more than beta blockade alone. During antagonism of the sympathomimetic response of cocaine, direct negative inotropic actions of this drug are unmasked.

Animal work has shown that carvedilol is a nonselective beta-blocking drug. It has a vasodilator action from alpha-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to alpha-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of beta- to alpha-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in alpha-blockade after 1 week of continuous administration.

Electroconvulsive therapy (ECT) under anesthesia is associated with hypertension and tachycardia. The cardiovascular effects of ECT were studied after pre-treatment of 10 patients with esmolol (1.0 mg/kg), fentanyl (1.5 micrograms/kg), labetalol (0.3 mg/kg), lidocaine (1.0 mg/kg), and saline solution (control), using a double-blind, randomized block-design. Each patient received all five pretreatment regimens over the course of five ECT sessions. During control studies, arterial blood pressure and heart rate increased significantly in all patients after ECT (P less than 0.05 and P less than 0.01, respectively). The rate-pressure product increased by an average of 336% +/- 14% (P less than 0.01). There were appreciable individual differences in the cardiovascular response to ECT, independent of pretreatment (P less than 0.01). Pretreatment with esmolol and labetalol significantly reduced the hemodynamic response to ECT, compared with fentanyl, lidocaine, or saline solution (P less than 0.05). Esmolol attenuated arterial blood pressure to a larger extent than did labetalol (P less than 0.05). Compared with saline solution (control), pretreatment with labetalol, fentanyl, or lidocaine significantly reduced seizure duration (P less than 0.05) and increased the frequency with which a second electrical stimulus was required. In contrast, esmolol pretreatment did not significantly affect seizure duration. Esmolol (1 mg/kg), administered 1 min before induction of anesthesia, produced significant amelioration of the cardiovascular response to ECT with minimal effect on seizure duration.

The short-term effect of 0.8 mg/kg of an intravenous bolus of labetalol on maternal and fetal hemodynamics was investigated in ten women with pregnancy-induced hypertension. The maximum effect occurred within 35 minutes after labetalol administration. At that point, the mean arterial pressure had decreased by 18% and there was a slight decrease in maternal heart rate. As to flow velocity waveforms, no significant change was found in mean systolic/diastolic (S/D) ratio of the uterine artery, umbilical artery or fetal middle cerebral artery. However, in two subjects with a marked reduction in blood pressure also the uterine artery S/D ratio decreased.

The effect of a single dose of 200 mg dilevalol, beta-adrenoceptor blocker with additional vasodilating properties, and 200 mg oxprenolol on haemodynamic changes induced by emotional stress have been compared in 12 male young Caucasian patients with newly diagnosed labile hypertension. No difference was noted in the stress-induced increase of total peripheral resistance (TPR) following administration of the two substances (11% versus 6%). However, dilevalol revealed a vasodilating action by decreasing TPR at rest (from 1004 to 951 dyn.s.cm-5) and diastolic blood pressure (BP) (from 87 to 75 mm Hg) whereas TPR at rest remained unchanged after the intake of oxprenolol.

The hemodynamic effects of labetalol and sodium nitroprusside were compared in 19 subjects who became hypertensive at the conclusion of elective carotid endarterectomy. Following randomization and standard anesthetic protocol, treatment was administered when blood pressure exceeded 160 mmHg systolic or 90 mmHg diastolic at the conclusion of surgery. Group 1 subjects (n = 9) received 0.25 mg/kg labetalol in divided doses, followed by repeat doses of 0.50 mg/kg until blood pressure was less than 160/90 mmHg or until they had received 300 mg total dose. Group 2 subjects (n = 10) were started on a nitroprusside infusion at 0.5 micrograms/kg/min, titrated to achieve blood pressure less than 160/90 mmHg, or up to a rate of 6.0 micrograms/kg/min. Data were collected at 15-minute intervals for 12 hours. Analysis with repeated measures analysis of covariance (p less than 0.05) found no significant differences between groups in any measured parameter. A significant time effect was found for both groups. The results suggest that labetalol is an effective alternative to nitroprusside for the management of postoperative hypertension in this patient population. For the majority of such patients, labetalol may be the drug of choice for postendarterectomy hemodynamic control.

Antihypertensive drugs may lower blood pressure through very different mechanisms, initially as well as during chronic use. This article is a review of the immediate hemodynamic changes induced by a beta blocker (visacor), an alpha-receptor blocker (doxazosin), two calcium antagonists (tiapamil and nisoldipine), an angiotensin-converting enzyme inhibitor (perindoprilat), two double-acting compounds (dilevalol and carvedilol), and placebo studied in 126 patients with mild to moderately severe essential hypertension. The patient populations of the different treatment groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure (BP) recording and measurements of cardiac output by cardiogreen, was the same in all studies. All antihypertensive compounds examined induced a rapid reduction in blood pressure both at rest and during exercise, while no significant changes occurred in the placebo group. This review shows the scope of hemodynamic responses, ranging from peripheral vasodilation to a reduction of heart rate and blood flow. Furthermore, different counterregulatory effects blunting the immediate BP reduction are demonstrated.

We describe two studies which investigate the beta 2-agonist properties of dilevalol. We have previously demonstrated, by giving an infusion of terbutaline to human volunteers, that beta 2-stimulation causes a rise in plasma glucose and a fall in plasma potassium. These metabolic effects can be prevented by prior beta-blockade. We now show that infusion of dilevalol produces similar, but quantitatively smaller, metabolic effects at a dose which also produces clinically significant beta-blockade, as judged by a fall in exercise heart rate. This adds support to the claim that dilevalol is a non-selective beta-blocker with selective beta 2-agonist activity.

A new non-imaging echo-Doppler cardiac output device that works on the principle of attenuated compensation volume flow (ACVF), has been used to assess the cardiovascular effects of atenolol and dilevalol in 24 patients with essential hypertension. Compared with the baseline, one month of atenolol reduced systemic mean arterial blood pressure (12 mmHg; P less than 0.01), heart rate (-24 bpm; P less than 0.001), aortic velocity integral (-2.1 cm/sec; P less than 0.01) without a change in cardiac output or systemic vascular resistance. Dilevalol reduced systemic mean arterial pressure (-12 mmHg; P less than 0.01) and heart rate (-13 bpm; P less than 0.01), without a change in cardiac output or aortic velocity integral; systemic vascular resistance fell (-149 dyne/sec; P less than 0.01). Thermography and skin thermal clearance techniques were used to assess the effects of each compound on the peripheral circulation; both compounds reduced skin temperature and thermal clearance but the changes were more marked for atenolol than dilevalol. These results suggest that the mechanism of action of dilevalol is, in part, different from atenolol and would be compatible with a direct vasodilator action on the peripheral vasculature.

Age may influence the response to antihypertensive drug treatment either indirectly, by altering the plasma drug concentrations, or directly, by altering the nature and magnitude of the blood pressure reduction. This study investigates the effect of age on the pharmacokinetics and antihypertensive responses following acute and chronic treatment with dilevalol in 18 patients (age range 28-73 years) with essential hypertension. There were no significant age-related changes in pharmacokinetics for either acute or chronic treatment with dilevalol. Correspondingly, there was no evidence of any age-related difference in the antihypertensive response and, in absolute terms, this was slightly greater in the six oldest patients in whom blood pressure fell by 18/10 mmHg, supine, and 16/8 mmHg, erect, after the first dose of dilevalol, compared to 4/3 and 6/3 mmHg, respectively, in the six youngest patients. When allowance was made for the differences in starting (pretreatment) blood pressure, there was no significant difference in the antihypertensive response of the elderly compared to the young patients. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no age-related differences either in pharmacokinetics or in antihypertensive responsiveness.

Dilevalol, the R-R1 isomer of labetalol, has been shown in animal studies to be a non-selective beta-adrenoceptor antagonist with beta 2-agonist activity and minimal alpha-antagonist activity. This paper describes the results of studies in man which have investigated the dose dependency and selectivity of dilevalol as an adrenoceptor antagonist and demonstrated its lack of alpha-antagonist activity. It also describes the results of studies which have investigated the magnitude of its partial agonist activity and demonstrated the selectivity of the partial agonist activity for the beta 2-adrenoceptor. Oral dilevalol 200 mg reduces an exercise tachycardia by about 25% and 400 mg does not increase the effect. Dilevalol 200 mg had no effect on the rise in blood pressure induced by infusions of phenylephrine, demonstrating its lack of alpha-antagonist activity. The increases in heart rate, systolic blood pressure, forearm blood flow and finger tremor induced by infusions of salbutamol are inhibited by dilevalol 200 and 400 mg and propranolol 80 mg to a similar degree indicating the lack of selectivity of the beta-antagonist activity of dilevalol. The effects of increasing oral doses of dilevalol on sleeping heart rate were used to assess the magnitude of its partial agonist activity. Heart rate four hours after dilevalol 200 and 400 mg was seven beats per minute higher than after placebo. Dilevalol 200 and 400 mg did not alter daytime supine heart rate, blood pressure or cardiac output but did increase forearm blood flow and finger tremor indicating that the partial agonist activity is mainly at the beta 2-adrenoceptor.

The hemodynamic and intrapulmonary shunt effects of intravenous labetalol and nitroprusside were compared during induced hypotension for major spinal surgery. A randomized, double-blind protocol was used in which 20 patients, ASA physical status I or II, received either nitroprusside infusion (n = 10) or labetalol bolus injections of 10 mg every 10 min (n = 10) until mean arterial blood pressure was reduced to 55-60 mm Hg. Pulmonary artery pressures were measured and mixed venous samples obtained via a pulmonary artery catheter. Nitroprusside increased heart rate significantly more than labetalol during the period of hypotension. When compared with prehypotension baseline values, nitroprusside increased heart rate significantly with a concomitant significant decrease in systemic vascular resistance. Cardiac output increased significantly 60 min after hypotension was achieved in patients treated with nitroprusside. Systemic vascular resistance decreased significantly below baseline levels in patients treated with labetalol but without changes in cardiac output, heart rate, or mean pulmonary artery pressure. There was a 122% increase in intrapulmonary shunt with nitroprusside administration, compared with an 11% increase with labetalol. Labetalol was effective for inducing hypotension and was not associated with an increase in heart rate, intrapulmonary shunt, or cardiac output as seen with nitroprusside.

The effects of labetalol and carvedilol on local cutaneous microvascular perfusion and calculated local cutaneous microvascular resistance were investigated in anesthetized rats at submaximal doses that produced equivalent reductions in blood pressure and heart rate. Labetalol decreased cutaneous perfusion (-25% +/- 3%) without significantly affecting cutaneous vascular resistance (-6% +/- 3%). In marked contrast, carvedilol dramatically increased cutaneous perfusion (+64% +/- 9%) and significantly reduced cutaneous vascular resistance (-57% +/- 3%). These results suggest that carvedilol and labetalol possess differences in the mechanisms by which they produce vasodilation in vivo.

Dilevalol is a novel antihypertensive drug that combines nonselective beta blockade with selective beta 2-receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first-pass hepatic extraction. Its elimination half-life of approximately 12 hours allows for once-daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin-converting enzyme inhibitors and comparable to beta blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high-density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

On the hypothesis that the addition of alpha-blockade would mitigate the haemodynamic disadvantages of beta-blockade alone in the early stages of uncomplicated acute myocardial infarction, 15 patients were studied during the intravenous infusion of labetalol (0.5 mg/kg/h). The mean systemic arterial pressure was reduced by an average of 15 mm Hg. In the nine patients haemodynamically evaluated, the cardiac output (thermal dilution) was reduced without change in the heart rate or left heart filling pressure (pulmonary artery occluded pressure); left ventricular stroke work was significantly decreased. The reduction in these major determinants of myocardial oxygen consumption suggests that the combination of alpha- and beta-blockade may be haemodynamically advantageous in normotensive patients in the early stages of uncomplicated acute myocardial infarction.

The acute hemodynamic and humoral responses to intravenous dilevalol (10 to 390 mg) were evaluated in 10 patients with moderate hypertension. Dilevalol, in doses of 30 mg or more, decreased arterial pressure (p less than 0.0001) through a decrease in total peripheral resistance (p less than 0.0001) associated with an increase in stroke volume and cardiac output (p less than 0.0001). Heart rate increased moderately at doses above 190 mg. Plasma norepinephrine levels increased (p less than 0.05), but epinephrine levels remained unchanged. Plasma renin activity and level of atrial natriuretic peptide decreased (p less than 0.01 and p less than 0.01, respectively). The hypotensive and humoral changes persisted 3 hours after the last dose. Dilevalol modified the pattern of hemodynamic response to isometric stress, slightly enhancing the increases in peripheral resistance and blunting increases in cardiac output and heart rate. The response in arterial pressure during administration of dilevalol remained similar to that seen in the pretreatment phase. The results show that dilevalol, when given intravenously in a dose of 30 to 90 mg, reduces arterial pressure by reducing total peripheral resistance without acceleration in heart rate. On the basis of these hemodynamic effects, dilevalol should be further evaluated for treatment of hypertensive emergencies.

The cardinal hemodynamic disturbance in established essential hypertension is an increased total peripheral resistance. Monotherapy with conventional beta-blockers lowers blood pressure usually without any significant fall in total peripheral resistance. Generally, cardiac output is reduced at rest as well as during exercise. In recent years, beta-blockers with vasodilating activity have been developed. Labetalol induces nonselective beta-blockade and in addition reduction in vascular resistance mainly through alpha-blockade. Long-term hemodynamic data indicate gradual normalization of cardiac output, stroke volume, and total peripheral resistance--possibly due to regression of structural changes in the left ventricle and in the arterioles. Prizidilol is a nonselective beta-blocker with a direct vasodilator effect. One year results showed a very marked fall in blood pressure and total peripheral resistance and dramatic increase in posttreatment exercise stroke volume. Cardiac output was unchanged in spite of a reduction in heart rate. Due to side effects, the drug has been withdrawn. Dilevalol, which is the R-R' isomer of labetalol, is also a nonselective beta-blocker, but its vasodilating activity seems to be mainly due to partial beta 2-agonist activity. Preliminary data indicate a reduction in blood pressure--mainly due to a fall in total peripheral resistance. Studies in elderly patients or in patients with reduced left ventricular function seem to indicate that the drug might be used without deterioration of the heart pump function. Although antihypertensive properties of dilevalol have been extensively studied and are defined, the exact position of dilevalol among antihypertensive drugs will be more precisely determined in future studies.

Maximal exercise capacity after control of resting blood pressure with labetalol was studied in nine hypertensive men aged 34 to 69 years (average 52 years). Subjects exercised to exhaustion on an upright cycle ergometer with workload increased as a step function by 25 watts every three minutes, both before and after control of blood pressure was obtained. Mean exercise capacity expressed as total time of exercise until exhaustion was 936 seconds prior to control of the resting blood pressure and 884 seconds (no significant difference) after control of resting blood pressure with labetalol. Double product at peak exercise fell from 254 X 10(2) mm Hg beats per minute prior to blood pressure control to 183 X 10(2) mm Hg beats per minute (p = 0.006) after control of blood pressure with labetalol. The difference in the means of resting heart rate and both peak blood pressure and peak heart rate with exercise were all statistically significant after control of blood pressure with labetalol. These findings suggest that labetalol has an ideal exercise profile affording a cardioprotective effect by decreasing double product but without sacrificing exercise capacity.

Central haemodynamic changes and regional blood flow were studied using the microsphere technique, during labetalol-induced hypotension in dogs anaesthetized with pentobarbitone and fentanyl. Labetalol 15 mg kg-1 decreased mean arterial pressure from an average of 88 mm Hg to 47 mm Hg. Mean pulmonary arterial pressure was unchanged. Cardiac output was reduced by decrease in stroke volume, while heart rate remained unchanged. Myocardial blood flow decreased approximately in parallel with left ventricular work. Perfusion of the brain and kidneys was unchanged.

The effects of a single intravenous bolus of labetalol (0.5 mg/kg) on the cardiovascular, hyperglycaemic and adrenocortical responses to major colonic surgery were studied in five patients. Results were compared with five patients who received the same anaesthetic and had similar operations performed but who did not receive labetalol. It was observed that labetalol reduced the rises in heart rate and rate-pressure product that occur at the time of skin incision but that it did not reduce the rise in mean arterial pressure. The rises in blood glucose and plasma cortisol were significantly less in the labetalol group after 30 minutes of surgery (p less than 0.05).

To simulate increased sympathoadrenal activity adrenaline was infused in normotensive subjects to achieve plasma adrenaline concentrations similar to those seen after myocardial infarction or hypoglycaemia. Adrenaline was infused after pretreatment for five days with labetalol 200 mg twice daily or placebo given in a random order. The rise in systolic blood pressure and the fall in diastolic blood pressure observed after the infusion of adrenaline (0.06 micrograms/kg/min) were prevented by labetalol and no increase in blood pressure was seen. Adrenaline infusion after pretreatment with placebo caused a profound fall in the serum potassium concentration (4.12-3.20 mmol(mEq)/l). Pretreatment with labetalol completely blocked adrenaline induced hypokalaemia (3.92-3.95 mmol(mEq)/l). Adrenaline induced T wave flattening and QTc prolongation were also prevented by labetalol. Thus labetalol can prevent the electrocardiographic, haemodynamic, and hypokalaemic effects of increased circulating adrenaline in man. The combination of alpha and beta blockade appears to be required to block the haemodynamic effects of adrenaline, and labetalol may, therefore, be useful in controlling both the metabolic and circulatory responses during increased sympathoadrenal activity.

The hemodynamic effects of intravenous injection of 1 mg/kg of labetalol were measured in eight healthy volunteers, using impedance cardiography and systolic time intervals. The mean systolic blood pressure was reduced by 10% (p less than 0.01) and diastolic by 6% (p less than 0.05) 30 min after the injection, and they had returned to pre-drug level 2 h after administration. Heart rate declined consistently throughout the observation period. Cardiac index was reduced by 16% (p less than 0.05), but the changes in stroke volume (- 6%) and peripheral resistance (+ 23%) were not statistically significant. Left ventricular ejection time index increased by 2% (p less than 0.05), and nonsignificant changes were found for pre-ejection period index (- 3%), total electromechanical time index (+ 1%), and PEP/LVET ratio (+ 5%). In healthy subjects resting supine the intravenous dose of 1 mg/kg of labetalol had predominantly beta-blocking effects.

1. Labetalol was administered to 18 hypertensive patients for an average duration of 2.44 weeks, with an average final daily dose of 1.65 g. 2. Labetalol decreased resting heart rate by 16% and maximal exercise heart rate by 21%; the phenylephrine-induced rise of systolic brachial artery pressure was reduced by 36%. 3. During labetalol brachial artery pressure was lowered by 29/15 mmHg in the recumbent position, by 41/23 mmHg at rest sitting, and by 53/23 mmHg at maximal exercise; total peripheral resistance was not significantly affected at rest recumbent, but was reduced at sitting and at exercise; cardiac output decreased in all conditions. 4. Labetalol reduced mean pulmonary artery and capillary wedge pressures only in the sitting position. Pulmonary vascular resistance remained unchanged. 5. The drug produced significant decreases of plasma renin activity and of plasma aldosterone concentration.

The acute hemodynamic effects of 50 mg. of the alpha- and beta-receptor blocking agent AH 5158, administered intravenously, on the systemic and pulmonary circulation were studied in 13 hypertensive patients at rest in the supine and erect positions, and during exercise, with right heart and brachial artery catheterization. AH 5158 induced a significant fall of systemic blooc pressures under all conditions, whereas the pulmonary systolic and mean pressures were lower at rest and unaltered during exercise. The left ventricular filling pressure largely remained unchanged. Blood pressure was lowered predominantly by a reduction in systemic vascular resistance together with a reduction in cardiac output. These effects were particularly pronounced in the erect position and during exercise. Cardiac output was lowered solely by the reduction of heart rate; stroke volume was unchanged or even increased. The arterial-mixed venous oxygen difference increased in the erect position and during exercise. The pattern of AH 5158-induced hemodynamic adaptation comprising a reduction of both vascular resistance and cardiac output, without evidence of significant negative inotropic action, offers a novel basis for treating hypertension with a single drug. Its pharmacological and hemodynamic profile suggests considerable potential in the treatment of hypertensive patients.

1 The effect of an intravenous bolus of labetalol (0.6--1.6 mg/kg body weight) on central and peripheral haemodynamics was studied in nine subjects with essential hypertension and in eleven subjects with chronic renal disease and hypertension. 2 The BP reduction amounting to 20/13 mmHg was entirely due to the lowering of the total peripheral vascular resistance. This also included the vascular resistance in the muscles. 3 This peripheral vasodilatation was not counteracted by a reflex increase of the cardiac output. 4 The reflex tachycardia and overshoot of BP in Valsalva's manoeuvre were largely abolished. 5 Central and peripheral venous BPs, vascular volume of the forearm and venous distensibility did not show any significant change after treatment with labetalol. 6 In spite of the lowering of the vascular resistance of the forearm by labetalol, forearm blood flow was not significantly affected due to the parallel decrease in the perfusion pressure. 7 Plasma renin activity fell after labetalol in all instances.

At rest supine acute intravenous administration of the combined adrenergic alpha- and beta-receptor blocking compound labetalol (1 mg/kg body weight) to young, healthy, male subjects, produced a clear-cut fall in arterial blood pressure. During dynamic forearm exercise, forearm blood flow decreased by 17.2%, and calculated vascular resistance increased by 11.3% after labetalol. Forearm oxygen uptake decreased (14.6%), suggesting an increased mechanical efficiency. Lactate release from the exercising forearm decreased (17.6%), probably because of the beta-receptor blockade. Forearm uptake of glucose and free fatty acids remained unchanged. Arterial blood glucose concentration attained a higher level after labetalol. Arterial plasma concentration of FFA was reduced during exercise and post-exercise probably because beta-receptor mediated lipolysis was antagonized.

The cardinal haemodynamic disturbance in established hypertension is an increased total peripheral resistance and a subnormal blood flow, particularly during exercise. The spontaneously occurring changes in central haemodynamics have been followed in young males with essential hypertension over a 17-year period: a gradual increase in total peripheral resistance and blood pressure, and a gradual fall in cardiac output and stroke volume, have been demonstrated. Labetalol is a unique antihypertensive agent which induces both alpha- and beta-blockade. Numerous studies have shown that when labetalol is given intravenously to patients with mild to moderate essential hypertension, blood pressure falls within a few minutes-partly due to reduction in cardiac output and heart rate and partly due to reduction in total peripheral resistance. In most series the average reduction in blood pressure was 17 to 22%, the reduction in total peripheral resistance 11 to 14%, and the reduction in cardiac output 2 to 10%. Thus, the reduction in cardiac output with labetalol is less than that seen after single-dose injection of beta-blockers without intrinsic sympathomimetic activity. After intravenous injection, the blood pressure-lowering effect is most marked in the upright position and during muscular exercise when cardiac output is usually significantly reduced. Labetalol reduces blood pressure in severe hypertension. Intravenous doses of 0.2 to 0.8 mg/kg bodyweight reduce blood pressure by approximately 20%. This hypotensive effect is partly due to a reduction in total peripheral resistance and partly due to a fall in cardiac index. When the reduction in blood pressure is gradual and moderate (less than 20%), it is mainly produced by a reduction in total peripheral resistance. During long term use labetalol induces haemodynamic changes rather similar to those seen after bolus injection. However, during prolonged use there is a tendency to normalisation in cardiac output and stroke volume; the sustained decrease in blood pressure is mainly due to a reduction in total peripheral resistance. In a recent 6-year follow-up study where 15 patients were studied before treatment and after 1 and 6 years on long term labetalol treatment, a tendency to normalisation of central haemodynamics was found. Over the years total peripheral resistance was gradually reduced by 15 to 20% at rest as well as during exercise. Stroke volume gradually increased and after 6 years of treatment was approximately 10% higher than the pretreatment value. This compensated for the reduced heart rate and no significant reduction in cardiac output was seen either during exercise or at rest.(ABSTRACT TRUNCATED AT 400 WORDS)

To investigate the safety of labetalol in the treatment of hypertension in patients with heart failure, sixteen hypertensive patients with a history of congestive heart failure and an ejection fraction at rest less than 45%, had measurements of ejection fraction and cardiac output by first pass radionuclide angiography at baseline, at the end of 2 weeks maintenance with labetalol (titrated to the effective antihypertensive dose of 200-1600 mg daily), and in the post-treatment placebo period. On labetalol, heart rate and blood pressure were significantly lower than placebo at rest and the ejection fraction was higher (30 vs 25%) (p less than 0.05). At maximal exercise on labetalol the heart rate and blood pressure were lower than at placebo maximal exercise (p less than 0.05) and the ejection fraction was higher (32 vs 27%) (p less than 0.01). Exercise tolerance was not changed by labetalol. No patient was discontinued from the study because of worsening heart failure. Dizziness was reported in 5 of 16 patients usually at one visit. Dyspnea that was reported in 4 of 16 patients improved with minor adjustments in digitalis or diuretic dose. In conclusion, labetalol reduces blood pressure in hypertensive patients with left ventricular dysfunction without reducing cardiac performance.

1 Fourteen patients whose lying diastolic blood pressure was persistently 110 mmHg or greater were given labetalol 0.5--1 mg/kg intravenously. 2 The maximum hypotensive effect developed between 20 and 40 min, and on average lasted 3 h. The lying systolic mean blood pressure fell by 30 mmHg and the lying diastolic blood pressure by 17 mmHg (P less than 0.001). 3 This acute hypotensive effect was associated with a significant reduction in the peripheral resistance (P less than 0.02). The hypotension was not associated with significant secondary changes in the stroke volume or pulse rate. 4 The above 14 patients plus 1 additional subject received labetalol orally at a daily dose ranging from 150-2400 mg. The mean lying systolic blood pressure fell by 22 mmHg (P less than0.01) and the mean lying diastolic blood pressure by 26 mmHg (P less than 0.001). The standing values were similar and postural hypotension at this dose did not develop. There was no significant change in the pulse rate. 5 Renal function was monitored by estimates of plasma creatinine and creatinine clearance. Some patients were followed for 2 yr and others for a few months. With the long-term patients, there was no significant reduction in either measurement although in a few patients a slight reduction in creatinine clearance was observed.

The acute haemodynamic effects of beta-blockade with propranolol and combined alpha-blockade and beta-blockade with labetalol were compared in a randomised study in 12 patients with coronary artery disease proved by angiography. Propranolol induced significantly greater depression of left ventricular function both at rest and during exercise than labetalol. This difference was probably attributable to the vasodilator activity of labetalol and the associated reduction in afterload offsetting the haemodynamic disadvantages of blockade of cardiac beta-adrenoceptors alone. The haemodynamic advantages of combined alpha-blockade and beta-blockade over beta-blockade alone may thus have therapeutic implications for the use of these treatments in patients with coronary heart disease.

1 Labetalol at a dose of 800 to 1600 mg daily inhibited isoprenaline-induced tachycardia and phenylephrine-induced elevation in arterial pressure in hypertensive subjects. The beta-adrenoreceptor effect was four times more potent than the alpha-adrenoreceptor effect. 2 Isoprenaline-induced tachycardia was more effectively blocked than isoprenaline-induced inotropism, thereby raising the possibility of a subselective effect on cardiac beta-adrenoceptors. 3 Labetalol reduced blood pressure in hypertensive subjects with no change in cardiac output in the supine or upright position and with marked inhibition of the heart rate and blood pressure response to treadmill exercise. 4 Labetalol administered in single doses to patients with stable, treated congestive heart failure impaired blood pressure support during exercise. 5 The unique adrenoceptor and haemodynamic effects of labetalol make it a potentially attractive drug for management of hypertension and other cardiovascular disorders.