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The beta-adrenoceptor antagonist dilevalol in a total dose of 430 micrograms/kg i.v., potently suppressed isoprenaline-induced increases in heart rate and max LVdP/dt (dose ratios of 42 +/- 6 and 38 +/- 5, respectively, in anesthetized pigs), but a dose of 1430 micrograms/kg did not appreciably modify phenylephrine-induced increases in arterial blood pressure (dose ratio less than 4) in both anesthetized and conscious pigs. The actions of dilevalol on ischemic myocardium of anesthetized pigs were investigated following a reduction of left anterior descending artery flow by 85-90%. Dilevalol (300 micrograms/kg), administered after 15 minutes of ischemia, did not affect the ischemia-induced changes in systemic hemodynamics (such as heart rate, max LVdP/dt and cardiac output), myocardial perfusion, and wall-thickening of the ischemic segment during the following 15 minutes of ischemia and 2 hours of reperfusion. The reasons for the lack of antiischemic actions are most likely the absence of negative chronotropy and an absence of afterload reduction by dilevalol.

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with cimetidine administration (58.7 +/- 23.3 to 32.9 +/- 13.2 ml/min/kg; p less than 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 +/- 5.3 to 17.7 +/- 3.7 ml/min/kg; p less than 0.05), but the volume of distribution was unchanged. Labetalol caused significant beta-blockade for 8 hours after the last oral dose, but cimetidine did not alter pharmacologic response. The Emax model provided a good description of the concentration-effect relationship. At peak labetalol concentrations after oral administration, (R,R)-labetalol concentrations were significantly lower than those of the other three stereoisomers (p less than 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p less than 0.05) for only the (S,R)-, (S,S)-, and (R,S)-isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)-labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)-labetalol.

The effects of dilevalol on vascular adrenoceptors were investigated using helical strips of cat arteries. In coronary arteries partially pre-contracted with prostaglandin F2 alpha (PGF2 alpha), the concentration-relaxant response curves for isoproterenol were shifted to the right by dilevalol with a potency similar to that of propranolol, although dilevalol itself did not relax the arteries. Contractions induced by norepinephrine of mesenteric arteries were attenuated by low concentrations of prazosin but were not influenced by yohimbine of up to 10(-8) M. In contrast, the norepinephrine-induced contractions of middle cerebral arteries were attenuated by yohimbine but only slightly attenuated by prazosin. With mesenteric arteries, treatment with dilevalol (10(-7) to 10(-5) M) attenuated the contractions induced by norepinephrine and phenylephrine in a concentration-dependent manner. On the other hand, contractions induced by norepinephrine and clonidine in middle cerebral arteries were not attenuated by treatment with dilevalol of up to 10(-6) M. Treatment with low concentrations of dilevalol (10(-8) to 10(-7) M) potentiated the contractile response to the electrical stimulation of adrenergic nerves in mesenteric arteries while high concentrations (3 x 10(-7) to 10(-5) M) attenuated it. The potentiation was reversed to attenuation by pretreatment with propranolol. Treatment with isoproterenol (10(-10) to 10(-9) M) also potentiated the contractile response to the electrical stimulation in the arteries. Isoproterenol did not cause any relaxation of mesenteric arteries precontracted with PGF2 alpha. Attenuations by clonidine of the response to the electrical stimulation in the arteries did not significantly differ in control arteries and those treated with a high concentration (10(-6) M) of dilevalol.(ABSTRACT TRUNCATED AT 250 WORDS)

The alpha, beta-adrenergic blocking, antihypertensive and vasodilating properties of N-1518 were compared with those of labetalol. N-1518 blocked alpha- and beta-adrenoceptors competitively as indicated by parallel rightward displacement of the dose-response curve of each agonist in isolated organs and in anesthetized dogs. As judged by pA2 values and DR10 values, N-1518 was as potent as labetalol in blocking alpha- and beta-adrenoceptors. The beta 1/alpha 1 ratio of N-1518 was 8.3 for pA2 values in isolated organs and 13.6 for DR10 values in anesthetized dogs, respectively. N-1518 inhibited dose-dependently the pressor response to intravenous administration of noradrenaline, but labetalol did not depress the response to noradrenaline in anesthetized dogs. N-1518 is composed of four optical isomers. The SR-isomer was the most potent in blocking beta-receptors, and the RR-isomer was the most potent in blocking alpha-receptors. N-1518 has no intrinsic sympathomimetic activity in reserpinized rats and has no local anesthetic activity in guinea pigs. Single oral administration of N-1518 produced a fall in blood pressure in conscious SHR and renal hypertensive dogs without causing tachycardia. Intra-arterially administered N-1518 in the dog hindlimb resulted in vasodilation as indicated by the increase in blood flow. The magnitude of the responses was approximately 3 times more potent than that of labetalol.

Antihypertensive medication has been reported to cause serious sexual side effects in men. Frequently mentioned as causing sexual dysfunction are beta-adrenergic receptor antagonists. The purpose of this study was to examine in detail the effects of beta blockers on adult male rat sexual behavior. Thirty minutes following a single subcutaneous injection of propranolol, pindolol, atenolol or labetalol, mating tests were conducted. The mixed beta 1- and beta 2-adrenergic antagonists, propranolol and pindolol, profoundly inhibited male sexual behavior. At the 5 and 10 mg/kg doses, propranolol inhibited ejaculatory behavior to the extent that only 9.1 and 8.3% respectively showed the behavior while pindolol reduced this behavior to 36.4% (16 mg/kg). These drugs also adversely affected various parameters of behavior in a dose-dependent manner. The selective beta 1 antagonist, atenolol, had only minor effects and labetalol even less so at the doses tested. It was suggested that the strongly inhibitory effects of propranolol and pindolol on male rat sex behavior may well be due to their 5-HT1A antagonistic binding properties rather than their beta-antagonistic properties.

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.

1. The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs. 2. Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg-1 90 min-1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3 mg kg-1 and up to 30 min after 3 mg kg-1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg-1 but was not significantly altered after 1 mg kg-1 labetalol. 3. Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV-conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD-area. With the exception of the alterations in the PQ interval and 2:1 AV-conduction point the effects described above were dose-dependent. 4. Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg-1). 5. The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.

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.

Effects of arotinolol, a combined alpha- and beta-adrenoceptor blocking agent, on regional myocardial dysfunction produced by severe coronary stenosis in anesthetized dogs were examined and compared with those of labetalol and propranolol. Doses of these three antagonists were selected to produce a comparable degree of the negative chrono- and inotropic effect but a different potency of alpha-adrenoceptor blockade (labetalol greater than arotinolol). Regional myocardial function measured as segment shortening (%SS) was decreased to around 2-3% by constriction of the left circumflex coronary artery (LCX), and then drug or saline was administered i.v. The stenosis of LCX was released 30 min after the administration. No significant alteration in hemodynamic and contractility parameters was seen as compared to the predrug value up to at least 30 min after saline i.v. Arotinolol and propranolol both reduced heart rate and peak positive left ventricular dP/dt (LVdP/dt) without a significant change in LCX flow. Concomitantly, %SS distal to a coronary stenosis was significantly improved by arotinolol and propranolol. On the other hand, labetalol significantly reduced LCX flow probably due to systemic hypotension and failed to improve %SS in the ischemic area, although the agent markedly decreased heart rate and LVdP/dt. These results indicate that arotinolol improves impaired regional myocardial function distal to a coronary stenosis in a similar manner with propranolol.

The efficacy, tolerability and safety of dilevalol in essential hypertension has been documented in an international clinical trials programme which was conducted with doses up to 1600mg daily. Initial double-blind trials confirmed the superiority of dilevalol over placebo in essential hypertensive patients and documented the suitability of a once-daily dosage. Almost all of the subsequent trials have been randomised, double-blind comparative trials of dilevalol versus established anti-hypertensive agents with the duration of treatment ranging from four weeks up to one year. The recommended dosage range of dilevalol, of 200-400 mg once-daily, has generally been shown to be at least as effective at lowering raised blood pressure as established antihypertensive agents given according to their recommended doses. In one study in elderly hypertensives, dilevalol was significantly more effective than atenolol in lowering systolic blood pressure. Safety data is available from a consolidated database of 2011 dilevalol-treated patients representing over 500 patient-years exposure. Overall, dilevalol was well tolerated and evidence of dose-related adverse effects became apparent only for nausea and dizziness above the recommended dose range. The most common adverse effects considered probably or definitely related to treatment were fatigue (2.5%), nausea (1.9%), headache (1.8%) and dizziness (1.7%). 'Typical' beta-blocker adverse effects were observed, though many of these effects were less frequent than seen with comparator beta-blockers. Evidence of excessive vasodilation was rarely found, consistent with the counter-balancing effect of beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

A 31-year-old man being treated for asthma accidently received 3 mg SQ epinephrine. He began retching and vomiting and developed agitation and profuse diaphoresis. He was treated with 5 mg IV labetalol. His symptoms improved significantly, and he required no further treatment. Although he felt a transient increase in his respiratory effort shortly after administration of the drug, he did not develop wheezing or require additional therapy for bronchospasm. The beta-blocking effect of labetalol is greater than the alpha antagonism. The patient exhibited evidence of mild alpha stimulation due to incomplete blockade. This is consistent with previous studies in that labetalol tends to less completely antagonize the alpha effects of a mixed alpha/beta agonist, resulting in a net clinical picture of mild alpha agonism.

Dilevalol, 100 mg, 200 mg and 400 mg, and placebo were given to eight normal volunteers and the effect on blood pressure and heart rate studied at rest and on exercise. There was a dose-dependent fall in exercising heart rate and in the increased heart rate on exercise with dilevalol, while exercising systolic blood pressure and the rise in systolic blood pressure on exercise fell dose-dependently up to 200 mg, but the effect of 400 mg was similar. Diastolic blood pressure was not affected. Supine heart rate and blood pressure changes were not different from placebo. Tilt heart rate fell most constantly from 200 mg. Some fall in tilt systolic blood pressure was seen but this was not dose-dependent, diastolic blood pressure was not affected. There was wide variation in plasma concentration of dilevalol, as might be expected from a liver metabolised drug, with a relatively larger amount absorbed of the 400 mg dose compared to the 100 or 200 mg doses.

The beta 1- and beta 2-adrenoceptor agonist effects of dilevalol on human heart tissue were studied in vitro. The receptors were studied independently of one another through the use of selective antagonists. Human right atrial appendages were generally cut into four strips which were then set up in parallel in an organ bath system. All tissues were incubated either with 300 nM CGP 20712A to block beta 1-adrenoceptors, or with 50 nM ICI 118551, to block beta 2-adrenoceptors. Alpha-adrenoceptors and tissue uptake of catecholamines were blocked using 5 microM phenoxybenzamine. The atrial strips from one patient were then exposed either to vehicle or to cumulative additions of dilevalol, (+)- pindolol or salbutamol (10(-8) to 10(-5) M) and the resulting force of contraction was expressed as a percentage of the inotropic response obtained with a saturating dose of (-)-isoprenaline. The beta-antagonist effects of the three substances were also studied, by running a dose-response curve to noradrenaline or adrenaline as appropriate following the addition of the substance of interest. Neither dilevalol nor (+)-pindolol had any intrinsic sympathomimetic activity at the atrial beta 1- or beta 2-adrenoceptors. Both dilevalol and (+)-pindolol caused marked antagonism of the atrial beta-adrenoceptors. They caused similar blockade of the beta 2-adrenoceptors but not of the beta 1-adrenoceptors.

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.

Adrenoceptor antagonists are being used increasingly for the treatment of pregnancy-induced hypertension (PIH). Previous studies have shown that these drugs can inhibit platelet aggregation and thromboxane production. The aims of this study were to determine (i) whether adrenoceptor antagonists had any effect on vascular prostacyclin (PGI2) production and (ii) whether these drugs acted synergistically with PGI2 and the PGI2-like activity derived from umbilical artery to inhibit platelet aggregation in vitro. The adrenoceptor antagonists labetalol, pindolol and propranolol were found to have no effect on PGI2 production from the umbilical artery at low drug concentrations. These agents were also found to act synergistically with both pure PGI2 and PGI2-like activity derived from umbilical artery to inhibit platelet aggregation. This synergistic effect may be beneficial in the treatment of disorders which are associated with reduced PGI2 production, such as PIH where such synergy may help compensate for PGI2 deficiency.

Alterations in myocardial mechanics and left ventricular myosin isoenzymes by long-term treatment of hypertension with arotinolol were examined in spontaneously hypertensive rats. Approximately 20 mg/kg/day arotinolol was administered to 22-week-old male spontaneously hypertensive rats for 8-10 weeks. There was no significant difference in systolic blood pressure between arotinolol-treated and untreated rats. However, ventricular weight tended to decrease in the arotinolol-treated group, although not significantly. There were no significant differences in isometric developed tension and dT/dtmax of isolated left ventricular papillary muscles between the arotinolol-treated and untreated groups. The left ventricular myosin isoenzyme pattern, on the other hand, obtained by pyrophosphate gel electrophoresis, showed a significant shift toward VM-1 as a result of long-term arotinolol treatment.

The antihypertensive agent dilevalol, a stereoisomer of labetalol, causes vasodilatation by combined beta-adrenergic blockade and direct beta 2-receptor agonism. The acute effect of a single oral dose of 400 mg dilevalol on cerebral blood flow (CBF), and its response to induced changes in arterial carbon dioxide tension (PaCO2), and the cerebral metabolic rate of oxygen (CMRO2) were studied after 1, 2, and 4 h in eight normotensive volunteers. Serum dilevalol 2 h after oral intake ranged between 22 and 49 ng/ml. Mean arterial blood pressure was reduced from 93 +/- 8 to 86 +/- 8 mm Hg (p less than 0.01). An analysis of variance of the successive differences of CBF during the study showed that dilevalol altered CBF significantly. After 1 h CBF had decreased by 4.4% (p less than 0.05), whereas the 2 and 4 h values were similar to the pretreatment level. CMRO2 showed a tendency for reduction (p = 0.086). The CBF response to changes in PaCO2 remained unchanged. It is concluded that a single dose of dilevalol induces a slight and short-lasting decrease in CBF, probably due to a direct effect on brain metabolism.

The aim of this study was to compare the effect of dilevalol and captopril on blood pressure and heart rate in hypertensive subjects, both at rest and during bicycle exercise. Thirty mild hypertensive patients (24 men, 6 women), aged 34-55, were studied in a randomized, double-blind, parallel group trial. After a 3-week placebo run-in, patients were randomized to receive either dilevalol (200 mg once daily) or captopril (50 mg twice daily) for 4 weeks. Dilevalol-treated patients whose diastolic blood pressure had not decreased by more than 8 mmHg from baseline (or to less than 95 mmHg) were given 400 mg once daily for a further 2 weeks. Treatment was stopped for all other patients. Blood pressure and heart rate were measured at rest and during bicycle exercise tests 4 ("peak") and 24 hours ("trough") after dosing in the dilevalol group and 4 ("peak") and 12 hours ("trough") after dosing in the captopril group. At the end of the placebo run-in, mean resting blood pressure was 156/102 mmHg in the dilevalol group and 157/103 in the captopril group. Six patients had blood pressure normalization with captopril and 9 with dilevalol 200 mg; a further 2 patients achieved normalized blood pressure levels with dilevalol 400 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10-minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 +/- 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.2 +/- 0.8 (N = 5) and 75.9 +/- 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty-five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion-induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.

1. A single oral dose of dilevalol (200 mg or 400 mg) or placebo was administered to 15 normal male volunteers in a double-blind, random order crossover study. 2. Dilevalol had no significant effect on supine blood pressures or heart rates, but caused a significant fall in systolic blood pressure 1 and 30 min following standing, and attenuated the rise in diastolic blood pressure and heart rate that accompanies standing. 3. Dilevalol caused a dose dependent increase in plasma noradrenaline levels from arterialized blood which was due to an increase in noradrenaline spillover with no change in clearance. 4. Dilevalol increased plasma levels of the noradrenaline metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) (which is formed in sympathetic nerves following neuronal uptake of noradrenaline), indicating that the increase in noradrenaline spillover was not due to the blockade of neuronal uptake. 5. Acute dilevalol administration had no effect on total plasma cholesterol, HDL-cholesterol or LDL-cholesterol levels.

The effects of labetalol and carvedilol and 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.

Stereoisomers of bioactive products, particularly drugs and pesticides, usually differ greatly in their biological properties. Usually only one of the enantiomers, the eutomer, is largely responsible for the therapeutic action. The distomer, the "isomeric ballast", must be considered an impurity which often contributes to, or is even the main cause of, the undesired actions of the racemate. A fundamental requirement is to "reduce the xenobiotic load" to the feasible minimum. This implies "avoiding isomeric ballast". The implications of the use of racemic products are largely ignored in scientific publications and in the marketing of drugs and pesticides. The problem is illustrated by the results of pharmacological investigations into the racemic drugs labetalol and medroxalol.

Dilevalol, the RR-stereoisomer of labetalol, is a non-cardioselective beta-adrenoceptor antagonist with substantial partial beta 2-agonist and negligible alpha 1-blocking activity. Reduction in blood pressure during dilevalol administration is associated with peripheral vasodilatation, and heart rate remains essentially unchanged. Following oral administration, dilevalol is completely absorbed. Once-daily administration is possible, due to a long elimination half-life. Large well-controlled trials reveal that dilevalol is equivalent in antihypertensive efficacy to metoprolol, the ACE inhibitors captopril and enalapril, and the calcium antagonist nifedipine. Smaller noncomparative and comparative trials demonstrate the blood pressure-lowering effects of dilevalol and suggest an efficacy at least equivalent to that of the 'pure' beta-blockers atenolol and propranolol and the alpha 1-blockers urapidil and doxazosin. Dilevalol appears to be well tolerated, the most frequent adverse effects being dizziness, headache and diarrhoea in only about 7% of patients each. Unlike alpha 1-blockers and labetalol, dilevalol is not commonly associated with orthostatic hypotension. Thus, data suggest that dilevalol, with its distinctive pharmacological profile, is likely to be a useful addition to the options currently available for treating patients with mild to moderate essential hypertension.

A number of in vivo studies suggest that hypothalamic somatostatin (SRIF) tone is stimulated by the beta-adrenergic system. Employing dispersed adult male rat hypothalamic cells, we studied the effects of beta-adrenergic antagonists on the release of hypothalamic SRIF. Propranolol, at concentrations of 1-100 microM, had no detectable effect on basal SRIF release, but caused dose-dependent inhibition of SRIF release stimulated by ouabain. Two other beta-adrenergic antagonists, labetolol and metoprolol, also caused inhibition of ouabain-stimulated SRIF release. The alpha 2-agonist clonidine was without effect on SRIF release under basal or stimulated conditions. GH secretion from monolayers of dispersed rat anterior pituitary cells was also examined. Propranolol (1-100 microM) had no significant effect on basal GH secretion or GH secretion stimulated by rat GRF. In conclusion, 1) beta-adrenergic antagonists caused inhibition of stimulated SRIF release; 2) clonidine had no detectable effect on SRIF release; and 3) propranolol did not affect GH secretion in vitro. These findings support the hypothesis that beta-adrenergic antagonists augment GH responsivity by inhibiting hypothalamic SRIF release.

1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta-adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol.

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.

Left ventricular diastolic filling was investigated in 12 black and 15 white subjects before and after double-blinded randomized treatment of mild to moderate hypertension with combined alpha- and beta-adrenergic receptor blockade (labetalol) and beta-blockade alone (atenolol). At baseline (off medication), both groups were similar for age (46 +/- 8 years v 48 +/- 12 years), mean blood pressure (121 +/- 8 mm Hg v 115 +/- 8 mm Hg), left ventricular dimensions, left ventricular mass index (118 +/- 24 g/m2 v 113 +/- 13 g/m2), and left ventricular filling as reflected by transmitral flow velocity ratio A/E (0.97 +/- 0.33 v 0.92 +/- 0.19, normal age-matched control A/E ratio is 0.64 +/- 14). There were 6 blacks and 6 whites in the labetalol group; 6 blacks and 9 whites in the atenolol group. At six weeks of treatment, whites in the labetalol group showed a significantly greater drop in mean blood pressure (114 +/- 7/102 +/- 11, P less than .007 v 123 +/- 9/114 +/- 11, P = NS) and correspondingly greater improvement in A/E ratio (1.04 +/- 0.14/0.74 +/- 0.23, P less than .024 v 1.02 +/- 0.23/0.89 +/- 0.16, P = NS). However, this difference was no longer significant when controlling for age and blood pressure level. In the atenolol group, whites showed a significant increase in the rapid filling phase velocity E, while late filling phase velocity A significantly dropped only in blacks, without significant improvement in A/E ratio in either subgroup. In conclusion, greater improvement in left ventricular filling is seen with combined alpha-beta-blockade than beta-blockade alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Several physiologic changes accompany the aging process and may alter the pharmacokinetics and pharmacodynamics of drugs given to elderly patients. The primary purpose of the present investigation was to compare the pharmacokinetics of labetalol in young and elderly hypertensive patients. Limited data regarding the pharmacodynamics of labetalol in each of these age groups were also evaluated. Ten young (age 32-48 yrs) and nine elderly (age 60-68 yrs) patients with essential hypertension were evaluated after the first and last doses of a 15-day regimen of labetalol. The young group received 200 mg orally at 9:00 P.M. and 9:00 A.M.; the elderly group received 200 mg once daily at 9:00 P.M. No significant differences in the mean (SD) apparent oral clearance of the drug existed between groups after the first [4.8 (1.9) and 4.3 (1.2) L/hr/kg] and final [4.4 (2.2) and 3.4 (1.0) L/hr/kg] doses of labetalol. No changes in any pharmacokinetic values for labetalol were detected as a function of age. Changes in standing blood pressure and heart rate after the first and last doses were generally similar between the young and elderly hypertensives. Labetalol was effective and well tolerated in both groups.

The effects of the novel antihypertensive agent, carvedilol, on renal hemodynamics and excretory function have been investigated and compared with the effects of labetalol in conscious, spontaneously hypertensive rats. Sustained intravenous infusion of carvedilol or labetalol at a rate of 10 micrograms/kg/min resulted in a significant decrease in blood pressure which was equivalent in magnitude for both drugs. Carvedilol had no effect on renal hemodynamic parameters; glomerular filtration rate, renal blood flow, and filtration fraction were unchanged. In contrast, labetalol decreased the glomerular filtration rate by 13% (p less than 0.01) and the filtration fraction was reduced from 28 to 24%. Inasmuch as renal blood flow was unchanged and perfusion pressure was reduced, both compounds decreased renal vascular resistance. Urine flow decreased and osmolality increased with both carvedilol and labetalol. However, excretion of electrolytes was affected differently with the two compounds. While sodium and potassium excretion were significantly decreased with labetalol, sodium and potassium excretion remained stable during carvedilol infusion, which represents an important beneficial effect for a potent systemic vasodilator. We conclude, therefore, that carvedilol does not compromise the renal autoregulatory integrity in hypertensive rats, and that the antihypertensive activity of the compound is associated with an apparent 'renal sparing' effect, in that the decrease in blood pressure does not compromise the urinary excretion of sodium.

1 The anti-hypertensive effects of labetalol have been compared and contrasted with other groups of anti-hypertensive drugs in this review of the published literature. 2 The data show that the pharmacological and haemodynamic profile of labetalol in man is distinctly different from that of other specific anti-hypertensive agents; namely the properties of competitive alpha-and beta-adrenoceptor blockade leading to haemodynamic effects of reduced blood pressure and peripheral vascular resistance with little accompanying changes in resting heart rate or cardiac output. 3 The anti-hypertensive effects of labetalol are dose related. In fixed dose comparative studies equivalent anti-hypertensive effects to those of labetalol have been shown for individual drugs of the beta-adrenoceptor-blocking and diuretic groups. In dose titration studies, equivalent anti-hypertensive effects at given doses of labetalol have been demonstrated for drugs of the following types: beta-adrenoceptor blockers, beta-blockers plus diuretics, methyldopa, adrenergic neurone blockers and the combination of beta-blockers plus a peripheral vasodilator. 4 Comparing side-effect liabilities, it is clear that quantitatively labetalol produces no greater burden of side-effects than drugs of the beta-adrenoceptor-blocking group. Qualitative differences, however, do exist; in particular, symptomatic postural hypotension is dose related and is more likely to occur when excessive doses (greater than 2 g daily) are used.

beta-Adrenergic blockade after single, oral doses of labetalol or propranolol was evaluated in a double-blind, placebo-controlled study by an isoproterenol sensitivity test and handgrip exercise in 10 healthy men. The tests were performed with subjects resting in a supine position. At the doses used, there was no effect on heart rate and blood pressure in either the resting position or in the isometric exercise phase. It is possible that exercise-induced changes in blood pressure and heart rate were reduced by higher vagal tone in this young group tested in the supine position. Isoproterenol increased heart rate and reduced diastolic blood pressure in a dose-dependent manner. The dose of isoproterenol at which heart rate increased 25 bpm above the resting rate (CD25; 1.36 +/- 0.18 microgram) was of the order of that at which diastolic blood pressure fell 25 mm Hg from baseline (HD25; 1.07 +/- 0.07 microgram). There was a significant positive correlation between CD25 and HD25 in the 10 subjects. Propranolol and labetalol induced a dose-dependent, parallel shift to the right in the dose-response curves of isoproterenol effects on heart rate and diastolic blood pressure, indicating that both drugs are nonselective, competitive antagonists of beta-adrenergic receptors. On the average, propranolol was 17 and 19 times more potent than labetalol in antagonizing the chronotropic and hypotensive actions of isoproterenol, respectively.

Acute hypotensive effects and the mechanisms of three beta-adrenergic blocking drugs with alpha-blocking activity were studied in comparison with those of prazosin, propranolol and hydralazine in the conscious spontaneously hypertensive rat (SHR). Prazosin lowered the blood pressure dose-dependently and inhibited the pressor response to phenylephrine. Three beta-adrenergic blocking drugs with alpha-blocking activity, labetalol (30 mg/kg), arotinolol (100 mg/kg) and nipradilol (100 mg/kg) also lowered the blood pressure to the same extent as prazosin (0.3 mg/kg), but the inhibition of the pressor response to phenylephrine produced by them was disproportionately slight. Propranolol (100 mg/kg) did not lower the blood pressure. These results suggest that the acute hypotensive effects of three beta-adrenergic blocking drugs with alpha-blocking activity were attributable only partially to the alpha-adrenergic blocking effect; a mechanism or mechanisms other than the alpha-adrenergic blocking effect must be invoked to explain the acute hypotensive effect produced by lower doses of these drugs in the conscious SHR.

In an observer-blind, randomised cross-over trial, in 12 patients, the effects on the peripheral circulation of antihypertensive doses of atenolol, labetalol and propranolol and placebo were compared. After a placebo period of at least 4 weeks, patients were allocated at random to one of the three active drug treatments. After active treatment for at least 6 weeks and a fall in diastolic pressure (DP) to less than 90 mmHg subjects were switched to the next medication. At the end of each period, photo-electric plethysmography (PHELP) was done on all fingers of one hand cooled over 4 min in water in steps of 3 degrees C from 33 degrees to 12 degrees C, and subsequently warmed in room air (20 degrees C) for a period of 10 min. Blood flow changes during cooling were expressed as a percentage of the initial PHELP value (% PHELP). Areas under the curves, representing the % PHELP/cooling period and % PHELP/warming-up period, showed that within the temperature range normally encountered in daily life, labetalol preserved finger blood flow significantly better than propranolol and marginally better than placebo. With atenolol, finger blood flow was not significantly different from that during the three other regimens, but there were significantly fewer other side-effects. It is concluded that labetalol may be the drug of choice for hypertensive patients treated with beta-blocking agents whose peripheral arterial circulation seems inadequate at low temperatures.

The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half-life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2-3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration-hypotensive effect relationship was described for each drug.

Adrenaline was infused into normal volunteers to produce plasma adrenaline levels similar to those found in acute myocardial infarction. These infusions were performed after pretreatment with labetalol or placebo. Adrenaline produced an increase in systolic blood pressure, a decrease in diastolic blood pressure and an increase in heart rate. All of these haemodynamic effects were blocked by labetalol. In particular, no increase in diastolic blood pressure was seen as occurs during increased sympatho-adrenal activity in the presence of non-sensitive beta-blockade. Thus labetalol maintains a different haemodynamic profile from non-selective beta-blockade during increased sympatho-adrenal activity.

The hemodynamic pattern in hypertension varies according to the age of the subject and the stage of the hypertensive disorder. In the early stage, both cardiac output and systemic vascular resistance tend to be elevated. Already at that stage, mild degrees of left ventricular function disturbance can be detected. Advanced stages are characterized by a hypokinetic type of circulation with subnormal cardiac output and considerably increased systemic vascular resistance. Both cardioselective and nonselective beta-receptor antagonists lower cardiac output and tend to raise systemic vascular resistance. Even left ventricular filling pressures tend to be higher. While these effects are most distinct in the acute experiment, cardiac output remains always depressed and systemic vascular resistance stabilizes often at a higher level, compared with pretreatment values, even during long-term therapy. The antihypertensive action of beta-receptor blockers appears to be mainly due to the reduction of cardiac output. Combined alpha--beta-adrenergic blockade lowers blood pressure predominantly by alpha-adrenoceptor-mediated reduction of systemic vascular resistance both when induced acutely and during long-term administration. Owing to its beta-adrenoceptor blocking component, the increase of cardiac output is abolished: cardiac output is maintained at pretreatment levels, as is left ventricular filling pressure. Since a well-balanced blockade of both alpha- and beta-adrenergic receptors counteracts the hemodynamic changes occurring in the course of hypertension and tends to restore cardiovascular dynamics towards normal, combined alpha--beta-adrenoceptor blockade appears to be one of the most logical and rational therapeutical approaches to hypertension.

The ocular effects in rabbits of topically applied labetalol hydrochloride, a new alpha- and beta-adrenergic receptor blocking agent, were studied. A dose-related reduction in intraocular pressure (IOP) followed treatment with 0.01% to 1% solutions. Labetalol at a 1% concentration had no effect on pupil diameter. The same dose blocked an increase in IOP after water loading but did not significantly alter the coefficient of aqueous outflow facility. Mydriasis induced by phenylephrine hydrochloride was competitively inhibited.

The usefulness of labetalol, a combined alpha and beta adrenoceptor antagonist, as a moderate hypotensive agent during combination anaesthesia in otological operations was studied. These preliminary results show that an intravenous dose of 2.0 mg/kg of body weight of labetalol causes a moderate decrease in blood pressure without a concomitant increase in heart rate or excessive hypotension. The half-life of the elimination phase of labetalol in plasma varied between 3.9 and 6.3 hours. A direct relationship between the intravenous dose of the drug (0.5, 1.0 and 2.0 mg/kg i.v.) and the increase in the AUC value was observed. No correlation was found between the decrease in either the systolic or diastolic blood pressure and the plasma level of labetalol. This new type of antagonist may possess advantages over other current hypotensive drugs, i.e lack of tachycardia and excessive hypotension.

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.