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Persistant myocardial propanolol levels in man
T~JE!SLJAY,MARCH 17, 1991 PM PHARMACOLOGY: ADRENERGIC 2:00-3:30
THE EFFECTS OF MODERATE AND HIGH DOSE PROPRANOLOL ON VENTRICULAR FUNCTION IN PATIENTS WITH CORONARY ARTERY DISEASE Kenneth G. Morris, MD, Sebastian T. Palmeri, MD, R. Edward Coleman, MD, David Shand, MD, Frederick R. Cobb, MD, Duke University and VA Medical Centers,-Durham, North Carolina
BLOCKING AGENTS
LABE'IALOI.THERAPY IN ANGINA PECTORIS AND SYSTEMIC HYPERTENSION: EFFECTS OF COMBINED ALPHA-BETA ADRENERGIC BLOCKAIJE William H.Frishman, MD,FACC; Marc Kirschner, MD; Joel Strom, MD; Neal Klein, MD; Stanley Halprin, MD; Susan Goldner; Thierry LeJemtel, MD; Marcia Poland, BA; Michael Kram, BA; Roger Strair, PhD; Edmund H. Sonnenblick, MD, FAX, Albert Einstein College of Medicine, Bronx, N.Y. The effects of oral labetalol (L), an alpha-beta adrenoceptor blocker, were evaluated in 10 patients (pts) with angina pectoris and h:Tpertension. After 3 weeks of placebo (Pl), increasing doses of L (300-1,200 mg/day) were given over 4 weeks followed by a rapid drug withdrawal phase. Angina1 attack frequency and exercise tolerance (treadmill) were measured; also assessed were non-invasive indices of LV function (echo, systolic time intervals), plasma renin activity (PRA) and platelet function (aggregability). Compared to pl, the frequency of angina attacks/week was reduced with L; exercise time increased from 4.1+1.0 to 6.3+ 0.5 min, ~~0.01. L lowered resting supine (sup7 and standing blood pressure (BP) and heart rate (HR) in allpts; sup systolic BP 154.5+6.1 to 121.5+7.9 mmHg, p
REDUCTION OF MYOCARDIAL ISCHEMIA BY BALANCED ALPHA AND BETA BLOCKADE WITH LABETALOL Dietmar H. Glogar, M.D.; Robert A. Kloner, M.D., Ph.D.; Harvard Med. School/Peter B. Brigham Hosp., Boston, MA It is known that beta blockade decreases blood flow to ischemic myocardium, but it is unknown whether this effect, which may be related to unopposed alpha stimulation, can be counteracted Labetalol (LAB) offers the opporby additional alpha blockade. tunity to study both types of blockade since it has been shown to block predominantly beta receptors at 0.5 mg/kg (LAB I) and both alpha and beta receptors at 5.0 mg/kg (LAB II). Therefore, 28 anesthetized dogs received left anterior descending coronary artery occlusions. After 15 min of occlusion 7 dogs received a 5 min bolus of LAB I, 7 dogs LAB II, 14 control dogs normal saline (NS). The myocardium at risk of necrosis (MR) was determined before the intervention by an autoradiographic technique (MR I) and also at 6 hours of occlusion by Thioflavin S (MR II). Infarct size (IS) in percent left ventricle below occlusion (%LV) was determined by triphenyltetrazoiium chloride stain. Regional myocardial blood flow (RMBF) was measured by microspheres before and I5 min following therapy. In LAB II vs. NS IS (%LV) was smaller (24+3 vs 30+2 respectively, p < 0.051, while MR I (%LVI was not different (30+2 vs 31+2, p=n.s.) Only 79+6% of MR I were infarcted in LAB II treated dogs vs 98f4% in NS (p< 0.01). Furthermore, RMBF immediately adjacent to the infarct increased from 0.61+0.05ml/min/g before to 0.80+0.07 mI/min/g following treatment (p< 0.05) leading to a reduction of the MR. In LAB I RMBF was decreased by the intervention from 0.60: 0.07 ml/min/g to 0.48+0.04 ml/min/g, while no significant effect Thus, the combination of alpha and beta on IS was observed. blockade achieved by high dose labetalol (LAB II) improved Also, LAB coronary blood flow to the ischemic myocardium. decreased IS. This indicates that balanced alpha and beta blockade reached with high dose LAB may overcome secondary vasoconstriction observed in predominant beta receptor blockade.
430
February 1981
The American Journal of CARDIOLOGY
Effects of moderate(l60 mg/d) and high dose(480 mg/d) propranolol(P) on rest(R) and exercise(Ex) left ventricular(LV) function were determined in 14 patients with symptomatic CAD. LV function was measured by multigated radionuclide angiography(RNA) in the upright position at control and after 2 weeks on each dose. Measurements included heart rate-pressure product(R*P), ejection fraction(EF), wall motion index(WMI) determined from 3 regions graded O-5 for normal, mild or Severe hypokinesis, akinesis or dyskinesis and plasma P levels. The following lists !?data ? SD at rest. *=p < .05 vs cant, t=p < .05 vs P-160.
Cont P-160 P-480
R*PxlO' 102+31 76+18* 69C15*
EF% 57*4 58?6 59+6
The following list !? data chest pain .ht control R*Px102 EF% Cont 52?8 214?60 P-160 146?37* 56?7 P-480 139r36* 57*8
WMI 1.9t1.4 1.4t1.8 .86?1.0
Plasma P ng/ml 69+41 288+136t
and no. patients with SST and maximum workload. AE% WMI +ST CP -5.Ok.8 5.3t1.5 12 11 -2.6k.6 3.3?2.1* 7* 5" 2.9?2.0* -2.lk.6 1*+ 1*t
These data indicate that at pretreatment max&mum workload, P-160 reduces regional dysfunction, R-P, +ST and CP but does not effect global EF; P-480 did not further improve Ex LV function or reduce R-P despite fhrther reduction in CST and CP.
PERSISTANT MYOCAROIAL PROPANOLOL LEVELS IN MAN John R. Plachetka, Pharm.D.; Neal 11. Salomon,M.D.; Jack G. COPeland, M.D., University of Arizona, Tucson, Arizona The physiologic effects of propanolol (P) are present after chronic oral dosing even when plasma levels are unmeasurable. The reason for this prolonged activity is unknown but may be related to large amounts of P remainina in the target organs. Since there is little information about the relationship between plasma and heart P concentrations in man,we obtained simultaneous plasma and right atria1 tissue samples prior to cardiopulmonary bypass from 19 patients maintained on chronic oral P for angina. 14 pts (group I) received O.lmg/kg P I.V. l-2 hrs. prior to sampling and 5 patients (group II) did not pet I.V. P but received their last oral dose lo-15 hrs before sampling. P in tissue homogenate extracts and plasma was assayed by fluorimetry. There is an excellent correlation between tissue and plasma concentrations of P in group I (r=0.943, p
Volume 47
THE EFFECTS OF MODERATE AND HIGH DOSE PROPRANOLOL ON VENTRICULAR FUNCTION IN PATIENTS WITH CORONARY ARTERY DISEASE Kenneth G. Morris, MD, Sebastian T. Palmeri, MD, R. Edward Coleman, MD, David Shand, MD, Frederick R. Cobb, MD, Duke University and VA Medical Centers,-Durham, North Carolina
BLOCKING AGENTS
LABE'IALOI.THERAPY IN ANGINA PECTORIS AND SYSTEMIC HYPERTENSION: EFFECTS OF COMBINED ALPHA-BETA ADRENERGIC BLOCKAIJE William H.Frishman, MD,FACC; Marc Kirschner, MD; Joel Strom, MD; Neal Klein, MD; Stanley Halprin, MD; Susan Goldner; Thierry LeJemtel, MD; Marcia Poland, BA; Michael Kram, BA; Roger Strair, PhD; Edmund H. Sonnenblick, MD, FAX, Albert Einstein College of Medicine, Bronx, N.Y. The effects of oral labetalol (L), an alpha-beta adrenoceptor blocker, were evaluated in 10 patients (pts) with angina pectoris and h:Tpertension. After 3 weeks of placebo (Pl), increasing doses of L (300-1,200 mg/day) were given over 4 weeks followed by a rapid drug withdrawal phase. Angina1 attack frequency and exercise tolerance (treadmill) were measured; also assessed were non-invasive indices of LV function (echo, systolic time intervals), plasma renin activity (PRA) and platelet function (aggregability). Compared to pl, the frequency of angina attacks/week was reduced with L; exercise time increased from 4.1+1.0 to 6.3+ 0.5 min, ~~0.01. L lowered resting supine (sup7 and standing blood pressure (BP) and heart rate (HR) in allpts; sup systolic BP 154.5+6.1 to 121.5+7.9 mmHg, p
REDUCTION OF MYOCARDIAL ISCHEMIA BY BALANCED ALPHA AND BETA BLOCKADE WITH LABETALOL Dietmar H. Glogar, M.D.; Robert A. Kloner, M.D., Ph.D.; Harvard Med. School/Peter B. Brigham Hosp., Boston, MA It is known that beta blockade decreases blood flow to ischemic myocardium, but it is unknown whether this effect, which may be related to unopposed alpha stimulation, can be counteracted Labetalol (LAB) offers the opporby additional alpha blockade. tunity to study both types of blockade since it has been shown to block predominantly beta receptors at 0.5 mg/kg (LAB I) and both alpha and beta receptors at 5.0 mg/kg (LAB II). Therefore, 28 anesthetized dogs received left anterior descending coronary artery occlusions. After 15 min of occlusion 7 dogs received a 5 min bolus of LAB I, 7 dogs LAB II, 14 control dogs normal saline (NS). The myocardium at risk of necrosis (MR) was determined before the intervention by an autoradiographic technique (MR I) and also at 6 hours of occlusion by Thioflavin S (MR II). Infarct size (IS) in percent left ventricle below occlusion (%LV) was determined by triphenyltetrazoiium chloride stain. Regional myocardial blood flow (RMBF) was measured by microspheres before and I5 min following therapy. In LAB II vs. NS IS (%LV) was smaller (24+3 vs 30+2 respectively, p < 0.051, while MR I (%LVI was not different (30+2 vs 31+2, p=n.s.) Only 79+6% of MR I were infarcted in LAB II treated dogs vs 98f4% in NS (p< 0.01). Furthermore, RMBF immediately adjacent to the infarct increased from 0.61+0.05ml/min/g before to 0.80+0.07 mI/min/g following treatment (p< 0.05) leading to a reduction of the MR. In LAB I RMBF was decreased by the intervention from 0.60: 0.07 ml/min/g to 0.48+0.04 ml/min/g, while no significant effect Thus, the combination of alpha and beta on IS was observed. blockade achieved by high dose labetalol (LAB II) improved Also, LAB coronary blood flow to the ischemic myocardium. decreased IS. This indicates that balanced alpha and beta blockade reached with high dose LAB may overcome secondary vasoconstriction observed in predominant beta receptor blockade.
430
February 1981
The American Journal of CARDIOLOGY
Effects of moderate(l60 mg/d) and high dose(480 mg/d) propranolol(P) on rest(R) and exercise(Ex) left ventricular(LV) function were determined in 14 patients with symptomatic CAD. LV function was measured by multigated radionuclide angiography(RNA) in the upright position at control and after 2 weeks on each dose. Measurements included heart rate-pressure product(R*P), ejection fraction(EF), wall motion index(WMI) determined from 3 regions graded O-5 for normal, mild or Severe hypokinesis, akinesis or dyskinesis and plasma P levels. The following lists !?data ? SD at rest. *=p < .05 vs cant, t=p < .05 vs P-160.
Cont P-160 P-480
R*PxlO' 102+31 76+18* 69C15*
EF% 57*4 58?6 59+6
The following list !? data chest pain .ht control R*Px102 EF% Cont 52?8 214?60 P-160 146?37* 56?7 P-480 139r36* 57*8
WMI 1.9t1.4 1.4t1.8 .86?1.0
Plasma P ng/ml 69+41 288+136t
and no. patients with SST and maximum workload. AE% WMI +ST CP -5.Ok.8 5.3t1.5 12 11 -2.6k.6 3.3?2.1* 7* 5" 2.9?2.0* -2.lk.6 1*+ 1*t
These data indicate that at pretreatment max&mum workload, P-160 reduces regional dysfunction, R-P, +ST and CP but does not effect global EF; P-480 did not further improve Ex LV function or reduce R-P despite fhrther reduction in CST and CP.
PERSISTANT MYOCAROIAL PROPANOLOL LEVELS IN MAN John R. Plachetka, Pharm.D.; Neal 11. Salomon,M.D.; Jack G. COPeland, M.D., University of Arizona, Tucson, Arizona The physiologic effects of propanolol (P) are present after chronic oral dosing even when plasma levels are unmeasurable. The reason for this prolonged activity is unknown but may be related to large amounts of P remainina in the target organs. Since there is little information about the relationship between plasma and heart P concentrations in man,we obtained simultaneous plasma and right atria1 tissue samples prior to cardiopulmonary bypass from 19 patients maintained on chronic oral P for angina. 14 pts (group I) received O.lmg/kg P I.V. l-2 hrs. prior to sampling and 5 patients (group II) did not pet I.V. P but received their last oral dose lo-15 hrs before sampling. P in tissue homogenate extracts and plasma was assayed by fluorimetry. There is an excellent correlation between tissue and plasma concentrations of P in group I (r=0.943, p
Volume 47