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Angiotensin antagonism vs converting enzyme inhibition; contrast and similarities of their hemodynamic effects
ABSTRACTS
ACUTE DOSE RESPONSE RELATIONSHIP AND DURATION OF ACTION OF ORAL ISOSORBIDE DINITRATE IN ANGINA PECTORIS. Udho Thadani, M B ~ F R C P ( C ) , John O. Parker, MD, FRCP(C), •FA-~CC, and Andrew C. Darke, Ph.D, Queen's University, Kingston, Ontario.
WEDNESDAY, MARCH 14, 1979 PM STUDIES IN HYPERTENSION 2:00-5:00
Dose response relationship with isosorbide dinitrate (ISD) in angina pectoris (AP) are not known. Twelve patients with exertional AP were studied before and 1,2, and 6 hours (h) after 15, 30, 60 and 120 mg ISD and placebo (PL). Heart rate (HR), systolic blood pressure (SBP) and treadmill walking time (WT) to moderate AP were measured. The end point was moderate AP before ISD and PL and moderate AP or fatigue after ISD and PL. SBP decreased and HR increased at lh, 2h and 6h in the standing position after each dose of ISD in comparison to PL values. Mean values during e x e r c i s e a r e tabulated.
ANGIOTENSIN ANTAGONISMVS CONVERTINGENZYME INHIBITION; CONTRAST AND SIMILARITIES OF THEIR HEMODYNAMIC EFFECTS Fetnat M. Fouad, MD; Joanne M.K. Ceimo,MD; Robert C. Tarazi, MD, FACC; Emmanuel L. Bravo, MD,Research Division, Cleveland Clinic, Cleveland, Ohio
WT (sec) PL ISD ISD ISD ISD
15 30 60 120
Oh 356 337 358 367 393
lh 393 452* 476* 491" 503*
2h 393 440* 483* 479* 499*
6h 373 419" 458* 467* 470*
HR Oh 223 240 231 218 245
x SBP x 102 lh 2h 6h 216 219 221 247 239 239 239 237 244 224 226 233 264 247 247
* = P<0.01 in comparison to PL. Increase in WT occurred at lh after each dose of ISD and the effects persisted for 6h. Increase in WT at i and 2 h but not at 6h was associated with reduction in ST segment depression after each dose of ISD. it is concluded that ISD 15 to 120 mg administered acutely improved exercise tolerance for at least 6 hours, but a dose response relationship between the increase in walking time and dose of ISD was not apparent.
The relationship of the hypotensive effect of converting enzyme inhibitor (CEI) to its interference with the renin angiotensin system has been questioned. This problem was investigated by comparing the early (30 min) hemodynamic effects of CEI (SQ14225; 25-150 mg) with those of a specific angiotensin II antagonist (AA)([SarIThrS]AII; lO00 ng /Kg/min) in 14 hypertensive patients with a wide spectrum of PRA (0.2 to 48 ng/ml/hr). Each patient received the two drugs in succession with suitable intervening recovery period. AA reduced mean arterial pressure (MAP) > lO mmHg only in 2/14 patients vs lO/14 who responded to CEI (p < 0.02). With both drugs, changes in MAP were not associated with significant changes in cardiac output (p > O.lO for both drugs) but correlated with changes in total peripheral resistance (TPR); r = 0.829, p
INABILITY OF OXYGEN ADMINISTRATION TO INFLUENCE EXERCISE INDUCED MYOCARDIAL ISCHEMIA IN CORONARY DISEASE Lawrence J. Laslett, MD; Garrett Lee, MD; Anthony N. DeMaria, MD, FACC; Mark P. Miller, MD; Ezra A. Amsterdam, MD, FACC; Dean T. Mason, MD, FACC, University of California, Davis, California
HEMODYNAMIC AND ANTIHYPE'RTENSIVE EFFECTS OF SQ 14,225, AN ORALLY ACTIVE CONVERTINGENZYME INHIBITOR Jay M. Sullivan, MD, FACC; Burt A. Ginsburg, MD; Thomas E. Ratts, MD; James G. Johnson, MD; Doris N. McKinstry, PhD; E. Eric Muirhead, MD, University of Tennessee Center for the Health Sciences, Memphis, TN
Little data are available regarding effects of 02 administration on relief or decrease of myocardial i s c h e m i a i n patients (pts) with coronary disease. Thus we evaluated ability of increased 02 inhalation to prevent active ischemia in ten pts with catheterization documented coronary disease (>75% stenosis of at least one major coronary vessel) and positive (>i mm ST depression) maximal treadmill exercise testing (ET). Two double-blind ET were performed while breathing either 100% oxygen or ambient air. 02 (100%) administration increased arterial O 2 tension (PO 2) significantly (83 + 410) (p<.001) while P02 was unchanged by ambient air (84). Exercise duration was not different during 100% 02, 332 seconds (sec) from that with ambient air, 337 sec (p>.05). Calculated total body 02 consumption was 23.2 cc/kg/min with 100% 02 and 23.4 with ambient air (p>.05). Maximum heart rate-blood pressure product (myocardial 02 consumption index) was also similar: 28.8 x 10 -.3 and 27.0 x 10 -3 during 100% 02 and ambient air. Maximal ST depression during ET was not different with 100% 02; i.i m m v e r s u s ambient air 1.6 mm (P>.05). Further, 1 mm ST-segment depression onset in six pts occurred earlier with 100% 02 than ambient air; 210 versus 225 sec. Only two pts with ST depression breathing ambient air had no ischemic E T r e s p o n s e on 100% 02. Thus these data indicate that inhalation of 100% oxygen neither prevents nor diminishes symptomatic occurrence or reduces the objective evidence of exercise-induced myocardial ischemia in patients with coronary artery disease during controlled maximal exercise testing.
SQ 14,225 inhibits angiotensin i i formation and bradykinin degradation in vivo. Eight patients with essential hypertension (EH) and 3 patients with renovascular hypertension (RVH) were treated with SQ 14,225 for periods ranging from 3 days to 9 mos. All patients had a diastolic blood pressure (DBP) over 95 mmHgfor 3 days on placebo. SQ 14,225, given in ascending doses (lO-lO00 mg/d) caused normalization of blood pressure in all but one patient with severe RVH whose pressure fell ll% and one patient with severe EH, whose pressure f e l l 27%. The average control DBP was I15_+5.6 S.E. and f e l l to 92.5_+3.8 mmHg. All patients were studied in balance on a lO0 mEq sodium (Na) diet. Plasma renin activity (PRA) versus 24 hr urinary Na excretion increased seven-fold during therapy while converting enzyme activity f e l l by half. Themagnitude of the BP response was not related to control PRA. Cardiac output was estimated by echocardiography during placebo administration and during maintenance therapy with SQ 14,225. Peripheral vascular resistance f e l l an average of 22% in 7 of the 9 patients in whom the measurement could be made. I t is concluded that SQ 14,225 effectively lowers blood pressure in patients with EH or RVH by reducing peripheral vascular res i stance.
February 1979
The American Journal of CARDIOLOGY
Volume 43
417
ACUTE DOSE RESPONSE RELATIONSHIP AND DURATION OF ACTION OF ORAL ISOSORBIDE DINITRATE IN ANGINA PECTORIS. Udho Thadani, M B ~ F R C P ( C ) , John O. Parker, MD, FRCP(C), •FA-~CC, and Andrew C. Darke, Ph.D, Queen's University, Kingston, Ontario.
WEDNESDAY, MARCH 14, 1979 PM STUDIES IN HYPERTENSION 2:00-5:00
Dose response relationship with isosorbide dinitrate (ISD) in angina pectoris (AP) are not known. Twelve patients with exertional AP were studied before and 1,2, and 6 hours (h) after 15, 30, 60 and 120 mg ISD and placebo (PL). Heart rate (HR), systolic blood pressure (SBP) and treadmill walking time (WT) to moderate AP were measured. The end point was moderate AP before ISD and PL and moderate AP or fatigue after ISD and PL. SBP decreased and HR increased at lh, 2h and 6h in the standing position after each dose of ISD in comparison to PL values. Mean values during e x e r c i s e a r e tabulated.
ANGIOTENSIN ANTAGONISMVS CONVERTINGENZYME INHIBITION; CONTRAST AND SIMILARITIES OF THEIR HEMODYNAMIC EFFECTS Fetnat M. Fouad, MD; Joanne M.K. Ceimo,MD; Robert C. Tarazi, MD, FACC; Emmanuel L. Bravo, MD,Research Division, Cleveland Clinic, Cleveland, Ohio
WT (sec) PL ISD ISD ISD ISD
15 30 60 120
Oh 356 337 358 367 393
lh 393 452* 476* 491" 503*
2h 393 440* 483* 479* 499*
6h 373 419" 458* 467* 470*
HR Oh 223 240 231 218 245
x SBP x 102 lh 2h 6h 216 219 221 247 239 239 239 237 244 224 226 233 264 247 247
* = P<0.01 in comparison to PL. Increase in WT occurred at lh after each dose of ISD and the effects persisted for 6h. Increase in WT at i and 2 h but not at 6h was associated with reduction in ST segment depression after each dose of ISD. it is concluded that ISD 15 to 120 mg administered acutely improved exercise tolerance for at least 6 hours, but a dose response relationship between the increase in walking time and dose of ISD was not apparent.
The relationship of the hypotensive effect of converting enzyme inhibitor (CEI) to its interference with the renin angiotensin system has been questioned. This problem was investigated by comparing the early (30 min) hemodynamic effects of CEI (SQ14225; 25-150 mg) with those of a specific angiotensin II antagonist (AA)([SarIThrS]AII; lO00 ng /Kg/min) in 14 hypertensive patients with a wide spectrum of PRA (0.2 to 48 ng/ml/hr). Each patient received the two drugs in succession with suitable intervening recovery period. AA reduced mean arterial pressure (MAP) > lO mmHg only in 2/14 patients vs lO/14 who responded to CEI (p < 0.02). With both drugs, changes in MAP were not associated with significant changes in cardiac output (p > O.lO for both drugs) but correlated with changes in total peripheral resistance (TPR); r = 0.829, p
INABILITY OF OXYGEN ADMINISTRATION TO INFLUENCE EXERCISE INDUCED MYOCARDIAL ISCHEMIA IN CORONARY DISEASE Lawrence J. Laslett, MD; Garrett Lee, MD; Anthony N. DeMaria, MD, FACC; Mark P. Miller, MD; Ezra A. Amsterdam, MD, FACC; Dean T. Mason, MD, FACC, University of California, Davis, California
HEMODYNAMIC AND ANTIHYPE'RTENSIVE EFFECTS OF SQ 14,225, AN ORALLY ACTIVE CONVERTINGENZYME INHIBITOR Jay M. Sullivan, MD, FACC; Burt A. Ginsburg, MD; Thomas E. Ratts, MD; James G. Johnson, MD; Doris N. McKinstry, PhD; E. Eric Muirhead, MD, University of Tennessee Center for the Health Sciences, Memphis, TN
Little data are available regarding effects of 02 administration on relief or decrease of myocardial i s c h e m i a i n patients (pts) with coronary disease. Thus we evaluated ability of increased 02 inhalation to prevent active ischemia in ten pts with catheterization documented coronary disease (>75% stenosis of at least one major coronary vessel) and positive (>i mm ST depression) maximal treadmill exercise testing (ET). Two double-blind ET were performed while breathing either 100% oxygen or ambient air. 02 (100%) administration increased arterial O 2 tension (PO 2) significantly (83 + 410) (p<.001) while P02 was unchanged by ambient air (84). Exercise duration was not different during 100% 02, 332 seconds (sec) from that with ambient air, 337 sec (p>.05). Calculated total body 02 consumption was 23.2 cc/kg/min with 100% 02 and 23.4 with ambient air (p>.05). Maximum heart rate-blood pressure product (myocardial 02 consumption index) was also similar: 28.8 x 10 -.3 and 27.0 x 10 -3 during 100% 02 and ambient air. Maximal ST depression during ET was not different with 100% 02; i.i m m v e r s u s ambient air 1.6 mm (P>.05). Further, 1 mm ST-segment depression onset in six pts occurred earlier with 100% 02 than ambient air; 210 versus 225 sec. Only two pts with ST depression breathing ambient air had no ischemic E T r e s p o n s e on 100% 02. Thus these data indicate that inhalation of 100% oxygen neither prevents nor diminishes symptomatic occurrence or reduces the objective evidence of exercise-induced myocardial ischemia in patients with coronary artery disease during controlled maximal exercise testing.
SQ 14,225 inhibits angiotensin i i formation and bradykinin degradation in vivo. Eight patients with essential hypertension (EH) and 3 patients with renovascular hypertension (RVH) were treated with SQ 14,225 for periods ranging from 3 days to 9 mos. All patients had a diastolic blood pressure (DBP) over 95 mmHgfor 3 days on placebo. SQ 14,225, given in ascending doses (lO-lO00 mg/d) caused normalization of blood pressure in all but one patient with severe RVH whose pressure fell ll% and one patient with severe EH, whose pressure f e l l 27%. The average control DBP was I15_+5.6 S.E. and f e l l to 92.5_+3.8 mmHg. All patients were studied in balance on a lO0 mEq sodium (Na) diet. Plasma renin activity (PRA) versus 24 hr urinary Na excretion increased seven-fold during therapy while converting enzyme activity f e l l by half. Themagnitude of the BP response was not related to control PRA. Cardiac output was estimated by echocardiography during placebo administration and during maintenance therapy with SQ 14,225. Peripheral vascular resistance f e l l an average of 22% in 7 of the 9 patients in whom the measurement could be made. I t is concluded that SQ 14,225 effectively lowers blood pressure in patients with EH or RVH by reducing peripheral vascular res i stance.
February 1979
The American Journal of CARDIOLOGY
Volume 43
417