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Effects of the angiotensin converting enzyme inhibitor (ACEI) quinaprilat in the rat, isolated perfused mesenteric vascular bed
J Mol
Cell
Cardiol
289
PREVENTION Communicable
21 (Supplement
II) (1989)
OF cARDIoVAsCULAR CALCIFICATION. R.J. Diseases. The University of Michigan,
Department of Levy. Ann Arbor, Michigan
Pediatrics
and
Cardiovascular calcification is an important disease process which complicates atherosclerosis and cardiac valvular disease, and also contributes to the deterioration of bioprosthetic heart valves and experimental artifical heart devices. Strategies for preventing cardiovascular calcification have focused on either the administration of anticalcification agents or pretreatment of implants to prevent mineral accumulation. Pretreatment of bioprosthetic heart valves with either detergents or with animopropanehydroxydiphosphonate has resulted in an apparent mitigation of calcification. However, diphosphonate therapy with ethanehydroxydiphosphonate (EHDP) administered either systemically or locally has caused a complete inhibition of bioprosthetic calcification, but with severe adverse effects on bone with systemic therapy. Local controlled release of EHDP directly into the annulus of the valve implant with a polymer matrix has been effective without adverse effects due to the very low dose required by this route. Furthermore, recent work has demonstrated that pretreatment of either bioprostheses or aortic homografts with dilute solutions (.OOlM) of AlC13 prevented subsequent implant calcification, suggesting that Al-H+ may represent a most potent anticalcification agent.
2%)
EFFECTS 3F THE ANGIOTENSIN CONVERTING ENZYME INHIBITOR (ACEI) QUINAPRILAT IN THE ISOLATED PERFUSED MESENTERIC VASCULAR BED. T. C. Major, B. Klinkefus, MT, 3. Panek, R. Weishaar, and D. Taylor. Parke-Davis Pharm. Res. Div., Warner-Lambert Co., Ann Arbor, MI 48105. The isolated perfused rat mesenteric vasculature preparation was used to study the effects of the ACEI, quinaprilat upon the tetradecapeptide renin substrate mediated facilitation of vasoconstrictor responses evokyfl by pgriarterial nerve stimulation (PNS). Infusion of renin substrate (10 - loM) into the perfusate produced a concentration-dependent potentiation of the vasoconstrictor responses to PNS (3 Hz, 1 msec duration for 30 sac). This potentiation was not different between mesenteric preparations from either spontaneously hypertensive i$HR) or ,Sprague-Dawley, normotensive (SD) rats. - lo-= M) suppressed Infusion of quinapriiat (10 renin substrate mediated responses to PNS in both SHR and SD mesenteric preparation although the degree of suppression was greater in SHR's. Chronic oral administration of quinapril to SHR's for one week (3 mg/Kg) also attenuated the renin substrate mediated pressor responses to PNS. These results demonstrate the existence of a vascular renin-angiotensin system in the rat mesenteric vasculature which can be regulated by oral treatment with the ACE1 quinapril and by direct in vitro administration of the active metabolite quinaprilat.
291
PERINDOPRIL PREVENTS FALL IN VENTRICULAR OUTPUT AFTER CORONARY LIGATION IN THE PIG. Ischaemic Cape Town,
Heart South
Disease Africa. Angiotensin
Research
Unit,
FIBRILLATION C Groote
Muller, Schuur
THRESHOLD H Basset, Hospital
AND IN CARDIAC L
and
Opie. University
MRC of
HYPOTHESIS: converting enzyme (ACE) inhibition prevents adrenergic activation during acute myocardial infarction and therefore prevents fatal arrhythmias. METHODS: Perindopril (P) is an ACE inhibitor of the carboxy alkyldipeptide class. The active metabolite of P, i.e. S9780, was administered 30 min prior to anterior descending coronary artery ligation (CAL) in anesthetized pigs. The ventricular fibrillation threshold (VFT) was measured by the train method. Cardiac output (CO) was measured by thermodilution. RESULTS: s9750 w CO % ecrease mq/kg IV post-CAL vs pre-CAL post-CAL vs pre-CAL pre-CAL post-CAL No drug (n=8 25.0 f 2.1 16.4 + 2.9 11.8 f 1.9 7.2 f 1.2** 0.06 (n=5)) 3.0 k 3.0' 5.3 + 6.9 14.6 f 1.1 15.0 f 2.7* Mean f SEM; * p
pre-CAL; A p
Cell
Cardiol
289
PREVENTION Communicable
21 (Supplement
II) (1989)
OF cARDIoVAsCULAR CALCIFICATION. R.J. Diseases. The University of Michigan,
Department of Levy. Ann Arbor, Michigan
Pediatrics
and
Cardiovascular calcification is an important disease process which complicates atherosclerosis and cardiac valvular disease, and also contributes to the deterioration of bioprosthetic heart valves and experimental artifical heart devices. Strategies for preventing cardiovascular calcification have focused on either the administration of anticalcification agents or pretreatment of implants to prevent mineral accumulation. Pretreatment of bioprosthetic heart valves with either detergents or with animopropanehydroxydiphosphonate has resulted in an apparent mitigation of calcification. However, diphosphonate therapy with ethanehydroxydiphosphonate (EHDP) administered either systemically or locally has caused a complete inhibition of bioprosthetic calcification, but with severe adverse effects on bone with systemic therapy. Local controlled release of EHDP directly into the annulus of the valve implant with a polymer matrix has been effective without adverse effects due to the very low dose required by this route. Furthermore, recent work has demonstrated that pretreatment of either bioprostheses or aortic homografts with dilute solutions (.OOlM) of AlC13 prevented subsequent implant calcification, suggesting that Al-H+ may represent a most potent anticalcification agent.
2%)
EFFECTS 3F THE ANGIOTENSIN CONVERTING ENZYME INHIBITOR (ACEI) QUINAPRILAT IN THE ISOLATED PERFUSED MESENTERIC VASCULAR BED. T. C. Major, B. Klinkefus, MT, 3. Panek, R. Weishaar, and D. Taylor. Parke-Davis Pharm. Res. Div., Warner-Lambert Co., Ann Arbor, MI 48105. The isolated perfused rat mesenteric vasculature preparation was used to study the effects of the ACEI, quinaprilat upon the tetradecapeptide renin substrate mediated facilitation of vasoconstrictor responses evokyfl by pgriarterial nerve stimulation (PNS). Infusion of renin substrate (10 - loM) into the perfusate produced a concentration-dependent potentiation of the vasoconstrictor responses to PNS (3 Hz, 1 msec duration for 30 sac). This potentiation was not different between mesenteric preparations from either spontaneously hypertensive i$HR) or ,Sprague-Dawley, normotensive (SD) rats. - lo-= M) suppressed Infusion of quinapriiat (10 renin substrate mediated responses to PNS in both SHR and SD mesenteric preparation although the degree of suppression was greater in SHR's. Chronic oral administration of quinapril to SHR's for one week (3 mg/Kg) also attenuated the renin substrate mediated pressor responses to PNS. These results demonstrate the existence of a vascular renin-angiotensin system in the rat mesenteric vasculature which can be regulated by oral treatment with the ACE1 quinapril and by direct in vitro administration of the active metabolite quinaprilat.
291
PERINDOPRIL PREVENTS FALL IN VENTRICULAR OUTPUT AFTER CORONARY LIGATION IN THE PIG. Ischaemic Cape Town,
Heart South
Disease Africa. Angiotensin
Research
Unit,
FIBRILLATION C Groote
Muller, Schuur
THRESHOLD H Basset, Hospital
AND IN CARDIAC L
and
Opie. University
MRC of
HYPOTHESIS: converting enzyme (ACE) inhibition prevents adrenergic activation during acute myocardial infarction and therefore prevents fatal arrhythmias. METHODS: Perindopril (P) is an ACE inhibitor of the carboxy alkyldipeptide class. The active metabolite of P, i.e. S9780, was administered 30 min prior to anterior descending coronary artery ligation (CAL) in anesthetized pigs. The ventricular fibrillation threshold (VFT) was measured by the train method. Cardiac output (CO) was measured by thermodilution. RESULTS: s9750 w CO % ecrease mq/kg IV post-CAL vs pre-CAL post-CAL vs pre-CAL pre-CAL post-CAL No drug (n=8 25.0 f 2.1 16.4 + 2.9 11.8 f 1.9 7.2 f 1.2** 0.06 (n=5)) 3.0 k 3.0' 5.3 + 6.9 14.6 f 1.1 15.0 f 2.7* Mean f SEM; * p
pre-CAL; A p