Do the Cardiovascular Effects of Angiotensin-Converting Enzyme (ACE) I Involve ACE-Independent Mechanisms? New Insights from Proline-Rich Peptides ofBothrops jararaca
| Autor: | Danielle Ianzer, Gisele M Etelvino, Carlos Henrique Xavier, Leonor Tapias Machado, Jerusa A. Santos, Vincent Dive, B.C. Prezoto, Robson A.S. Santos, Antonio C.M. Camargo, Elizabeth Pereira Mendes |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Guinea Pigs Bradykinin Angiotensin-Converting Enzyme Inhibitors Blood Pressure CHO Cells In Vitro Techniques Peptidyl-Dipeptidase A Pharmacology Cardiovascular System chemistry.chemical_compound Cricetulus Heart Rate Ileum In vivo Cricetinae Rats Inbred SHR Crotalid Venoms Renin–angiotensin system medicine Animals Humans Bothrops Rats Wistar Antihypertensive Agents chemistry.chemical_classification Oligopeptide Dose-Response Relationship Drug biology Angiotensin-converting enzyme Rats Enzyme chemistry Mechanism of action Enzyme inhibitor biology.protein Molecular Medicine Female Angiotensin I medicine.symptom Oligopeptides Muscle Contraction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 322:795-805 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Angiotensin-converting enzyme (ACE) inhibitors were developed based on proline-rich oligopeptides found in the venom of Bothrops jararaca ( Bj ) previously known as bradykinin-potentiating peptides (BPPs). However, the exact mechanism of action of BPPs remains unclear. The role of the ACE in the cardiovascular effects of two of naturally proline-rich oligopeptides ( Bj -BPP-7a and Bj -BPP-10c) was evaluated in vitro and in vivo. Bj -BPP-7a does not potentiate the cardiovascular response to bradykinin and is a weak inhibitor of ACE C and N sites ( K i = 40,000 and 70,000 nM, respectively), whereas Bj -BPP-10c is a strong bradykinin potentiator and inhibitor of the ACE C site ( K i = 0.5 versus 200 nM for N site). Strikingly, both peptides, in doses ranging from 0.47 to 71 nmol/kg, produced long-lasting reduction (>6 h) in the mean arterial pressure of conscious spontaneously hypertensive rats (maximal change, 45 ± 6 and 53 ± 6 mm Hg for Bj -BPP-7a and Bj -BPP-10c, respectively). The fall in blood pressure was accompanied by variable degrees of bradycardia. In keeping with the absence of relationship between ACE-inhibitory and antihypertensive activities, no changes in the pressor effect of angiotensin I or in the hypotensive effect of bradykinin were observed at the peak of the cardiovascular effects of both peptides. Our results indicate that the antihypertensive effect of two Bj -BPPs containing the motif Ile-Pro-Pro is unrelated to their ability for inhibiting ACE or potentiating bradykinin (BK), indicating as a major component ACE and BK-independent mechanisms. These results are in line with previous observations suggesting ACE inhibition-independent mechanisms for angiotensin I-converting enzyme inhibitor. |
| Databáze: | OpenAIRE |
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