Ciprokiren (Ro 44-9375). A renin inhibitor with increasing effects on chronic treatment.

The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IC50 of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IC50, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with the minimal oral dose of 3 micrograms/kg. Daily oral doses of 1 microgram/kg showed a progressive blood pressure decrease, with a maximal response reached after 1 week. The drug could also be applied transdermally with similar hemodynamic effects without any decrease of plasma renin activity or plasma immunoreactive angiotensin II. Thus, ciprokiren is characterized in squirrel monkeys as a renin inhibitor with high in vivo potency that might act mainly in the tissular compartment.

[1]  S. Ball,et al.  A study of the renin inhibitor H142 in man. , 1985, Journal of hypertension.

[2]  H. Pieterman,et al.  Metabolism and Production of Angiotensin I in Different Vascular Beds in Subjects With Hypertension , 1990, Hypertension.

[3]  J. Ménard,et al.  Effects of the blockade of the renin–angiotensin system in cyclosporin-induced hypertension , 1993, Journal of hypertension.

[4]  K. Misono,et al.  Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. , 1990, The Journal of biological chemistry.

[5]  A. J. Man in 't Veld,et al.  Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension. , 1990, BMJ.

[6]  R. Andersson,et al.  Angiotensin-Converting Enzyme Inhibitors and Their Influence on Inflammation, Bronchial Reactivity and Cough , 1989, Medical toxicology and adverse drug experience.

[7]  W. Neidhart,et al.  Ro 42‐5892 Is a Potent Orally Active Renin Inhibitor in Primates , 1991, Hypertension.

[8]  J. Wood,et al.  Could the pharmacological differences observed between angiotensin II antagonists and inhibitors of angiotensin converting enzyme be clinically beneficial? , 1992, Pharmacology & toxicology.

[9]  D. Ganten,et al.  Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene , 1990, Nature.

[10]  B. Wílkes,et al.  Plasma Angiotensins and Blood Pressure During Converting Enzyme Inhibition , 1987, Hypertension.

[11]  P. Kovar,et al.  Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy. , 1992, Science.

[12]  J. Ménard,et al.  Direct immunometric assay of active renin in human plasma. , 1985, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[13]  J. Clozel,et al.  Discovery of remikiren as the first orally active renin inhibitor. , 1993, Arzneimittel-Forschung.

[14]  J. Clozel,et al.  Comparative effects of three different potent renin inhibitors in primates. , 1993, Hypertension.

[15]  M. Weber,et al.  Clinical experience with the angiotensin II receptor antagonist losartan. A preliminary report. , 1992, American journal of hypertension.

[16]  G. Chatellier,et al.  Blood pressure effects of acute intravenous renin or oral angiotensin converting enzyme inhibition in essential hypertension , 1994, Journal of hypertension.

[17]  M. Packer,et al.  Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure. , 1991, The American journal of cardiology.

[18]  A. J. Man in't veld,et al.  Nonparallel effects of renin inhibitor treatment on plasma renin activity and angiotensins I and II in hypertensive subjects. An assay-related artifact. , 1991, American Journal of Hypertension.

[19]  J. Reid,et al.  Acute and chronic effects of the converting enzyme inhibitors enalapril and lisinopril on reflex control of heart rate in normotensive man. , 1985, Journal of hypertension.

[20]  B. Healy,et al.  The renin-angiotensin system and treatment of heart failure. , 1988, The American journal of medicine.

[21]  E. Fleck,et al.  Hemodynamic and Neurohormonal Effects of the Angiotensin II Antagonist Losartan in Patients With Congestive Heart Failure , 1993, Circulation.

[22]  R. Luther,et al.  Effects of the Renin Inhibitor A‐64662 in Monkeys and Rats with Varying Baseline Plasma Renin Activity , 1988, Hypertension.

[23]  H. Glassman,et al.  Assessment of renin dependency of hypertension with a dipeptide renin inhibitor. , 1990, Circulation.

[24]  M. Miyazaki,et al.  Marked species-difference in the vascular angiotensin II-forming pathways: humans versus rodents. , 1993, Japanese journal of pharmacology.

[25]  J. Ménard,et al.  Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients. , 1989, American journal of hypertension.

[26]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[27]  K. Hiwada,et al.  [Renin inhibitors]. , 1970, Nihon rinsho. Japanese journal of clinical medicine.

[28]  B. Waeber,et al.  Repeated Administration of the Converting Enzyme Inhibitor Cilazapril to Normal Volunteers , 1987, Journal of cardiovascular pharmacology.

[29]  K. Poulsen,et al.  An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody. , 1974, The Journal of clinical endocrinology and metabolism.

[30]  G. Chatellier,et al.  Renin Release Regulation During Acute Renin Inhibition in Normal Volunteers , 1991, Hypertension.

[31]  P. Timmermans,et al.  Angiotensin II monoclonal antibody: blood pressure effects in normotensive and spontaneously hypertensive rats. , 1990, European journal of pharmacology.

[32]  D. Mcareavey,et al.  Exchangeable sodium in DOC-salt and post-DOC-salt hypertension in rats. , 1985, Journal of hypertension.

[33]  R. Luther,et al.  Immediate blood pressure effects of the renin inhibitor enalkiren and the angiotensin-converting enzyme inhibitor enalaprilat. , 1991, American heart journal.

[34]  N. Toda,et al.  Conversion of Angiotensin I to Angiotensin II in Dog Isolated Renal Artery: Role of Two Different Angiotensin II‐Generating Enzymes , 1990, Journal of cardiovascular pharmacology.

[35]  A. Munafo,et al.  Effect of the Renin Response During Renin Inhibition: Oral Ro 42–5892 in Normal Humans , 1991, Journal of cardiovascular pharmacology.

[36]  M. Peach.  Renin-angiotensin system: biochemistry and mechanisms of action. , 1977, Physiological reviews.

[37]  J. Clozel,et al.  Cyclosporin‐Induced Hypertension in Marmosets: A New Model of Hypertension Sensitive to Angiotensin‐Converting Enzyme Inhibition , 1989, Journal of cardiovascular pharmacology.