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Thromb Haemost 2000; 83(05): 722-727
DOI: 10.1055/s-0037-1613899
Review Article
Schattauer GmbH

Protective Effects of Imidapril on He-Ne Laser-Induced Thrombosis in Cerebral Blood Vessels of Stroke-Prone Spontaneously Hypertensive Rats

Yasuto Sasaki
1   From the Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan
,
Takanori Noguchi   *
1   From the Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan
,
Junji Seki
2   Department of Biomedical Engineering, National Cardiovascular Center Research Institute, Suita, Japan
,
J. C. Giddings
3   Department of Haematology, University of Wales College of Medicine, Cardiff, UK
,
Junichiro Yamamoto
1   From the Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan
› Author AffiliationsWe thank to Tanabe Pharmaceutical Co. LTD. for providing imidapril and imidaprilat and we also appreciate to Grants-in-Aid for Scientific Research (No. 09670678) from the Ministry of Education and Sports and Health Science Research of Kobe Gakuin University.
Further Information

Publication History

Received 22 March 1999

Accepted after resubmission 11 January 2000

Publication Date:
08 December 2017 (online)

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Summary

Inhibitors of angiotensin converting enzyme (ACE) have been developed recently for therapeutic purposes in hypertension and ischemic cardiovascular diseases. Ogiku et al. (1) reported that one such inhibitor, imidapril, significantly prolonged survival in stroke-prone spontaneously hypertensive rats (SHRSP). The present study was designed to investigate the effect of imidapril on cerebral blood vessels in SHRSP to clarify role of the ACE inhibitor in mechanisms of cerebral thrombosis and stroke. Imidapril was administered orally at 1.0 and 5.0 mg/kg/day for 3 weeks from the age of 7 weeks, and was shown to prevent the usual increase in blood pressure seen in these animals. It also delayed He-Ne laser-induced cerebral thrombosis and increased significantly the plasma concentration of nitric oxide metabolites (NO2/NO3). To confirm the association between nitric oxide (NO) and these effects of imidapril, an inhibitor of nitric oxide synthase, NG - nitro-L-arginine methyl ester hydrochloride (L-NAME) was dissolved in drinking water and administered to the animals for 3 weeks. Four of six rats died from stroke when L-NAME was given alone. When imidapril (5.0 mg/kg/day) was administered with L-NAME, however, the animals showed no signs or symptoms of stroke. In these instances, therefore, the concurrent administration of L-NAME with imidapril reversed significantly the effects of imidapril. Intravenous injection of imidaprilat (100 µg/kg), an active metabolite of imidapril, also decreased blood pressure significantly and increased the plasma levels of NO2/NO3 after 5 min. Moreover, imidaprilat enlarged arteriolar diameters and caused an increase in red cell velocity and mean blood flow in pial arterioles after 15 min.

The results strongly suggested that imidapril protects cerebral vessels in SHRSP by elevating the release of NO, thereby improving the cerebral circulation and reducing the tendency to thrombosis and stroke.

Keywords

ACE-inhibitor - imidapril - thrombosis - nitric oxide - pial vessel

* Present address: Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan


 

  • References

  • 1 Ogiku N, Sumikawa H, Hashimoto Y, Ishida R. Prophylactic effect of imidapril on stroke in stroke-prone spontaneously hypertensive rats. Stroke 1993; 24: 245-52.
    CrossrefPubMedGoogle Scholar
  • 2 Mombouli JV. ACE inhibition, endothelial function and coronary artery lesions. Role of kinins and nitric oxide. Drugs 1997; 54: 12-22.
    CrossrefPubMedGoogle Scholar
  • 3 Mombouli JV, Illiano S, Nagao T, Scott-Burden T, Vanhoutte PM. Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and hyperpolarizing factors. Circ Res 1992; 71: 137-44.
    CrossrefPubMedGoogle Scholar
  • 4 Vanhoutte PM, Boulanger CM, Mombouli JV. Endothelium-derived relaxing factors and converting enzyme inhibition. Am J Cardiol 1995; 76: 3E-12E.
    CrossrefPubMedGoogle Scholar
  • 5 Keidar S, Oiknine J, Leiba A, Shapira C, Leiba M, Aviram M. Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients. J Cardiovasc Pharmacol 1996; 27: 183-6.
    CrossrefPubMedGoogle Scholar
  • 6 Sayer JW, Timmis AD. Angiotensin-converting enzyme inhibitors and coronary artery disease. Cardiovasc Drugs Ther 1996; 10 (Suppl. 02) 631-7.
    CrossrefPubMedGoogle Scholar
  • 7 Okrucka A, Pechan J, Kratochvilova H. Effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril on endothelial and platelet functions in essential hypertension. Platelets 1998; 09: 63-7.
    CrossrefPubMedGoogle Scholar
  • 8 Fennessy PA, Campbell JH, Campbell GR. Perindopril inhibits both the development of atherosclerosis in the cholesterol-fed rabbit and lipoprotein binding to smooth muscle cells in culture. Atherosclerosis 1994; 106: 29-41.
    CrossrefPubMedGoogle Scholar
  • 9 Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol 1990; 15: S65-72.
    PubMedGoogle Scholar
  • 10 Yang ST, Faraci FM, Heistad DD. Effects of cilazapril on cerebral vasodilatation in hypertensive rats. Hypertension 1993; 22: 150-5.
    CrossrefPubMedGoogle Scholar
  • 11 Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension 1990; 16: 532-40.
    CrossrefPubMedGoogle Scholar
  • 12 Stier Jr CT, Benter IF, Ahmad S, Zuo HL, Selig N, Roethel S, Levine S, Itskovitz HD. Enalapril prevents stroke and kidney dysfunction in saltloaded stroke-prone spontaneously hypertensive rats. Hypertension 1989; 13: 115-21.
    CrossrefPubMedGoogle Scholar
  • 13 Linz W, Jessen T, Becker RH, Scholkens BA, Wiemer G. Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation 1997; 96: 3164-72.
    CrossrefPubMedGoogle Scholar
  • 14 Takahashi M, Fritz-Zieroth B, Ohta Y, Chikugo T. Therapeutic effects of imidapril on cerebral lesions observed by magnetic resonance imaging in malignant stroke-prone spontaneously hypertensive rats. J Hypertens 1994; 12: 761-8.
    PubMedGoogle Scholar
  • 15 Hirata Y, Hayakawa H, Kakoki M, Tojo A, Suzuki E, Kimura K, Goto A, Kikuchi K, Nagano T, Hirobe M, Omata M. Nitric oxide release from kidneys of hypertensive rats treated with imidapril. Hypertension 1996; 27: 672-8.
    CrossrefPubMedGoogle Scholar
  • 16 Okamoto K, Yamori Y, Nagaoka A. Establishment of the stroke-prone spontaneously hypertensive rats (SHRSP). Circ Res. 1974 34/35(Suppl I): I-143-53.
    PubMedGoogle Scholar
  • 17 Yamori Y. Overview: studies on spontaneous hypertension-development from animal models toward man. Clin Exp Hypertens [A] 1991; 13: 631-44.
    PubMedGoogle Scholar
  • 18 Tagami M, Yamori Y. Morphological analysis of the pathogenesis of hypertensive cerebrovascular lesions: role of monocytes and platelets in intracerebral vessel occlusions. Jpn Circ J 1988; 52: 1351-6.
    CrossrefPubMedGoogle Scholar
  • 19 Tagami M, Ikeda K, Nara Y, Fujino H, Kubota A, Numano F, Yamori Y. Detailed examination of vascular lesions triggered by an inhibitor of endothelium-derived relaxing factor. Lab Invest 1995; 72: 174-82.
    PubMedGoogle Scholar
  • 20 Morikawa E, Moskowitz MA, Huang Z, Yoshida T, Irikura K, Dalkara T. L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke 1994; 25: 429-35.
    CrossrefPubMedGoogle Scholar
  • 21 Zhang F, Iadecola C. Nitroprusside improves blood flow and reduces brain damage after focal ischemia. Neuroreport 1993; 04: 559-62.
    CrossrefPubMedGoogle Scholar
  • 22 Sasaki Y, Seki J, Giddings JC, Yamamoto J. Effects of NO-donors on thrombus formation and microcirculation in cerebral vessels of the rat. Thromb Haemost 1996; 76: 111-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Noguchi T, Sasaki Y, Seki J, Giddings JC, Yamamoto J. Effects of voluntary exercise and L-arginine on thrombogenesis and microcirculation of stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1999; 26: 330-5.
    CrossrefPubMedGoogle Scholar
  • 24 Morii S, Ngai AC, Winn HR. Reactivity of rat pial arterioles and venules to adenosine and carbon dioxide: with detailed description of the closed cranial window technique in rats. J Cereb Blood Flow Metab 1986; 06: 34-41.
    CrossrefPubMedGoogle Scholar
  • 25 Sasaki Y, Morii S, Yamashita T, Yamamoto J. Antithrombotic effect of argatroban on the pial vessels of the rat: a study with He-Ne laser-induced thrombus formation. Haemostasis 1993; 23: 104-11.
    PubMedGoogle Scholar
  • 26 Noguchi T, Sasaki Y, Seki J, Giddings JC, Yamamoto J. Enhanced thrombogenicity and altered hemodynamics in the cerebral microvasculature of stroke-prone spontaneously hypertensive rats. Haemostasis 1997; 27: 237-45.
    PubMedGoogle Scholar
  • 27 Seki J. Fiber-optic laser-Doppler anemometer microscope developed for the measurement of microvascular red cell velocity. Microvasc Res 1990; 40: 302-16.
    CrossrefPubMedGoogle Scholar
  • 28 Seki J, Sasaki Y, Oyama T, Yamamoto J. Fiber-optic laser-Doppler anemometer microscope applied to the cerebral microcirculation in rats. Biorheology 1996; 33: 463-70.
    PubMedGoogle Scholar
  • 29 Turitto VT, Baumgartner HR. Initial deposition of platelets and fibrin on vascular surfaces in flowing blood. In: Haemostasis and Thrombosis. Basic Principles and Clinical Practice. 3 rd edn.. Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia: JB Lippincott; 1994: 805-22.
    Google Scholar
  • 30 Tojo A, Kobayashi N, Kimura K, Hirata Y, Matsuoka H, Yagi S, Omata M. Effects of antihypertensive drugs on nitric oxide synthase activity in rat kidney. Kidney Int Suppl 1996; 55: S138-40.
    PubMedGoogle Scholar
  • 31 Povlishock JT, Rosenblum WI. Injury of brain microvessels with a heliumneon laser and Evans blue can elicit local platelet aggregation without endothelial denudation. Arch Pathol Lab Med 1987; 111: 415-21.
    PubMedGoogle Scholar
  • 32 Adams MR, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer DS. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery diseases. Atherosclerosis 1997; 129: 261-9.
    CrossrefPubMedGoogle Scholar
  • 33 Arvidsson S, Haggendal E, Winso I. Influence on cerebral blood flow of infusion of sodium bicarbonate during respiratory acidosis and alkalosis in the dog. Acta Anaesthesiol Scand 1981; 25: 146-52.
    CrossrefPubMedGoogle Scholar