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(Hypertension. 1997;29:478.)
© 1997 American Heart Association, Inc.

State-of-the-Art-Lecture

Blockade of Bradykinin B₂ Receptors Prevents the Increase in Capillary Density Induced by Chronic Angiotensin-Converting Enzyme Inhibitor Treatment in Stroke-Prone Spontaneously Hypertensive Rats

Peter Gohlke; Ingo Kuwer; Angela Schnell; Kerstin Amann; Gerhard Mall; Thomas Unger

From the Department of Pharmacology, Christian-Albrechts University of Kiel and German Institute for High Blood Pressure Research, University of Heidelberg; and Department of Pathology (K.A., G.M.), University of Heidelberg, Germany.

Correspondence to Peter Gohlke, PhD, Department of Pharmacology, Christian-Albrechts University of Kiel, Hospitalstr 4, 24105 Kiel, Germany

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B₂-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B₂-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577±279, n=11 and 3988±300 mm/mm³; n=10; P<.05) compared with vehicle-treated animals (2935±137 mm/mm³; n=13). These effects were abolished by chronic bradykinin B₂-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429±309 mm/mm³; n=7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B₂-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Key Words: angiotensin-converting enzyme inhibitor • bradykinin • bradykinin antagonist • heart • SHRSP • ramipril • angiogenesis • capillary density

Abbreviations: ANG II = angiotensin II • AT1 = angiotensin type 1 • LVH = left ventricular hypertrophy • RAS = renin-angiotensin system • SHR = spontaneously hypertensive rats • SHRSP = stroke-prone spontaneously hypertensive rats • VSMC = vascular smooth muscle cell

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