Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.

Abstract

We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 nig/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10~8 to 10~6 mol/L), decreased vasoconstrictor responses to norepinephrine (10~8 mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B 2 -receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors. (Hypertension. 1993;22:682-687.) KEY WORDS • angiotensin converting enzyme inhibitors • guanosine cyclic monophosphate • perindopril • ramipril • rats, inbred SHR • bradykininS pontaneously hypertensive rats (SHR) and strokeprone SHR (SHRSP) develop hypertension during their first 12 weeks of life. The increase in blood pressure is associated with functional changes of the vascular wall. It has been reported that the endothelium-dependent relaxation of blood vessels to different agonists is impaired in hypertensive compared with normotensive animals.16 Endothelium-derived relaxing factor (EDRF) can be released by the endothelium in response to a number of agonists, including acetylcholine, bradykinin, and norepinephrine (for review, see References 7 and 8). EDRF causes vascular relaxation by stimulation of soluble guanylate cyclase, leading to a rise in the intracellular cyclic GMP (cGMP) content. The formation of cGMP in rabbit aortic segments and bovine endothelial cells can be stimulated in a concentration-dependent fashion by the angiotensin converting enzyme (ACE) inhibitor ramipril.9 This effect may be the result of an ACE inhibitor-induced potentiation of endogenous kinins, leading to enhanced EDRF release and, subsequently, cGMP formation.

Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides.

“…In support of our finding that low doses of ACE inhibitor increase vascular levels of BK-(l-9), Gohlke et al 22 reported that low-dose (0.01 mg/kg per day) ramipril and perindopril increased aortic levels of cyclic GMP in the rat. Moreover, Linz and Scholkens 11 reported that a low, nonhypotensive dose of ramipril (0.01 mg/kg per day) prevented or reversed cardiac hypertrophy in rats with aortic coarctation, an action that was reversed by Hoe 140 effect of low-dose ramipril was not confirmed by Rhaleb et al 56 Several lines of evidence support the proposal that ACE inhibitors increase BK-(l-9) levels by a mechanism independent of inhibition of "classic" ACE.…”

“…20 This perindopril dose also decreased the lesions of hypertensive microangiopathy in the undipped kidney. 21 Gohlke et al 22 have reported that 0.01 mg/kg per day perindopril increased aortic levels of cyclic GMP in spontaneously hypertensive rats. Taken together with the present data, these studies suggest that perindopril has effects on blood pressure and cardiac and renal function at doses below the threshold for reduction in circulating and tissue (other than kidney) levels of Ang II and raise the possibility that the effects of perindopril are mediated by effects on renal Ang II levels and/or effects on tissue BK-(l-9) levels.…”

Tissue Inhibition of Angiotensin-Converting Enzyme Activity Stimulates Angiogenesis In Vivo

“…First, endothelial ACE degrades bradykinin; ACE inhibition blocks this effect, potentiating the accumulation of bradykinin, a potent activator of the L-arginine-NO pathway, which has been shown to promote growth of ECs from postcapillary venules via B1 receptors. 36 The observations that intracellular augmentation of cGMP with low doses of ramipril or perindopril 37 and cardiac capillary length density induced by ACE inhibition are both inhibited by the B 2 -receptor antagonist icatibant 15 constitute inferential evidence that bradykinin may mediate angiogenesis in response to ACE inhibitors.…”

Dermal Neurovascular Dysfunction in Type 2 Diabetes

“…Interestingly, ACE is identical to kininase II, which degrades bradykinin and other kinins to inactive metabolites. Blockade of ACE is therefore associated with increased levels of bradykinin and substance P, which are direct vasodilators and are known to stimulate the production of nitric oxide (NO), cGMP, prostaglandin E 2 and prostacyclin release from endothelium (21,22). These substances are all vasodilators and exert antiproliferative properties.…”