Angiotensin, ACE-inhibitors and endothelial control of vasomotor tone.

The renin angiotensin system and endothelium-derived vasoactive substances are both important regulators of vascular tone. Recent evidence suggests that the two systems may be tightly interconnected and drugs interfering with one system may also affect the other. Beside the circulating renin angiotensin system, a vascular wall renin angiotensin system has been postulated and various components of it have been demonstrated in endothelial and vascular smooth muscle cells. Of particular importance is the angiotensin converting enzyme (ACE) which is identical to kininase II, which breaks down bradykinin into inactive components. Bradykinin is a potent activator of the L-arginine nitric oxide system (endothelium-derived relaxing factor). Hence, ACE-inhibitors not only deactivate the pressor system, but increase the local concentrations of bradykinin and thereby stimulate a potent endothelium-derived vasodilator system. Angiotensin II not only can activate vascular smooth muscle cells (where it causes contraction and proliferation), but also endothelial cells. In certain blood vessels, angiotensin II can stimulate prostacyclin production; in addition, angiotensin II activates endothelin messenger RNA in endothelial cells. This activation of the endothelin vasopressor system increases vascular tone and enhances the local vasoconstrictor responses (due to the amplifying effects of endothelin on noradrenaline- and serotonin-induced contractions). Although the acute effects of ACE-inhibitors in isolated blood vessels are restricted to inhibition of angiotensin I-induced contractions and augmentation of bradykinin-induced endothelium-dependent relaxations, chronic therapy with the drugs appears to enhance endothelium-dependent responses to several agonists, particularly in hypertensive animals. Hence, this mechanism of action of ACE-inhibitors may account for an important vascular protective effect of the drugs. Thus, in summary, the renin angiotensin system and endothelium-derived vasoactive substances are tightly interconnected. This may be important under physiological and pathophysiological conditions, and is of importance for the action of currently available cardiovascular drugs, in particular, ACE-inhibitors.