Reflex-hemodynamic adjustments and baroreflex sensitivity during converting enzyme inhibition with MK-421 in normal humans.

Abstract

SUMMARY Invasive hemodynamic measurements and determination of baroreflex sensitivity were carried out in 12 mildly sodium-depleted normotensive volunteers in a randomized double-blind crossover study with a single dose of converting enzyme inhibitor, MK-421, and placebo. In supine humans at rest, MK-421 caused a reduction in blood pressure through a fall in total peripheral resistance and an increase in arterial compliance. Thus, MK-421 appears to dilate both resistance vessels and larger arteries. Cardiac output increased, but contrary to the effects of other vasodilators, the increase was due to a higher stroke volume with an unchanged heart rate. The lack of heart rate response may well reflect enhanced central parasympathetic cardiac inhibition. Head-up tilt on MK-421 caused an additional decrease in blood pressure in 65% of the subjects. The major determinant for the blood pressure fall during tilt and converting enzyme inhibition was a decrease in cardiac performance, while the reflex increase of arteriolar and venous tone was largely unimpaired. The decreased stroke volume may be secondary to elimination of a positive inotropic effect of angiotensin II (All). It is also conceivable that in the absence of AH the inotropic response to sympathetic activation is inadequate during tilt in these sodium-depleted normotensive individuals. Baroreflex sensitivity to blood pressure increase (i.v. phenylephrine) was enhanced after MK 421. Arterial compliance was increased, and this may explain the altered baroreceptor sensitivity. However, a possible central nervous enhancement of baroreceptor sensitivity after MK-421 could not be ruled out in this study.

The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.

“…By that time, PCEA was dramatically decreased, PRA was increased and PA tended to decline. Systolic blood pressure was reduced by 9 ± 1 mm Hg (P < 0.05), a value in agreement with previous data in normotensive subjects (McGregor et al, 1981;Ibsen et al, 1983), but heart rate was not drug-affected. This lack of reflex tachycardia, a classical finding with all ACEIs, has led many authors to investigate the possible interference between ACEIs and BR function, since it could be accounted for either by an alteration of the BRS or by a modification of the BR set-point.…”

“…Hence, only studies in normotensive subjects really allow an assessment of the effects of a given drug on baroreflex function. Recently, Ibsen et al (1983) have shown that in those conditions enalapril displaces to the left the BR set-point and induces a slight potentiation of BRS during activation by phenylephrine. However, the study was conducted in mildly sodium depleted subjects and in addition BRS to deactivation was not investigated.…”

“…The absence of reflex tachycardia during the blood pressure fall has led a number of investigators to study the possible interferences of ACEIs with the arterial baroreflex (BR) function (Mancia et al, 1982;Warren et al, 1983;Ibsen et al, 1983). However, conflicting conclusions have often been reached, that may be accounted for by the fact that the studies were performed either in normotensive or in hypertensive subjects who in addition were often on different types of sodium diets.…”

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

“…[13][14][15] The mechanism for this increased efficacy with chronic administration is not clear but may involve the kallikreinkinin system or production of vasodilatory prostaglandins. 16 One of the characteristics of ACEis is that they lower peripheral vascular resistance without causing a compensatory increase in heart rate [17][18][19][20] or changing baroreceptor activity. 21 They also show lack of reflex tachycardia 22 and cause inhibition of the normal tonic influence of Ang II on the sympathetic nervous system.…”

Role of Norepinephrine in the Lack of Reflex Tachycardia after Angiotensin Converting Enzyme Inhibitor Treatment.

“…In some studies (Petty and Reid 1981;Mancia et al 1982 ;Ibsen et al 1983 ), angiotensin converting enzyme inhibitors have been found to increase baroreflex sensitivity, while in other studies (Coleman et al 1974) captopril appeared to have no effect on the baroreflex sensitivity. Hatton et al (1981) reported that a converting enzyme inhibitor, SQ 20881, shifted the baroreflex curve toward the left without modifying reflex sensitivity, and concluded that this shift was responsible for the lack of reflex tachycardia.…”