(Circulation. 1997;96:148-153.)
© 1997 American Heart Association, Inc.
Articles |
Intracoronary Angiotensin II Potentiates Coronary Sympathetic Vasoconstriction in Humans
From the Centro di Fisiologia Clinica e Ipertensione, Università
di Milano, Ospedale Maggiore, (A.S., G.P., R.P., A.R., G.M.); Cattedra di
Medicina Interna, Università di Milano, Ospedale San Gerardo, Monza
(G.M.); Ospedale di Vimercate, (R.V.); and Centro Cuore Columbus
(L.D.F.),
1 Milan, Italy.
Correspondence to Prof Giuseppe Mancia, Cattedra di Medicina Interna, Ospedale S. Gerardo, via Donizetti 106, Monza, Milano, Italy.
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Abstract |
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Background In humans with coronary artery disease, ACE inhibition attenuates coronary sympathetic vasoconstriction. Whether this is due to removal of angiotensin (Ang) II production or to a reduced bradykinin breakdown, however, is unknown.
Methods and Results In eight normotensive patients with
angiographic evidence of mild left coronary artery lesions
(
50%), mean arterial pressure (MAP,
intra-arterial catheter), heart rate (HR, ECG lead),
coronary sinus blood flow (CBF, thermodilution method), and
coronary vascular resistance (CVR, ratio between MAP and CBF)
were measured before and during a 15-minute left intracoronary
infusion of Ang II at a dose that had no direct coronary or
systemic vasomotor effects. The same measurements were made before and
during a 15-minute infusion of saline. A 2-minute cold pressor test
(CPT) and a 45-second diving were performed at the end of either
infusion period. These maneuvers were used because their
coronary vasomotor effects are abolished by
phentolamine and thus depend on sympathetic activation. During
saline infusion, both CPT and diving caused a marked increase in MAP.
HR increased with CPT and fell with diving. CBF increased in parallel
to the MAP increase, with little change in CVR. The MAP and HR
responses were similar during Ang II infusion, which, however, caused
either no change or a reduction in CBF with a consequent marked
increase in CVR with both CPT and diving. In four additional patients,
the diameter of the stenotic vessels remained unchanged during
the CPT performed under saline and Ang II infusion.
Conclusions Ang II markedly enhances sympathetic influences on coronary circulation in humans, presumably by acting at the arteriolar level. This may explain the blunting effect of ACE inhibition on sympathetic coronary vasoconstriction in patients with coronary artery disease.
Key Words: angiotensin • nervous system, autonomic • reflex • coronary disease
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Introduction |
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We have previously shown that in subjects with angiographic evidence of severe coronary artery lesions, the marked coronary vasoconstrictor response to diving and CPT is attenuated after administration of a 25-mg dose of captopril.1 Because in both instances this vasoconstriction is mediated by an increased
-adrenergic drive,1 this demonstrates the ability of
ACE inhibition to substantially interfere with sympathetic modulation
of coronary vasomotor tone in subjects with coronary
artery disease. The mechanisms responsible for the attenuation of the sympathetic influences on human coronary circulation by ACE inhibition have never been directly investigated. It is possible that this attenuation is accounted for by a direct depressor effect of ACE inhibitors.2 3 4 It is also possible, however, that either removal of the production of Ang II and/or reduction of the breakdown of bradykinins5 6 is responsible for this phenomenon, because in animals, Ang II enhances and bradykinins reduce sympathetic vasomotor effects.7 8 9 10 11 12 13
CPT and diving cause little or no coronary vasoconstriction in subjects with normal or near-normal coronary arteries.14 15 This offered us the possibility of testing one of the above hypotheses, ie, whether in humans, Ang II enhances sympathetic coronary influences and thus allows sympathetic coronary vasoconstriction to appear when no or little vasoconstriction normally occurs.
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Methods |
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Population
We studied 8 normotensive patients (5 men and 3 women) 45 to 69 years old (56.6±2.7 years) who underwent cardiac catheterization and coronary arteriography for a history of chest pain, downward displacement of the ST segment at an exercise stress test (5 patients), or a thallium scintigram positive for myocardial ischemia (3 patients). No patient had a history or an ECG indicative of myocardial infarction, and none had clinical evidence of unstable angina, congestive heart failure, valvular heart disease, metabolic disorders, or hypertension. The patients recruited had a stenosis of the LAD ranging from 30% to 50% of the lumen, with no lesion of the left main trunk, a >50% stenosis of the right coronary artery (4 patients), and a mild stenosis (from 30% to 40%) of the left circumflex coronary artery (4 patients). Vasospasm was never found during coronary angiograms, although provocative tests were regarded as unnecessary and were not performed. We excluded patients with a stenosis of the LAD >50%, because these patients show a marked increase in CVR to CPT and diving15 even in baseline conditions. We also excluded patients with normal coronary arteries to avoid individuals with a possible syndrome X16 and thus with an abnormal reactivity to vasoconstrictor stimuli.
At measurements performed before the study proper, left ventricular end-diastolic pressure (measured by a 7F pigtail catheter) was 9.2±1.6 mm Hg, left ventricular ejection fraction (left ventricular angiography) was 69±3%, and CO (see below) was 5.9±0.8 L/min. All values were within normal limits. Each patient agreed to participate in the study after being informed of its nature and purpose. The protocol of the study was approved by the Ethical Committee of our institution.
Hemodynamic Variables
In each patient, systolic and diastolic BPs
were obtained via an 8F introducer sheath inserted
percutaneously into a femoral artery after local
anesthesia with a 2% lidocaine solution and connected to a
Statham-Gould P23ID pressure transducer (Gould Medical BV). HR was
derived from the reciprocal of the RR interval recorded by a
standard ECG lead. CBF was measured by the continuous-thermodilution
method described by Ganz et al.17 To this end, a 7F
Wilton-Webster catheter was percutaneously introduced
into a basilic vein and guided under fluoroscopy to lie in the
midproximal portion of the coronary sinus. The position of the
catheter was checked at the beginning of the study by the injection of
3 to 4 mL of contrast medium (Iopamidol 75.5 g/100 mL) and thereafter
confirmed by the spatial relationship of the catheter radiopaque
markers with the surrounding reference points. CBF measurements were
obtained by infusing a 5% glucose solution kept at room temperature
through the catheter tip at a rate of 60 mL/min and sampling the
temperature of the injectate and venous blood via a thermistor
positioned on the catheter at a level closer to the right atrium. The
pulsatile BP tracing, the ECG tracing, and the conductance at injection
and sampling sites of the thermodilution catheter were recorded on
a paper polygraph (Mingograph 7, Siemens Elema) at a speed of 10
mm/s.
Other hemodynamic measurements were (1) MAP, which was calculated as the diastolic BP plus one third of pulse pressure; (2) HR–systolic BP product, which was used as an index of myocardial metabolic requirements18 ; (3) CVR, which was calculated as the ratio between MAP and CBF; and (4) CO, which was calculated by the method of Sandler and Dodge,19 ie, by a computer-assisted analysis of the left ventricular end-diastolic and end-systolic contours as visualized by a left ventricular angiogram obtained by direct injection of contrast medium into the left ventricle via the 7F pigtail catheter.
Protocol
The protocol of the study was as follows. (1) In all patients,
antianginal drugs were withdrawn 72 hours before the study, with the
exception of short-acting nitrates, which were administered as needed.
Five patients also continued their previous intake of aspirin at a
daily dose of 100 mg. (2) The patients were brought to the
hemodynamic laboratory in the morning after a fasting
night and a premedication with 10 mg oral diazepam and 5000 U heparin
IV. (3) Coronary angiography and left ventriculography were
performed along with the measurements of left ventricular
end-diastolic pressure, left ventricular
ejection fraction, and CO. (4) After a 30- to 45-minute delay (to
minimize the potential influence of contrast medium on coronary
hemodynamics20 ), the thermodilution
catheter was positioned in the coronary sinus and the 6F left
Judkins catheter used for the coronary angiography was advanced
under fluoroscopic control into the proximal portion of the left main
coronary artery. (5) Saline was infused into the
coronary artery by a pump set at a constant rate of 1 mL/min,
and coronary and systemic hemodynamic
variables were measured at the beginning of the infusion and at the
end of a 15-minute infusion. (6) The measurements were repeated
immediately before and during the final 10 seconds of (a) a 2-minute
CPT, which was performed by immersing one patient's hand into melting
ice water, and (b) a 45-second diving, which was performed by applying
a thin plastic bag filled with ice and water to the lower face of the
patient, who was asked to hold his or her breath in moderate
inspiration. (7) Saline coronary infusion was substituted with
coronary infusion of Ang II (Hypertensin) diluted in saline to
obtain a concentration of 10 ng/mL. In each patient, the starting
infusion dose was derived from the dose of 0.625 ng·kg body
wt-1·min-1 times
the ratio between CBF and CO. The dose was doubled every 5 minutes
while CBF and BP were continuously monitored to adjust the infusion
rate at a dose immediately below the one that caused a reduction in CBF
and/or an increase in CVR. This rate was maintained for 15 minutes,
after which CPT and diving were performed again as described at
point 6.
Angiographic Study
An increase in the CVR response to CPT and diving by Ang II may
occur not only because of a potentiation of arteriolar vasoconstriction
but also because of a reduction of the vessel diameter at a site of an
atherosclerotic lesion. To investigate the latter possibility, in 4
additional normotensive patients with angiographic evidence of mild
left coronary artery disease (see below), left coronary
angiography was obtained through the manual injection of 7 to 8 mL of
contrast medium with Optimus M200 Poly Diagnostic C x-ray
equipment (Philips MSD). The injection was made (1) in baseline
conditions, (2) at the end of a 2-minute CPT performed at the 15th
minute of intracoronary saline infusion, and (3) at the end of
a 2-minute CPT performed at the 15th minute of intracoronary
infusion of Ang II at a dose (0.73±0.05 ng/min) known from data
obtained in the previous 8 patients to be devoid of direct systemic and
coronary vasomotor effects. The patients were selected because
of the visual appearance of a stenosis of the LAD (plus, in 1
patient, a stenosis of the circumflex artery) that was 50%
of the normal lumen diameter, with a concentric shape and a regular
contour, at a site not involving bifurcations. The same projection,
selected from those that allowed the best visualization of the
stenosis with no overlapping with surrounding vessels and a
good detail of the distal end of the catheter, was used in all three
conditions. The angiograms were analyzed by computer-assisted
QCA (Cardiovascular Measurement System, version 3.0,
MEDIS), the analysis being performed by an independent
observer. Catheter calibration and computer-assisted edge detection
(minimum-cost algorithm) were used to obtain the reference diameter of
normal vessel segments and the minimal lumen diameter at the
stenotic site that allowed percent values of the
stenosis to be obtained before and during CPT both during
saline and during Ang II infusions (see the example shown in Fig 4
).
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Data Analysis
CBF, BP, and HR values were calculated over periods of 10
seconds. The values obtained during application of CPT or diving were
compared with those taken immediately before the CPT and diving. Data
from individual subjects were averaged to obtain mean values (±SEM)
for the group as a whole. The differences in mean values before and
during CPT and diving were assessed by the Student's t test
for paired observations. This was done also for the differences in the
mean percent responses to CPT and diving during saline and Ang II
infusion and for the data obtained by QCA. Mean baseline values before
and after saline infusion, before and after infusion of Ang II at
subvasoconstrictor doses, and before and after infusion of Ang II at
vasoconstrictor doses were compared by ANOVA. This was done also for
the dose-finding data for intracoronary infusion of Ang II. A
value of P<.05 was always taken as the level of statistical
significance. Throughout the text, the symbol ± refers to the
SEM.
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Results |
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Saline Infusion
As shown in Table 1
, systolic BP,
diastolic BP, MAP, HR, CBF, and CVR were similar at the
beginning and after 15 minutes of saline infusion. During saline
infusion, CPT was accompanied by a marked increase in MAP and HR, a
marked increase in CBF, and no change in CVR (Fig 1).
Diving was accompanied by a marked increase in MAP, a clear-cut
reduction in HR, an increase in CBF, and a modest and not significant
increase in CVR (Fig 2).
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Ang II Dose Finding
The maximal intracoronary dose of Ang II devoid of effects
on CBF and BP ranged from 0.82 to 2.13 ng/min (average value,
1.27±0.19 ng/min). At a dose ranging from 1.63 to 4.26 ng/min (average
value, 2.54±0.39 ng/min), Ang II caused a significant reduction in CBF
(-17.5±2.1%, P<.01), with a corresponding increase in
CVR (+21.0±1.8%, P<.01).
Ang II Infusion
Table 1
shows that systemic and coronary
hemodynamics were similar before and after 15 minutes
of Ang II infusion and not significantly different from the values
observed at corresponding times of saline infusion. As shown in Figs 1 and 2, the MAP and HR responses to CPT and diving observed during
saline infusion were not modified by Ang II infusion. During Ang II
infusion, in contrast, CBF did not change with CPT and decreased with
diving, with a consequent marked and significant increase in CVR in
either condition. With both CPT and diving, the increases in CVR were
greater during Ang II than during saline infusion in each patient (Fig 3), and the difference between average responses
observed during the two infusions were highly statistically significant
(P<.01 for both stimuli). During saline infusion, there was
no relationship between the CVR increase induced by CPT and diving and
the degree of LAD stenosis (r=.21 and
r=.30, respectively, P=NS). Similarly, there was
no relationship between the LAD stenosis and the enhancement of
the CVR response to CPT and diving induced by Ang II infusion
(r=.49 and r=.30, respectively,
P=NS).
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Angiographic Study
As shown in Table 2, in the 4 patients who
underwent the angiographic study and the QCA analysis of the
data, in baseline conditions the stenosis of the affected
vessels was on average 49.4±3.0%. The stenosis was not
significantly different during the CPT performed at the end of saline
infusion. It was also not significantly different during the CPT
performed at the end of Ang II infusion. An example of the unchanged
diameter of the stenotic vessel in the three conditions is
shown in Fig 4.
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Discussion |
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In our patients with no substantial impairment of coronary circulation, CPT and diving markedly increased BP and CBF without affecting CVR to any major degree. However, when CPT and diving were performed in the same patients during intracoronary infusion of a dose of Ang II devoid of direct coronary vasomotor effects, the increase in BP was accompanied by no change or a reduction of CBF, thus indicating a marked coronary vasoconstriction. Because this vasoconstriction is due to sympathetic activation,1 this suggests that Ang II enhances sympathetic influences on coronary circulation. This is the first direct evidence of this phenomenon in humans. This evidence suggests that the blunting effect of ACE inhibition on sympathetic coronary vasoconstriction is probably accounted for by removal of Ang II formation rather than by an increase in bradykinin levels.
After intracoronary infusion of Ang II, the coronary vasoconstrictor response to diving and CPT increased several times compared with the original response, which was often barely visible. Thus, the potentiating effect of Ang II on sympathetic coronary modulation was not just a slight but rather a very marked one. An issue of major importance, however, is whether this marked potentiation is a pharmacological phenomenon or has a pathophysiological relevance. In our opinion, the latter possibility is more likely, because in our patients, baseline plasma renin activity was in the low range of normal (never >0.8 ng·mL-1·h-1) and the Ang II administered was such as to produce arterial concentrations on the order of 10 pg/mL, based on calculations of the amount of the substance infused and the CBF value. This is a concentration that can be reached in conditions in which plasma Ang II is increased, such as renal artery stenosis,21 congestive heart failure,22 23 "high-renin" essential hypertension,24 and treatment with high doses of thiazide diuretics.25 26 An enhancement of coronary sympathetic vasoconstriction may thus be among the adverse effects of an abnormal stimulation of the renin-angiotensin system. Indeed, because Ang II infusion reduced baseline CBF at a greater dose, this adverse effect may be established at a lower level of stimulation than that required for Ang II to directly increase coronary vasomotor tone.27
Our data also clarify the site at which Ang II enhances sympathetic vasoconstrictor influences. In principle, the enhancement can be due to either a greater constrictor response of arterioles or a greater reduction of arterial diameter at the stenotic level during the increase in sympathetic drive accompanying CPT and diving, because overall CVR is influenced by large artery diameter when arteries are stenotic. In our patients, however, the degree of coronary stenosis did not correlate either with the increase in CVR induced by CPT and diving during saline infusion or with the enhancement of this increase during infusion of Ang II. Furthermore, and more importantly, when quantified by QCA, the diameter of the stenotic vessels was similar before and during CPT performed under either saline or Ang II infusion. This means that the arterioles are the site at which Ang II exerts its potentiating effect on the coronary sympathetic responses.
The mechanisms through which Ang II enhances sympathetic vasoconstrictor influences are not explained by our data. However, since the amount of Ang II infused in the coronary circulation was small, it is unlikely that the systemic concentration of Ang II was sufficient to stimulate sympathetic activity at a central level,4 28 a possibility also denied by the absence of any pressor effect. A local enhancement of sympathetic influences by Ang II is therefore more likely because of (1) an augmented response of adrenergic receptors to sympathetic stimuli,9 10 11 (2) an increased norepinephrine secretion from sympathetic nerve terminals12 29 30 induced by stimulation of presynaptic angiotensinergic receptors,31 and/or (3) an increased expression of endothelial factors (eg, endothelin)32 with sympathetic excitatory effects.33 None of these possibilities can be excluded, although the interaction of an angiotensin-endothelial-sympathetic mechanism is probably less likely, because during the Ang II infusion, greater coronary sympathetic vasoconstrictions were observed in aspirin-treated patients as well, ie, when release of cyclooxygenase-dependent endothelial contracting factors was inhibited. Furthermore, recent animal data question the importance of the endothelial-sympathetic interactions in the conscious state.34 At any rate, combined with our previous observation that sympathetic vasoconstrictor responses are attenuated by ACE inhibition,1 our data unequivocally demonstrate that the renin-angiotensin system importantly affects sympathetically dependent myocardial perfusion in subjects with myocardial ischemia and that, although already occurring at the existing Ang II levels, this becomes most significant when Ang II production is increased. Whether this is the case in subjects with normal coronary arteries remains to be seen.
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Selected Abbreviations and Acronyms |
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Footnotes |
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1 Quantitative cineangiographic analysis was performed at the Centro Cuore Columbus.
Received October 28, 1996; revision received December 18, 1996; accepted January 15, 1997.
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