Antonio Saino

ACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease.

BackgroundIn humans, angiotensin converting enzyme (ACE) inhibition attenuates the vasoconstriction induced by sympathetic stimulation in a number of peripheral districts. Whether this is also the case in the coronary circulation is unknown, however. Methods and ResultsIn nine normotensive patients with angiographically assessed coronary atherosclerosis, we measured the changes in mean arterial pressure (intra-arterial catheter), heart rate, rate-pressure product (RPP), coronary sinus blood flow (CBF, thermodilution method), and coronary vascular resistance (CVR, ratio between mean arterial pressure and CBF) induced by the cold pressor test (CPT, 2 minutes) and diving (30 seconds), i.e., two stimuli eliciting a sympathetic coronary vasoconstriction. The measurements were performed in the control condition and 30 minutes after captopril 25 mg p.o. In the control condition, CPI caused an increase in mean arterial pressure and heart rate. Despite the increase in RPP (+20.7±3.2%, p<0.01), CBF did not change and CVR increased (+12.2±4.0%, p<0.05); diving caused an increase in mean arterial pressure and a reduction in heart rate. RPP increased (+14.3±3.5%, p<0.01), but despite this increase, there was a reduction in CBF and a marked increase in CVR (+37.3±7.4%, p<0.01). Captopril did not modify the blood pressure and heart rate responses to both stimuli except for a slight accentuation of the bradycardia to diving. Despite the unchanged or only slightly reduced RPP response, the increase in CVR was markedly and significantly attenuated (p<0.01). ConclusionsACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease. This is probably due to removal of the facilitating influence of angiotensin II on sympathetic modulation of coronary vasomotor tone.

Baroreflex and non-baroreflex modulation of vagal cardiac control after myocardial infarction

Vagal control of sinus node exerted by arterial baroreceptors is markedly impaired 48 hours after acute myocardial infarction (AMI), but it recovers 10 days later. However, it is unknown whether this recovery is peculiar to baroreceptor vagal control or reflects normalization of the overall vagal modulation of heart rate. In 21 untreated patients (aged 51+/-3 years, mean +/- SEM) studied 10+/-1 and 21+/-1 days after an AMI and in 13 healthy controls (aged 47+/-2 years), we examined the increases in RR interval (electrocardiogram) induced by carotid baroreceptor stimulation via a neck chamber and by immersion of the face in iced water for 15 seconds (diving reflex). Both 10 and 21 days after AMI, baseline blood pressure and RR interval values were superimposable to those obtained in controls. Ten days after AMI, the bradycardic responses to carotid baroreceptor stimulation were similar to those seen in controls (maximal RR interval lengthenings: 248+/-34 vs 270+/-31 ms, respectively, p = NS) and remained virtually unchanged later. In contrast, the bradycardic response to diving was reduced in patients after AMI compared with controls (maximal RR interval lengthenings: 203+/-43 vs 325+/-52 ms, respectively, p <0.05) and did not improve later. Thus, in AMI recovery of the early impairment of baroreceptor-heart rate control does not reflect normalization of vagal cardiac control, which remains lower than normal values at a time when the baroreflex is restored.

Intracoronary Angiotensin II Potentiates Coronary Sympathetic Vasoconstriction in Humans

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 (< or = 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.

Cardiopulmonary receptor modulation of plasma renin activity in normotensive and hypertensive subjects.

Cardiopulmonary receptors modulate renin release in several animals species. However, their involvement in reflex control of this humoral substance in humans is controversial. Furthermore, no information is available on the alteration of this control in hypertension. We studied the modulation of plasma renin activity (radioimmunoassay) in 12 normotensive subjects and in 12 age-matched subjects with untreated hypertension of mild or moderate degree. Cardiopulmonary receptors were stimulated by increasing central venous pressure (right atrial catheter) and cardiac volume (echocardiographic measurement) through passive leg raising and deactivated by reducing central venous pressure and cardiac volume through lower body negative pressure. The stimuli were maintained for 20 to 30 minutes, and their degree was set to avoid changes in blood pressure (indirect or direct measurements) and heart rate, thus avoiding involvement of arterial baroreceptors. In normotensive subjects, deactivation of cardiopulmonary receptors induced a progressive rise in plasma renin activity and stimulation of cardiopulmonary receptors induced a progressive fall. The reflex gain (ratio between plasma renin activity and central venous pressure or cardiac volume changes) was similar for deactivation and stimulation. During cardiopulmonary receptor deactivation, the gain corresponded to that obtained by dividing the increase in plasma renin by the reduction in central venous pressure induced by tilting. Cardiopulmonary receptor deactivation and stimulation also induced clear-cut changes in plasma renin activity in hypertensive subjects, but the percent magnitude of the reflex plasma renin activity excursion was less than that in normotensive subjects. These observations indicate that cardiopulmonary receptors modulate plasma renin activity in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of angiotensin converting enzyme inhibition on cardiovascular regulation during reflex sympathetic activation in sodium-replete patients with essential hypertension

In order to investigate whether angiotensin II (Ang II) may contribute to cardiovascular regulation through facilitation of the adrenergic function, we examined the haemodynamic and humoral effects of the application of lower-body negative pressure (LBNP) in sodium-replete patients with essential hypertension before and after acute and chronic angiotensin converting enzyme (ACE) inhibition. We measured the changes in blood pressure, heart rate, central venous pressure, forearm blood flow, plasma noradrenaline, renin activity and Ang II induced by LBNP of two different magnitudes: a milder one deactivating predominantly the cardiopulmonary receptors (mild LBNP), and a greater one deactivating both the cardiopulmonary and the arterial baroreceptors (strong LBNP). We found that during mild LBNP systemic blood pressure was maintained after acute and chronic ACE inhibition, as in control studies; however, the decrements in forearm blood flow and the increments in forearm vascular resistance caused by LBNP were diminished after ACE inhibition (the latter by 69 and 67%, respectively, in acute and chronic studies), in spite of the fact that the falls in central venous pressure and the increases in noradrenaline (NA) were similar to those observed in control conditions. During strong LBNP, the fall in systemic blood pressure was greater after acute and chronic ACE inhibition than in control conditions and was associated with a reduction in the response of forearm vascular resistance similar to that observed during mild LBNP, while the increments in NA were again superimposable to those seen before ACE inhibition. These alterations in the haemodynamic responses to LBNP induced by ACE inhibition were associated with significant increments in basal plasma renin activity and with marked reductions in Ang II. These findings suggest that even in the sodium-replete state, Ang II exerts a facilitatory action on adrenergic function that is physiologically relevant for the regulation of forearm blood flow and the maintenance of blood pressure during the application of gravitational stresses.

Modulation of Sympathetic Coronary Vasoconstriction by Cardiac Renin-Angiotensin System in Human Coronary Heart Disease

BACKGROUND In humans, angiotensin II enhances the sympathetic coronary vasoconstriction elicited by the cold pressor test (CPT) and diving. Whether this enhancement depends on the circulating angiotensin II or on the locally produced angiotensin II is unknown, however. METHODS AND RESULTS We addressed this issue in 14 patients with severe coronary artery disease by evaluating the effects of a 2-minute CPT (n=14) and a 30-second dive (n=8) on mean arterial pressure (MAP, arterial catheter), heart rate (ECG), coronary sinus blood flow (CBF, thermodilution technique), and coronary vascular resistance (MAP/CBF ratio). The 2 stimuli were applied at the end of left intracoronary infusion of either saline or benazeprilat diluted at the concentration of 25 microgram/mL. The rate of benazeprilat infusion had been preliminarily demonstrated to reduce angiotensin II concentration in the coronary sinus without affecting its arterial concentration. The changes in MAP and heart rate induced by CPT and diving were superimposable during saline and benazeprilat infusions. The decrease in CBF induced by CPT and diving during saline infusion was changed into an increase during benazeprilat infusion with a significant attenuation of the coronary vasoconstrictor response. CONCLUSIONS In patients with coronary artery disease, an attenuation of sympathetic coronary vasoconstriction can be obtained by reducing cardiac angiotensin II formation without involving circulating angiotensin II. This suggests a role of the tissue renin-angiotensin system in modulating autonomic cardiac drive in humans.

Impairment of the arterial baroreflex during symptomatic and silent myocardial ischemia in humans

OBJECTIVES The aim of this study was to assess whether transient episodes of symptomatic or silent myocardial ischemia after baroreceptor modulation of heart rate. BACKGROUND Animal and human studies have shown that myocardial infarction is accompanied by an impairment of the baroreceptor influences on the sinus node. However, whether this also occurs during transient myocardial ischemia has never been documented. METHODS In 12 patients undergoing coronary angiography, systolic blood pressure (intraarterial catheter) was reduced by an intravenous bolus of nitroglycerin during a spontaneous episode of transient chest pain and myocardial ischemia (ST segment depression on the electrocardiogram) and 30 min after recovery. The slope of the linear regression between the decrease in systolic blood pressure and the RR interval shortening was taken as the measure of baroreflex sensitivity. RESULTS During ischemia, baroreflex sensitivity was 1.3 +/- 0.3 ms/mm Hg (mean +/- SEM), whereas after recovery it was markedly and significantly greater (2.6 +/- 0.5 ms/mm Hg, p < 0.01). Similar results were obtained in eight other patients who experienced a silent ischemic episode either spontaneously or during coronary angioplasty. The reduction in baroreflex sensitivity was similarly pronounced during inferior (10 patients) and anterior (10 patients) ischemia, and its magnitude showed little or no relation to the ischemia-dependent changes in blood pressure and heart rate. CONCLUSIONS Transient myocardial ischemia is associated with marked baroreflex impairment. The impairment occurs even during symptomless ischemic episodes and is therefore not related to pain or to other nonspecific influences on the baroreflex.

Control of circulation by arterial baroreceptors and cardiopulmonary receptors in hypertension.

This article reviews observations made on reflex control of circulation in essential hypertension and in a few models of experimental hypertension. It is emphasized that a wide consensus exists on the fact that baroreceptor control of heart rate is impaired in essential hypertension and that this occurs not only in severe but also in mild and borderline hypertensive conditions. On the other hand, baroreceptor control of blood pressure is much less affected by chronic elevations in arterial blood pressure due to central or peripheral factors that differentially affect cardiac and vascular responses to the vagus and the sympathetic drive, respectively. Cardiopulmonary receptor control of peripheral circulation and renin release is also little affected by hypertension, and the suggestion has been made that its sensitivity may even be enhanced in early hypertensive stages and then undergoes a subsequent reduction as cardiac hypertrophy develops. Finally, the possible consequences of preservation of reflex control of circulation in hypertension are discussed. It is speculated that this phenomenon may be in part responsible for the similar percentage of blood pressure oscillations that can be observed in normotensive and borderline, moderate, and severe hypertensive subjects.

Calcium antagonists and neural control of circulation in essential hypertension.

Data from animals and from man suggest that calcium antagonists interfere with aadrenergic receptors and that this mechanism may be responsible for some of the vasodilation induced by these drugs. However, a-adrenergic receptors play a primary role in baroreceptor regulation of the cardiovascular system and blood pressure homeostasis, which might therefore be adversely affected by calcium antagonist treatment. We addressed this question in 14 essential hypertensives studied before treatment, 1 h after 20 mg oral nitrendipine and 5-7 days after daily administration of 20 mg oral nitrendipine. Blood pressure was measured by an intra-arterial catheter, heart rate by an electrocardiogram, cardiac output by thermodilution and forearm blood flow by venous occlusion plethysmography. Total peripheral and forearm vascular resistances were calculated by dividing mean blood pressure by blood flow values. Plasma norepinephrine was also measured (high performance liquid chromatography) in blood taken from the right atrium. Compared with the pretreatment values, acute nitrendipine administration caused a fall in resting blood pressure, an increase in the resting heart rate and cardiac output, and a fall in resting peripheral and forearm vascular resistance. The resting hypotension and vasodilation were also evident during the prolonged nitrendipine administration, which was, however, accompanied by much less resting cardiac stimulation than that observed in the acute condition. Baroreceptor control of the heart rate (vasoactive drug method) was similar before and after acute and prolonged nitrendipine treatment. This was also the case for carotid baroreceptor control of blood pressure (neck chamber technique) and for control of forearm vascular resistance as exerted by receptors in the cardiopulmonary region (lower-body negative- pressure and passive leg-raising techniques). The increases in blood pressure, cardiac output and total peripheral resistance induced by a cold pressor test and isometric exercise were also superimposable before and after the acute and more prolonged administration of nitrendipine. Even the cardiovascular adjustments to dynamic exercise (increase in blood pressure, heart rate and cardiac output, decrease in peripheral resistance) were superimposable before and after drug administration. These observations show that reflex control of circulation and blood pressure homeostasis are not adversely affected by acute and prolonged administration of nitrendipine at doses capable of exerting an antihypertensive effect. Although this does not exclude an a-blocking action by this drug, it indicates that any such action does not interfere with sympathetic cardiovascular control.

Hemodynamic effects of acute and prolonged administration of nitrendipine in essential hypertension

In six hospitalized subjects with mild or moderate and untreated essential hypertension, we measured mean blood pressure (MBP, brachial artery catheter), heart rate (HR, electrocardiogram), cardiac output (CO, thermodilution), and total peripheral resistance (TPR, MBP divided by CO) at rest and during a cold pressor test (CPT, 60 s), a hand-grip exercise (HG, 40% maximum strength for 90 s), and a cyclette exercise (CE, 50 W for 5 min). The study was performed in a no-drug condition, 1 h after 20 mg oral nitrendipine (aN) and 1 week after daily administration of 20 mg oral nitrendipine (pN). Compared with the no-drug condition, aN reduced resting MBP from 137.3 +/- 7.3 (mean +/- SEM) to 112.3 +/- 9 mm Hg (p less than 0.05), increased resting HR from 72.3 +/- 6.9 to 85.3 +/- 8.8 beats/min) (p less than 0.05), increased resting CO from 6,191 +/- 508, to 8,700 +/- 1,050 ml/min (p less than 0.05), and reduced resting TPR from 1,807 +/- 119 to 1,140 +/- 228 dynes/s/cm5 (p less than 0.05). The reduction in resting MBP and TPR were unchanged by pN, whereas the increase in HR and CO were attenuated by 47 and 42%, respectively (p less than 0.05). Neither aN nor pN altered the hemodynamic responses to CPT, HG, and CE. As a result, the peak MBP and TPR values that were measured during these maneuvers were always lower (p less than 0.05) during aN and pN than in the no-drug condition. Thus, nitrendipine exerts marked antihypertensive and vasodilatatory effects that are evident at rest and during conditions elevating BP.(ABSTRACT TRUNCATED AT 250 WORDS)