Role of the sympathetic nervous system in the pathogenesis of chronic stable angina. Implications for the mechanism of action of beta-blockers.

Thirteen patients with chronic stable effort angina underwent continuous ambulatory electrocardiographic and intra-arterial blood pressure monitoring during normal unrestricted daily activity. Each patient underwent two studies, the first while on no treatment and the second while on beta-blocker therapy. During the control period, we recorded 182 episodes of transient ST-segment depression, of which only 30 were associated with angina, and 43 (24%) were apparently caused by increased myocardial oxygen demand. Although the majority of ischemic events (139) were not preceded by an increase in either heart rate or systolic arterial pressure, most occurred during the daytime when the levels of the rate-pressure product were higher. Throughout the day, beta-blockade significantly decreased the levels of heart rate and blood pressure and reduced the number of ischemic attacks by 56%, particularly if such attacks were not caused by increased myocardial demand. The diurnal distribution of ischemic events was not significantly affected by beta-blockade, and again, the majority were observed during the day, in coincidence with high resting levels of rate-pressure product. Whatever the behavior of heart rate and blood pressure before ischemia, ST-segment depression was invariably associated with a parallel increase in these parameters, highly suggestive of cardiac sympathetic nerve activation. We conclude that: 1) The majority of ischemic events that occurred in patients with stable angina during normal daily activity were apparently not precipitated by an excessive increase in myocardial oxygen demand but rather by transient impairment of regional myocardial perfusion. 2) The observation that most ischemic events occur when the levels of sympathetic nerve activity are high suggests that the sympathetic nervous system may play a key pathophysiological role in this syndrome, as cardiac sympathetic nerve activation can both increase metabolic demand and impair myocardial perfusion. 3) beta-Blockers significantly reduced episodes of transient myocardial ischemia in these patients, primarily by reducing cardiac metabolic requirements. The possibility that sympathetically mediated coronary vasoconstriction may also be affected by these drugs needs further investigation.

Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension.

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.