Angiotensin II and norepinephrine release: interaction and effects on the heart.

BACKGROUND: Angiotensin (Ang) II may enhance the influence of the sympathetic nervous system at various levels by facilitating norepinephrine (NE) release. We investigated whether such an interaction is evident in the human heart and whether it has an impact on left ventricular (LV) structure. METHODS AND RESULTS: Ang I and Ang II concentrations were determined in arterial and coronary sinus (CS) plasma samples in a group of normotensive (n = 10) and hypertensive (n = 18) subjects. Total systemic and cardiac NE spillover was measured using isotope dilution methodology and LV structure by echocardiography. Arterial and CS concentrations of Ang I and Ang II were similar in both groups (Ang II CS, 5.8 +/- 4.0 versus 3.7 +/- 3.1 fmol/ml; P = not significant), as was the Ang II/Ang I ratio (CS, 0.56 +/- 0.17 versus 0.54 +/- 0.22 fmol/fmol; P = not significant). Total systemic (223 +/- 145 versus 374 +/- 149 ng/min; P < 0.05) and cardiac NE spillover (11.7 +/- 6.3 versus 19.4 +/- 10.5 ng/min; P < 0.05) were increased in hypertensive patients, as was LV mass index (LVMI) (86.7 +/- 14.7 versus 117.2 +/- 19.4 g/m; P < 0.001). LVMI correlated with cardiac NE spillover (r = 0.47; P < 0.02). No correlation was evident between CS Ang II and cardiac NE spillover (r = 0.001; P = not significant) or LVMI (r = -0.20; P = not significant). Arterial Ang II tended to correlate with total systemic NE spillover (r = 0.34; P = 0.081). When hypertensive subjects were divided into two groups with either high or low CS Ang II concentration, cardiac NE spillover and LVMI did not differ between the two groups. CONCLUSION: These findings suggest a growth-promoting effect of increased cardiac sympathetic tone on cardiomyocytes in hypertensive patients, but do not support the notion of a significant role of Ang II for norepinephrine release and LV hypertrophy in the hypertensive human heart.

Rilmenidine sympatholytic activity preserves mental stress, orthostatic sympathetic responses and adrenaline secretion.

BACKGROUND: Heightened central sympathetic nervous outflow is common in essential hypertension, contributing to hypertension development and possibly also to complications. Acute sympathetic nervous activation is a proven trigger for adverse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympathetic outflow represent a theoretically attractive therapeutic option. OBJECTIVES: To study the sympatholytic and blood pressure-lowering activity of the imidazoline binding agent rilmenidine at rest and during reflex sympathetic activation. DESIGN AND METHODS: We used a randomized, double-blind, 6-week cross-over study, with a 1-week placebo run-in period, two 2-week active treatment intervals (rilmenidine 1 mg twice daily or placebo) and intervening 1-week placebo washout. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intra-arterial blood pressure measurements were performed at rest, after mental stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. RESULTS: The noradrenaline spillover rate, indicative of whole body sympathetic activity, was reduced 35% by rilmenidine at rest (P < 0.01) and remained significantly lower during mental stress and tilting, although the increases in noradrenaline spillover with both stimuli were preserved. The effects on intra-arterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in blood pressure rise during mental stress and a lack of fall in blood pressure with tilting. On placebo, adrenaline secretion was 0.88 +/- 0.15 nmol/min (mean +/- SE) at rest, increased by 0.42 +/- 0.23 nmol/min with mental stress (P = 0.019) and was unchanged with tilting. Rilmenidine left adrenaline secretion untouched under all conditions. CONCLUSIONS: The present study confirms a sympatholytic effect of rilmenidine during supine rest but preservation of sympathetic responses during mental stress and tilting, with the latter underlying a freedom from postural hypotension on the drug. The absence of suppression of reflexive sympathetic responses contrasts with the described effects of rilmenidine in experimental animals, and emphasizes the previously demonstrated unique importance in humans of suprabulbar noradrenergic neuronal projections from the brainstem in regulating tonic sympathetic activity, with these being inhibited by imidazoline binding agents. Sympathetic nervous inhibition with rilmenidine contrasted with an absence of suppression of adrenaline secretion, affirming that sympathetic nervous and adrenal medullary function can be disconnected.

Cardiac sympathetic nerve biology and brain monoamine turnover in panic disorder.

Panic disorder serves as a clinical model for testing whether mental stress can cause heart disease. Our own cardiologic management of panic disorder provides case material of recurrent emergency room attendances with angina and electrocardiogram ischemia, triggered arrhythmias (atrial fibrillation, ventricular fibrillation), and documented coronary artery spasm, in some cases with coronary spasm being complicated by coronary thrombosis. Application of radiotracer catecholamine kinetics and clinical microneurography methodology suggests there is a genetic predisposition to panic disorder that involves faulty neuronal norepinephrine uptake, possibly sensitizing the heart to symptom generation. During panic attacks there are large sympathetic bursts, recorded by clinical microneurography in the muscle sympathetic nerve neurogram, and large increases in cardiac norepinephrine spillover, accompanied by surges of adrenal medullary epinephrine secretion. In other conditions such as heart failure and presumably here also, a high level of sympathetic nervous activation can mediate increased cardiac risk. The sympathetic nerve cotransmitter, neuropeptide Y (NPY), is released from the cardiac sympathetics during panic attacks, an intriguing finding given that NPY can cause coronary artery spasm. There is ongoing, continuous release of epinephrine from the heart in panic sufferers, perhaps attributable to epinephrine loading of cardiac sympathetic nerves by uptake from plasma during panic attacks, or possibly to in situ synthesis of epinephrine through the action of intracardiac phenylethanolamine-N-methytransferase (PNMT) activated by repeated cortisol responses. We have used internal jugular venous sampling and measurement of overflowing lipophilic brain monoamine metabolites to quantify brain norepinephrine and serotonin turnover in untreated patients with panic disorder. We find normal norepinephrine turnover but a marked increase in brain serotonin turnover in patients with panic disorder, in the absence of a panic attack, which presumably represents an underlying neurotransmitter substrate for the condition.

Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation.

There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.