The 'adrenaline hypothesis' of hypertension revisited: evidence for adrenaline release from the heart of patients with essential hypertension.

OBJECTIVE: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. METHODS: Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. RESULTS: At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). CONCLUSIONS: This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.

Neural mechanisms in human obesity-related hypertension.

OBJECTIVE: Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder. DESIGN AND METHODS: Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure. RESULTS: In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals. CONCLUSIONS: The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.

The sympathetic neurobiology of essential hypertension: disparate influences of obesity, stress, and noradrenaline transporter dysfunction?

Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. This review details three relatively new findings of disturbed sympathetic neurobiology in hypertension. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, as it is in patients with panic disorder, providing presumptive evidence of exposure to high levels of mental stress in hypertensive patients. In lean patients with hypertension there is also evidence of faulty noradrenaline reuptake into the sympathetic nerves of the heart, an abnormality amplifying the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft. If both abnormalities are present in the sympathetic nerves of the kidneys also (which we did not test), there would most probably be a direct contribution to hypertension development. In the kidneys the causal chain between sympathetic overactivity and the development of hypertension is stronger than for the heart. In obesity-related hypertension there is evidence that renal sympathetic tone is high, based on approximately a doubling of the measured rate of spillover of noradrenaline into the renal veins. This increase in sympathetic outflow to the kidneys appears to be a necessary but apparently not a sufficient cause for the development of clinical hypertension, commonly being present also in overweight people with blood pressure in the normotensive range. High renal sympathetic tone in the latter, of course, may well still contribute to elevation of their pressure level, although not on such a scale as to cause clinical hypertension.

Sympathetic nervous system and insulin resistance: from obesity to diabetes.

As the world faces an obesity "epidemic," the mechanisms by which overweight is translated into insulin resistance, hypertension, and diabetes need to be better understood. Although the processes of transition remain uncertain, overactivity of the sympathetic nervous system appears pivotal. In obesity, there is stimulation of sympathetic outflow to the kidneys, evident in increased rates of spillover of noradrenaline into the renal veins, and to skeletal muscle vasculature, demonstrated with microneurography. The cause is unclear, but possibly involves the stimulatory action of leptin released from adipose tissue, or from within the brain, for which there is recent evidence in human obesity. The high renal sympathetic tone contributes to hypertension development by stimulating renin secretion and through promoting renal tubular reabsorption of sodium. Neurally mediated skeletal muscle vasoconstriction reduces glucose delivery and uptake in muscle. Impairment of glucose uptake by skeletal muscle is a hallmark of insulin resistance syndromes. Pharmacologic sympathetic nervous suppression within the central nervous system with imidazoline receptor-binding agents such as rilmenidine is a logical therapeutic approach for lowering blood pressure (BP) in patients with essential hypertension, in whom sympathetic activity is often increased. In addition, drugs of this class appear to have the capacity to favorably modify insulin sensitivity, which has particular relevance in the treatment of hypertensive diabetic patients. In the hypertension accompanying maturity onset obesity, with recent recommendations from advisory bodies setting lower goal BP, and with these lower targets often being reached only with combinations of antihypertensive agents, it is advisable that all drugs used in combination therapy have a favorable or at least a neutral effect on insulin resistance.

Sympathetic nerve biology in essential hypertension.

1. Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. There are several possible explanations for the increased spillover of noradrenaline from the kidneys and heart to plasma, a key piece of evidence supporting the neurogenic basis of essential hypertension, in addition to the obvious one of an increased rate of sympathetic nerve firing. 2. The possibility that there may be an increase in the density of sympathetic innervation in human hypertension, well documented in the spontaneously hypertensive rat, is currently under investigation by us. 3. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, presumptive evidence of their exposure to high levels of stress and a possible basis for the observed increase in cardiac noradrenaline spillover, through presynaptic augmentation of noradrenaline release. 4. Phenotypic evidence exists also of faulty noradrenaline reuptake into the sympathetic nerves of the heart in essential hypertension, an abnormality that would amplify the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft.

Phenotypic evidence of faulty neuronal norepinephrine reuptake in essential hypertension.

Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m(2)), 19 overweight (body mass index >28.0 kg/m(2)) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean+/-SD 33.4+/-20.6 versus 16.1+/-11.7 ng/min in lean normotensives, P<0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942+/-1068 versus 3055+/-888 pg/mL in healthy subjects, P:<0.05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65+/-0.19 versus 0.81+/-0.11 in healthy subjects, P<0.05). Cardiac release of the tritiated NE metabolite [(3)H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [(3)H]NE by the transporter, was reduced in lean hypertensives only (992+/-1435 versus 4588+/-3189 dpm/min in healthy subjects, P<0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.