Sensitization of human alpha 1- and alpha 2-adrenergic venous responses by guanadrel sulfate

The alpha 1- and alpha 2-adrenergic venoconstriction in dorsal hand veins of normal subjects was determined by infusion of phenylephrine or clonidine. Oral administration of prazosin reduced the constriction response to phenylephrine but not to clonidine. Subjects were treated for 3 weeks in a randomized crossover design with placebo or guanadrel sulfate. Guanadrel reduced sympathetic tone (i.e., plasma norepinephrine and norepinephrine release rate), whereas venous responses to phenylephrine and clonidine were both augmented during guanadrel treatment. The effect on phenylephrine responses was primarily attributable to a decrease in the median effective concentration with a small increase in maximum response. Clonidine showed a markedly increased maximum response with a small increase in the median effective concentration. Platelet alpha 2-adrenergic receptors increased slightly but there was no change in the amount of platelet pertussis toxin substrate during guanadrel treatment. Thus reduction in sympathetic tone in normal young men results in increased venous responses to both alpha 1- and alpha 2-agonists.     

Variations in circulating catecholamines fail to alter human platelet alpha-2-adrenergic receptor number or affinity for [3H]yohimbine or [3H]dihydroergocryptine.

A series of studies were performed to determine the relationship between physiologic levels of circulating plasma norepinephrine and epinephrine and human platelet alpha-2 binding site number and the affinity (KD) of these sites for antagonist radioligands. In one study, alpha-2-adrenergic binding site number and affinity were compared using both [3H]yohimbine and [3H]dihydroergocryptine as radioligands. There was good absolute and relative comparison for binding site number, but only a relative relationship for KD. In 46 normal subjects, there was no significant relationship between site number or KD and age, plasma epinephrine, or plasma norepinephrine concentration. Even after plasma epinephrine was raised nearly 20-fold by means of an intravenous infusion for 4 h in seven normal subjects, neither sites (608 +/- 68 vs. 567 +/- 120 sites/platelet) nor KD (2.01 +/- 0.94 vs. 2.14 +/- 1.15 nM) were significantly changed. Similarly, neither sites (445 +/- 55 vs. 421 +/- 53 sites/platelet) nor KD (1.44 +/- 0.29 vs. 2.10 +/- 0.75 nM) were significantly changed in six normal subjects when plasma norepinephrine levels increased during oral administration of prazosin for 1 wk. Thus, in a cross-sectional analysis and after a change in plasma catecholamine concentrations, there was no relationship in normal subjects between platelet alpha-2 binding site number or affinity of these sites for antagonist radioligands and the circulating catecholamine levels to which the platelets were exposed. In a group (n = 7) of patients who lack epinephrine-induced platelet aggregation due to abnormal thrombopoiesis, binding site number was decreased (304 +/- 36 vs. 572 +/- 29 sites/platelet, P less than 0.001) and KD tended to be greater (8.69 +/- 2.44 vs. 5.40 +/- 0.31 nM, P = NS) than in normal subjects (n = 46), despite having similar plasma catecholamine levels. There was no difference in binding site number (491 +/- 116 sites/platelet) and KD (5.61 +/- 0.84 nM) in patients (n = 5) with autonomic insufficiency and low levels of upright plasma norepinephrine when compared with the normal subjects. Two patients were examined before and after the removal of a pheochromocytoma. Their binding site number and KD were normal before the operation and essentially unchanged after the tumor removal and fall of plasma catecholamines. Thus, this study demonstrates that within the physiologic and pathophysiologic range of plasma catecholamines (in men), there is no relationship between the circulating catecholamine concentration and either platelet alpha-2 adrenergic binding site number or the affinity of these sites for antagonist radioligands.     

The effects of ramipril on sympathetic nervous system function in older patients with hypertension

BACKGROUND: There are important interactions between the renin-angiotensin system and the sympathetic nervous system. Therapy with angiotensin-converting enzyme (ACE) inhibitors may suppress sympathetic nervous system activity. OBJECTIVE: To test the hypothesis that long-term ACE inhibition by ramipril will suppress sympathetic nervous system activity and up-regulate alpha-adrenergic receptor responsiveness in older patients with hypertension. METHODS: This placebo-controlled, double-blind randomized study was conducted at the University Hospital, General Clinical Research Center, University of Michigan Medical Center. Fifteen healthy older patients with mild to moderate hypertension received 8 weeks of ramipril therapy with doses ranging from 5 mg to 20 mg. The following measurements were obtained: plasma norepinephrine levels; norepinephrine kinetic parameters derived from plasma norepinephrine and 3H-norepinephrine levels obtained during infusion and disappearance of 3H-norepinephrine, including the extravascular norepinephrine release rate, norepinephrine clearance, spillover fraction, and volume of distribution; forearm blood flow; platelet membrane alpha2-receptor binding characteristics, and adenylyl cyclase activity. RESULTS: Although plasma norepinephrine levels increased in the subjects treated with ramipril, there were no significant differences from baseline in the rate of norepinephrine appearance into the vascular compartment (P = .76) or in the rate of norepinephrine release into the extravascular compartment (P = .92). In addition, no differences were observed in other norepinephrine kinetic parameters (norepinephrine spillover fraction, norepinephrine volume of distribution, or clearance) between the ramipril and placebo groups. Consistent with this, there was no apparent change in measures of vascular or platelet alpha-adrenergic receptor responsiveness. CONCLUSIONS: Ramipril therapy did not suppress systemic sympathetic nervous system activity, alter other norepinephrine kinetic parameters, or alter alpha-adrenergic responsiveness in older patients with hypertension.     

Mechanism of increased alpha adrenergic vasoconstriction in human essential hypertension.

Multiple components of vascular alpha adrenergic responsiveness were investigated in twenty-four men with mild hypertension and eighteen age- and weight-matched normotensive controls. Arterial plasma norepinephrine (paNE), an index of sympathetic drive, was increased in hypertensives compared to normotensives (mean +/- SE), 199 +/- 24 vs. 134 +/- 11 pg/ml, P less than 0.02. The effective concentration of intra-arterial (iaNE) increasing forearm vascular resistance (FAVR) 30% (NE-EC30, an index of vascular alpha-receptor sensitivity) was similar in normotensives and hypertensives, 9 +/- 1 vs. 13 +/- 3 ng/100 ml per min, respectively, P greater than 0.3. The phentolamine induced reduction in FAVR, an index of vascular alpha-tone, was greater in hypertensives, -21.3 +/- 1.8 vs. normotensives, -14.9 +/- 1.2 U, P less than 0.02. We interpret these data as evidence for normal vascular alpha-receptor sensitivity to norepinephrine in mild hypertensives. Consequently, the increased sympathetic drive in mild hypertensives explains the elevated vascular alpha-tone. Although vascular alpha-receptor sensitivity to iaNE was normal, the FAVR responses at high doses (reactivity) were greater in hypertensives to regional infusion of both NE and angiotensin II. This "nonspecific" enhancement of vascular reactivity is probably explained by structural vascular changes in hypertensives.     

Homologous upregulation of human arterial alpha-adrenergic responses by guanadrel.

The purpose of this study was to test the hypothesis that there is homologous upregulation of arterial alpha-adrenergic responsiveness during suppression of sympathetic nervous system (SNS) activity in humans. 10 subjects (19-28 yr) were studied during placebo and when SNS activity was suppressed by guanadrel. Changes in forearm blood flow (FABF) mediated by the intraarterial infusion of norepinephrine (NE), angiotensin II (AII), and phentolamine were measured by plethysmography. During guanadrel compared with placebo, plasma NE levels (1.28 +/- 0.09-0.85 +/- 0.06 nM; P = 0.0001) and the extra vascular NE release rate derived from [3H]NE kinetics were lower (7.1 +/- 0.7-4.0 +/- 0.2 nmol/min per m2; P = 0.0004), suggesting suppression of SNS activity. During guanadrel, there was increased sensitivity in the FABF response to NE (analysis of variance P = 0.03). In contrast, there was no difference in the FABF response to AII (analysis of variance P = 0.81), suggesting that the upregulation observed to NE was homologous. The increase in FABF during phentolamine was similar during guanadrel compared with placebo (guanadrel: 141 +/- 37 vs. placebo; 187 +/- 27% increase; P = 0.33), suggesting that there was at least partial compensation to maintain constant endogenous arterial alpha-adrenergic tone. We conclude that there is homologous upregulation of arterial alpha-adrenergic responsiveness in humans when SNS activity is suppressed by guanadrel.     

Increase in human platelet alpha 2-adrenergic receptor affinity for agonist in unstable angina

Spontaneous increase in platelet activity and change in coronary vasomotor tone have been implicated in the pathogenesis of acute myocardial ischemia. To define the mechanism of platelet "hypersensitivity" in acute myocardial ischemia, we examined the status of platelet alpha 2-adrenergic receptors in patients hospitalized with severe unstable angina. With the use of the specific alpha 2-receptor antagonist 3H-yohimbine, we identified a 26% decrease in the receptor binding sites on platelet membranes from patients with unstable angina compared with controls (155 +/- 32 vs. 210 +/- 29 fmol/mg protein, P less than or equal to 0.005). The dissociation constants of 3H-yohimbine binding to platelet alpha 2-receptors were similar in both groups (3.3 +/- 1.1 and 4.1 +/- 1.6 nmol/L, P not significant). To study the alterations in the affinity of platelet alpha 2-receptors for the agonists, effects of 1-epinephrine on specific binding of 3H-yohimbine were examined. We observed a marked reduction in 1-epinephrine concentration for inhibition of antagonist binding by 50% in acute myocardial ischemia (IC50: 4.2 +/- 3.9 X 10(-8) vs. 6.7 +/- 3.4 X 10(-7) mol/L, P less than or equal to 0.01), indicating increase in platelet alpha 2-receptor affinity for the agonist. Platelet aggregation and thromboxane A2 generation in response to epinephrine were also significantly increased in the acute phase of myocardial ischemia. This study suggests enhanced affinity of platelet alpha 2-receptors to the agonist 1-epinephrine as a possible mechanism of platelet hypersensitivity in acute myocardial ischemia.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Propranolol decreases sympathetic nervous activity reflected by plasma catecholamines during evolution of myocardial infarction in man.

Plasma 1-norepinephrine and epinephrine contents were strikingly elevated in 70 patients during evolution of myocardial infarction. Propranolol or placebo, 0.1 mg/kg i.v., was administered randomly an average of 10 h after infarction and continued orally for 3 d. Propranolol, but not placebo, acutely decreased 1-norepinephrine contents from 2.24 +/- 1.33 (mean +/- SD) to 1.31 +/- 0.74 microgram/liter, P less than 0.001, and epinephrine contents from 0.97 +/- 0.42 to 0.74 +/- 0.42 microgram/liter, P less than 0.02. Decreases in 1-norepinephrine contents were related to the initial plasma concentrations, r = 0.85, P less than 0.001. A similar, but less strong relationship was observed between the initial epinephrine contents and propranolol-induced changes, r = -0.51, P less than 0.01. Propranolol reduced plasma-free fatty acid contents from 1,121 +/- 315 to 943 +/- 274 mumol/liter, P less than 0.001. Decreases in plasma contents of free fatty acids were related to decreases in epinephrine, r = 0.66, P less than 0.001. Propranolol did not cause significant additional changes in plasma catecholamine contents during the subsequent 3 d. In the placebo group 1-norepinephrine contents had decreased 24 h after infarction from 1.92 +/- 0.99 to 1.37 +/- 0.93 microgram/liter, P less than 0.02. Plasma epinephrine contents did not change. Heart rate remained below the control values during the entire study period in the propranolol, but increased in the placebo group. The data indicate that sympathetic hyperactivity, indirectly reflected by plasma catecholamine contents, is acutely reduced by propranolol during evolution of myocardial infarction.     

Effects of enalapril maleate on blood pressure, renin-angiotensin-aldosterone system, and peripheral sympathetic activity in essential hypertension

Recent experimental studies showed that inhibition of angiotensin II synthesis may reduce sympathetic activity as evaluated by plasma catecholamine assay, sharing in the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. Fifteen patients with essential hypertension were studied. Blood pressure and heart rate were evaluated both at rest and after stressor laboratory tests, before and four hours after administration of 20 mg of enalapril maleate and on the 14th and 120th days of continued administration. At the same time, blood samples were drawn for determinations of plasma renin activity, ACE, angiotensin II, plasma aldosterone concentration, and plasma norepinephrine levels. Enalapril in a dosage of 20 mg/day significantly and progressively lowered systolic and diastolic blood pressure at rest, with maximal decreases observed on the 120th day of the study period (P less than 0.001). Heart rate at rest and after exercise showed no significant differences throughout the study period. Good blood pressure control was observed during stressor laboratory tests. The greatest impact of blood pressure was observed on the 120th day during dynamic exercise (mean blood pressure from 139 +/- 3.9 to 111.5 +/- 6.3 mmHg; P less than 0.01) and on the 14th day during the cold pressure test (mean blood pressure from 133.3 +/- 3.9 to 111.2 +/- 4.7 mmHg; P less than 0.005). A marked and persistent ACE inhibition and a gradual and progressive decrease of angiotensin II (from 12.42 +/- 2.15 to 5.45 +/- 1.68 pg/ml; P less than 0.005) characterized the humoral activity of enalapril maleate. Moreover, a significant decrease of plasma norepinephrine levels was observed during the follow-up period with maximal reduction on the 120th day (from 311 +/- 34 to 197 +/- 33 pg/ml; P less than 0.01). It has been demonstrated that the pressor effect of angiotensin II was blunted during exercise. Our hemodynamic and humoral results appear to confirm the hypothesis that enalapril maleate may reduce blood pressure by direct inhibition of ACE and of kininase II as well as by a decreased sympathetic output, which may be secondary to angiotensin II inhibition. These results agree with the recent experimental demonstration of a reduced sympathetic nervous response to nerve stimulation during ACE inhibition.     

Cold-induced changes in plasma norepinephrine, epinephrine and dopamine concentrations in patients with Raynaud's phenomenon

To investigate the role of the sympathetic system in Raynaud's phenomenon, which has not yet been elucidated, we measured the levels of norepinephrine, epinephrine and dopamine before, immediately and 30 min after the cold pressor test in plasma from 17 patients with primary, 6 with secondary Raynaud's phenomenon and 19 volunteers, matched for age and sex. Patients had significantly low baseline epinephrine (0.13 +/- 0.02 vs 0.37 +/- 0.04, nmol/l, p less than 0.001, mean +/- S.E.), but normal norepinephrine and dopamine (norepinephrine: 1.77 +/- 0.16 and 2.06 +/- 0.18; dopamine: 0.10 +/- 0.01 and 0.11 +/- 0.02, patients and controls). Immediately after the cold test norepinephrine significantly increased (p less than 0.001) in patients (2.42 +/- 0.22) and controls (3.24 +/- 0.28); epinephrine increased in patients (0.18 +/- 0.02, p less than 0.02); dopamine did not show any significant change (0.13 +/- 0.01 and 0.13 +/- 0.02, patients and controls). In the recovery period, while norepinephrine and epinephrine returned to baseline in both groups, dopamine increased in controls (0.21 +/- 0.04, p less than 0.005) but remained unchanged in patients (0.11 +/- 0.01). We conclude that there is no sympathetic overactivity in Raynaud's phenomenon and propose a role for circulating dopamine in post-ischaemic vasodilatation as an explanation for the particular behaviour of dopamine.     

Venous responsiveness to norepinephrine in healthy subjects: effects of single doses of 325 mg aspirin

BACKGROUND: Antithrombotic doses of aspirin, which are widely used in patients with cardiovascular disease, may inhibit prostaglandin synthesis but the physiologic significance with regard to vascular tone is not well defined. We hypothesized that inhibition of vasodilator prostaglandin synthesis by aspirin would significantly increase sympathetic-mediated venoconstriction. METHODS: Twelve healthy volunteers (mean age, 24.5 +/- 0.8 years; age range, 19 to 30 years) were studied on two mornings approximately 7 days apart and not less than 90 minutes after a randomized single dose of 325 mg aspirin or matching placebo. Distension of dorsal hand veins was measured with use of the linear variable differential transformer technique during local infusions of exogenous norepinephrine (0.125 to 1,024 ng/min) and during release of endogenous norepinephrine from sympathetic activation by a forehead cold pressor test. Hemodynamic parameters and venous plasma catecholamine levels were measured. Antiplatelet activity of the dose of aspirin was confirmed in three subjects. RESULTS: Aspirin increased venoconstriction to norepinephrine, causing a significant shift to the left (P < .03) of the norepinephrine dose-response curve and a significant decrease in logED50 (P < .03), representing a decrease in the dose of norepinephrine required to reduce vein distension by 50% from 50 to 25 ng/min. Venoconstriction to the cold pressor test was significantly increased by aspirin (10% +/- 3% versus 3% +/- 1% for placebo; P < .02). Cold pressor-induced increases in mean arterial pressure were significantly larger with aspirin compared with placebo (18 +/- 1 versus 14 +/- 1 mm Hg, respectively; P < .03). Baseline levels and stress-induced increases in plasma norepinephrine were not different between days. CONCLUSIONS: The results suggest that aspirin inhibits the role of vasodilator prostaglandins in modulating peripheral venoconstriction and increases vascular resistance during physiologic stress in young healthy subjects.     

Direct relationship between mononuclear leukocyte and lung beta-adrenergic receptors and apparent reciprocal regulation of extravascular, but not intravascular, alpha- and beta-adrenergic receptors by the sympathochromaffin system in humans.

To examine putative relationships between adrenergic receptors on accessible circulating cells and relatively inaccessible extravascular catecholamine target tissues, we measured mononuclear leukocyte (MNL) and lung beta-adrenergic receptors and platelet and lung alpha-adrenergic receptors in tissues obtained from 15 patients undergoing pulmonary resection. Plasma catecholamine concentrations were measured concurrently to explore potential regulatory relationships between the activity of the sympathochromaffin system and both intravascular and extravascular adrenergic receptors. MNL and lung membrane beta-adrenergic receptor densities were correlated highly (r = 0.845, P less than 0.001). Platelet alpha 2-adrenergic receptor and lung alpha 1-adrenergic receptor densities were not. Lung alpha 1-adrenergic receptor densities were positively related to plasma norepinephrine (r = 0.840, P less than 0.01) and epinephrine (r = 0.860, P less than 0.01) concentrations; in contrast, lung beta-adrenergic receptor densities were not positively related to plasma catecholamine concentrations (they tended to be inversely related to plasma norepinephrine and epinephrine [r = -0.698, P less than 0.05] levels). This apparent reciprocal regulation of alpha- and beta-adrenergic receptors by the sympathochromaffin system was only demonstrable with adrenergic receptor measurements in the extravascular catecholamine target tissue. Neither MNL beta-adrenergic receptor nor platelet alpha-adrenergic receptor densities were correlated with plasma catecholamine levels. Thus, although measurements of beta-adrenergic receptors on circulating mononuclear leukocytes can be used as indices of extravascular target tissue beta-adrenergic receptor densities (at least in lung and heart), it would appear that extravascular tissues should be used to study adrenergic receptor regulation by endogenous catecholamines in humans. These data provide further support for the concept of up regulation, as well as down regulation, of some adrenergic receptor populations during short-term activation of the sympathochromaffin system in humans.     

Alpha-adrenergic responses in asthma

Medication-free subjects with asthma who had normal pulmonary function were evaluated for alpha 1-adrenergic sensitivity by determination of the dose of topical phenylephrine required for mydriasis and for alpha 2-adrenergic responsiveness by determination of the inhibition by norepinephrine of adenosine 3',5'-cyclic monophosphate synthesis in platelets. Asthmatic subjects required significantly lower concentrations of phenylephrine for mydriasis than normal individuals (1.20 +/- 0.38% vs. 1.53 +/- 0.57%, p less than 0.05), indicating increased sensitivity. However, platelet alpha 2-adrenergic responses were normal in these same asthmatic subjects, as were alpha 2-receptor number and antagonist affinity determined by Scatchard analysis of equilibrium binding of [3H]-yohimbine to platelet particulates. These data suggest that the autonomic aberrations associated with asthma do not extend to the alpha 2-adrenergic system of the platelet, and that the alpha 1-adrenergic hypersensitivity cannot be attributed to medication use or pulmonary dysfunction, but might be an intrinsic property of the disease.     

Alpha-1-adrenergic blockade and lipoprotein metabolism in essential hypertension

The effect of the selective alpha 1-antagonist terazosin on serum lipoproteins and certain blood pressure-regulating factors was assessed in 15 patients with essential hypertension. Terazosin given during 8 weeks reduced arterial pressure (from 153/103 +/- 3/2 (SE) to 143/96 +/- 5/2 mm Hg; P less than 0.02) but did not modify body weight, heart rate, blood volume, plasma renin activity, aldosterone and catecholamine levels, or serum cholesterol, triglycerides, and their lipoprotein fractions. In nine of the patients, blood pressure control was not achieved with terazosin monotherapy and the diuretic methyclothiazide, 2.5 mg, was added. After 8 weeks of combined treatment, blood pressure decreased further (P less than 0.05); serum lipids and lipoprotein fractions did not change as compared with placebo or terazosin conditions. These findings indicate that terazosin in monotherapy does not unfavorably influence lipid metabolism.     

Alterations in norepinephrine content and beta adrenoceptor regulation in myocardium bordering aneurysm in human heart: their possible role in the genesis of ventricular tachycardia

On the assumption that alterations in the adrenergic system may play a role in generating ventricular tachycardia in patients with myocardial post-infarction apical aneurysm, we evaluated norepinephrine concentration, number and affinity of both beta 1 and beta 2 adrenoceptors in perianeurysmatic tissue in twelve patients operated upon for congestive heart failure and recurrent sustained ventricular tachycardia. Concentration of norepinephrine in perianeurysmatic tissue was 0.1 +/- 0.05 micrograms g-1 tissue (n = 8), this value being much lower than that found in papillary muscle (n = 10) from patients with mitral valve stenosis (0.8 +/- 0.02 micrograms g-1 tissue) (P less than 0.01). The total number of beta adrenoceptors (71.4 +/- 7.8 v. 48.0 +/- 5.1 fmol mg-1 protein; P less than 0.01) and the percentage of beta 1 subtype were found to be higher in perianeurysmatic tissue (approximately 90%) than in papillary muscle (approximately 68%). Out of twelve patients with aneurysm, beta 2 adrenoceptors had considerably decreased in three patients and were absent in the remaining nine. Decrease in the neuronally released norepinephrine associated with contrasting behaviours of beta 1 and beta 2 adrenoceptors suggests the presence of a profound alteration in the sympathetic innervation of the perianeurysmatic myocardial tissue that may contribute to the genesis of sustained ventricular tachycardia in patients with postinfarction apical aneurysm.     

Decreased myocardial adenyl cyclase activity in hypothyroidism

It has been suggested that hypothyroidism may alter the responsiveness of the heart to sympathetic stimulation. To define more precisely the interrelationship between hypothyroidism and catecholamine responsiveness we: (a) studied the effects of norepinephrine and fluoride on the activation of adenyl cyclase in the particulate fraction of heart homogenates from euthyroid and hypothyroid cats; and (b) assessed the contractile response of isolated right ventricular papillary muscles from the same cats to increasing concentrations of norepinephrine. It was found that maximal accumulation of cyclic 3',5'-adenosine monophosphate (3',5'-AMP) was significantly lower at peak norepinephrine concentrations in the hypothyroid (284 +/-5 pmoles) than in the euthyroid group (326 +/-10 pmoles) (P < 0.02). However, the K(m) for norepinephrine was similar in both groups (1-2 x 10(-5) moles/liter), and there was no apparent change in the threshold concentration. Fluoride-mediated increases in Cyclic 3',5'-AMP accumulation were also significantly lower in the hypothyroid (585 +/-25 pmoles) as compared to the euthyroid group (790 +/-20 pmoles) (P < 0.02). In contrast, norepinephrine produced a similar augmentation of contractility in isolated papillary muscles from the hypothyroid and euthyroid cats. It thus appears that although the hypothyroid state is associated with a decrease in the total amount of myocardial adenyl cyclase per milligram of tissue capable of being activated by norepinephrine or fluoride, there is no change in the sensitivity of the enzyme to norepinephrine stimulation. Moreover, the finding that the inotropic response to norepinephrine is unaltered in hypothyroidism is compatible with the hypothesis that only a fraction of the total intracellular cyclic 3',5'-AMP produced by norepinephrine activation of adenyl cyclase is required to elicit the inotropic response.     

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.     

Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system.

We studied the effects of clonidine, an alpha 2-adrenoreceptor agonist, and yohimbine, an alpha 2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18 +/- 3 torr in six subjects and raised it 5 +/- 1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P less than 0.05). Yohimbine (4-64 micrograms/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P less than 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree of autonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.     

Influence of body weight on plasma catecholamine patterns in middle-aged, normotensive men

To study the influence of body weight on plasma catecholamine patterns, 34 healthy, normotensive men aged 51 +/- 1 years were stratified into lean (n = 22) and overweight (n = 12) subjects according to Thomas' body mass index. No significant differences on supine arterial and venous catecholamines or standing venous adrenaline and dopamine appeared. However, the lean men had an increased orthostatic venous noradrenaline response (477 +/- 38 ng/l) compared to the overweight (319 +/- 46 ng/l, P less than 0.02). The present findings may indicate an inverse relationship between the sympathetic noradrenergic responsiveness and body weight in healthy, normotensive men while no differences were found in basal catecholamine levels.     

Functional characterization of the alpha adrenergic receptor modulating the hydroosmotic effect of vasopressin on the rabbit cortical collecting tubule.

To characterize the type of alpha adrenergic receptor, the effects of specific alpha adrenergic agonists and antagonists on antidiuretic hormone [( Arg8]-vasopressin [AVP])-induced water absorption were evaluated in cortical collecting tubules isolated from the rabbit kidney and perfused in vitro. In the presence of AVP (100 microU/ml), net fluid volume absorption (Jv, nanoliters per minute per millimeter) was 1.39 +/- 0.09 and osmotic water permeability coefficient (Pf, X 10(-4) centimeters per second) was 150.2 +/- 15.0. The addition of 10(-6) M phenylephrine (PE), an alpha adrenergic agonist, resulted in a significant decrease in Jv and Pf to 0.72 +/- 0.11 (P less than 0.005) and 69.9 +/- 10.9 (P less than 0.005). The addition of 10(-4) M prazosin (PZ), an alpha adrenergic antagonist, did not cause any significant change in Jv and Pf, which were 0.71 +/- 0.09 (P = NS vs. AVP + PE) and 67.8 +/- 9.5 (P = NS vs. AVP + PE), respectively. In a separate group of tubules, in the presence of AVP (100 microU/ml) and PE (10(-6) M), Jv and Pf were 0.78 +/- 0.17 and 76.1 +/- 18.0, respectively. The addition of 10(-6) M yohimbine (Y), an alpha 2 adrenergic antagonist, resulted in a significant increase in Jv to 1.46 +/- 0.14 (P less than 0.01) and Pf to 157.5 +/- 22.3 (P less than 0.005). Y (10(-4) M) or PZ (10(-4) M) alone did not significantly affect Jv and Pf in the presence of AVP )100 microU/ml). The effect of the natural endogenous catecholamine norepinephrine (NE) on Jv and Pf in the presence of AVP and propranolol (PR) was next examined. Jv and Pf were 1.53 +/- 0.07 and 176.3 +/- 5.2, respectively, in the presence of AVP (100 microU/ml) and PR (10(-4) M). The addition of NE (10(-8) M) resulted in a significant decrease in Jv to 1.19 +/- 0.11 (P less than 0.05) and Pf to 127.0 +/- 11.3 (P less than 0.02). Increasing the concentration of NE to 10(-6) M resulted in a further decrease in Jv and Pf to 0.70 +/- 0.10 (P less than 0.01 vs. NE 10(-8) M) and 68.5 +/- 10.6 (P less than 0.01 vs. NE 10(-8) M), respectively. The inhibitory effect of NE on AVP-induced water absorption was blocked by Y, but not by PZ. The effect of the alpha 2 adrenergic agonist clonidine (CD) on Jv and Pf was also examined. In the presence of AVP (10 microU/ml) Jv and Pf were 1.65 +/- 0.04 and 175.1 +/- 13.1, respectively. The addition of CD (10(-6) M) resulted in a significant decrease in Jv to 1.08 +/- 0.12 (P < 0.01) and Pf to 108.1 +/- 15.4 (P < 0.01). Increasing the concentration of CD to 10(-4) M resulted in a further significant decrease in Jv and Pf to 0.57 +/- 0.13 (P < 0.02 vs. CD 10(-6) M) and 54.7 +/- 13.8 (P < 0.01 vs. CD 10(-6) M), respectively. Similar results were obtained in the presence of AVP (100 microU/ml). The inhibitory effect of CD on AVP-induced water absorption was blocked by Y. CD did not significantly affect Jv and Pf in the presence of 8-bromo adenosine 3',5'-cyclic monophosphate. These studies indicate that alpha adrenergic agonists directly inhibit AVP-mediated water absorption at the level of renal tubule, an effect that can be blocked by specific alpha2 adrenergic antagonists, but not by specific alpha1 adrenergic antagonists. Alpha2 adrenergic stimulation directly inhibits AVP-mediate water absorption at the level of the tubule, an effect that can be blocked by a specific alpha2 adrenergic antagonist. This effect appears to be exerted at the level of activation of adenylate cyclase, since it is absent in the present of cyclic AMP.