Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

Pregnancy-associated plasma protein-A is positively correlated with first-trimester skin microvascular reactivity.

OBJECTIVE: To investigate the relationship between levels of circulating maternal pregnancy-associated plasma protein-A (PAPP-A) and first-trimester maternal vascular function. METHODS: This was a cross-sectional study of 53 healthy, non-smoking, nulliparous pregnant women in Stockholm, Sweden. PAPP-A levels and vascular function were assessed during gestational weeks 11-14. Forearm skin microcirculation was investigated by laser Doppler perfusion imaging during iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess endothelium-dependent and -independent microvascular vasodilatation, respectively. Microvascular endothelial function index was calculated as peak ACh/peak SNP. Endothelium-dependent and -independent vasodilatation in the brachial artery was evaluated, respectively, by postischemic hyperemia-induced flow-mediated vasodilatation (FMD) and by response to sublingual intake of glyceryl trinitrate (GTN). RESULTS: PAPP-A was correlated with skin microvascular endothelial function index (ß = 1.008 (95% CI, 0.34-1.68), r2  = 0.17, P = 0.004). PAPP-A also correlated inversely with FMD (ß = -0.052 (95% CI, -0.094 to -0.011), r2  = 0.13, P = 0.014) but did not relate to forearm endothelial function index (i.e. FMD/GTN). The results were retained in multivariate analyses including known confounding factors. CONCLUSIONS: First-trimester endothelium-dependent skin microvascular reactivity was positively related to PAPP-A levels. If confirmed, these novel findings suggest that first-trimester skin microvascular reactivity could be a useful early pregnancy marker of placental function. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo.

BACKGROUND: Angiotensin (Ang) II may be involved in the development of cardiovascular disease. We examined the potential proinflammatory and prothrombotic effects of Ang II in 16 healthy subjects and in 16 subjects with familial combined hyperlipidemia (FCHL), a condition associated with an increased risk of cardiovascular complications. METHODS: We studied the effects of a three hour intravenous infusion of Ang II (10 ng/kg/min) on plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), circulating leukocyte count, tissue plasminogen activator/plasminogen activator inhibitor-1 (t-PA/PAI-1) complexes, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) complexes. Blood was collected before, during and 1 h after Ang II infusion. RESULTS: IL-6 was higher in subjects with FCHL at rest (P < 0.05) and increased (P < 0.001) similarly in both groups by Ang II infusion. Also leukocyte count was higher in subjects with FCHL at rest (P < 0.001) and increased (P < 0.001) similarly in both groups by Ang II infusion. T-PA/PAI-1 complexes were higher in subjects with FCHL at rest (P < 0.001) and decreased (P < 0.001) similarly in both groups during Ang II infusion. TNF-alpha, F1+2 and TAT complexes were similar in the two groups at rest and did not change during or after the Ang II infusion. CONCLUSIONS: A three hour Ang II infusion increases inflammation and may enhance fibrinolysis but does not affect short term thrombin generation. Subjects with FCHL have signs of increased inflammation and impaired fibrinolysis.

Economic evaluation of ASCOT-BPLA: antihypertensive treatment with an amlodipine-based regimen is cost effective compared with an atenolol-based regimen.

OBJECTIVE: To compare the cost effectiveness of an amlodipine-based strategy and an atenolol-based strategy in the treatment of hypertension in the UK and Sweden. DESIGN: A prospective, randomised trial complemented with a Markov model to assess long-term costs and health effects. SETTING: Primary care. PATIENTS: Patients with moderate hypertension and three or more additional risk factors. INTERVENTIONS: Amlodipine 5-10 mg with perindopril 4-8 mg added as needed or atenolol 50-100 mg with bendroflumethiazide 1.25-2.5 mg and potassium added as needed MAIN OUTCOME MEASURES: Cost per cardiovascular event and procedure avoided, and cost per quality-adjusted life-year gained. RESULTS: In the UK, the cost to avoid one cardiovascular event or procedure would be euro18 965, and the cost to gain one quality-adjusted life-year would be euro21 875. The corresponding figures for Sweden were euro13 210 and euro16 856. CONCLUSIONS: Compared with the thresholds applied by NICE and in the Swedish National Board of Health and Welfare's Guidelines for Cardiac Care, an amlodipine-based regimen is cost effective for the treatment of hypertension compared with an atenolol-based regimen in the population studied.

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study.

Hypertensive left ventricular (LV) hypertrophy is associated with a substantial risk for malignant arrhythmias and sudden death. According to recent results, antihypertensive therapy with the angiotensin II type 1 receptor blocker irbesartan reverses both structural and electrical remodelling. However, the relation between the LV geometric pattern (concentric vs eccentric) and electrical reverse remodelling has not been characterized, neither has the relation between repolarization and rate (QT/RR and JT/RR relation), which presumably reflects the propensity for bradycardia-dependent ventricular arrhythmia. In this study, repeat echocardiographic and electrocardiographic measurements were performed in hypertensive patients with LV hypertrophy, randomized to double-blind therapy with irbesartan (n = 44) or the beta(1)-adrenoceptor blocker atenolol (n = 48) for 48 weeks; 53 patients had concentric and 39 eccentric LV hypertrophy. In addition, 37 matched hypertensive subjects without LV hypertrophy and no current therapy served as controls. Irbesartan induced structural and electrophysiological reverse remodelling, independent of LV geometry. In contrast, atenolol had similar beneficial effect only in patients with concentric LV hypertrophy, while the response in those with eccentric hypertrophy was unfavourable with both prolonged repolarization time and an increased QT/RR slope (suggesting reverse-use dependence). In conclusion, there is a significant geometry-related difference in the reverse remodelling processes induced by irbesartan and atenolol. Echocardiographic characterization of the geometry in hypertension-induced LV hypertrophy might become an important step in the selection of optimal antihypertensive therapy.

A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients. The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA).

Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.

Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals.

OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.

Risk factors in established coronary heart disease: evaluation of a secondary prevention programme.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death in the developed world. We studied compliance to a secondary prevention programme for CHD patients and possible gender differences. DESIGN AND METHODS: Cross-sectional survey of CHD patients aged up to 75 years attending a hospital cardiology outpatient clinic (n = 441; 16 cardiologists) and 12 primary care centres (n = 319; 28 primary care physicians), by means of a questionnaire. RESULTS: Therapeutic goals in hospital care and in primary care were reached by 36% and 29% (P < 0.05) for cholesterol, 42% and 50% (P < 0.01) for triglycerides, 66% and 72% for blood glucose, 84% and 86% for blood pressure, and 16% and 20% for smoking, respectively. Echocardiography was more frequent in hospital care patients (odds ratio 2.69, P < 0.001). ACE-inhibitors, beta-blockers, antiplatelet and anticoagulant therapy were prescribed similarly in both groups, antidiabetics were less common in hospital care (odds ratio 0.53, P < 0.05). Men were more often subject to echocardiography (odds ratio 2.59, P < 0.001). ACE-inhibitors (odds ratio 2.04, P < 0.01), beta-blockers (odds ratio 1.82, P < 0.001) and antiplatelet or anticoagulant drugs (odds ratio 1.82, P < 0.01) were more common in men; diuretics (odds ratio 0.49, P < 0.01) were more common in women. CONCLUSIONS: CHD patients have a high prevalence of modifiable risk factors. Few reach therapeutic goals for lipid levels, whereas other risk factors are better controlled. A secondary prevention programme is an important aid in preventing CHD but must be followed by further educational efforts in order to be more effective.

A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden.

BACKGROUND: During the last decades substantial temporal changes, as well as population differences, in coronary heart disease mortality have occurred in Sweden. There is little information to what extent these changes and differences also apply to myocardial infarction incidence. The aim of this paper was to describe the methods used to identify cases in a recently developed National Acute Myocardial Infarction Register in Sweden, and to present estimates of incidence and case fatality in Sweden. MATERIAL AND METHODS: Incident cases of acute myocardial infarction (AMI) were identified by record linkage of routinely collected data on hospital discharges and deaths. Case fatality within 28 days was ascertained by linkage of incident cases to the National Cause of Death Register. RESULTS: About 40 000 new cases of AMI per year were recorded in Sweden during 1987-1995. Well-known differences in incidence with regard to age and gender were observed, as well as a decline in incidence between 1987 and 1995. A similar case fatality was seen in men and women aged 30-89 among hospitalized cases. When fatal cases outside hospital were also considered the case fatality was somewhat higher in men. Examination of medical records for a national sample of ischaemic heart disease patients suggested a high sensitivity (94%) and a high positive predictive value (86%) for ICD-9 code 410 in hospital discharge data with regard to definite AMI. CONCLUSIONS: The National Acute Myocardial Infarction Register offers a new possibility to study the incidence of AMI, as well as case fatality, in Sweden.

Greater than normal prevalence of seropositivity for Helicobacter pylori among patients who have suffered myocardial infarction.

BACKGROUND: There is evidence to suggest that inflammation plays a role in the development of atherosclerosis. Chronic infections may activate an inflammatory response in the walls of blood vessels. OBJECTIVE: To investigate the possibility of there being an association between infection with Helicobacter pylori (H. pylori) and coronary heart disease. METHODS: We examined 100 consecutive patients documented to have recently suffered acute myocardial infarction and 100 control subjects from the same geographical area for whom there was no evidence of coronary heart disease, carefully matched both for age and sex. Blood samples were tested for the presence of immunoglobulin G antibodies against H. pylori with a serological test. RESULTS: In comparison with controls, patients were more commonly smokers (26 versus 12%/0, P < 0.05) and had more commonly been treated for hypertension (37 versus 20%, P< 0.01). There was a significant association between seropositivity for H. pylori and having previously suffered acute myocardial infarction (68 versus 53%, odds ratio 1.36 with 95% confidence interval 1.02-1.82, P=0.034). These findings remained valid in a multivariate analysis including possible confounding factors (age, sex, smoking and hypertension; odds ratio 1.35 with 95% confidence interval 1.01-1.83, P=0.046). CONCLUSIONS: The positive association between seropositivity for H. pylori and having previously suffered acute myocardial infarction found in this study provides further support for the hypothesis that there is a causal association between chronic infection with H. pylori and the development of coronary heart disease.

Adrenaline responsiveness in mild hypertension: no evidence for altered beta-adrenoceptor sensitivity.

The effects of circulating adrenaline on cardiovascular function were studied in 14 subjects (mean age, 36.5 years; range, 19-46 years) with mild hypertension and in 14 normotensive controls, matched for age and sex. Adrenaline was infused i.v. in step-wise increasing doses (0.1, 0.2, 0.4, and 0.8 nmol/kg/min). Cardiovascular responses were evaluated by echocardiography and noninvasive blood pressure measurements. Noradrenaline, adrenaline, potassium, and cyclic adenosine monophosphate (cAMP) were determined in venous plasma. Systolic and diastolic blood pressure responses to adrenaline were similar in both groups. Adrenaline increased myocardial contractility and stroke volume, but less so in the hypertensive patients. Cardiac output was increased in the hypertensive patients at rest, but the signs of increased myocardial contractility disappeared during adrenaline infusion, most likely because of a reduced myocardial compliance. Increased heart rate and systemic vascular resistances were displayed by the hypertensive patients at all adrenaline concentrations studied, but the responses were similar in both groups. The adrenaline-induced decreases in potassium and increases in cAMP were also similar in both groups. The increases in myocardial contractility and in heart rate are compatible with an increased arousal in mild hypertension at rest. Mild hypertension does not appear to be associated with alterations of beta2-adrenoceptor sensitivity, and the findings do not support that adrenaline is involved in the pathogenesis of primary hypertension.

Stress-induced changes in blood pressure and left ventricular function in mild hypertension.

Left ventricular function was studied by M-mode echocardiography at rest and during a mental arithmetic stress test and a cold-pressor test in 14 patients with mild hypertension and in 14 matched normotensive subjects. The elevation of blood pressure at rest in the hypertensive group (154 +/- 4/87 +/- 3 vs. 120 +/- 3/66 +/- 3 mmHg in the control group) was due mainly to a higher cardiac output (6.0 +/- 0.3 vs. 5.0 +/- 0.3 L/min), which was related to elevations of stroke volume and heart rate (73 +/- 2 vs. 66 +/- 2 beats/min). Venous plasma catecholamines were similar in the two groups. Mental stress induced cardiac output-dependent increases in blood pressure in both groups; systemic vascular resistance tended to decrease. The relative increases in diastolic and mean arterial blood pressure were smaller in the hypertensive group (15 vs. 26% and 15 vs. 21%, respectively), which exhibited signs of a reduced cardiac compliance, possibly related to a left ventricular hypertrophy. Mental stress elevated venous plasma adrenaline similarly in the two groups; effects on noradrenaline were small. The cold-pressor test increased blood pressure similarly in the two groups, largely due to increased systemic vascular resistance; plasma noradrenaline responses were also similar. Mental stress appears to elicit a differentiated sympathetic nerve activation pattern resembling the hypothalamic defense reaction. Mild hypertension seems to be associated with increased arousal and cardiac activation at rest. However, an attenuated blood pressure reactivity to mental stress may reflect reduced stroke volume responsiveness, which is related to structural changes, as heart rate reactivity tended to be enhanced in mild hypertension.

Neuropeptide Y and reserpine-resistant vasoconstriction evoked by sympathetic nerve stimulation in the dog skeletal muscle.

1. The effects of sympathetic nerve stimulation (evoked by recordings of authentic irregular vasoconstrictor nerve fibre discharge with average frequencies of 0.59, 2.0 and 6.9 Hz) on the perfusion pressure and the overflow of noradrenaline (NA) and neuropeptide Y-like immunoreactivity (NPY-LI) were investigated in the blood-perfused gracilis muscle of the dog in situ. 2. Nerve stimulation in the untreated control group evoked a frequency-dependent increase in perfusion pressure and overflow of NA. A significant overflow of NPY-LI was found at the highest frequency only. 3. In a separate group of animals, the sympathetic supply was unilaterally interrupted by preganglionic decentralization before the administration of reserpine (1 mgkg-1 i.v.) 24 h before the experiment. Reserpine reduced the NA content of the intact and decentralized gracilis and gastrocnemius muscle by 98-99%. Reserpine also induced a marked (80%) reduction of the muscular content of NPY-LI. The depletion of NPY-LI was, in contrast to that of NA, prevented by the decentralization, suggesting that nerve impulse activity was of primary importance for the reserpine-induced depletion of NPY-LI. 4. A slowly developing and long-lasting perfusion pressure increase was evoked by nerve stimulation, at 2.0 and 6.9 Hz after reserpine treatment. These responses were larger in the decentralized, as compared to the intact gracilis muscle and correlated with the nerve stimulation evoked overflow of NPY-LI (r = 0.79, P less than 0.001). Stimulation at 0.59 Hz caused vasoconstriction in the decentralized but not in the intact gracilis. 5. Administration of alpha,beta,-methylene adenosine triphosphate did not evoke an increase in perfusion pressure in the gracilis muscle of reserpine-treated animals. 6. In conclusion, a large perfusion pressure increase to sympathetic nerve stimulation occurs in the reserpine-pretreated skeletal muscle vasculature of the dog in vivo, providing that preganglionic decentralization has been performed. It is suggested that the released NPY-LI may mediate this vasoconstrictor response.

Possible involvement of neuropeptide Y in sympathetic vascular control of canine skeletal muscle.

Sympathetic nerve stimulation (2 min, 2 and 10 Hz) increased perfusion pressure in the blood perfused canine gracilis muscle in situ after pretreatment with atropine, desipramine and beta-adrenoceptor antagonists. This vasoconstriction was accompanied by clear-cut increases in the overflow of endogenous noradrenaline (NA) at both frequencies and, at 10 Hz but not at 2 Hz, also of neuropeptide Y-like immunoreactivity (NPY-LI). The irreversible alpha-adrenoceptor antagonist phenoxybenzamine enhanced the nerve stimulation induced overflows of NA and NPY-LI five- to eightfold and threefold, respectively. The fractional overflows of NA and NPY-LI per nerve impulse were similar in response to the high-frequency stimulation, indicating equimolar release in relation to the tissue contents of the respective neurotransmitter. The maximal vasoconstrictor response elicited by 10 Hz was reduced by about 50% following a dose of phenoxybenzamine which abolished the effect of exogenous NA and the remaining response was more long-lasting. Local i.a. infusion of NPY evoked long-lasting vasoconstriction in the presence of phenoxybenzamine, while the stable adenosine 5(1)-triphosphate (ATP) analogue alpha-beta-methylene ATP was without vascular effects. Locally infused NPY reduced the nerve stimulation evoked NA overflow by 31% (P less than 0.01) at 1 microM in arterial plasma, suggesting prejunctional inhibition of NA release. In conclusion, NPY-LI is released from the canine gracilis muscle upon sympathetic nerve stimulation at high frequencies. There is nerve stimulation evoked vasoconstriction, which is resistant to alpha-adrenoceptor blockade. This may in part be mediated by NPY released together with NA from the sympathetic vascular nerves.

Responses to mental stress and physical provocations before and during long term treatment of hypertensive patients with beta-adrenoceptor blockers or hydrochlorothiazide.

1 Cardiovascular and sympatho-adrenal responsiveness to mental stress (CWT; a colour word test), orthostatic testing (ORT) and a cold pressor test (CPT) were examined in three groups of hypertensive patients (n = 14-16) before and after 6 months treatment with metoprolol (243 +/- 26 mg daily), propranolol (149 +/- 16 mg daily) or hydrochlorothiazide (50 +/- 8 mg daily) in an open trial design. 2 Treatment reduced outpatient blood pressures in the three groups similarly (from approximately 155/102 to 135/90 mm Hg). During treatment resting blood pressures in the laboratory were clearly reduced by beta-adrenoceptor blockade but not by thiazide treatment. Metoprolol and propranolol caused similar reductions of basal heart rates and plasma glycerol levels, whereas only propranolol reduced cyclic AMP concentrations in plasma. 3 Before treatment CWT and CPT increased systolic and diastolic blood pressures by about 30%. Heart rate increased by about 30 beats min-1 during CWT and 10-15 beats min-1 during CPT and ORT. Small venous plasma adrenaline responses were evoked by all tests, whereas noradrenaline was elevated mainly by CPT and ORT. Dopamine levels did not change. 4 Heart rate responses to all stressors were markedly and similarly reduced, whereas blood pressure responses were essentially unchanged during metoprolol or propranolol treatment. In the thiazide group circulatory responses to CWT were slightly attenuated, whereas responses to ORT and CPT were unchanged. 5 The systolic blood pressure levels were reduced throughout the test session in all three groups, although less so in the hydrochlorothiazide group. Both beta-adrenoceptor antagonists clearly reduced diastolic blood pressure and heart rate levels at rest and during stress, whereas thiazide treatment caused no significant changes in these respects. 6 The rate pressure product, which increased by 80-100% in response to CWT before treatment, was more markedly reduced by beta-adrenoceptor blockade than by thiazide treatment both at rest and during stress. 7 Self ratings (visual analogue scales) of stress and irritation were increased by CWT in a similar fashion before and during treatment in all groups. beta-adrenoceptor blockade was associated with higher subjective ratings of tiredness at rest, but not after CWT. Performance in the CWT increased slightly more in the thiazide group. The physiological responses to CWT were not correlated to the subjective responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenaline responsiveness in borderline hypertension.

The effects of circulating adrenaline on cardiovascular function were studied in 14 subjects with borderline hypertension (BHT) and in 14 matched normotensive controls. Adrenaline was infused in stepwise increasing doses (0.1, 0.2, 0.4, and 0.8 nM/kg/min, i.v.). Noninvasive measurements of cardiac function (M-mode echocardiography) and blood pressure and blood sampling for determinations of venous plasma noradrenaline, adrenaline, cyclic AMP, and potassium were performed. Systolic and diastolic blood pressure responses to adrenaline were similar in both groups. Cardiac output was increased in BHT at rest but the signs of an increased myocardial contractility disappeared during adrenaline infusion. The BHT group displayed elevated heart rates and systemic vascular resistances over the full range of adrenaline concentrations studied but the responsiveness was similar in both groups. The beta 2-adrenoceptor-mediated increases in plasma cyclic AMP and decreases in plasma potassium were similar in the BHT and control groups. The results suggest an increased arousal in BHT at rest. Furthermore, beta 2-adrenoceptor sensitivity appears to be unaltered in BHT.

Influence of acetylcholine, peptides, and other vasodilators on endogenous noradrenaline overflow and vasoconstriction in canine blood perfused gracilis muscle.

The effects of acetylcholine, substance P and vasoactive intestinal polypeptide (VIP) on the endogenous noradrenaline (NA) overflow were compared to those of two other vasodilators, nitroglycerin and felodipine, neither of which are thought to influence NA neurotransmission in blood perfused skeletal muscle. The lack of prejunctional effects of nitroglycerin was verified in vitro. The sympathetic nerve stimulation (SNS) evoked NA overflow was reduced by 37 +/- 9% by a dose of acetylcholine which reduced the perfusion pressure at rest by 44 +/- 6%. Conversely, atropine tended to enhance SNS evoked NA overflow. Acetylcholine reduced the vasoconstrictor responses to SNS when compared to the responses observed with an equipotent vasodilatory dose of, e.g. nitroglycerin. The SNS evoked NA overflow was not influenced by a moderate mechanical blood flow reduction or by pronounced reductions of vascular resistance induced by either substance P, VIP, nitroglycerin or felodipine, supporting the idea that the transport of NA from nerve terminal to blood is not importantly influenced by moderate decreases in blood flow or vascular tone. Prejunctional muscarinic inhibition of NA release in skeletal muscle was verified under in vivo conditions, but the other substances tested did not influence sympathetic neurotransmission. Endogenous NA overflow appears to mirror NA release in vivo also when diffusion is influenced by changes in blood flow or vascular tone in this experimental model.