Long-term neurodevelopment in children with resected congenital lung abnormalities.

To determine whether children who underwent resection of a congenital lung abnormality (CLA) are at higher risk for neurodevelopmental impairments than peers in the general population. The study population consisted of children born between 1999-2018 who underwent resection of a symptomatic CLA. Neurocognitive development (intelligence, memory, attention, visuospatial processing, executive functioning) and motor function of this population are monitored through our structured, prospective longitudinal follow-up program at the ages of 30 months, 5, 8, and 12 years. We compared study population scores with Dutch norm values using one-sample t-tests and one-sample binominal proportion tests. Forty-seven children were analyzed. The 8-year-olds showed significant impairments in sustained attention through the Dot Cancellation Test (mean z-scores -2.4; [-4.1; -0.8], p = 0.006 and -7.1; [-12.8; -1.4], p = 0.02 for execution speed and fluctuations respectively). Visuospatial memory was impaired at 8 years, though only in 1 out of 3 assessment tools (Rey Complex Figure Test z-scores (-1.0; [-1.5; -0.5], p < 0.001). Further neurocognitive outcomes were unimpaired at all tested ages. Regarding motor function outcomes, mean z-scores of total motor functioning were unimpaired across assessed ages. However, at 8 years, significantly more children than expected had definite motor problems (18% vs 5%, 95% CI [0.052; 0.403], p = 0.022).   Conclusion: This evaluation reveals impairment in some subtests of sustained attention, visuospatial memory and motor development. However, globally, normal neurodevelopmental outcomes were found throughout childhood. We recommend testing for neurodevelopmental impairments in children who underwent surgery for CLA only if associated morbidities are present or if caregivers express doubts about their daily functioning. What is Known: • In general, surgically managed CLA cases seldom suffer from long-term surgery-related morbidity and show favorable lung function. What is New: • Long-term neurocognitive and motor function outcome appear unimpaired within surgically managed CLA cases. We recommend testing for neurodevelopmental impairments in children who underwent surgery for CLA only if associated morbidities are present or if caregivers express doubts about their daily functioning.

Postnatal chest X-ray in children with asymptomatic congenital lung malformations.

OBJECTIVE: The clinical implications of a postnatal chest X-ray (CXR) in asymptomatic children with a prenatally diagnosed congenital lung malformation (CLM) are uncertain. We assessed the justification for the postnatal use of CXR in these children. METHODS: We included patients with CLM confirmed through chest computed tomography angiography or histopathological analysis who were asymptomatic at birth, underwent routine postnatal CXR, and participated in our standard of care prospective structured longitudinal follow-up program. Children with major associated morbidities were excluded. Primary outcomes were the positive and negative predictive values (PPV and NPV) of CXR findings for symptom development at 4 weeks and 6 months of age. Secondarily, we sought to establish whether CXR findings were associated with undergoing additional diagnostics during the initial observational hospital stay or prolonged postnatal hospital admission. RESULTS: Among 121 included patients, CXR showed no abnormalities in 35 (29%), nonspecific abnormalities in 23 (19%), and probable CLM in 63 (52%). The PPV of CXR in relation to symptom development at 4 weeks and 6 months was 0.05 and 0.25, respectively. Corresponding NPVs were 0.96 and 0.91. An association was identified between CXR findings and undergoing further diagnostics during the initial observational hospital stay (p = .047). Additional diagnostic findings did not influence clinical management. CXR findings were not associated with prolonged initial hospital stay (p = .40). CONCLUSION: The routine practice of postnatal CXR in asymptomatic patients with prenatally diagnosed CLM can be omitted, as CXR findings do not influence subsequent clinical management.

COllaborative Neonatal Network for the first European CPAM Trial (CONNECT): a study protocol for a randomised controlled trial.

INTRODUCTION: Consensus is lacking on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM). For future studies, the CONNECT consortium (the COllaborative Neonatal Network for the first European CPAM Trial)-an international collaboration of specialised caregivers-has established consensus on a core outcome set of outcome parameters concerning respiratory insufficiency, surgical complications, mass effect and multifocal disease. These outcome parameters have been incorporated in the CONNECT trial, a randomised controlled trial which, in order to develop evidence-based practice, aims to compare conservative and surgical management of patients with an asymptomatic CPAM. METHODS AND ANALYSIS: Children are eligible for inclusion after the CPAM diagnosis has been confirmed on postnatal chest CT scan and they remain asymptomatic. On inclusion, children are randomised to receive either conservative or surgical management. Subsequently, children in both groups are enrolled into a standardised, 5-year follow-up programme with three visits, including a repeat chest CT scan at 2.5 years and a standardised exercise tolerance test at 5 years.The primary outcome is exercise tolerance at age 5 years, measured according to the Bruce treadmill protocol. Secondary outcome measures are molecular genetic diagnostics, validated questionnaires-on parental anxiety, quality of life and healthcare consumption-, repeated imaging and pulmonary morbidity during follow-up, as well as surgical complications and histopathology. This trial aims to end the continuous debate surrounding the optimal management of asymptomatic CPAM. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol (MEC-2022-0441). Results will be disseminated through peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05701514.

Acute myocardial uptake of digoxin in humans: correlation with hemodynamic and electrocardiographic effects.

Acute myocardial uptake of digoxin was measured at a constant paced heart rate (75 beats/min) for 30 min after an intravenous bolus injection of 500 micrograms of digoxin in 14 patients with ischemic heart disease. Myocardial digoxin content, determined by serial measurement of aortocoronary sinus digoxin concentration gradients and coronary sinus blood flow, was expressed relative to coronary sinus blood flow at rest and correlated with simultaneous hemodynamic and electrocardiographic changes. Myocardial digoxin uptake was extensive (4.1 +/- 0.7% of total injected dose at 30 min) and prolonged, with rapid initial uptake (75.3 +/- 6.6% of maximum at 3 min), followed by a variable phase of slower accumulation. Peak left ventricular positive first derivative of left ventricular pressure (dP/dt) increased progressively (p less than 0.01), with a similar time course to that of myocardial digoxin accumulation; maximal change was 18.5 +/- 4.7% at 27 min. The ratio of inotropic effect to myocardial digoxin content did not vary significantly over the period of the experiment. However, peak inotropic effects in individual patients were not significantly related to peak myocardial digoxin content. The spontaneous PR interval increased transiently, with a peak increase of 5.9 +/- 1.8% (p less than 0.05) 12 min after digoxin administration. It is concluded that after intravenous bolus administration, 1) peak effects of digoxin on atrioventricular (AV) conduction occur early, whereas positive inotropic effects increase progressively for greater than or equal to 27 min; and 2) digoxin accumulation in the human myocardium is prolonged and is a determinant of inotropic effects, but not of prolongation of AV node conduction.

Long-term use of intranasal insulin in insulin-dependent diabetic patients.

This study, in 3 phases, compared the long-term acceptability and efficacy of insulin administered by nasal spray with an intensified subcutaneous regimen in nine type I (insulin-dependent) diabetic subjects on baseline therapy with ultralente insulin. In phase 1, patients were begun and stabilized on a regimen of ultralente daily and Actrapid insulin three times daily. Phase 2 consisted of 4 mo of this intensified subcutaneous regimen. In phase 3, intranasal administration of insulin, with 1% (wt/vol) sodium glycocholate, replaced Actrapid insulin for 4 mo. Glycemic control was compared in each of the three phases. It was possible to maintain the dose of ultralente insulin relatively constant in only six of the nine subjects during the intranasal phase of the study. The six subjects showed a significant rise in glycosylated hemoglobin during the intranasal phase (10.4 +/- 0.6% intranasal vs. 9.1 +/- 0.3% subcutaneous, P less than .05) but not in plasma or urinary glucose levels. There was no significant change in the incidence of hypoglycemic episodes during intranasal insulin therapy in this group. The other three subjects were considered treatment failures. Six of the nine original subjects expressed a preference for intranasal insulin, and one subject complained of mild nasal irritation insufficient to cease treatment. The intranasal route of administration of insulin has the potential to replace short-acting insulin as an adjunct to longer-acting insulin in some insulin-treated diabetic patients.

Altered cardiac hormone and contractile protein messenger RNA levels following left ventricular myocardial infarction in the rat: an in situ hybridization histochemical study.

OBJECTIVES: Cardiac remodeling secondary to myocardial infarction is associated with hypertrophy of surviving myocardium and altered cardiac gene expression. The present study examined the spatiotemporal expression of cardiac contractile protein and peptide hormone mRNA following left ventricular myocardial infarction (LVMI) in the rat heart. METHODS: LVMI was produced in Wistar rats by ligation of the left anterior descending coronary artery and mRNA levels of cardiac alpha-action (sACT), ventricular myosin light chain-2(MLC-2v), beta-myosin heavy chain (beta-MHC) and pre-proatrial natriuretic peptide (ppANP) were examined at 24 h, 1 and 4 weeks) post-LVMI by in situ hybridization histochemistry with 35S-labeled oligonucleotide probes. RESULTS: Infarct size, determined at 1 week post-LVMI, was 44.5 +/- 2.7% of the combined left ventricular epi- and endocardial surface area. Myocyte fiber width, reflecting cellular hypertrophy, was increased in left ventricular, mid-septal and mid-right ventricular muscle fibers by 11-20% at 1 week post-LVMI (P < 0.05) and by 24-29% at 4 weeks (P < 0.05). At 24 h, 1 and 4 weeks post-LVMI, heart- and lung/body weight ratios were significantly elevated compared to sham-operated rats (1.3-1.8-fold, P < 0.01 and 1.6-2.9-fold, P < 0.005, respectively). PpANP mRNA levels in the left ventricle were increased 3.8- and 3.3-fold at 1 and 4 weeks (P < 0.05), with highest levels in the epicardium, papillary muscle, infundibulum and apex of the chamber. Septal and right ventricular ppANP mRNA levels were highest at 24 h post-LVMI (2.1- and 2.6-fold increase, P < 0.05) and remained elevated at 4 weeks, with maximum levels at the left endocardial surface of the septum and apex of the chambers. Atrial levels of cACT mRNA were increased 1.9-fold at 1 week post-LVMI (P < 0.05) and remained elevated at 4 weeks. Skeletal ACT mRNA, not normally expressed in the adult rat heart, was induced as early as 24 h post-LVMI in both atria, the septum and right ventricle, with discrete hybridization signal detected at the apex of the chambers and in the right ventricular free-wall, and later (1 week) in the left ventricular epicardium. MLC-2v mRNA levels were unaltered post-LVMI, except for a transitory loss of expression at 24 h in the left atria, ventricle and apical septum. In contrast, ventricular beta-MHC mRNA was markedly induced in regions containing increased ppANP mRNA, with a maximal 3.0- and 4.0-fold induction (P < 0.05) seen at 1 and 4 weeks in the left ventricle and a 3.7-fold induction at 4 weeks in the septum and right ventricle (P < 0.05). CONCLUSION: The regional increases in induced cardiac hormone and contractile protein mRNA in similar subchamber regions of the rat heart post-LVMI implies mutual activation by mechanical and/or neuroendocrine stimuli in the transcriptional response to myocardial overload.

Effects of methyldopa metabolites on amine transmitters and adrenergic receptors in rat brain.

Studies of catecholamine concentrations in defined nuclei from the anterior hypothalamic-preoptic regions and the medulla oblongata, known to contribute to cardiovascular control, were measured following acute or chronic methyldopa administration. These studies indicated that methyldopa was enzymatically converted to methyldopamine and methylnorepinephrine, and in some areas to methylepinephrine which replaced endogenous epinephrine. The predominant metabolite was methylnorepinephrine, which accumulated in concentrations higher than endogenous norepinephrine levels. (-)Methylnorepinephrine was found to be 6 times more potent and 75 times more selective for alpha 2-adrenergic receptors than (-) norepinephrine, and it is suggested that this alpha 2-adrenergic receptor action, particularly in the nucleus tractus solitarius, contributes to a major part of the antihypertensive effect of methyldopa.

Acute effects of blood pressure elevation on insulin clearance in normotensive healthy subjects.

Reduced clearance of insulin from plasma contributes to the hyperinsulinemia associated with essential hypertension (EH); however, the association between impaired insulin clearance and EH remains unexplained. Whether elevated blood pressure (BP) affects insulin clearance is unknown; therefore, we used the hyperinsulinemic euglycemic clamp to determine the effects of BP elevation on insulin clearance and sensitivity in eight healthy volunteers. Placebo infusion increased mean BP by 2.6+/-1.6 mm Hg, which was significantly less than rises produced by phenylephrine, an alpha1-adrenoceptor agonist (+11+/-1.8 mmHg, P<.05), or by angiotensin II (+13+/-1.3 mmHg, P<.01). Although beta-adrenoceptor stimulation with isoproterenol did not change mean BP (+3.6 mm Hg, P=NS), it significantly increased systolic pressure (+23+/-2.8 mm Hg versus +2.3+/-4.6 mm Hg with placebo P<.01). Insulin secretion (ie, C-peptide concentrations) was not affected by any of the treatments; however, phenylephrine significantly reduced the metabolic clearance rate of insulin (MCRinsulin) (16.6+/-1.0 mL/kg per minute with placebo versus 13.6+/-0.7 mL/kg per minute with phenylephrine, P<.01) and thereby increased plasma insulin concentrations (66+/-5.1 microU/mL with placebo versus 79+/-4.1 microU/mL with phenylephrine, P<.05). Phenylephrine also increased glucose utilization (42+/-5.8 micromol/kg per minute during placebo versus 58+/-4.8 micromol/kg per minute during phenylephrine, P<.05); however, this was proportional to the increased insulin concentrations; therefore, insulin sensitivity was unchanged. MCRinsulin and plasma insulin concentrations were not affected by angiotensin II; however, glucose utilization increased to 51+/-2.7 micromol/kg per minute (P<.01 versus placebo), indicating insulin sensitivity was increased. MCRinsulin was unaffected by isoproterenol. Thus, alpha-adrenergic stimulation but not increased BP per se is a potent regulator of insulin clearance and plasma insulin concentrations.

Hypotensive effect of low-fat, high-carbohydrate diet can be independent of changes in plasma insulin concentrations.

To examine the relationship between diet, blood pressure, and plasma insulin concentrations, we studied 14 healthy males who were prescribed low-fat and high-fat diets. The low-fat diet contained 25% (of energy intake) fat and 54% carbohydrate; the high-fat diet was 45% fat (predominantly saturated fat) and 36% carbohydrate. The diets were consumed over consecutive 2-week periods in random sequence, separated by a 2-week washout period. Resting supine systolic and diastolic blood pressures decreased significantly by 7 and 3 mm Hg, respectively, and plasma total cholesterol, LDL cholesterol, and HDL cholesterol concentrations all fell (by 21.6%, 25.7%, and 18.0%, respectively; all P<0.001) on the low-fat compared with the high-fat diet. Fasting glucose and the glucose area under the curve during the frequently sampled intravenous glucose tolerance test (300 mg/kg glucose load with blood sampling for 180 minutes) were significantly lower, and the glucose disappearance rate tended to be faster after the low-fat diet. In contrast, fasting insulin concentrations and the insulin response (insulin area under the curve) to glucose challenge were unchanged. Insulin sensitivity (defined as the rate of glucose disappearance per unit of insulin increase during the period 0 to 40 minutes after the glucose load) was significantly higher on the low-fat diet. These results suggest that the hypotensive effects of a low-fat, high-carbohydrate diet, although associated with an improvement in insulin sensitivity, are not mediated by changes in plasma insulin concentration.

Angiotensin II receptors and angiotensin converting enzyme in the medulla oblongata.

Quantitative in vitro autoradiography was used to map angiotensin II (ANG II) receptors and angiotensin converting enzyme (ACE) in sections from rat, rabbit, sheep, and human medulla oblongata and to follow changes in receptor and ACE density after disruption of vagal projections by nodose ganglionectomy in the rat. ANG II receptors and ACE are both concentrated in the nucleus of the solitary tract and dorsal motor nucleus of vagus of the rat, rabbit, sheep, and human. An ANG II receptor-containing band connecting the nucleus of the solitary tract with the dorsolateral medulla was seen in rabbit and human tissue, providing evidence for association of ANG II receptors with vagal afferent fibers. ANG II receptors were found to be concentrated in the rostral and caudal ventrolateral medulla, which corresponded to the region of C1 and A1 catecholamine-containing cell groups in the rabbit. This localization was also evident in rat and human tissue. In all four species, a prominent, ANG II receptor-rich band in the intermediate reticular nucleus was found to connect the ventrolateral medulla and the dorsal vagal complex. In humans and sheep, this band contains puncta that overlie cell bodies. One week after nodose ganglionectomy in the rat, the density of ANG II receptors in the ipsilateral dorsal vagal complex fell markedly. This fall was most prominent in the rostral dorsal motor nucleus of vagus (to 46% of control density) and in the nucleus of the solitary tract (to 56% of control). ACE levels and calcitonin gene-related peptide receptor density were unchanged in both nuclei after ganglionectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Clopamide: plasma concentrations and diuretic effect in humans.

Clopamide pharmacokinetics were determined after oral doses of 5, 10, and 20 mg in normal volunteers. Maximum plasma concentrations occurred within 2 hours and were followed by a monoexponential decline with an elimination half-life of approximately 10 hours. There was an approximately linear relationship between dose and the AUC. Urinary sodium, chloride, and potassium excretion rates indicated that the peak diuretic activity corresponded with peak plasma drug concentrations and probably continued for 12 to 24 hours. There was little difference between the total sodium and chloride output after each dose of clopamide, suggesting that 5 mg may have been close to the top of the dose-response curve. Chlorothiazide, 500 mg, caused less sodium and chloride output with similar potassium loss. During chronic administration to patients with hypertension, hypokalemia was more marked with clopamide, 10 mg daily, than with clopamide, 5 mg, or chlorothiazide, 500 mg daily.

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine.

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.

Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension: results of a double-blind multicenter study versus atenolol.

A 3-month double-blind multicenter trial compared the efficacy and safety of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor, with atenolol in mild-to-moderate essential hypertension. A total of 190 patients, 49 of whom were diabetic, entered the perindopril-atenolol comparison. Of these, 163 had been previously treated and had a 4-week run-in period on placebo; 27 had previously been untreated and received placebo for 2 weeks. At entry, all patients who had a supine diastolic blood pressure (DBP) of 95-115 mm Hg were randomized to receive perindopril 2 mg or atenolol 25 mg, once daily. Patients were assessed at 2 weekly intervals for the first month and then monthly for 2 more months. If supine DBP was greater than 90 mm Hg, treatment was increased by stepwise doubling of dose up to 8 mg perindopril or 100 mg atenolol once daily, and later by the addition of hydrochlorothiazide 25 mg, (indapamide 2.5 mg in diabetic patients) once daily. The two groups were homogeneous prior to treatment except for supine and erect heart rate, which were higher in the perindopril group than in the atenolol group (p less than 0.05). Mean supine DBP was 101.1 +/- 0.6 mm Hg in the perindopril group (n = 94) and 99.9 +/- 0.6 mm Hg in the atenolol group (n = 96). After 3 months' active treatment, 74% of patients in the perindopril group achieved a supine DBP of less than or equal to 90 mm Hg and 73% of patients in the atenolol group achieved the same goal. Monotherapy controlled supine DBP in 67% of the perindopril group and 63% of the atenolol group. The decrease in supine DBP was not significantly different between the two groups (-12.9 +/- 0.9 versus -14.7 +/- 0.9 mm Hg) but the decrease in erect DBP was lower in the perindopril group (-10.3 +/- 0.9 versus - 13.4 +/- 1.0 mm Hg, p less than 0.02). Heart rate was reduced in the atenolol group (p less than 0.001). Sixteen patients withdrew from the study; nine were attributed to adverse events, two in the perindopril group and seven, including one death, in the atenolol group. Cough was spontaneously reported by 13% patients of the perindopril group and 1% patients of the atenolol group. In 5% of the perindopril cases this was mild and associated with upper respiratory tract infection. The nature and incidence of other symptoms were similar with both drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, attenuates the Bezold-Jarisch reflex in the anaesthetized rat.

The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on the Bezold-Jarisch reflex elicited by i.v. doses of 5-hydroxytryptamine (5-HT) was investigated in urethane-anaesthetized rats. Activation of the Bezold-Jarisch reflex with 5-HT (0.5-16 microgram/kg) produced pronounced dose-dependent hypotensive and bradycardic responses which were attenuated by MK-801 (1 mg/kg, i.v.) but not by saline. The data suggests that activation of the Bezold-Jarisch reflex by 5-HT involves a glutamatergic synapse presumably located within the brainstem vagal reflex arc.

Medial prefrontal cortical lesions and baroreceptor heart rate reflex sensitivity in the spontaneously hypertensive rat.

Previous investigations have shown that an excitotoxic lesion of the medial prefrontal cortex (MPFC) in normotensive Sprague-Dawley rats results in a reduction in the sensitivity of the baroreceptor heart rate reflex. The aim of this study was to examine the importance of the MPFC in regulation of the heart rate reflex in conscious, unrestrained spontaneously hypertensive rats (SHR). The MPFC was lesioned by bilateral microinfusions of the excitotoxin N-methyl-D-aspartic acid (NMDA). Baroreceptor heart rate reflex testing was performed by measuring reflex heart rate changes in response to blood pressure alterations induced by nitroprusside and phenylephrine with subsequent computerized sigmoidal curve-fitting of the data. Lesion of the MPFC did not significantly alter resting, systolic and diastolic blood pressure, heart rate or baro-reflex parameters (gain, thresholds, range or plateaus). These observations suggest that the putative descending facilitatory influence from the MPFC to brainstem areas, involved in baroreceptor reflex regulation observed in normotensive rats, may be defective in SHR.

Failure of psychosocial stress to induce chronic hypertension in the rat.

The effect of psychosocial stress produced by aggregation in a special cage designed by Henry was investigated in three separate experiments using Wistar-Kyoto (WKY), Sprague-Dawley (SD) and F1 hybrids of the Japanese spontaneously hypertensive and Wistar-Kyoto (SHR-WKY F1) rats. Each aggregated group displayed typical 'stressed' behavioural disturbances. Adrenal hypertrophy, elevation of plasma renin activity and gastric erosions were noted in male aggregated SD rats; while adrenal enlargement, elevation of plasma noradrenaline and gastric erosions were found in male aggregated SHR-WKY F1 rats. Sustained hypertension, however, did not develop in any strain nor in any subgroup within each strain. Gastric erosions were also noted in isolated SD and SHR-SKY F1 rats suggesting that long term isolation of rats also induces stress. Isolated rats also remained normotensive throughout. Reduced haematocrit was found in both aggregated and isolated male SHR-WKY F1 rats suggesting increased plasma volume. We conclude that neither stress due to psychosocial disturbances nor that due to isolation produces chronic hypertension in the three strains of rat studied.

Impaired arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious spontaneously hypertensive rats.

The activity of baroreceptor reflexes and cardiopulmonary reflexes was examined in conscious spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. The baroreceptor heart rate reflex, elicited by phenylephrine- and nitroprusside-induced changes in blood pressure, had a reduced range and lower heart rate plateau in SHR than in WKY rats, which suggests impaired vagal control of the heart rate in SHR. Cardiopulmonary receptor reflex activity was assessed by intravenous injections of phenyldiguanide which evoke the Bezold-Jarisch reflex. Phenyldiguanide elicited dose-dependent bradycardic and hypotensive responses in WKY rats, but these were significantly attenuated in SHR. This is the first demonstration of impaired Bezold-Jarisch responses in conscious SHR and provides evidence of both impaired vagally mediated arterial baroreceptor activity and impaired cardiopulmonary receptor activity in this rat strain.

A study of the interactive effects of oral contraceptive use and dietary fat intake on blood pressure, cardiovascular reactivity and glucose tolerance in normotensive women.

OBJECTIVE: To investigate the interactive effects of oral contraceptive pill use and dietary fat intake on cardiovascular haemodynamics and metabolic parameters in young normotensive women. DESIGN: Thirty-two women participated, of whom 16 were taking oral contraceptive pills (ethinyl-oestradiol plus levonorgestrel) and 16 were age-matched and weight-matched controls not taking such pills. Subjects consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study lasting 6 weeks. Investigations were performed at the end of each diet during the luteal phase of the menstrual cycle. METHODS: Blood pressure was measured by 24 h ambulatory recording; cardiovascular reactivity was determined by examining blood pressure responses to systemic infusions of noradrenaline and angiotensin II and to the cold pressor test; and carbohydrate metabolism was investigated by an intravenous glucose-tolerance test. RESULTS: Plasma triglyceride levels were significantly higher in women taking oral contraceptive pills compared with non-users on both diets; however, responses of lipoprotein levels to the two diets did not differ between study groups (total and low-density lipoprotein cholesterol levels decreased by 15 and 17% in oral contraceptive pill users and by 14% each in non-users, on the low-fat compared with the high-fat diet). Fasting plasma insulin levels, the insulin-production response to administration of glucose (insulin area under the curve) and resting clinic and night-time systolic blood pressures were all significantly reduced on the low-fat diet, but only in non-users. Blood pressure responses to noradrenaline and maximal heart rate response to cold were significantly attenuated during the low-fat diet in oral contraceptive pill users. During the low-fat diet, resting systolic, 24 h systolic and diastolic blood pressures and insulin area under the curve were all significantly higher for women taking the oral contraceptive pills. Users of these pills also exhibited a greater systolic sensitivity to administration both of noradrenaline and of angiotensin II and had a higher plasma renin activity irrespective of dietary phase. CONCLUSIONS: These results confirm that oral contraceptive pills have the potential to cause adverse effects on blood pressure, cardiovascular reactivity and the insulin-production response to administration of glucose and suggest that some of the beneficial effects of a low-fat diet on these parameters may be negated in women taking oral contraceptive pills.

PIP: The interactive effects of combined oral contraceptive (OC) use and dietary fat intake on cardiovascular hemodynamics and metabolic parameters were investigated in a comparative study of 16 normotensive OC users from Australia and 16 age- and weight-matched nonuser controls. The 6-week study's crossover design allocated women to consume either a high- or low-fat diet for 2-week periods. Analyses were performed at the end of each diet during the luteal phase of the menstrual cycle. Plasma triglyceride levels were significantly higher in OC users than nonusers in both diet groups; however, responses of lipoprotein levels to the 2 diets did not differ between study groups. Total and low-density lipoprotein cholesterol levels decreased by 15% and 17%, respectively, in OC users, and by 14% each in non-OC users on the low-fat, compared to the high-fat, diet. Fasting plasma insulin levels, the insulin production response to administration of glucose, and resting clinic and night-time systolic blood pressures were all significantly reduced on the low-fat diet, but only in nonusers. In OC users, blood pressure responses to noradrenaline and maximal heart rate response to cold were significantly attenuated by the low-fat diet. During the low-fat diet, resting systolic, 24-hour systolic, and diastolic blood pressures and areas under the curve were significantly higher in the OC group. OC users also demonstrated a greater systolic sensitivity to administration of both noradrenaline and angiotensin II, and had a higher plasma renin activity, regardless of diet. Overall, these findings confirm that OCs can cause adverse effects on blood pressure, cardiovascular reactivity, and the insulin production response to glucose administration, and negate some of the beneficial effects of a low-fat diet.

The effects of dietary lipid modification on blood pressure, cardiovascular reactivity and sympathetic activity in man.

OBJECTIVES: To examine the effect of dietary lipid modification on 24-h ambulatory blood pressure, cardiovascular reactivity and sympathetic activity in man. DESIGN: Twenty-four normal volunteers consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study of duration 6 weeks. Diets were isocaloric and balanced for sodium and potassium content. METHODS: Cardiovascular reactivity was assessed by measurement of blood pressure responses to incremental infusions of angiotensin II and noradrenaline, and to sympathetic reflex testing. Plasma noradrenaline spillover and clearance rates were estimated using [3H]-noradrenaline infusion. RESULTS: Total plasma cholesterol and low-density lipoprotein-cholesterol levels both fell significantly on the low-fat compared with the high-fat diet, as did heart rate and mean arterial pressure (recorded by 24-h ambulatory monitoring). These changes were accompanied by reductions in blood pressure responses to cold pressor testing and to noradrenaline infusion on the low-fat diet. Plasma noradrenaline spillover and clearance rates did not change. Post hoc analysis showed an association between oral contraceptive use and increased noradrenaline sensitivity on the high-fat diet among the females tested. CONCLUSION: Dietary fat intake alters heart rate, blood pressure and cardiovascular reactivity to noradrenaline in man without changes in basal noradrenaline metabolism.

Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.

OBJECTIVE: To assess the relative contribution of impaired baroreceptor reflexes and enhanced cardiovascular reactivity to the exaggerated blood pressure rises which occur in quadriplegic spinal cord injury patients with automatic hyperreflexia. DESIGN: Pressor dose responsiveness was evaluated by determining the steady-state dose of phenylephrine, alpha-methylnoradrenaline and angiotensin II required to achieve a blood pressure rise of 20 mmHg and the steady-state dose of isoprenaline required to increase heart rate by 20 beats/min in eight quadriplegic spinal cord injury patients and eight control subjects. RESULTS: The dose of phenylephrine alpha-methylnoradrenaline and angiotensin II to achieve a rise in blood pressure of 20 mmHg was significantly reduced in the spinal cord injury group, whilst the dose of isoprenaline required to raise heart rate by 20 beats/min did not differ significantly from the control group. Baroreceptor sensitivity, assessed by straight line regression of change in heart period with change in blood pressure during steady-state infusions of phenylephrine, did not differ statistically between the two groups, but the results could not exclude some evidence of impairment in the spinal cord injury patients. Baroreceptor sensitivity was much less variable in spinal cord injury patients than in controls. CONCLUSIONS: These findings suggest that quadriplegic patients with spinal cord injury have exaggerated pressor responses with significantly less variability in baroreflex sensitivity. The former probably contributes to the autonomic hyperreflexia seen in these patients. The latter provides some support to the suggestion that centrally mediated psychogenic responses contribute to the variability in baroreceptor sensitivity seen in normal subjects.