Effects of endothelin-1 on arterial pressure: a comparison of intravenous and intra-arterial administration in conscious rabbits.

1. Intravenous endothelin-1 releases endothelium-derived relaxing factor (EDRF) and prostacyclin from the lungs, and substantial pulmonary clearance is claimed. Since these vaso-active substances could alter the haemodynamic effects of endothelin-1, the effects of boluses of endothelin-1 injected intravenously and into the left ventricle (intra-arterial) were compared, measuring arterial pressure and heart rate in conscious male New Zealand rabbits. The pulmonary clearance of endothelin-1-like immunoreactivity (Et-1LI) and initial plasma half-life were measured in anaesthetized rabbits during and after intravenous infusion of endothelin-1. 2. The effects of intravenous and intra-arterial routes of administration were not significantly different. Arterial pressure decreased (intravenous: 21.6, intra-arterial: 24.2 mmHg, P = 0.12, n = 10, t-test, 9 d.f.), then increased (intravenous: 21.2, intra-arterial: 16.4 mmHg, P = 0.33), while heart rate increased (intravenous: 66, intra-arterial: 53 beats/min, P = 0.09), then decreased (intravenous: 50, intra-arterial: 54 beats/min, P = 0.30). 3. Arterial and venous plasma levels of Et-1LI were not significantly different, venous levels increasing from 30 +/- 3 pg/mL (12 +/- 1 pmol/L) at 1 pmol/kg per min to 770 +/- 78 pg/mL (308 +/- 31 pmol/L) at 16 pmol/kg per min (n = 5). Mean initial plasma half-life was 0.6 min (range: 0.25-1.1 min). 4. It was concluded that there is no significant net pulmonary clearance of exogenously administered endothelin-1 in the conscious rabbit, and that any vaso-active factors released in the lungs by endothelin-1 do not have a significant effect on systemic arterial pressure.

Atrial natriuretic factor release during rapid ventricular pacing: interplay between autonomic and hemodynamic stimulants.

Plasma levels of atrial natriuretic factor (ANF) and norepinephrine are markedly elevated during episodes of ventricular tachycardia. Although atrial distention appears to be the major stimulus for ANF release, reflex changes in autonomic tone might also contribute. Plasma ANF and norepinephrine levels, sinus node cycle length, systolic blood pressure, and mean right atrial pressure were therefore assessed during rapid right ventricular pacing at 150 beats/min for 10 minutes. In five patients (group 1) observations were made without autonomic blockade, and another five patients (group 2) had ventricular pacing after cardiac autonomic blockade. In group 1 systolic blood pressure fell during ventricular pacing from 122 +/- 4 to 105 +/- 5 mm Hg (p < 0.02), norepinephrine levels increased from 195 +/- 26 to 411 +/- 71 pg/ml (p < 0.02), and sinus node cycle length decreased from 936 +/- 99 to 688 +/- 58 msec (p < 0.02). Right atrial pressure was elevated from 2.6 +/- 0.6 to 7.4 +/- 0.6 mm Hg (p < 0.02), and ANF levels increased from 161 +/- 23 to 240 +/- 26 pg/ml (p < 0.05). Whereas systolic blood pressure, norepinephrine, sinus cycle length, and right atrial pressure returned promptly to baseline levels when ventricular pacing was stopped, ANF levels continued to rise (296 +/- 37 pg/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diltiazem and atenolol in essential hypertension: additivity of effects on blood pressure and cardiac conduction with combination therapy.

In 15 patients with mild to moderate essential hypertension, the effects of diltiazem (120 mg twice daily) were compared with those of atenolol (50 mg once daily), the two drugs in combination, and placebo in a randomized double-blind cross-over study with treatment phases of 4 weeks duration. Blood pressure was reduced in the active treatment phases (supine blood pressure: diltiazem, 172/92 mmHg; atenolol, 172/92 mmHg; diltiazem plus atenolol, 164/88 mmHg; pooled estimate of s.e.m. by analysis of variance = 3/1) compared with placebo (180/101 mmHg). Factorial analysis confirmed fully additive antihypertensive effects of the drugs in combination. The time interval from the beginning of the P wave to the beginning of the QRS complex (P-R interval) was longer during combination therapy (0.184s) compared with either diltiazem (0.175s) or atenolol (0.174s) alone, or placebo (0.164s); s.e.m. by analysis of variance = 0.003. No clinically significant conduction disturbances occurred. Plasma atrial natriuretic peptide was elevated by atenolol but not diltiazem. Thus, in subjects with uncomplicated essential hypertension, diltiazem and atenolol had equal antihypertensive efficacy when used alone, and fully additive effects in combination, on both blood pressure and cardiac conduction.

Neuropeptide Y-like immunoreactivity of plasma during hypoglycaemia in man.

Previous studies have demonstrated that plasma Neuropeptide Y-like immunoreactivity (NPY-LI) increases after activation of sympathetic nerves. To test the hypothesis that the adrenal medulla may also be a significant source of circulating plasma NPY-LI and to determine if NPY is co-released with adrenal catecholamines, we have measured the peripheral venous concentrations of NPY-LI, adrenaline and noradrenaline in six patients, before and after induction of hypoglycaemia as part of pituitary function tests that also tested gonadotrophin and thyroid stimulating hormone release. The plasma adrenaline concentration was increased approximately 15 times (p less than 0.05) relative to baseline at 30 mins and remained elevated for the 90 minutes of the study. The plasma concentration of both noradrenaline and NPY-LI remained unchanged. These results failed to demonstrate an increase in the amount of NPY-LI released into the plasma during stimulation of the adrenal medulla with hypoglycaemic stress in man. They do not support significant co-release of NPY with adrenaline from the adrenal medulla in man, nor a physiological role for NPY as an adrenal hormone in human subjects in this situation.

Plasma neuropeptide Y and atrial natriuretic peptide concentrations in man.

1. In order to examine the concentration of neuropeptide Y-like immunoreactivity (NPY-LI) and atrial natriuretic peptide (ANP) in the circulation in man, blood was sampled from the iliac vein, the inferior vena cava, the superior vena cava, the pulmonary artery and the femoral artery in 13 patients undergoing cardiac catheterization. 2. Plasma NPY-LI levels were similar at all points sampled and no arteriovenous differences were found. Plasma ANP concentration in the pulmonary artery was greater than in peripheral venous blood but there was a strong correlation between the two. 3. The concentration of NPY-LI and ANP in peripheral venous blood reflects central venous and arterial concentrations.

Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination.

In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures (group means) were 171/97 (placebo), 147/85 (enalapril), 154/84 (atenolol) and 144/78 (enalapril plus atenolol) (S.E.M. +/- 2/+/- 1-ANOVA), and standing blood pressures were 170/105 (placebo), 146/92 (enalapril), 154/92 (atenolol) and 147/86 (enalapril plus atenolol) (S.E.M. +/- 3/+/- 1). In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker.

Plasma atrial natriuretic peptide is increased during atrial pacing in conscious rabbits.

The effect of increases in heart rate on plasma atrial natriuretic peptide (ANP) concentrations was investigated in conscious rabbits. Plasma ANP concentrations were significantly increased following abrupt increases in heart rate produced by atrial pacing at 400 beats/min. Pacing at 300 beats/min resulted in smaller increases in plasma ANP concentration. Stepwise increases in heart rate produced by atrial pacing at 250, 300, 350 and 400 beats/min resulted in increases in plasma ANP concentrations at 400 beats/min only. The increase in plasma ANP concentration during atrial pacing correlated significantly with the increase in heart rate achieved.

Increases in plasma neuropeptide Y concentrations during sympathetic activation in man.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons. In order to test the hypothesis that NPY may be released along with catecholamines by activation of the sympathoadrenal system we measured plasma NPY-like immunoreactivity (NPY-LI) concentrations during cold pressor test, head up tilt and bicycle exercise in healthy volunteers. All 3 manoeuvres resulted in elevation of blood pressure, heart rate and plasma noradrenaline and adrenaline concentrations. These were accompanied by increases in plasma NPY-LI concentrations on cold pressor test and exercise, but not with head up tilt. The increases in both NPY-LI and catecholamines were greatest with exercise. These findings suggest that NPY is released at the same time as noradrenaline when sympathetic noradrenergic nerves are activated.

Effects of enalapril and hydrochlorothiazide on blood pressure, renin-angiotensin system, and atrial natriuretic factor in essential hypertension: a double blind factorial cross-over study.

The hypotensive and hormonal effects of the angiotensin converting enzyme (ACE) inhibitor enalapril (10 mg twice daily) were compared with those of hydrochlorothiazide (25 mg twice daily), with the two drugs in combination and with placebo in 21 patients with essential hypertension. For each patient there were four randomised double-blind treatment phases, each of four weeks' duration, which comprised a 2 X 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine mean blood pressures were 119 mmHg (placebo), 113 mmHg (hydrochlorothiazide), 108 mmHg (enalapril), and 98 mmHg (hydrochlorothiazide plus enalapril) (SEM 3 mmHg, ANOVA). Enalapril and hydrochlorothiazide were equally effective and well tolerated and their hypotensive effects were additive. Enalapril increased plasma renin activity (PRA), reduced plasma angiotensin II (AII) and aldosterone concentrations, and reduced ACE activity, whereas hydrochlorothiazide increased PRA, plasma AII, and aldosterone concentrations without altering ACE activity. With combination treatment the effects of enalapril on PRA and plasma AII concentrations were potentiated whereas those on plasma aldosterone concentration and ACE activity were additive. Atrial natriuretic factor plasma concentration in the placebo phase was 92 pg/ml and increased to 145 pg/ml in the hydrochlorothiazide phase (p less than 0.001, SEM 13 pg/ml), but there was no significant change in either the enalapril or combination phases.

Plasma neuropeptide y levels rise in patients undergoing exercise tests for the investigation of chest pain.

Neuropeptide Y (NPY) is colocalised with noradrenaline in post-ganglionic sympathetic neurons. In order to examine the possibility that activation of the sympathetic nervous system might cause release of NPY into the plasma NPY levels were measured in 16 patients undergoing exercise tests for investigation of chest pain. Plasma NPY concentrations rose in 14 out of the 16 patients, and the mean level of plasma NPY increased from 335 (s.e.m. = 37) to 455 (s.e.m. = 41) pg/ml. Plasma noradrenaline and adrenaline levels increased four- and two-fold respectively. The increase in NPY correlated with the increase in noradrenaline, suggesting that NPY may be released with noradrenaline when sympathetic noradrenergic nerves are activated.

Hypertension due to a renin-secreting tumour localised by segmental renal vein sampling.

An 18-year-old female was found to be hypertensive on routine medical examination. Further investigation disclosed persistent hypokalaemia and elevated plasma renin activity in peripheral venous blood. Segmental renal vein sampling with assay of blood samples located the source of excess renin secretion in the lower mid-zone of the left kidney. This localization was not confirmed by either angiography or by palpation of the exposed kidney before nephrectomy but macroscopic examination of the freshly sectioned kidney revealed a small tumour in the region suggested by renal vein sampling. The tumour had the morphologic pattern fo an haemangiopericytoma with abundant ultrastructural specific granules and very high renin activity by tissue assay. Plasma renin activity fell precipitously after nephrectomy and remained very low for the first week. Although the immediate post-operative blood pressure fell to normal, hypertension recurred temporarily and was associated with elevated plasma aldosteron, producing a syndrome similar to primary aldosteronism. All variables returned to normal without specific therapy and hypertension has not subsequently recurred.

Evidence for a significant contribution from central effects of angiotensin in the development of acute renal hypertension in the greyhound.

1. The importance of central vasomotor effects of endogenously generated angiotensin in the acute hypertensive response to renal artery constriction has been investigated in the anaesthetized greyhound. 2. When the central cardiovascular action of angiotensin was abolished by thermocoagulation of the areas postrema, the hypertensive response to renal artery constriction was reduced by half while the increase in plasma renin activity was unchanged. 3. It is concluded that central vasomotor effects of angiotensin play a significant role in renin-dependent hypertension.