R. J. McRitchie

Automated non-invasive measurement of cardiac output by the carbon dioxide rebreathing method: comparisons with dye dilution and thermodilution.

The accuracy and reproducibility of indirect measurement of cardiac output at rest by the carbon dioxide rebreathing (indirect Fick) method with an automated respiratory analysis system (Gould 9000IV) were compared with simultaneous measurements made in duplicate by dye dilution and thermodilution in 25 patients having cardiac catheterisation studies. Measurements of cardiac output by the carbon dioxide rebreathing method were not significantly different from those obtained with dye dilution (mean difference -0.3 l/min, SD 0.76, 95% confidence interval -0.7 to 0.1). Thermodilution significantly over-estimated cardiac output by a mean of 2.2 l/min or 39% (SD 1.5, 95% confidence interval 1.6 to 2.8) compared with the carbon dioxide rebreathing method and significantly overestimated cardiac output by 1.9 l/min or 31% (SD 1.2, 95% confidence interval 1.2 to 2.5) compared with dye dilution. The reproducibility of measurements of cardiac output in individual patients was satisfactory with the dye dilution method but was poor with carbon dioxide rebreathing and thermodilution. Indirect measurement of resting cardiac output by the Gould 9000IV automated carbon dioxide rebreathing method is more accurate but the variability inherent with this method requires that multiple measurements be taken for each determination. Measurement of cardiac output by the thermodilution method by a commercially available cardiac output computer was not satisfactory because not only was there considerable variability between repeat measurements but the method also consistently overestimated cardiac output compared with the dye dilution method.

Baroreflex control of myocardial contractility in conscious normotensive and renal hypertensive rabbits.

We have assessed resting myocardial contractility and its baroreflex control in normotensive and hypertensive conscious rabbits. Hypertension was induced by bilateral cellophane wrapping of the kidneys with experiments performed 6 weeks later during the established phase of hypertension. The peak rate of change of left ventricular pressure (peak LV dP/dt) was used as the index of myocardial contractility. Baroreflex control of contractility and heart period (HP) was assessed by constructing stimulus response curves relating change in mean arterial pressure (MAP), induced by balloon occluders around the abdominal aorta and inferior vena cava, to change in peak LV dP/dt and HP. These stimulus response curves were obtained in normotensive rabbits with and without cardiac pacing, and in both normotensive and hypertensive animals after cardiac beta sympathetic blockade with propranolol, vagal blockade with methylscopolamine, and combined cardiac autonomic blockade with propranolol and scopolamine, as well as in rabbits with intact autonomic effectors. Resting MAP was significantly higher in the hypertensive rabbits (119 +/- 2 mm Hg) compared to normotensive controls (76 +/- 1 mm Hg). Resting peak LV dP/dt was also greater by 51% in the hypertensive animals (7054 +/- 287 mm Hg sec-1) compared to controls (4690 +/- 223 mm Hg sec-1). There was no significant difference in the resting heart period or resting left ventricular end diastolic pressure. Transient changes in MAP induced by occlusion of the aortic or venous balloons produced significant alterations in peak LV dP/dt in normotensive animals with and without pacing and in hypertensive control animals. In animals with cardiac sympathetic block, the range and slope or sensitivity of the stimulus response curves were not significantly changed but in animals with vagal blockade the sensitivity was reduced by 90% and the range at 30 mm Hg by 88%. After propranolol and methylscopolamine were administered together, the stimulus no longer evoked a response. These experiments demonstrate that myocardial contractility is under baroreflex control and suggest that this is mediated principally via parasympathetic nerves to the heart. There was no significant difference between the sensitivity of baroreflex control of myocardial contractility in the normotensive (-84 +/- 14 mm Hg sec-1 per mm Hg) and the hypertensive (-110 +/- 14 mm Hg sec-1 per mm Hg) rabbits, unlike the baroreflex control of heart period where sensitivity was markedly impaired in the hypertensive (sensitivity 3.8 +/- 0.8 msec/mm Hg) compared to the normotensive (6.9 +/- 1.0 msec/mm Hg) animals.

Effects of neuropeptide Y on the renal mesenteric and hindlimb vascular beds of the conscious rabbit

The effects of neuropeptide Y (NPY, 10 micrograms/kg bolus i.v.) on renal, mesenteric and hindlimb blood flow were determined in intact conscious rabbits with chronically implanted Doppler ultrasonic flow transducers. The role of sympathetic neuro-effectors was assessed using inhibition of peripheral alpha-adrenoceptors with phentolamine in each group, and in the renal flow group following chemical sympathectomy with 6-hydroxydopamine. In controls, NPY caused markedly non-uniform peak responses. Renal blood flow fell from 2.16 +/- 0.12 kHz to a minimum of 0.26 +/- 0.07 kHz following NPY administration (P less than 0.05). Mesenteric blood flow was reduced from 2.04 +/- 1.17 to 1.54 +/- 0.11 kHz (P less than 0.05). blood flow increased transiently from 2.33 +/- 0.15 to a peak of 3.33 +/- 0.19 kHz (P less than 0.05). Renal vascular resistance rose by 1189 +/- 309% and mesenteric resistance by 54 +/- 9% (P less than 0.05), while hindlimb resistance fell by 24 +/- 3% (P less than 0.05). Pretreatment with phentolamine accentuated the peak pressor response and the reduction in heart rate induced by NPY administration but had little effect on the local haemodynamic changes in each vascular bed. There was no change in the renal vascular response to NPY following sympathectomy. Indeed, the peak NPY-induced reduction in renal blood flow seen in control animals (87 +/- 4%) was unaffected by either alpha-adrenoceptor inhibition (90 +/- 5%) or by sympathectomy (86 +/- 5%). In conscious rabbits with intact cardiovascular reflexes, pharmacological doses of NPY cause profound renal vasoconstriction with smaller changes in mesenteric and hindlimb flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.

Comparative hemodynamic effects of amiodarone, sotalol, and d-sotalol

The effects of intravenous boluses of amiodarone (5 mg/kg), racemic sotalol (enantiomeric ratio d/l-sotalol 1:1;1.5 mg/kg), and d-sotalol (0.75 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), left ventricular end-diastolic pressure (LVEDP), and peak rate of change of left ventricular pressure (LV dp/dt) were assessed in conscious rabbits. Amiodarone and sotalol had a modest negative inotropic effect: amiodarone reduced peak LV dp/dt by 8 +/ 2% (mean +/- SEM) (p < 0.05) and sotalol by 6 +/- 2% (p < 0.05). These two drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: amiodarone caused a 13 +/- 3% (p < 0.05) increase in CO associated with a substantial vasodilatory effect (TPR reduced 25 +/- 3%; p < 0.01); sotalol did not produce any substantial change in either CO or TPR. Bolus intravenous injection of amiodarone was associated with a significant increase in HR (12 +/- 3%; p < 0.01), whereas sotalol reduced HR by 7 +/- 1% (p < 0.05). In contrast, administration of the dextro-rotatory optical isomer, d-sotalol, produced no significant change in peak LV dp/dt, LVEDP, CO, TPR, or HR. These results confirm that amiodarone and racemic sotalol have a comparatively weak cardiodepressant action. The experiments also show that the reduction in cardiac performance associated with racemic sotalol is mediated predominantly through the beta-adrenoreceptor blocking action of the levo-rotatory isomer (l-sotalol) rather than any substantial cardiodepressant effect of the dextro-rotatory isomer.

EXPERIMENTAL HYPERTENSION PRODUCES DIVERSE CHANGES IN THE REGIONAL VASCULAR RESPONSES TO ENDOTHELIN-1 IN THE RABBIT AND THE RAT

Objective: To examine the effects of hypertension on systemic and regional haemodynamic responses to endothelin-1. Design: Comparison of responses between age-matched control and hypertensive rabbits (two-kidney, two wrapped), and between spontaneously hypertensive rats (SHR) and control Wistar—Kyoto rats. Methods: Arterial pressure, heart rate and blood flow responses to 0.2 nmol/kg intravenous endothelin-1 were measured in conscious animals. Blood flow was measured by pulsed ultrasound Doppler in the ascending aorta, distal abdominal aorta, left renal artery and superior mesenteric artery. Results: Endothelin-1 produced qualitatively similar effects in the hypertensive and control animals. In the systemic circulation, brief initial vasodilation preceded sustained vasoconstriction. In the hindlimb, marked vasodilation preceded relatively minor vasoconstriction, and profound vasoconstriction occurred in the renal and mesenteric vascular beds. In the rats but not the rabbits, fleeting vasodilation preceded the renal and mesenteric vasoconstriction. Significant differences between hypertensive and control animals were: accentuation of the pressor effect and heart rate responses in hypertensive animals of both species, and accentuation of hindlimb vasodilation in hypertensive rabbits but not SHR; and attenuation of the depressor effect in SHR but not hypertensive rabbits, attenuation of the mesenteric vasoconstriction in both hypertensive rabbits and rats, and attenuation of renal vasoconstriction in SHR. Conclusions: The increased responses to endothelin-1 of some variables in the hypertensive animals may involve structural changes in the resistance vessels. However, the reduced responses in the mesenteric vasculature of both species and the renal vasculature of the SHR are due to some mechanism other than structural change.

Effects of neuropeptide Y on cardiac performance and renal blood flow in conscious normotensive and renal hypertensive rabbits

The effects of neuropeptide Y (NPY, 10 micrograms/kg bolus iv) on cardiac output, renal blood flow and myocardial contractility were determined in intact renal hypertensive and normotensive rabbits instrumented with ultrasonic flow transducers or left ventricular catheters. The basal plasma concentration of NPY-like immunoreactivity in arterial blood was greater in the hypertensive rabbits (4.2 +/- 0.7 micrograms/l) than in normotensive animals (2.2 +/- 0.4 micrograms/l, p less than 0.05). There were similar moderate increases in arterial blood pressure and total peripheral resistance following NPY, but a small NPY-induced reduction in cardiac output in normotensive rabbits was not seen in hypertensive animals. Resting peak left ventricular dP/dt (an index of myocardial contractility) was higher in hypertensive rabbits (7397 +/- 619 vs 5551 +/- 342 mmHg/sec, p less than 0.05), but there was no significant difference between the maximum NPY-induced falls in peak dP/dt. NPY produced significant peak reductions in renal blood flow in both hypertensive (from 2.5 +/- 0.2 to 1.2 +/- 0.2 kHz, p less than 0.05) and in normotensive rabbit groups (from 2.2 +/- 0.1 to 0.3 +/- 0.1 kHz, p less than 0.05), but the fall in renal blood flow and the corresponding rise in renovascular resistance were smaller in the hypertensive animals (p less than 0.05). The cause of this apparent decrease in renovascular reactivity in the renal hypertensive model was not determined.

Effects of neuropeptide Y on the heart and circulation of the conscious rabbit.

Summary: The direct and reflex-mediated components of the cardiovascular response to administration of neuropeptide Y (NPY) in intact conscious rabbits were determined by studies with cardiac β adrenoceptor and vagal blockade, and during total autonomic blockade. Cardiac pacing was used to prevent bradycardia, and sinoaortic denervation (SAD) was used to remove afferent baroreflex input. In control animals, NPY (10 μg/kg bolus i.v.) caused arterial pressure to increase from 77.4 ± 1.5 mm Hg (mean ± SEM) to a maximum of 91.4 ± 1.6 mm Hg (p < 0.05). This pressor response was independent of autonomic effectors but was buffered by arterial baroreflexes. The fall in heart rate (HR) from 281 ± 14 to 252 ± 18 beats/min (p < 0.05) was mediated in part through baroreceptor-dependent changes in cardiac autonomic efferent activity, but was in part independent of autonomic neural mechanisms. Peak left ventricular (LV)dP/dt fell from 5,551 ± 342 to 4,182 ± 394 mm Hg/s (p < 0.05) following NPY in control rabbits. This reduction was maintained during pacing and following SAD, and was caused partly by a withdrawal of cardiac β-adrenergic tone and partly through a non-β-mediated myocardial depression. Small changes in cardiac output (CO) and in LV end-diastolic pressure (LVEDP) after NPY were secondary to bradycardia. Total autonomic blockade did not impair the NPY-induced rise in total peripheral resistance (TPR), suggesting a direct vasoconstrictor action that was independent of neural mechanisms.

Effects of neuropeptide Y on baroreflex control of heart rate and myocardial contractility in conscious rabbits

1. The effects of intravenous (i.v.) neuropeptide Y (NPY, 10 μg/kg bolus) on the stimulus‐response curves relating changes in heart period (HP) and in peak left ventricular (LV) dP/dt to acute changes in mean arterial pressure (MAP) were determined in conscious, normotensive rabbits.

Effects of neuropeptide Y on left ventricular function in the conscious rabbit

1. Changes in arterial pressure, heart rate and left ventricular contractility induced by intravenous injections of neuropeptide Y (NPY; 1–30 μg/kg) were studied in the conscious rabbit.