Infusion Of Methoxamine Research Articles

Further evidence for the existence of alpha 2-mediated adrenergic vasoconstriction in human vessels.

To confirm the presence of alpha 2-mediated vasoconstriction in human vasculature, the effect of selective alpha 1- and alpha 2-agonists (methoxamine and B-HT 933) and antagonists (indoramin and Yohimbine) was studied in fourteen patients with mild, uncomplicated, essential hypertension. Drugs were infused, into the brachial artery at systemically ineffective rates, and concomitant changes in forearm blood flow were measured by strain gauge venous plethysmography. During control conditions, cumulative infusions either of methoxamine or B-HT 933 caused dose-related vasoconstriction, while both indoramin and yohimbine doubled forearm blood flow. Subsequently, the alpha 1-adrenoceptor mediated vasoconstriction produced by methoxamine was shown to be completely blocked by indoramin pretreatment, and to be left unchanged by yohimbine. The alpha 2-vascular stimulation by B-HT 933 was antagonized by previous yohimbine but not by indoramin pretreatment, thus fulfilling the pharmacological requirements for identification of distinct alpha-adrenoceptor mediated excitation-contraction pathways. The data provide further evidence of the existence of alpha 2-mediated vasoconstriction in human forearm vessels.

Methoxamine is an effective unconditioned stimulus for cardiovascular conditioning

New Zealand albino rabbits received classical conditioning training in which a 35-sec tone conditioned stimulus was paired with a bolus injection of methoxamine hydrochloride (Vasoxyl), an α 1-adrenergic agonist. Heart rate (HR) and blood pressure (BP) responses were recorded. Methoxamine produced a precipitous rise in BP and bradycardia as an unconditioned response (UR); pairings of tone and methoxamine over a 5-day period resulted in a gradually appearing tachycardiac conditioned response (CR) which occurred shortly following tone onset. On the other hand, the BP CR was a pressor response. Accordingly, the HR CR was opposite in direction and, thus, apparently compensatory to the UR, whereas the BP CR was similar in direction to the UR. Neither of these cardiovascular changes were observed in control animals receiving either unpaired presentations of tone and methoxamine or tones paired with physiological saline. Most animals receiving either paired or unpaired infusions of methoxamine also showed consistent elevations in baseline HR as training progressed, relative to their respective day 1 levels, thus suggesting the development of compensatory HR CRs to the contextual cues associated with training.

Supersensitivity to norepinephrine in chronically denervated kidneys: evidence for a postsynaptic effect.

Denervation supersensitivity in chronically denervated kidneys increases renal responsiveness to increased plasma levels of norepinephrine. To determine whether this effect is caused by presynaptic (i.e., loss of uptake) or postsynaptic changes, we studied the effect of continuous infusion of norepinephrine (330 ng/min, i.v.) and methoxamine (4 micrograms/min, i.v.), an alpha 1-adrenergic agonist that is not taken up by nerve terminals, on renal function of innervated and denervated kidneys. Ganglionic blockade was used to eliminate reflex adjustments in the innervated kidney and mean arterial pressure was maintained at preganglionic blockade levels by an infusion of arginine vasopressin. With renal perfusion pressure controlled there was a significantly greater decrease in renal blood flow (-67 +/- 9 vs. -33 +/- 8%), glomerular filtration rate (-60 +/- 9 vs. -7 +/- 20%), urine flow (-61 +/- 7 vs. -24 +/- 11%), sodium excretion (-51 +/- 15 vs. -32 +/- 21%), and fractional excretion of sodium (-50 +/- 9 vs. -25 +/- 15%) from the denervated kidneys compared with the innervated kidneys during the infusion of norepinephrine. During the infusion of methoxamine there was a significantly greater decrease from the denervated compared with the innervated kidneys in renal blood flow (-54 +/- 10 vs. -30 +/- 14%), glomerular filtration rate (-51 +/- 11 vs. -19 +/- 17%), urine flow (-55 +/- 10 vs. -39 +/- 10%), sodium excretion (-70 +/- 9 vs. -59 +/- 11%), and fractional excretion of sodium (-53 +/- 10 vs. -41 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

FOOD‐INDUCED CORTISOL SECRETION IS MEDIATED BY CENTRAL ALPHA‐1 ADRENOCEPTOR MODULATION OF PITUITARY ACTH SECRETION

Food ingestion stimulates cortisol secretion in man, but the mechanism of this effect is unknown. We have investigated the possible role of adrenoceptors in the mediation of this effect. Six normal males were given continuous 3 h i.v. infusions of normal saline, methoxamine (alpha-1 adrenoceptor agonist) and thymoxamine (alpha-1 adrenoceptor antagonist). Methoxamine enhanced and thymoxamine attenuated the ACTH and cortisol responses to a standard meal given 60 min after commencement of the infusion. The drugs had no effect on nutrient absorption. Four patients with recent onset of pituitary ACTH deficiency and normally responsive adrenal glands showed no ACTH or cortisol rises after the standard meal, demonstrating that postprandial cortisol secretion is mediated by pituitary rather than gut ACTH. Our previous investigations have demonstrated that alpha-1 adrenoceptors stimulate pituitary ACTH secretion in man by an action within the blood brain barrier. We therefore conclude that postprandial cortisol secretion is mediated by central stimulant alpha-1 adrenoceptors modulating pituitary ACTH secretion.

実験的うっ血性心不全モデルに対するα‐ヒト心房性ナトリウムポリペプチド（α‐ｈＡＮＰ）の効果

Effects of alpha-human atrial natriuretic polypeptide (alpha-hANP) on a model of congestive heart failure (CHF), we established in dogs, were investigated. The model was made by protease injection into the left ventricular free wall, saline loading, and dextran and methoxamine infusion. By this maneuver, left atrial pressure (LAP), systemic vascular resistance (SVR) and left ventricular end-diastolic pressure (LVEDP) were markedly increased, aortic blood flow (AoBF) was decreased and systemic blood pressure (SBP) was unchanged. Following intravenous application of 0.50 microgram/kg alpha-hANP, LAP was reduced from 18.9 to 14.0 mmHg (N = 7, mean); SBP, from 114.4 to 105.1 mmHg; SVR, from 21603 to 15602 dyne sec/cm5; and LVEDP, from 22.2 to 17.6 mmHg; while AoBF was increased from 0.46 to 0.54 l/min. Vmax and T were little influenced. The results indicate that alpha-hANP improved canine CHF mainly through its vasodilating action.

Sympathetic modulation of the pressure-dependent renin release in conscious dogs.

The relationship between mean renal artery pressure and renal venous-arterial plasma renin activity-difference (renin stimulus-response curve; RSRC) was studied in 15 conscious dogs by a stepwise reduction of renal artery pressure down to the lower limit of renal blood flow (RBF)-autoregulation. The RSRC has a flat section above threshold and a steep slope - indicating a 100% increase of renin release per 2.5 mmHg - below a well defined threshold pressure (Pth). Pth may remain unchanged for 4 weeks. A reflex activation of the renal sympathetic nerves by common carotid occlusion increased Pth by 16.5 +/- 3.2 mmHg (P less than 0.01); this effect was abolished by intrarenal alpha-blockade (prazosin). A low dose intrarenal infusion of methoxamine, which did not change RBF, increased Pth by 8.5 +/- 0.7 mmHg (P less than 0.001). We conclude that in the resting conscious dog renal perfusion pressure is a powerful factor in the control of renin release. The renal sympathetic nerves modulate the pressure-dependent mechanism within the autoregulatory range of renal blood flow by an alpha-adrenergic adjustment of threshold pressure.

Effects of alpha-adrenergic stimulation and beta-adrenergic blockade on azygos blood flow and splanchnic haemodynamics in patients with cirrhosis

The effects of beta-blockade with propranolol and of alpha-adrenergic stimulation with methoxamine, a powerful alpha-agonist, on azygos blood flow and on systemic and hepatic haemodynamics were investigated in 26 cirrhotic patients with portal hypertension. Beta-adrenergic blockade with propranolol (n = 12), evidenced by a significant reduction of heart rate (-17 +/- 1%, P less than 0.001) and cardiac index (-17 +/- 2%, P less than 0.001), caused a mild but significant decrease of hepatic venous pressure gradient (-10 +/- 2%, P less than 0.05) and a marked fall of azygos venous blood flow (-31 +/- 5%, P less than 0.05). Alpha-adrenergic stimulation with methoxamine (n = 14), manifested by a significant increase of mean arterial pressure (19 +/- 2%, P less than 0.001), mimicked the effects of propranolol on hepatic venous pressure gradient (-10 +/- 4%, P less than 0.05) and cardiac index (-11 +/- 2%, P less than 0.001). However, azygos blood flow was not significantly reduced by methoxamine (0.7 +/- 0.1 vs 0.6 +/- 0.1 l/min). On the contrary, hepatic blood flow was significantly reduced by methoxamine (-19 +/- 4%, P less than 0.01) but not by propranolol (-7 +/- 7%, ns). Similarly, in 8 patients who received methoxamine after being beta-blocked by propranolol, azygos blood flow, that was markedly reduced by beta-blockade, did not experience a further reduction but increased slightly by alpha-adrenergic stimulation, while hepatic blood flow, that was not reduced by propranolol, decreased significantly during the subsequent methoxamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of noradrenaline, B-HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats.

The effects of vasoactive substances on mean circulatory filling pressure (MCFP), an index of total body venous tone, were determined in conscious rats. Cumulative doses of saline (0.9% w/v NaCl solution), methoxamine (alpha 1-adrenoceptor agonist), B-HT920 (alpha 2-adrenoceptor agonist) noradrenaline and vasopressin, and individual doses of angiotensin II (AII), were infused into the rats. Mean arterial pressure (MAP), MCFP and heart rate (HR) were determined before and during the plateau responses to infusions of the vasoactive substances. The infusions of all the agonists caused a dose-dependent increase in MAP and a decrease in HR. The infusion of saline affected neither MAP nor HR. The infusions of saline and methoxamine did not affect MCFP while the infusions of B-HT 920, noradrenaline and AII increased MCFP. MCFP was slightly increased during the infusion of high doses of vasopressin. It was concluded that receptors for the alpha 2-adrenoceptor agonist and AII are involved in the control of venous tone. Receptors for the alpha 1-adrenoceptor agonist and vasopressin are not important for the control of venous tone.

Absence of functioning alpha-adrenergic receptors in mature canine coronary collaterals.

To determine if mature coronary collateral vascular smooth muscle contains functioning alpha-adrenergic receptors, we studied 13 dogs, 6-10 months after circumflex ameroid occlusion. Regional myocardial blood flow was measured with radioactive microspheres in a blood-perfused heart preparation at constant aortic pressure (80 mm Hg). Normal zone resistance was calculated as aortic pressure divided by normal zone flow, and transcollateral resistance was calculated as aortic pressure minus circumflex pressure distal to the ameroid constrictor divided by coronary collateral flow. Flow and resistance were measured during adenosine vasodilation before and during graded doses of a constant infusion of the alpha-adrenergic agonist methoxamine (n = 6) or the alpha 2-adrenergic agonist clonidine (n = 7). In the hearts that received methoxamine, normal zone resistance increased from a control of 0.29 +/- 0.06 to 0.39 +/- 0.06 mm Hg X min/ml per 100 g (resistance units) during infusion of 10(-5)M methoxamine (p less than 0.05). In contrast transcollateral resistance averaged 0.24 +/- 0.02 resistance units under control conditions and did not change during methoxamine infusion. In the hearts that received clonidine, normal zone resistance averaged 0.24 +/- 0.03 resistance units and increased to 0.39 +/- 0.07 resistance units (p less than 0.05) with the highest dose of clonidine administered (10(-5) M). Transcollateral resistance averaged 0.17 +/- 0.03 resistance units during control conditions and did not change with clonidine infusion. In separate studies isometric tension development by the left anterior descending and coronary collateral vessels was examined in organ baths. The left anterior descending coronary artery demonstrated dose-dependent constriction to phenylephrine (peak response 22 +/- 5% of the response to 100 mM KCl). Clonidine produced weak constrictor responses in the left anterior descending coronary artery (5 +/- 2.5% maximal KCl response). In contrast, neither phenylephrine nor clonidine produced responses in mature collaterals. We also examined responses of mature collateral vessels to nonadrenergic agonists. In the vascular ring preparation the mature collaterals developed tension in the presence of KCl (2.3 +/- 0.9 g), prostaglandin F2 alpha (16 +/- 18% of the KCl responses), and vasopressin (90 +/- 30% of the KCl response). In adenosine-vasodilated hearts, pharmacologic doses of vasopressin caused a two-fold increase in transcollateral resistance. Thus, these studies performed on intact hearts and isolated vascular rings demonstrate that mature coronary collaterals do not contain functioning alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Glomerulotubular balance during renal sympathetic stimulation.

In volume-expanded dogs receiving ethacrynic acid, a linear relationship, glomerulotubular balance (GTB), applies between the remaining sodium reabsorption and the glomerular filtration rate (GFR) during mechanical aortic constriction. To examine whether GTB applies during sympathetic stimulation, the GFR was progressively reduced by 70-75% in anaesthetized dogs by renal nerve stimulation, intrarenal norepinephrine infusion or by selective stimulation of alpha-adrenoceptors by intrarenal methoxamine infusion. Linear relationships (GTB) were obtained (r greater than 0.9). Reabsorption was not different during the various kinds of sympathetic stimulation, but less than during aortic constriction; the largest difference in NaCl reabsorption at comparable GFR amounted to 10-15% and was obtained 30-40% below control GFR, whereas inhibition of NaHCO3 reabsorption was uncertain. To inhibit NaHCO3 reabsorption and associated NaCl reabsorption in the proximal tubules, acetazolamide (30 mg kg-1) was administered instead of ethacrynic acid. No difference in reabsorption was observed at comparable GFR during norepinephrine infusion and mechanical aortic constriction. Hence, GTB applies during sympathetic stimulation. Compared with data obtained during aortic constriction, alpha-adrenergic stimulation reduces proximal reabsorption of NaCl and, possibly, NaHCO3 and exerts no effect on distal transcellular NaCl reabsorption.

Hypertension alters slope and range but not sensitivity to vasoconstrictor and vasodilator agents in the rabbit hindquarter.

The vascular reactivity (slope and range) and location parameter (ED50) of dose-response curves in the hindquarter vascular bed in conscious rabbits previously subjected to renal cellophane wrapping or sham operation were examined. The animals were instrumented with pulsed Doppler flow transducers and chronic indwelling aortic catheters for intra-arterial drug infusion. The rabbits were ganglion-blocked with mecamylamine before constructing full dose-response curves to intra-arterial infusions of methoxamine, noradrenaline, angiotensin II, acetylcholine, adenosine and serotonin. Curves relating dose to conductance were fitted to the experiments involving constrictors and curves relating dose to vascular resistance fitted to those involving dilator drugs. With both classes of drugs the reactivity was significantly higher in the hypertensive animals than in sham-operated rabbits. There was no difference in sensitivity (ED50 value) between the hypertensive and control animals for any agonist tested. The increased reactivity, but not sensitivity, could be entirely accounted for by the vascular amplifier action of medial hypertrophy in hypertension.

Right atrial pressure-volume relationships in tricuspid regurgitation.

Pressure-volume relationships in the right atrium were examined before and after the creation of acute experimental tricuspid regurgitation in pigs. A 1.3 kHz multielectrode impedance catheter with a measuring current of 4 mA was used to determine instantaneous right atrial pressure and relative blood volume; right atrial dimension was assessed simultaneously with ultrasonic crystals attached to the atrial walls. Impedance volume waveforms and ultrasonic crystal dimensions closely paralleled each other at baseline and after the induction of tricuspid regurgitation. The normal right atrial pressure-volume plot exhibited a figure-of-eight configuration, with an "a-loop" and a "v-loop" corresponding to the a-wave and v-wave of the right atrial pressure tracing. With severe tricuspid regurgitation, atrial pump function was abolished, and the pressure-volume plot exhibited a single clockwise loop, consistent with complete ventricularization of the right atrium. Intermediate degrees of tricuspid regurgitation preserved the figure-of-eight loop, but the size of both the a-loop and the v-loop were increased, consistent with a Starling-type load imposed on the atrium by the regurgitant blood volume. Increased right ventricular afterload mediated by constriction of the pulmonary artery and infusion of methoxamine reversibly converted the right atrial pressure-volume loop from that of mild to that of severe tricuspid regurgitation. Alternatively, constriction of the inferior vena cava and infusion of nitroprusside changed the right atrial pressure-volume loop from that of a severe pattern of tricuspid regurgitation to a less severe type of pattern. Infusion of dobutamine increased the size of the a-loop relative to the v-loop both at baseline and after induction of tricuspid regurgitation. We conclude that tricuspid regurgitation induces changes in right atrial mechanics that can be detected and quantified with an impedance catheter.

Altered sensitivity to increases in vascular resistance in rats with hypertension and myocardial infarction

Lett ventricular dysfunction reduces the ability of the heart to maintain forward output when subjected to the additional stress of an increased vascular resistance. To determine the extent to which hearts from rats with both hypertension and myocardial infarction are sensitive to increases in vascular resistance, spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) with and without myocardial infarction (coronary artery ligation) were infused with methoxamine (0.08 to 1.6 mg/kg/min). Mean arterial pressure during methoxamine infusion was significantly lower in infarcted rats than in noninfarcted rats in each strain, due largely to a lower cardiac output in infarcted rats. When compared at equal pressures, the infarcted groups of each strain generated a lower cardiac output than did the respective noninfarcted groups, as a result of both a lower stroke volume and heart rate. During the methoxamine infusion, absolute pressure levels in SHR with large infarcts were similar to those in NWR. Thus, infarcted hearts from both hypertensive and normotensive rats, when subjected to the stress of an increase in vascular resistance, demonstrated an impairment of pumping ability that was related to the extent of left ventricular damage. Impaired pressure-generating capacity was most pronounced in SHR with large infarcts, which were unable to generate hypertensive levels of blood pressure.

実験的うっ血性心不全モデルに対するＦｏｒｓｋｏｌｉｎの効果

Forskolin is a diterpene of the labdane family which activates adenylate cyclase. The effects of forskolin were investigated in a congestive heart failure (CHF) model that we newly established using anesthetized dogs. The model was made by the intramural injection of protease into the left ventricular free wall, saline loading, and dextran and methoxamine infusion. By this maneuver, aortic blood flow (AoBF) was decreased; left atrial pressure (LAP), systemic vascular resistance (SVR) and left ventricular endodiastolic pressure (LVEDP) were markedly increased; and systemic blood pressure was unchanged. A bolus injection of 5.0 micrograms/kg forskolin reversed the hemodynamic findings of CHF. It reduced LAP (17.5----7.9 mmHg) (mean, N = 7), SVR (19980----10390 dyne sec/cm5), time constant T (90.7----59.2 msec) and LVEDP (22.8----16.8 mmHg); and it increased Vmax (2.32----2.82 l/sec) and AoBF (0.50----0.72 l/min). Forskolin improved the CHF mainly through its vasodilator and positive inotropic actions.

Relative contribution of different vascular beds to the pressor effects of alpha-adrenoreceptor agonists and vasopressin in pithed rats: radioactive microsphere determination.

The relative fractional distribution of 51Cr-labelled microspheres was evaluated in pithed rats during equieffective vascoconstrictor responses evoked by infusions of the alpha-adrenoreceptor agonists methoxamine (alpha 1-selective), UK-14,304 (alpha 2-selective) or vasopressin. The proportion of injected radioactive microspheres trapped in each tissue during a sustained pressor response relative to saline treated controls is considered a reflection of the degree of local vascoconstriction in the tissue analysed. All three agonists (methoxamine, UK-14,304 and vasopressin) decreased the number of microspheres trapped in the mesentery and tail. Only methoxamine reduced the blood flow to the kidney and spleen. UK-14,304 did not modify the number of microspheres in the sample of skeletal muscle, however, both vasopressin and methoxamine reduced the blood flow to this tissue. Vasopressin increased the counts in the lungs and particularly in the liver but decreased the number of spheres trapped in the stomach and skin. In contrast to the alpha-adrenoreceptor agonists, vasopressin did not increase the number of microspheres trapped in the heart. Since a reduction in the number of microspheres trapped in the tissue reflects a decrease in blood flow, to that organ it is reasonable to conclude that alpha 1-adrenoreceptor stimulation increases kidney, spleen, mesentery, caudal and skeletal muscle vascular resistance, whereas alpha 2-adrenoreceptors appear to preferentially vasoconstrict the mesenteric and the caudal vascular beds.

Change in ventricular cavity size: differential effects on QRS and T wave amplitude.

Although many factors have been reported to change the R wave amplitude of the electrocardiogram (ECG), few observations have been made of the associated changes in T wave amplitude. We hypothesized that changes in R and T wave amplitude should parallel each other. To test this hypothesis, R and T wave amplitudes were measured in 15 normal subjects during increased and decreased left ventricular dimensions induced by infusion of methoxamine and by Valsalva maneuver, respectively, as well as during changes in the proximity of the left ventricle to the chest wall (i.e., shift in patient position from supine to left lateral position). Simultaneous nine-lead ECGs and two-dimensional-guided M mode echocardiograms of the left ventricle were recorded at rest and under each experimental condition. R wave amplitude increased as the left ventricular lateral wall moved closer to the V5 and V6 electrodes. Alterations in R wave amplitude seen with changes in left ventricular chamber size were primarily caused by radial movement of the left ventricle in relation to the chest wall. Proximity of the left ventricle to the chest wall was therefore a major determinant of R wave amplitude. In contrast, T wave amplitude varied directly with alterations in left ventricular chamber size but was unaffected by changes in proximity to the recording electrode on the chest wall. Left ventricular chamber size, and possibly the associated alteration in endocardial-to-epicardial surface area ratio, appeared to be the major determinants of T wave amplitude.

Adverse cardiac effects of acute alcohol ingestion in young adults.

Previous studies of the effects of acute alcohol ingestion in normal subjects have used measures of left ventricular performance that are altered by changes in preload and afterload and in contractile state. In studies involving nine healthy, young adults, we measured sensitive load-independent end-systolic indices of left ventricular contractility over a wide range of pressures generated by methoxamine infusion before and after oral alcohol administration. Echocardiography was used in conjunction with calibrated carotid pulse tracings. Alcohol ingestion resulted in a fall (p less than 0.01) in left ventricular end-diastolic dimension (a measure of preload), end-systolic wall stress (a measure of afterload), and systemic vascular resistance, while not changing the left ventricular shortening fraction. In contrast, the end-systolic pressure-dimension slope decreased (p less than 0.001) and the rate-corrected velocity of left ventricular fiber shortening at an end-systolic wall stress of 50 g/cm2 fell (p less than 0.001). Thus, when load-independent assessment of left ventricular contractility is done, acute alcohol ingestion has a myocardial depressant effect greater than previously suspected.

Left ventricular contractility and contractile reserve in humans after cardiac transplantation.

Limited data are available concerning left ventricular contractility and contractile reserve in the chronically denervated, transplanted human heart. This is primarily because of the inability of traditional tests of left ventricular performance to distinguish changes in contractility from alterations in ventricular loading conditions. In this study, load-independent end-systolic indexes of left ventricular contractility were measured by echocardiography and calibrated carotid pulse tracings in 10 patients who had undergone orthotopic cardiac transplant (age 48 +/- 4 years; interval from operation to study 1.2 +/- 0.8 years) and in 10 normal control subjects (age 25 +/- 4 years) matched for donor heart age (25 +/- 6 years). None of the transplant patients had evidence of rejection as determined by endomyocardial biopsy. Baseline left ventricular contractility was assessed over a wide range of afterload generated by infusion of methoxamine. Contractile reserve was measured as the response to an infusion of dobutamine plus methoxamine. Before afterload challenge, baseline left ventricular percent fractional shortening was higher for the transplant patients than for the control subjects (36.5 +/- 5.7% vs 32.1 +/- 2.1%; p less than .05). These differences occurred at a time that end-systolic wall stress (a measure of afterload) was significantly lower for the transplant patients (38 +/- 16 vs 50 +/- 9 g/cm2; p less than .05). When the left ventricular end-systolic pressure-dimension and stress-shortening relationships were determined for the transplant and control subjects, no differences in contractility or contractile reserve were noted. Thus the chronically denervated, transplanted, nonrejecting human left ventricle demonstrates normal contractile characteristics and reserve.

Physiologic assessment of the inotropic, vasodilator and afterload reducing effects of milrinone in subjects without cardiac disease

Milrinone increases left ventricular (LV) shortening. Whether these changes result from vasodilation alone or from a combination of vasodilation and a positive inotropic action is controversial. Load-independent end-systolic indexes of LV contractility were measured over a wide range of aortic pressures generated by methoxamine infusion before and during milrinone administration. Sixteen studies were performed using echocardiography and calibrated carotid pulse tracings in 11 normal subjects. Milrinone loading doses of 30, 45 or 60 μg/kg were given intravenously over 10 minutes, followed by a maintenance infusion to achieve steady-state drug levels. Milrinone induced a dose-dependent decrease in baseline (i.e., before methoxamine) total systemic resistance (p < 0.05) and afterload as measured by end-systolic wall stress (p < 0.001). The associated changes in the end-systolic pressure-dimension, stress-shortening and stressvelocity of fiber shortening relations were characteristic of a positive inotropic intervention. All end-systolic indexes of LV contractility demonstrated greater inotropic effect at the higher milrinone plasma concentrations. Thus, load-independent indexes of LV contractility show that milrinone has a dose-related positive inotropic effect separate from its vasodilator (total systemic resistance) and afterload (end-systolic stress) reducing effects.

Relation of electrocardiographic R-wave amplitude to changes in left ventricular chamber size and position in normal subjects

Although exercise-induced changes in electrocardiographic R-wave amplitude have been ascribed to changes in left ventricular (LV) size, QRS axis, heart rate and ischemia, the physiologic mechanism remains unclear. To clarify the relation between R-wave amplitude and changes in LV size and position, simultaneous 9-lead electrocardiograms and targeted M-mode echocardiograms were recorded from 15 normal subjects. Recordings were made at rest, during Valsalva maneuver and during methoxamine infusion. LV diastolic dimension increased with methoxamine and decreased with Valsalva maneuver (p < 0.001). R-wave amplitude in leads V 5 and V 6 varied directly with LV dimensions (p < 0.001). The correlation coefficient between the change in R-wave amplitude in V 5 or V 6 and the change in LV dimension was 0.81 (p < 0.001). No significant changes in R-wave amplitude were seen in electrocardiographic leads I, II, III, aVR, aVL, aVF or V 1. Distance from the chest wall to the LV posterior wall correlated with change in R-wave amplitude (r = 0.79, p < 0.001). Change from supine to left lateral position moved the left ventricle closer to the lateral chest wall in association with a 41 ± 8% increase in R-wave amplitude in V 5 and V 6 (p < 0.001). In conclusion, there is a direct and a dynamic relation between R-wave amplitude and LV chamber size. Chamber size and distance from the left ventricle to leads V 5 or V 6 interact as major determinants of R-wave amplitude.