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Cardiovascular Research 1998 40(2):282-289; doi:10.1016/S0008-6363(98)00185-0
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Copyright © 1998, European Society of Cardiology

Increased aortic blood pressure contributes to potentiated dobutamine inotropic responses after systemic NO synthase inhibition in sheep

Daniel J Pennya,b,c, Hong Chenb and Joseph J Smolicha,b,*

aInstitute of Reproduction and Development, Monash University, Clayton, Victoria, Australia
bCentre for Heart and Chest Research, Monash University, Clayton, Victoria, Australia
cDepartment of Cardiology, Royal Children's Hospital, Melbourne, Australia

* Corresponding author. Tel.: +61-3-9550-5470; Fax: +61-3-9550-5554; E-mail: joe.smolich@med.monash.edu.au

Received 26 November 1997; accepted 14 April 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: To determine whether inotropic responses to the β-adrenergic agonist dobutamine are potentiated by systemic inhibition of nitric oxide synthase (NOS) with the L-arginine analogue N{omega}-nitro-L-arginine (L-NNA), and to establish to what extent any observed responses are related to the increase in aortic blood pressure accompanying systemic NOS inhibition. Methods: Dobutamine was infused incrementally at rates of 1, 2.5, 5 and 10 µg/kg/min in 15 open-chest, anaesthetised ewes before and after inhibition of NO synthesis with i.v. L-NNA (n=8), or elevation of mean aortic blood pressure to the same extent as attained with NOS inhibition using proximal arterial occlusion (n=7). Results: By the peak infusion rate, dobutamine increased the maximal rate of rise of left ventricular pressure (LV dP/dtMAX) by 100% (p<0.001) and reduced LV stroke work by 18% (p<0.01). L-NNA and arterial occlusion increased resting mean aortic blood pressure by 55±4 and 51±3 mmHg respectively. Compared to dobutamine alone, subsequent peak dobutamine-related increases in LV dP/dtMAX were augmented by 76% after L-NNA and by 88% after arterial occlusion (both p<0.001). Moreover, dobutamine increased LV stroke work by 23% at infusion rates of 1–5 µg/kg/min (p<0.001) after L-NNA, and by 17% at an infusion rate of 1 µg/kg/min (p<0.01) after arterial occlusion. Conclusions: Systemic NOS inhibition potentiates the effects of dobutamine on LV isovolumic and pumping performance in the intact circulation, but this potentiation is in large part related to the increase in arterial blood pressure accompanying NOS inhibition.

KEYWORDS Nitric oxide; Ventricular function; Inotropic agents; Adrenergic agents; Blood pressure


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
β-adrenergic agonists, via stimulation of adenylate cyclase and enhanced myocardial production of cyclic AMP, constitute a powerful mechanism for augmenting the performance of the heart [1]. Recent in vitro and in vivo findings suggest, however, that β-adrenergic inotropic actions in the heart may normally be limited by nitric oxide (NO), a ubiquitous compound which is synthesised from the amino acid L-arginine by the constitutive isoform of the enzyme NO synthase (NOS) [2–4]. Thus, provision of exogenous NO decreased contractile responses to noradrenaline in isolated papillary muscles [5]and to isoproterenol in isolated myocytes and hearts [6]. Conversely, inhibition of NOS with N{omega}-nitro-L-arginine (L-NNA), a stereospecific analogue of L-arginine, enhanced the positive inotropic action of isoproterenol in isolated rat ventricular myocytes [7]. Moreover, infusion of a NOS inhibitor into the left main coronary artery augmented increases in the maximal rate of rise of left ventricular (LV) pressure during subsequent intracoronary administration of dobutamine in humans [8]and anaesthetised dogs [9].

It is unknown, however, if changes in LV function induced by intravenous infusion of β-adrenergic agents are influenced by systemic inhibition of NO synthesis, a question with potentially important clinical implications because the combined use of β-adrenergic agonists and NOS inhibitors has been advocated in the setting of conditions such as endotoxaemia [10], which are characterised by poor responsiveness to inotropic agents [11]. In addition, it is unknown to what extent any changes in β-adrenergic inotropic responses are related to the vascular effects of NOS inhibition, an issue of particular relevance because systemic administration of a NOS inhibitor raises aortic blood pressure [2, 12, 13]and it has been previously demonstrated that inotropic responses to isoproterenol can be augmented by superimposed increases in aortic blood pressure [14, 15].

Accordingly, this study had two aims. The first was to examine the effect of systemic NOS inhibition produced by intravenous infusion of the L-arginine analogue L-NNA on LV inotropic responses during an incremental intravenous infusion of the β-adrenergic agonist dobutamine in the intact circulation. The second was to compare these responses with those produced by a non-pharmacological elevation of arterial pressure to a similar mean level as attained with NOS inhibition via the use of partial arterial occlusion.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
All experiments were performed in accordance with the guidelines of the National Health and Medical Research Council of Australia and were approved by the Monash University Animal Experimentation Ethics Committee.

2.1 Acute surgical preparation
Fifteen Border–Leicester cross sheep, weighing 49.5±1.4 kg (mean±SEM) were anaesthetised with an intramuscular injection of ketamine (5 mg/kg) and xylazine (0.1 mg/kg), and an intravenous bolus of {alpha}-chloralose (25–50 mg/kg). Anaesthesia was maintained with a continuous intravenous infusion of {alpha}-chloralose at a rate of 12–25 mg/kg/h. Animals were intubated with a cuffed endotracheal tube and ventilated with oxygen-enriched air using a large animal respirator (model 607, Harvard Apparatus, Dover, MA, USA). Ventilation was adjusted to maintain arterial O2 tension between 100 and 120 mmHg, and arterial CO2 tension between 35 and 40 mmHg. Blood acid–base status was monitored with frequent arterial blood gas determinations and base deficits were corrected with sodium bicarbonate as required. Body temperature was maintained between 38.5 and 40°C with a combination of a heating pad and towel covering.

The neck was incised in the midline and polyvinyl catheters were advanced through the left external jugular vein into the superior vena cava for fluid and drug infusion. After a left thoracotomy was performed in the fourth intercostal space, the fourth and fifth ribs were sectioned anteriorly and posteriorly to increase exposure of the heart and great vessels. A 20 mm diameter perivascular ultrasonic flow probe (model 20SS, Transonic Systems, Ithaca, NY, USA) was placed around the ascending aorta. A Teflon cannula was inserted through an adventitial purse-string suture into the proximal descending aorta and connected to a polyvinyl extension tubing for blood sampling and pressure measurement. A catheter was passed into the left atrial cavity via the appendage for pressure measurement, while a 5F micromanometer-tipped catheter (MPC-500, Millar Instruments, Houston, TX, USA) was inserted through the roof of the left atrium and passed transmitrally into the LV cavity to measure LV pressure. The edges of the pericardial incision were then loosely re-approximated using a continuous suture.

2.2 Experimental protocol
After the completion of surgery, haemodynamics were monitored for at least 15 min to ensure stability of the experimental preparation. Subsequently, baseline haemodynamic variables were recorded before dobutamine (David Bull, Victoria, Australia), a synthetic sympathomimetic with potent β1-adrenoceptor-mediated inotropic actions as well as minor β2 and {alpha}1-adrenoceptor effects [16], was infused continuously into the superior vena cava in incremental steps of 1, 2.5, 5 and 10 µg/kg/min using a roller pump (model MS 4-Reglo, Ismatec, Zürich, Switzerland). After steady-state conditions had been attained 5–10 min into each dobutamine dose, haemodynamic measurements were repeated and the dobutamine infusion was increased to the next dose. Following completion of measurements at the highest dose, the dobutamine infusion was progressively reduced over a period of 15 min and then stopped. A 30 min recovery period, which corresponded to more than ten dobutamine circulating half times [17], was then allowed to ensure adequate clearance of this compound from the circulation.

Following the initial dobutamine infusion, animals were allocated into one of two groups. In eight animals, NO synthesis was inhibited with the stereospecific NOS inhibitor, L-NNA (Sigma, St. Louis, MO, USA), administered intravenously over 15 min at a dose of 25 mg/kg. Preliminary studies indicated that no further increases in mean systemic arterial blood pressure occurred above this dose of L-NNA in our experimental preparation. In the remaining seven animals, mean arterial pressure was increased to a similar level as obtained with L-NNA by combining partial inflation of a 5F Fogarty atrial septostomy catheter (Baxter Healthcare, IL, USA) which was passed into the brachiocephalic trunk via the left axillary artery, with subtotal occlusion of the descending thoracic aorta produced by tightening of a mechanical snare. Mechanical occlusion of distal segments of the central arteries was specifically chosen to increase aortic pressure because it generates a large arterial reflected wave in the latter part of systole that imposes a load on the left ventricle akin to that produced by an increase in peripheral resistance [18, 19], i.e., the haemodynamic change which accompanies systemic inhibition of NO synthesis [2, 12, 13].

Following administration of L-NNA or the institution of partial arterial occlusion, haemodynamics were allowed to stabilise for 10–15 min. Haemodynamic measurements were then repeated in each group of animals, before and during a second incremental infusion of dobutamine at dose rates of 1, 2.5, 5 and 10 µg/kg/min. At the end of the experiment, the animal was killed with an overdose of pentobarbitone sodium.

2.3 Physiological variables
Aortic and left atrial pressures were measured with silicon chip pressure transducers (CDX-111, COBE Laboratories, Lakewood, CO, USA), which were calibrated against a water manometer before each experiment. Vascular pressures were referenced to atmospheric pressure at the level of the midthoracic vertebral spines. Ascending aortic blood flow was measured with an ultrasonic flowmeter (model T208, Transonic Systems). The maximal rate of rise of LV pressure (dP/dtMAX), which was used to assess LV isovolumic function, was obtained using an on-line differentiator (model 100, Baker Institute, Victoria, Australia) having an output that was directly proportional to frequency (±5%) up to 90 Hz. The outputs from the pressure and flow transducers were amplified using an eight-channel programmable signal conditioner (Cyberamp 380, Axon Instruments, Foster City, CA, USA) and displayed continuously on a direct-writing recorder (Neotrace 800Z, Neomedix Systems, New South Wales, Australia). Following passage through a 24 Hz low-pass filter to prevent aliasing, pressure and flow signals were digitised at a sampling rate of 500 Hz for 20 s, and the data stored on computer for subsequent off-line analysis using customised interactive software.

LV stroke volume was calculated as ascending aortic blood flow divided by the heart rate. The total LV work performed during each cardiac cycle (i.e. the LV stroke work) was calculated from the digitised data as the integral of the instantaneous product of LV pressure (mmHg) and ascending aortic blood flow (L) during the period of forward ascending aortic flow [20], and was converted to SI units using the relation 1 mmHg·L=0.1334 J.

2.4 Statistical analysis
Data were analysed with standard statistical tests [21]. Repeated measures one-way analysis of variance was used to evaluate: (1) changes in haemodynamic variables during the initial dobutamine infusion; (2) haemodynamic responses to L-NNA or partial aortic occlusion; (3) differences in haemodynamic responses between the initial dobutamine infusion and after either NOS inhibition or partial arterial occlusion. To evaluate specific dose-related effects, the sums of squares from the analysis of variance were partitioned into individual degrees of freedom, while differences between the initial and post-L-NNA or post-arterial occlusion dobutamine infusions were assessed with paired t-tests, using the Bonferroni procedure as required for multiple tests [22]. Differences in haemodynamic responses between L-NNA and aortic occlusion groups were evaluated with unpaired t-tests. Results are expressed as mean±SEM and the null hypothesis was rejected at p<0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Effect of dobutamine infusion
Responses to infusion of dobutamine alone were similar in the L-NNA and aortic occlusion groups, and the data have therefore been combined. Stepwise infusion of dobutamine to a peak dose of 10 µg/kg/min was associated with progressive increases in heart rate, ascending aortic flow and LV dP/dtMAX (all p<0.001). Mean aortic pressure increased by 4±2 mmHg between baseline and 1 µg/kg/min dobutamine (p<0.01), but then fell to a level 7±3 mmHg lower than baseline at the highest dobutamine infusion rate (p<0.005). LV stroke volume decreased by 10.1±1.5 ml between baseline and 5 µg/kg/min dobutamine (p<0.001) and was unchanged at the higher dose, whereas LV stroke work fell between baseline and 2.5 µg/kg/min dobutamine (p<0.01), and then plateaued at higher infusion rates (Table 1).


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  		Table 1 Haemodynamic variables and LV performance during the initial dobutamine infusion

 
3.2 Effect of L-NNA or partial arterial occlusion
Administration of L-NNA increased mean aortic pressure by 55±4 mmHg (p<0.001) and was accompanied by rises in mean left atrial pressure (p<0.001) and LV stroke work (p<0.001), decreases in heart rate (p<0.025) and ascending aortic flow (p<0.01), but no significant change in LV stroke volume or dP/dtMAX (Table 2, Fig. 1).


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  		Table 2 Haemodynamic variable and LV performance before (pre-L-NNA) and after inhibition of NO synthesis with N{omega}-nitro-L-arginine (post-L-NNA), as well as before (pre-occlusion) and after partial occlusion of the descending aorta and brachiocephalic trunk (post-occlusion).

 

Figure 1
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  		Fig. 1 Illustrative tracings of changes in aortic pressure, left ventricular (LV) pressure, mean left atrial (LA) pressure and the maximum rate of rise of left ventricular pressure (LV dP/dtMAX) after administration of N{omega}-nitro-L-arginine (L-NNA) (left panel) or partial arterial occlusion (right panel).

 
Partial arterial occlusion elevated mean aortic pressure by 51±3 mmHg (p<0.001) and was associated with increases in left atrial pressure (p<0.001), LV dP/dtMAX (p<0.025), ascending aortic flow (p<0.025) and LV stroke work (p<0.001), but no significant alteration in heart rate or LV stroke volume (Table 2, Fig. 1). Despite the similarity of aortic blood pressure changes produced by L-NNA and arterial occlusion, the latter resulted in a larger rise in LV stroke work (25.7±3.5 vs. 11.8±1.9 J·10–2, p<0.005) and a smaller increase in mean left atrial pressure (3.3±0.5 vs. 5.4±0.5 mmHg, p<0.05).

3.3 Effects of dobutamine after L-NNA or partial arterial occlusion
3.3.1 Haemodynamics
Over the dose range examined, dobutamine-related increases in heart rate were attenuated by 41% after L-NNA (p<0.05) and by 26% after partial arterial occlusion (p<0.05; Fig. 2A), but ascending aortic flow responses were not significantly affected by either intervention (Fig. 2B). After L-NNA, LV stroke volume did not change significantly at infusion rates ≤5 µg/kg/min, but fell to a value 6.0±2.9 ml lower than baseline at the highest dose (p<0.05). On the other hand, after arterial occlusion, LV stroke volume was unchanged at 1 µg/kg/min and then paralleled the initial decline, albeit at a higher value (p<0.01; Fig. 2C). After L-NNA, dobutamine initially increased aortic pressure more than observed with dobutamine alone (27±4 vs. 2±3 mmHg, p<0.001), and subsequently reduced aortic pressure to a greater extent by the highest dobutamine infusion rate (36±7 vs. 11±3 mmHg, p<0.001). By contrast, changes in aortic pressure after arterial occlusion tracked those observed with dobutamine alone (Fig. 2D). In both the L-NNA and arterial occlusion groups, mean left atrial pressure fell after commencement of dobutamine, and was not significantly different from the initial infusion at dobutamine doses ≥2.5 µg/kg/min (Fig. 2E)


Figure 2
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  		Fig. 2 Effect of dobutamine on heart rate (A), ascending aortic blood flow (B), left ventricular stroke volume (C), mean aortic blood pressure (D) and left atrial pressure (E), before (closed symbols) and after (open symbols) L-NNA (left panel) or partial arterial occlusion (right panel).

 
3.3.2 LV isovolumic function
Both L-NNA and partial arterial occlusion enhanced dobutamine-related increases in LV dP/dtMAX (p<0.001) to a similar degree. This enhanced effect was most pronounced at dobutamine infusion rates of ≥2.5 µg/kg/min and, at the highest dobutamine dose, amounted to an increment of 1390±155 mmHg/s (p<0.001) and 1520±230 mmHg/s (p<0.001) for the L-NNA and arterial occlusion groups respectively (Fig. 3A).


Figure 3
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  		Fig. 3 Effect of dobutamine on LV dP/dtMAX (A) and LV stroke work (B), before (closed symbols) and after (open symbols) L-NNA (left panel) or partial arterial occlusion (right panel).

 
3.3.3 LV stroke work
In contrast to the initial reduction, dobutamine after L-NNA increased LV stroke work between infusion rates of 1 and 5 µg/kg/min (average increment 9.7±2.1 J·10–2, p<0.001), before falling to a level 6.5±4.0 J·10–2 lower than baseline at the highest dobutamine dose (p<0.025). After partial arterial occlusion, LV stroke work exceeded the baseline value at the initial dobutamine dose (increment 9.4±4.1 J·10–2; p<0.01), and then declined progressively to a level not statistically different from baseline at the 10 µg/kg/min infusion rate (Fig. 3B).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
Two main findings have emerged from this study, which sought to determine whether LV inotropic responses to the β-adrenergic agonist dobutamine were potentiated by systemic inhibition of NO synthesis with the L-arginine analogue L-NNA, and to what extent any observed responses were related to the increase in aortic blood pressure accompanying NOS inhibition. First, NOS inhibition not only augmented increases in LV isovolumic function occurring with dobutamine infusion but, in contrast to the reduction observed with dobutamine alone, also increased LV stroke work at low and intermediate infusion rates. Second, following elevation of aortic pressure via partial arterial occlusion to a level equivalent to that produced by NOS inhibition, dobutamine infusion resulted in a similar augmentation of LV isovolumic function and, at the initial infusion rate, a rise in LV stroke work. These observations suggest that systemic inhibition of NO synthesis potentiates the LV inotropic actions of β-adrenergic stimulation in the intact circulation, but that this potentiation is in large part related to the rise in aortic blood pressure accompanying NOS inhibition.

In accord with its potent β1-adrenoceptor activity [16], infusion of dobutamine alone substantially increased heart rate, cardiac output and LV dP/dtMAX in our anaesthetised experimental preparation [23–25]. An initial rise in mean aortic blood pressure (Table 1) was mostly likely due to {alpha}1-adrenoceptor-mediated vasoconstriction which is known to occur at low dobutamine doses [26], whereas the subsequent reduction in aortic blood pressure below baseline levels was consistent with a predominance of β2-adrenoceptor-mediated vasodilation at higher dobutamine doses [16, 26].

Despite the similar rise in mean aortic pressure induced by L-NNA and aortic occlusion, these interventions differed in a number of other haemodynamic respects. Thus, while NOS inhibition was accompanied by well-documented reductions in cardiac output and heart rate [2, 12, 13], cardiac output increased and heart rate remained unchanged after partial aortic occlusion. On the other hand, LV dP/dtMAX was unchanged after systemic L-NNA administration whereas, in accord with previous reports [19, 27], it rose after arterial occlusion. Increases in left atrial pressure, which presumably represented the recruitment of a preload reserve mechanism in response to marked increase in LV afterload [28], were more prominent after NOS inhibition than arterial occlusion. Finally, an increase in LV stroke work, which has previously been reported in anaesthetised dogs after elevation of aortic blood pressure with aortic constriction or angiotensin infusion [14], was less pronounced with NOS inhibition than with arterial occlusion. Taken together, these findings suggest that the cardiac manifestations of systemic NOS inhibition occur via multifactorial actions and are not solely a consequence of rises in aortic blood pressure. This is consistent with the presence of NOS in a range of cell types including endothelial and endocardial cells, neurons and myocytes, and the implication of NO not only in the modulation of vascular tone, but also processes such as central and peripheral sympathetic neurotransmission and myocardial relaxation [2–4, 29].

While haemodynamic changes occurring with dobutamine infusion after L-NNA or aortic occlusion were similar with respect to blunting of heart rate responses, falls in mean left atrial pressure and a dampening of reductions in LV stroke volume, aortic blood pressure responses differed substantially. Thus, whereas dobutamine-induced blood pressure changes before and after arterial occlusion paralleled one another, both the initial rise and subsequent fall in arterial blood pressure were accentuated during dobutamine infusion after NOS inhibition. The former is consistent with results which indicate that {alpha}1-adrenoceptor-mediated vasoconstrictor effects are enhanced by NOS inhibition [30, 31]. By contrast, the greater reduction in aortic blood pressure occurring at dobutamine infusion rates ≥5 µg/kg/min was somewhat surprising, given that NO appears to play a contributory role in β-adrenoceptor-mediated vasodilation [32, 33]. However, a plausible explanation for this greater reduction was that, akin to the pulmonary circulation [34], systemic β-adrenoceptor vasodilator responses after L-NNA were enhanced as a consequence of the elevation of arterial tone accompanying NOS inhibition.

In our study, systemic NOS inhibition augmented rises in LV dP/dtMAX elicited by intravenous dobutamine infusion. At first glance, this result would appear to imply that, as with intracoronary co-infusion of a NOS inhibitor and dobutamine in anaesthetised dogs [9], an NO-mediated mechanism had attenuated increases in LV isovolumic performance during infusion of dobutamine alone. However, our findings differed in a major respect from that of Keaney et al. [9]because the demonstration of enhanced LV dP/dtMAX responses in their experimental preparation was not evident in autonomically-intact animals, but instead required abolition of autonomic reflexes with bilateral vagotomy and hexamethonium-induced ganglionic blockade [35, 36]. More importantly, dobutamine-induced rises in LV dP/dtMAX in our study were potentiated to a similar extent as after NOS inhibition following elevation of aortic blood pressure via arterial occlusion. Taken together, our L-NNA and aortic occlusion data therefore imply that the potentiation of dobutamine-related LV isovolumic responses occurring after systemic NOS inhibition was predominantly related to the effect of a peripheral vascular action of NOS inhibition on the heart, rather than the inhibition of myocardial NO synthesis per se.

Our conclusion that increased aortic blood pressure, whether produced by NOS inhibition or mechanical means, played a major role in the potentiation of LV isovolumic responses to dobutamine is consistent with previous studies in conscious and in anaesthetised dogs which noted that rises in LV dP/dtMAX elicited by infusion of isoproterenol could be further enhanced by a superimposed increase in aortic blood pressure produced by either constriction of the descending thoracic aorta or administration of angiotensin [14, 15]. The potential importance of changes in systemic blood pressure in the modulation of β-adrenergic inotropic responses is also emphasised by a patient study which noted that, following myocardial NOS inhibition, concomitant intracoronary infusion of dobutamine was accompanied by a potentiation of dP/dtMAX responses in the presence, but not the absence of rises in LV systolic pressure [8].

In conjunction with a potentiation of LV dP/dtMAX responses, a decline in LV stroke work evident with dobutamine alone in our experimental preparation was reversed to an increase in LV stroke work at low to intermediate dobutamine doses after L-NNA, suggesting that at least a portion of the increase in LV isovolumic function occurring after NOS inhibition was translated into an augmented LV pumping performance. In accord with previous studies which employed isoproterenol [14, 15], an augmentation of LV stroke work was also observed during infusion of dobutamine after arterial occlusion. However, it remains to be clarified why the latter effect was less pronounced than after L-NNA, particularly given the similarity in the potentiation of LV isovolumic responses.

The precise nature of the mechanism(s) responsible for the potentiation of LV isovolumic and pumping performance evident with dobutamine after L-NNA or partial arterial occlusion in our study remain to be resolved. One possibility was that, because of the increase in left atrial pressure occurring with NOS inhibition or arterial occlusion, the potentiation was simply due to a Frank–Starling mechanism related to an increase in diastolic length [37]. However, while this may have been a contributory factor at the initial dobutamine dose, it is unlikely to have underpinned the more striking potentiation of LV isovolumic function evident at higher doses, because left atrial pressure then fell to a level similar to that observed during the initial dobutamine infusion. A second possibility, which has been proposed as the explanation for the augmented contractile response to β-adrenergic stimulation observed in isolated myocytes after exposure to a NOS inhibitor [7]and in in situ hearts after direct intracoronary infusion of a NOS inhibitor [9], was that inhibition of NO synthesis resulted in a decrease of myoplasmic cyclic GMP synthesis, with a resultant increase in myofilament sensitivity to calcium [36], and removal of the inhibitory effect of cyclic GMP on the cyclic AMP-stimulated slow inward calcium current [38]. However, this mechanism cannot explain the potentiation of β-adrenergic inotropic responses observed after aortic occlusion, because elevations in arterial blood pressure increase coronary blood flow [39], which is a potent stimulus for increased NO production within endothelial cells [40].

In summary, systemic NOS inhibition potentiates the effects of dobutamine on LV isovolumic and pumping performance in the intact circulation, but this potentiation is in large part related to the increase in arterial blood pressure accompanying NOS inhibition. Further investigation is required to establish the precise nature of the mechanism underpinning the potentiating effect of systemic NOS inhibition on the inotropic actions of β-adrenergic agents.

Time for primary review 33 days.


   Acknowledgements
 
This work was performed with the assistance of a Grant-in-Aid from the National Heart Foundation of Australia and a Project Grant from the National Health and Medical Council of Australia. We thank Ms. Karyn Forster for her technical assistance with this study.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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