Why does acidosis decreased heart contractility

Empty columns, control Tyrode solution. Solid columns, acidic solution Tyrode solution with a pH of 7. A Effects of acidic solution on contraction force in trabeculae from control pigs cycle length of , 1,, and 2, ms.

Left panel, pooled data. Right panel, representative contraction traces at stimulation frequency of 1 Hz in control and acidic solutions. B Effects of acidic solution on contraction force in trabeculae from pigs with MAC cycle length of , 1,, and 2, ms.

C Effects of acidic solution on contraction force in trabeculae from pigs with HCA cycle length of , 1,, and 2, ms. The membrane potential recordings revealed no effects of acidosis on the membrane electrogenesis; neither the resting membrane potential levels nor the action potentials were influenced by acidosis.

The action potentials were of a similar shape, amplitude, and duration APD 50 , APD 90 in all three groups, and the application of the acidic solution did not exert any effects Figure 4. The lack of the effect of acidosis on the action potential was observed at all stimulation frequencies tested 0. Effects of acidosis on ventricular action potential. A Effects of acidic solution on action potential in trabeculae from control pigs cycle length of , 1,, and 2, ms. Left panel, pooled data, APD Right panel, representative action potentials at stimulation frequency of 1 Hz in control and acidic solutions.

B Effects of acidic solution on action potential in trabeculae from pigs with MAC cycle length of , 1,, and 2, ms. C Effects of acidic solution on action potential in trabeculae from pigs with HCA cycle length of , 1,, and 2, ms. This study documents that systemic acidosis, both HCA and MAC, exerts significant effects on the cardiovascular system. In the pulmonary circulation, the effects of both types of acidosis were similar: increased pulmonary vascular resistance and mean pulmonary artery pressure.

The systemic circulation was affected differentially: whereas MAC did not influence the systemic hemodynamic parameters, HCA increased the mean arterial pressure, despite a reduction in the systemic vascular resistance.

Both types of acidosis were associated with a decreased stroke volume and an increased heart rate. Similar effects of acute respiratory acidosis increase in cardiac output, decline in peripheral resistance were reported previously in dogs [ 21 ].

In the same study, however, acute metabolic acidosis showed similar effects on both cardiac output and peripheral resistance. This discrepancy with our results may be attributed either to the mode of the metabolic acidosis induction lactic acid versus hydrochloric acid , or to the species-specific differences dog versus pig. In humans, an administration of CO 2 produced an increase in cardiac output, stroke volume and heart rate, together with a reduction of the peripheral resistance [ 22 ].

This is in good agreement with our results, with the exception of the increase in stroke volume. This difference is probably related to the level of hypercapnia that was much lower in the study with human volunteers the mean increase in P a CO 2 was These data indicate that in the pulmonary circulation, the main stimulus is the hydrogen ion concentration, because the effects of both types of acidosis were similar.

This interpretation is supported by earlier studies in isolated cat lungs [ 11 ], isolated rat lungs [ 12 ], as well as in healthy humans [ 13 ]. Nevertheless, significant species differences may exist, because in the isolated rabbit lung, no effect of HCA on the normoxic pulmonary vascular tone was found [ 14 ].

The contributions of CO 2 in our experiments cannot be excluded, because a significant increase in the partial pressure of CO 2 in the venous blood was found for both types of acidosis; however, in MAC, it was much less pronounced.

Conversely, the lack of the effects of MAC in the systemic circulation strongly suggests that CO 2 is a dominant stimulus for the systemic vasculature. The heart itself seems to be affected, preferentially, by hydrogen ions, as both types of acidosis were associated with similar changes in the cardiac function. To distinguish the direct cardiac effects from those induced secondarily because of primary vascular effects, the in vitro experiments with isolated cardiac tissues right ventricular trabeculae were performed, and they confirmed the in vivo findings.

In agreement with the in vivo reduction of stroke volume, the contraction force of the trabeculae was decreased in the acidic solution. A similar reduction of the myocardial contractility by hypercapnic acidosis was observed in the isolated perfused rat heart [ 23 ]. In contrast to that in our study, however, this cardiac effect was attributed to hypercapnia rather than to acidosis. Conversely, in a number of studies, the negative inotropic effects of acidosis per se were demonstrated for example, see [ 7 — 9 , 24 ].

The diversity of earlier reports with regard to the effects of hypercapnia versus acidosis is probably related to differences in the experimental design for example, differences in the time courses of the effects and the experimental animal species. The reduction in the contraction force was present at all stimulation frequencies tested 0. The heart rates reached in vivo , however, were substantially higher up to bpm , and the short filling times in such a tachycardia may significantly contribute to the reduction in the stroke volume.

The lack of change in the global end-diastolic volume clearly indicates that the cardiac filling was not affected. Shortening of the QT c interval suggests that a shortening of the cardiac APD, associated with a reduction of the calcium influx into the cell through ICaL channels, may contribute to the impaired contractile function.

To test this hypothesis, cardiac action potentials were measured in vitro , and no effects of acidosis were found. Therefore, the membrane electrogenesis and the trans-sarcolemmal calcium influx are not likely to contribute to the reduction in the contraction force.

Any correction formula including the Fridericia formula used in this study is likely to introduce an error [ 25 ]. Such an increase may be due to autonomic cardiac regulation, or due to the direct effect of acidosis on sinoatrial-node cells. In isolated rabbit sinoatrial nodes, a negative chronotropic effect of the acidosis was described, and it was attributed to the protonation of ionic channels [ 26 ].

Similar results were obtained in canine sinoatrial node tissues [ 27 ]. In our experimental conditions, the absence of any effect of acidosis on the membrane action potential in ventricular tissues indicates that a major effect of acidosis on electrogenesis in the sinoatrial node is unlikely. These results suggest that the observed increase in the heart rate is related to the autonomic cardiac regulation. A sympathetic neural activation, by acute HCA with increased plasma levels of both norepinephrine and epinephrine, in vivo in swine, was reported [ 28 ].

However, a stimulated norepinephrine release directly in the heart was shown to be reduced by acidosis [ 29 , 30 ], but only at pH values of 6. Our analysis of the heart-rate variability, revealing no shift in the sympathovagal balance no change in LF and HF components or their ratios , argues against a general elevation of the plasma levels of catecholamines, and suggests a more-complex feedback mechanism such as a presynaptic inhibition being involved.

This view is supported by a recent study [ 31 ], in which a presynaptic autoregulatory feedback mechanism was suggested to explain the paradoxic decrease in LF oscillations that normally reflect the magnitude of the sympathetic activation in conditions of elevated levels of circulating norepinephrine.

Besides the peripheral effects of acidosis, the role of the central chemoreceptors in the medulla should be considered. A reduction in cardiac contractility was confirmed in vitro in isolated preparations. A major contribution of the autonomic regulation to the negative inotropic effect is, therefore, unlikely, and a direct effect of acidosis on the processes of excitation-contraction coupling must be further scrutinized. The membrane electrogenesis was insensitive to the acidosis: at the pH of 7.

At this pH, the ionic currents including ICaL are not influenced, and their modification for example, a reduction of ICaL does not contribute to the reduced contractility.

Most likely, intracellular acidosis develops and affects a number of intracellular mechanisms involved in calcium handling and contraction; for example, a deactivation of contractile proteins including impaired calcium binding to troponin C, impaired interaction of the troponin-tropomyosin complex, and impaired actin-myosin interactions [ 8 , 32 , 33 ].

It should be emphasized that the results of these studies were obtained at a more-pronounced acidosis level pH about 6. The right ventricular stroke work per minute was increased by both types of acidosis; however, the left ventricular stroke work per minute was increased by HCA only. Therefore, acidosis places an increased work demand on the heart: MAC perhaps on the right ventricle only, and HCA on both ventricles.

This finding may substantially weaken the emerging paradigm of therapeutic HCA, especially in conditions of compromised cardiac function.

It should be noted that the negative inotropic effect was accompanied by an increased heart rate to maintain MAC , or even increase HCA , the cardiac output. Consequently, the development of acidosis although in our conditions of HCA, with rather extreme values of pCO 2 may be especially dangerous in clinical conditions that are associated with an elevated heart rate for example, sepsis , in which an additional increase in heart rate is limited, and therefore, the cardiac output cannot be maintained.

In sharp contrast to the uniform effects of both types of acidosis on pulmonary circulation, we observed quite a heterogeneous response in the hepato-splanchnic region. We are not aware of any other study that simultaneously compares the effects of both MAC and HCA on multiple vascular beds.

First, the lack of a measurable effect of HCA on the global renal blood flow is in contrast to several previous studies reporting both increased [ 34 ] and reduced renal perfusion, in response to acute hypercapnia [ 35 ]. Second, our results suggest that the liver circulation might behave differently in subjects exposed to HCA increased as opposed to MAC unchanged.

Interestingly, HCA increased the portal venous flow without affecting the hepatic arterial blood flow. Taken together, these findings suggest that the vasodilatory effect of carbon dioxide on the hepato-splanchnic circulation is largely independent of the changes in pH, and indicate the different effects of HCA on the arterial versus portal venous blood supply in the liver.

Nonetheless, the exact mechanism and clinical importance of these physiological responses cannot be answered from the present data. The intracellular mechanisms underlying the negative inotropic and chronotropic cardiac effects, as well as the vascular effects, were not addressed in this study. Instead, the study was oriented toward integrative physiology, with an emphasis on clinically relevant in vivo phenomena, which were verified and further elucidated in experiments with isolated tissues.

We assessed the effects of acidosis at only a single pH level. Therefore, the dose-effect relation could not be established. The level of hypercapnia needed to achieve a pH of 7. It is of note that the rather high values of pCO 2 limit the clinical relevance of this study, and that in conditions of milder permissive hypercapnia, the beneficial effects may prevail.

Because of the relatively short-term duration of our experiment, our observations may not apply to prolonged acidosis. The distal organ-perfusion experiments were performed by using probes placed around the major arteries, and consequently, only information about the total organ perfusion was obtained. Possible changes in small arteries-arterioles may not have been detected.

Does Bicarbonate improve cardiac function in acidosis? Bicarbonate administration, therefore, worsens intracellular acidosis when you administer it to acidotic subjects. Indeed most of the studies confirm the lack of benefit or an adverse effect. In this study for example, Shapiro JI. Functional and metabolic responses of isolated hearts to acidosis: effects of sodium bicarbonate and Carbicarb.

Basir MA, et al. Effects of Carbicarb and sodium bicarbonate on hypoxic lactic acidosis in newborn pigs. Journal of investigative medicine. Nudel DB, et al. Comparative effects of bicarbonate, tris- hydroxymethyl aminomethane and dichloroacetate in newborn swine with normoxic lactic acidosis. Dev Pharmacol Ther. So to summarize, metabolic acidosis in the newborn has little or no effect on myocardial contractility in several mammalian animal models of isolated myocardial preparations lambs, rabbits and rats.

Even in the mature myocardium, the impact of organic acidosis is relatively modest. And there is no evidence that response to catecholamines in the newborn myocardium is affected by acidosis.

In that context looking for a benefit of bicarbonate in the newborn would be a bit of a lost cause, which may be why there are no relevant studies that I could find. But even in the mature myocardium, the impact of bicarbonate use during acidosis has usually been shown to be a negative effect on contractility. What data there are in the newborn intact mammalian models show that cardiac function in some models is actually increased in acidosis, and decreased by the use of bicarbonate.

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Email Address:. Follow Neonatal Research. RSS - Posts. Administration of cariporide during hypoxia resulted in a less severe reduction of LV contraction parameters and to a recovery to baseline levels within 5 min. Diastolic left ventricular function i. Diastolic cardiac function was ameliorated by cariporide in the hypoxia group, in such a way that on one hand both parameters declined to a lesser extent and on the other hand recovered to control levels within 5 min of reperfusion Table 1.

This impairment was not affected by cariporide treatment Table 1. Cariporide administration during normal O 2 concentration and normal pH did not influence cardiac hemodynamics Figures 1 , 2 and Table 1. The prolongation of ARI during acidosis was significantly mitigated by cariporide Table 2.

Figure 3. Cariporide administration had no influence on the increase or decrease of electrophysiological parameters. Interestingly, under control conditions cariporide itself led to a slight reduction of ARI and heart rate, however, this reduction was not significant Figures S1, S2.

The propagation of the activation wave front also exhibited changes with hypoxia and acidosis. This became obvious from changes in the self-similarity of vector fields during treatment as compared to those under control conditions.

During reperfusion vector field similarity did not return to control levels in the hypoxia group. Cariporide had only minor effects on changes in vector field similarity Figure 4. Figure 4. Peroxynitrite radicals induce nitrosylation of tyrosine residues, which can be detected as nitrotyrosines. This elevation was blocked by cariporide application during hypoxia. Figure 5.

Upper NT nitrotyrosine expression in ventricular tissue. Arrows point toward positive cells. We have investigated the end-product of this process, PAR. Figure 6. Acidosis alone or cariporide application during control conditions did not significantly alter AIF translocation Figure 7. Figure 7. Upper AIF apoptosis inducing factor expression in ventricular tissue. If the extrinsic apoptosis pathway is initiated an early step in the cascade is the activation of caspase 3 by cleavage, as can be detected by cC3 immonohistology.

Figure 8. Upper cC3 cleaved caspase 3 expression in ventricular tissue. Lower Original pictures of cC3 immunohistology LV. At the end of the experiments, i. As shown in Table 2 , we found that despite the 60 min reperfusion period in hypoxia-treated hearts ATP was still decreased. Additional cariporide resulted in unchanged ATP as compared to control.

Acidosis alone and in combination with hypoxia lead to an increase in tissue ATP. Cariporide did not exhibit effects on ATP under the combination of hypoxia and acidosis. The data of the present study show differential effects of hypoxia and acidosis on cardiac hemodynamics and electrophysiology. It is clinically well-known that cardiac ischemia results in reduced contractile force. Interestingly the combination of acidosis and hypoxia resulted in less severe loss in contractility in particular during recovery indicating a possible mitigating effect of acidosis on hypoxia, which should be discussed here.

Acidosis counteracted this effect, which can be explained by the finding that acidosis prevents from the formation of mitochondrial transition pores and from mitochondrial hypoxia-induced injury Baines, ; Chi et al.

Ischemia-reperfusion injury typically leads to formation of nitrotyrosine, activation of PARP with consecutive PAR production, nuclear translocation of AIF and cleavage of C3, which are processes involved in the early initiation of apoptosis. These effects are known to be mainly induced by free radicals. Regarding the electrophysiological effects of acidosis, hypoxia and their combination, our data is in good accordance with cellular investigations using voltage clamp techniques.

Kanaporis et al. L L-type calcium current. The authors attributed the reduction in I Ca. L to the occurrence of intracellular acidosis, due to the reverse mode of mitochondrial ATP-synthase during metabolic inhibition. Elevation of intracellular pH alleviated this effect.

Thus, inhibition of I Ca. L probably contributes to the loss in contractility in ischemia. The effect of metabolic inhibition on I Ca.

L however is biphasic Treinys et al. L is increased followed by the known decrease in I Ca. L during continued metabolic inhibition. These observations of a reduction in I Ca. L by acidosis and metabolic inhibition can help to explain the loss of contractile force seen in our experiments. However, the combined effect of acidosis and hypoxia requires additional considerations.

In our study additional acidosis lead to a faster recovery of most hypoxic-induced changes in hemodynamics and electrophysiology but did not or only marginally affect hypoxia-induced pro-apoptotic changes as AIF-translocation, C3 cleavage, NT-formation or PAR-synthesis. Regarding the electrophysiological changes, on the one hand it was shown that extracellular acidosis can reduce I Ca. L Cheng et al. On the other hand Cheng et al.

Moreover, acidosis also affects the shape of the action potential. This involves also effects on I K. Extracellular acidosis reduced the amplitude of I K. Interestingly, Saegusa et al.

These authors found that intracellular acidification reduced the transient outward current I t. L during the action potential. Extracellular acidification shifted I t. ATP Moncada et al. This may -at least partially- be explained by the antagonization of hypoxia-induced ATP-loss see Table 2 ; from L influx. In accordance with these considerations the effects of acidosis on EDP are less pronounced than those of hypoxia and the combined effect is mitigated in comparison to hypoxia alone.

Regarding the propagation of the cardiac action potential, this is dependent on I Na fast sodium current availability and on gap junction coupling. The parameter related to ventricular conduction is total activation time Dhein et al. The present data show an increase in TAT, i. A change in TAT can be expected to result in a change of the activation pattern, i. Accordingly, this could be verified in the present study by reduced vectorfield similarity during hypoxia, showing changes in the direction and velocity of the activation vectors.

By comparison of the effects of intracellular and extracellular acidification Watson and Gold found that reduction of peak I Na is a function of pH extracellular , while steady-state inactivation was modulated by pH intracellular Watson and Gold, In these experiments the time course of activation and inactivation depended on both pH extracellular and pH intracellular.

However, the acidified pH extracellular in these experiments was about 6. Accordingly, we did not observe a clear depressant effect of acidosis on TAT. However, a small effect on vectorfield similarity was observed showing that there was a slight deviation of the activation vectors. It should be noted at that point that activation vectors depend not only on I Na and gap junction opening but also on the foregoing repolarization since this affects I Na availability.

The other factor regulating ventricular conduction is the opening of gap junctions. These also close at very low pH near 6. Thus, it is reasonable that in the present experiments acidosis alone did not slow conduction.