Copyright © 2005, European Society of Cardiology
Coronary circulation: Nitric oxide and hypercapnic acidosis
Department Neurological Science and Vision. Sect. Physiology, Faculty of Exercise and Sports Science, University of Verona, Via Casorati, 43, 37131 Verona, Italy
* Tel.: +39 45 8952634; fax: +39 45 580881. Email address: antonio.cevese{at}univr.it
Received 21 January 2005; accepted 27 January 2005
See article by Heintz et al. [4] (pages 55–63) in this issue.
In the past two decades, nitric oxide (NO), a molecule whose natural biological role was recognized in a relatively recent period [1], has gained wide credit as a possible agent of physiological and pathological reactions, including those related to the heart and the cardiovascular system. The rapidly increasing wealth of scientific evidence, however, often led to unresolved contradictory results [2], to the extent that, in a recent review on "Nitric oxide and cardiovascular function," Kelly et al. [3] concluded that the explosion of new information over the past 5 years "has generated much light as well as smoke and heat."
The study by Heintz et al. [4] in this issue of Cardiovascular Research casts a new light on the specific role of NO in a well-known (patho)physiological response, namely, the coronary vasodilatation elicited by hypercapnia and/or acidosis. They relied on previous observations of their own [5] that suggested that the coronary vasodilator response to hypercapnia was biphasic. They argued that the mechanisms involved in the two phases could be different. The study was performed on Langendorff preparations of guinea pig hearts, either under constant pressure or under constant flow conditions, which allows disclosure of the possible role of shear stress-induced NO release that was obviously prevented in the latter preparation. They also used pharmacological blockade of endothelial NO synthase (eNOS) and of KATP channels and determined the release of cGMP during hypercapnic perfusion. The conclusion they reached is straightforward: "the steady-state decrease of coronary resistance during arterial hypercapnia requires a primary rise of flow and an intact NO production ..." (point 3 of the discussion of [4]). On the contrary, the first phase of the response is NO independent, although the mechanism has not been disclosed.
This paper is, in my opinion, a paradigmatic example of what basic research should be, because it describes a function that is verified in a clean, uncomplicated situation, such as an in vitro preparation, with crystalloid perfusion. The real in vivo situation should account for several additional effects, which are discussed below, that could obscure the basic function. On the other hand, this paper [4] thoroughly explains a mechanism that had been overlooked in previous studies that have not accounted for the biphasic nature of the phenomenon [6]. Indeed, any situation leading to hypercapnia and acidosis must be presumed to last (at least) for minutes, not just for a few seconds: thus, the first, rapidly (20–30 s) ensuing vasodilatation is indeed relevant, but essentially in as much as it triggers the second, sustained phase. In the first minute or so, a large increase in cGMP levels was also found that was blunted in the following minutes: this is also a demonstration of the physiological nature of the phenomenon, indicating that the NO increase, elicited as a first effect of the increased shear stress due to initial vasodilatation, is kept within regulatory levels. The cardiovascular effects of NO strongly depend on its concentration: within the nanomolar range, it enhances heart contractility and vessel relaxation and causes a relative vasodilatation, although these effects still compete with the other regulatory mechanisms, especially sympathetic vasoconstriction [7]. On the contrary, if the NO concentration rises to the micromolar range, heart function is hampered and an uncontrolled vasodilatation, leading to cardiovascular shock, ensues [7]. These divergent effects parallel the influence of NO on cGMP production, which is enhanced by NO, but is then limited by NO itself, in nanomolar concentrations, in a sort of negative feedback control loop [8], while it is further enhanced in micromolar concentrations [7].
Several other issues were addressed in the work by Heintz et al. [4], including hypercapnia-induced changes in myocardial oxygen consumption and performance, but the NO-related vasodilatation did not appear to be influenced by those changes.
Despite the clarity of the results discussed above, the problem of the real importance of this mechanism in the physiological control of coronary circulation remains to be assessed, as thoroughly discussed in the same paper [4]. Comparison with previous works on in situ heart preparations raises several questions. Eliades and Weiss [9], by measuring coronary blood flow with radioactive microspheres in open chest rabbits, found that hypercapnia-induced vasodilatation required intact chemoreflex mechanisms and sympathetic activity. In addition, they did not obtain any vasodilator effect with metabolic acidosis and concluded that "the vasodilatory effect of carbon dioxide on the coronary circulation is related to the change in arterial PCO2 and not pH." This is in contrast with the results discussed here [4]. They also remarked that carbon dioxide is a relatively weak coronary vasodilator, in agreement with other authors [10,11] who had studied the response to hypercapnia in dogs. Gurevicious et al. [12], also using in situ canine heart preparations, found an effect of hypercapnia on coronary conductance that was somewhat similar to that described by Heintz et al. [4], albeit much larger; however, the vasodilatation was not abolished during constant-flow perfusion. This discrepancy is accurately dealt with in the discussion by Heintz et al. [4].
The examples given above show that the situation of the working blood-perfused heart is much more complicated than that of in vitro Langendorff preparations [4]. In the case of a study on the effects of hypercapnia, the interrelations between PCO2 and oxygen delivery to the cells (Bohr effect) must be accounted for when the organ under study is perfused with whole blood [9]: the shift to the right of the oxyhemoglobin dissociation curve elicited by high PCO2 and concurrent lowered pH adds a vasoconstrictor stimulus that can change the extent of the response. Also, the buffering power of whole blood can contribute to alter the results. On the other hand, with systemic hypercapnia and acidosis, the chemoreceptor-controlled autonomic drive to the heart is altered, further contributing to make the pattern of the response more difficult to be understood.
Another controversial point is related to the role of K+ATP channels, which was claimed to be important in several previous papers [13,14]. This finding was not confirmed by the results of Heintz et al. [4]. The authors attribute this discrepancy to possible species-related differences. This explanation, however, is not completely satisfactory, and further research should be done to clarify this point.
In spite of any possible criticism, the assessment of NO-related vasodilatation as a basal mechanism of the hypercapnic response [4] is nevertheless of great importance in view of the recognized role of endothelial dysfunction in human cardiovascular pathology [15].
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