Changes in endothelium-derived hyperpolarizing factor and myogenic response in rats with chronic renal failure and their association with hypertension

Patients with chronic renal failure often develop hypertension but the causes of hypertension are not fully understood. The experimental animal model to produce renal failure by partial ablation of the renal parenchyma has been in use for almost a century [1]. Other models to produce renal failure include the use of nephrotoxins, interruption of the blood supply to a major part of renal parenchyma and destruction or removal of renal mass in one kidney with contralateral nephrectomy [2]. The reduced renal mass model, where the right kidney is removed and two of the major branches of left renal artery are ligated to induce infarction, is one of the commonly used models to study changes associated with chronic renal failure, including vascular functional changes. This model is also referred to as the remnant kidney model, subtotal or 5/6 nephrectomized rats, or rats with renal mass reduction. In the rat, it is characterized by moderate systemic hypertension, proteinuria and progressive focal glomerular sclerosis and functional deterioration [3]. Studies on vascular function change have focused mostly on endothelial dysfunction as a contributing factor to hypertension development, with fewer studies investigating contractile response changes. In the current issue of the Journal, Vettoretti et al. [4] report their results on the alteration in both the relaxation response mediated by endothelium and the contractile response of small mesenteric arteries from rats with reduced renal mass, and provide some surprising and interesting findings. Endothelium-mediated relaxation response Endothelium controls vascular tone not only by releasing nitric oxide (NO) and prostacyclin, but also by other pathways causing hyperpolarization of vascular smooth muscle cells [5]. The identity of this endothelium-derived hyperpolarizing factor (EDHF) is unknown, but may consist of different pathways [5]. The common approach to study EDHF is to use a combination of an NO synthase inhibitor (such as nitro-L-argine methyl ester) to block the synthesis of NO and a cyclooxygenase inhibitor (such as indomethacin) to abolish the production of prostaglandins, allowing investigation of the endothelium-dependent relaxation response to acetylcholine (ACh). The other approach is to use a combination of charybdotoxin and apamin to block small and intermediate calcium-dependent potassium channels [6,7]. Using these methods, it was found that in small mesenteric arteries from rats, EDHF plays a major role in mediating the ACh-induced endothelium-dependent relaxation response because the use of these inhibitors almost completely inhibited the relaxation response induced by ACh [6–8]. This is in contrast to large conducting vessels, such as the aorta where endothelium-dependent relaxation to ACh involved NO exclusively [6,8]. In the superior mesenteric artery, a major portion (approximately 75%) of the relaxation response was mediated through NO, with the remaining portion through EDHF [9]. EDHF-mediated vasodilation was found to be impaired in the carotid [10] and superior mesenteric artery [9] of hypertensive rats with reduced renal mass. However, these vessels are large conducting vessels. Therefore, Vettoretti et al. [4] decided to study whether EDHF-mediated relaxation is also altered in small mesenteric arteries of subtotally nephrectomized hypertensive rats. The authors found that, similar to large conduit vessels, EDHF-mediated relaxation was also impaired in these rats. However, even though treatment with lisinopril lowered blood pressure and restored the EDHF-mediated relaxation response, their correlation analysis showed that changes in EDHF did not correlate with blood pressure, but correlated with proteinuria, a marker of renal failure. This is somewhat surprising because, in most hypertension models, endothelial dysfunction, as shown by a reduced dilatory response to stimulation by ACh, is commonly present, and treatment that reduces blood pressure, such as the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, usually restores the function of the endothelium [11–14]. These results are generally used to demonstrate that endothelial dysfunction is associated with hypertension development. The results obtained by Vettoretti et al. [4] are in agreement with a previous study where hypertension development in uremic rats was prevented by a combined treatment with reserpine, hydralazine and hydrochlorothiazide [10]. The loss of functional KCa channels in the endothelium and the impairment of EDHF-mediated vasodilation were both still present in these treated uremic rats without hypertension compared to those with hypertension, suggesting that these changes were related to uremia and not to hypertension. As noted by Vettoretti et al. [4], EDHF is differently modulated in different forms of hypertension, and the role of EDHF in uremic hypertension requires further study. However, the results obtained to date certainly do not support the idea that changes in EDHF are related to hypertension development in chronic renal failure. Altered contractile response Essential hypertension is associated with an increased peripheral resistance, and changes in the structure and functions of small resistance arteries are considered to be important contributing factors to this increased peripheral resistance [15]. An increase in myogenic constriction in response to pressure increase, or stimulation with agonists, could be one of the contributing factors to vascular functional alterations. Vettoretti et al. [4] therefore hypothesized that small mesenteric arteries from subtotally nephrectomized rats with hypertension will display an increased myogenic reactivity. Instead, they found that the myogenic response in the hypertensive rats due to chronic renal failure was reduced compared to sham animals, which was contrary to their hypothesis. This conclusion was based on their observation that the maximal myogenic tone (calculated as a percentage of passive diameter) and peak myogenic index were lower in the hypertensive rats compared to sham rats. There are several possible explanations for this discrepancy. First, could there be a change in the relaxation or contractile property of the arteries? This does not appear to be the case. The passive diameter at the pressure range that they studied was similar among the three groups of rats, suggesting no change in the relaxation property of the vessels, as noted by the authors themselves [4]. The contractile response to thromboxane A2 analogue was also similar, suggesting there was no change in the contractile ability of the vessels. Second, can the change in threshold for the development of myogenic constriction be the basis for the change in reduced myogenic response? In hypertension, it is possible that there is a change in the threshold response of the arteries to pressure change due to the chronic exposure of the arteries to different pressure in the hypertensives compared to normotensives. Indeed, Vettoretti et al. [4] found that the threshold for the development of myogenic constriction in hypertensive rats was shifted to a higher pressure range compared to normotensives. However, over the range where the myogenic response was observed, the response was lower in hypertensives than in normotensives, suggesting a real change in the contractile response to pressure. If the change in threshold response were the contributing factor, a parallel shift in the myogenic response curves would be expected. A decreased myogenic response was also found in the cerebral arteries [16], but not in the skeletal arteries [17], of uremic Wistar–Kyoto rats. One interesting aspect of the myogenic response change was that treatment with lisinopril, which normalized blood pressure, also restored the myogenic response of arteries from uremic rats to the level of sham rats, suggesting that the functional change of the arteries was probably related to a blood pressure increase. However, their correlation analysis did not demonstrate a correlation between blood pressure and myogenic tone, which is surprising. Based on the results presented by Vettoretti et al. [4], can we conclude that alterations in the constrictive (myogenic) and dilatory (EDHF) mechanisms observed do not participate in the development of hypertension in this uremic model? I think the evidence to date is in strong support of this conclusion. It is possible that these changes are an adaptive response to chronic renal failure independent of hypertension development, as suggested by Vettoretti et al. [4]. Results obtained using in vitro methods are often conflicting due to differences in the methodology, animal model, tissue source and duration of hypertension, and this can often result in lively debate [15]. As pointed out by Vettoretti et al. [4], under in vivo conditions and in the presence of various hormones and vasoactive substances, the reduced myogenic response may be an adaptive response to chronic overactivation by various agonists. Other mechanisms, such as volume overload, overactivation of renin–angiotensin or the sympathetic system, are probably responsible for increased peripheral resistance in uremic rats [4]. On the other hand, issues related to EDHF are rather complex. Feletou and Vanhoutte [5] have suggested that the acronym ‘EDHF’ is not appropriate because it implies that a single diffusible substance is involved when in fact numerous endothelium-derived factors, including NO and prostacyclin, can hyperpolarize smooth muscle. The use of an NO synthase inhibitor and a cyclooxygenase inhibitor, such as indomethacin, to study EDHF is no longer sufficient to establish that the response observed was due to some unknown EDHF because NO can be stored in the endothelium and adventitia, which are not affected by these inhibitors [5].

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