Divergent Mechanisms of ATP-Sensitive K+ Channel–Induced Vasodilation in Renal Afferent and Efferent Arterioles
Evidence of L-Type Ca2+ Channel–Dependent and –Independent Actions of Pinacidil
Abstract K+ channel openers (PCOs), such as pinacidil, elicit vasodilation primarily by hyperpolarization-induced inhibition of L-type Ca2+ channel activation. The physiological role of other mechanisms suggested to contribute to PCO-induced vasodilation is not well established. In the renal microcirculation, L-type Ca2+ channels play a prominent role in vasoconstriction of the afferent arteriole (AA) but are absent or physiologically silent in the efferent arteriole (EA). Thus, L-type Ca2+ channel–dependent and –independent mechanisms can readily be distinguished in this model. In the present study, we found that pinacidil potently inhibited Bay K 8644–induced AA vasoconstriction. Pinacidil also preferentially inhibited angiotensin II–induced AA vasoconstriction (approximately ninefold greater potency than EA). These results are consistent with an AA effect of pinacidil on L-type Ca2+ channel activation. Unexpectedly, 10 μmol/L pinacidil inhibited AA and EA responses to similar extents (84±10% and 71±9%, respectively). In both AAs and EAs, glibenclamide restored normal reactivity, indicating an involvement of the ATP-sensitive K+ channels. In the EA, however, pretreatment with diltiazem did not alter the effects of pinacidil. Nevertheless, 45 mmol/L KCl reversed the EA actions of pinacidil, indicating an essential requirement for a normal K+ gradient. These findings suggest that the EA actions of pinacidil involve alterations in membrane potential but not changes in L-type Ca2+ channel activity. Overall, our findings do support the premise that L-type Ca2+ channel modulation is involved in PCO-induced vasodilation in the renal microcirculation. The EA actions of pinacidil, however, suggest important additional vasodilatory mechanisms that also involve ATP-sensitive K+ channel–induced hyperpolarization but are independent of L-type Ca2+ channel modulation.
- ATP-sensitive K+ channels
- angiotensin II
- renal microcirculation
- arterioles, afferent and efferent
Pinacidil is a member of the heterogeneous group of vasodilators known as PCOs. The potent vasodilatory effects of these agents are thought to be mediated by the opening of KATP.1 2 Although it is generally considered that activation of KATP elicits vasodilation by causing membrane hyperpolarization, thereby preventing the activation of L-type Ca2+ channels,3 several lines of evidence suggest that PCOs may also promote vasodilation via hyperpolarization and/or L-type Ca2+ channel–independent mechanisms (for review see References 4 and 54 5 ). These novel vasodilatory actions have been demonstrated by indirect measurements in perfused vascular beds and in isolated large arteries and single cells, typically under nonphysiological conditions (eg, Ca2+ free), but not at the level of the arteriole. It is not known whether these mechanisms might also contribute to PCO-induced vasodilation of resistance vessels under physiological conditions.
The effects of PCOs on the renal microcirculation have not been previously investigated. The renal microvasculature represents a unique example of vascular heterogeneity in which L-type Ca2+ channel–dependent and –independent mechanisms can readily be distinguished. The two segmental resistance vessels in the kidney, the afferent arteriole (preglomerular) and efferent arteriole (postglomerular), are known to have different dependencies on L-type Ca2+ channels (for review see Reference 66 ). For example, the vasoconstrictor response of the afferent arteriole to Ang II is inhibited by dihydropyridines and other L-type Ca2+ channel blockers, whereas the efferent arteriole is not affected. Furthermore, KCl-induced depolarization, which elicits vasoconstriction via activation of potential-dependent Ca2+ channels, preferentially constricts the afferent arteriole7 and has been demonstrated to have no stimulatory effect on Ca2+ signaling in the efferent arteriole.8 These observations suggest that L-type Ca2+ channels are either absent or physiologically silent in the efferent arteriole.
If pinacidil acts exclusively by hyperpolarization-induced alterations in L-type Ca2+ channel activity, its effects should be limited to the afferent arteriole. In contrast, if pinacidil also alters efferent arteriolar reactivity, this would suggest that L-type Ca2+ channel–independent mechanisms may contribute importantly to the vasodilatory actions of this PCO.
Materials and Methods
The Isolated Perfused Hydronephrotic Kidney
The isolated hydronephrotic rat kidney was used to examine the effects of pinacidil on the vasoconstrictor responses of renal afferent and efferent arterioles. Unilateral hydronephrosis was produced by ligating the left ureter during halothane-induced anesthesia. Hydronephrotic kidneys were harvested after 4 to 6 weeks. Rats were anesthetized with methoxyflurane, the renal artery of the hydronephrotic kidney was cannulated, and the kidney was excised for in vitro perfusion. During the initial cannulation and throughout the excision, kidneys were continuously perfused with medium to avoid a disruption of nutritive flow.
The perfusing apparatus used in the present study has been described in previous publications9 and involves a single-pass presentation of medium to the kidney. The medium was pumped on demand through a heat exchanger to a pressurized reservoir, supplying the renal artery. Perfusion pressure was monitored within the renal artery and controlled by adjusting the pressure within the reservoir. In the present study, kidneys were perfused at 80 mm Hg with modified Dulbecco’s medium containing (mmol/L) bicarbonate 30, glucose 5, and HEPES 5. The perfusate was equilibrated with 95% air/5% CO2 (Po2, 150 mm Hg). Temperature and pH were maintained at 7.4 and 37°C, respectively. In all experiments, 10 μmol/L ibuprofen was added to the perfusate to eliminate the effects of renal prostaglandins. Under these conditions, KATP is quiescent,9 and dihydropyridines have no effect on basal afferent arteriolar diameter.6
To examine the ability of pinacidil to influence L-type Ca2+ channel–dependent vasoconstriction in the afferent arteriole, kidneys were treated with either 0.1 μmol/L Bay K 8644 (n=5) or 20 to 30 mmol/L KCl (n=4). These treatments have previously been demonstrated to constrict only preglomerular vessels in this model.7 10 The effects of increasing concentrations of pinacidil on afferent arteriolar vasoconstriction were then determined.
To compare the actions of pinacidil on afferent versus efferent arteriolar vasoconstriction, Ang II was used as the vasoconstrictor stimulus. In these studies, the diameters of paired afferent and efferent arterioles from the same glomerulus (n=8) were measured before and after treatment with 0.1 nmol/L Ang II. The kidneys were then treated with increasing concentrations of pinacidil, and the effects on basal diameter and Ang II–induced vasoconstriction were assessed in each vessel.
A separate series of experiments was used to assess the effects of diltiazem on the efferent arteriolar actions of pinacidil. In a subset of these studies (five of eight), 10 μmol/L diltiazem had no effect on Ang II–induced efferent arteriolar vasoconstriction (see below), so in the remaining experiments (n=3), kidneys were pretreated with the Ca2+ antagonist. The effects of pinacidil on the efferent arteriolar actions of Ang II were then assessed by using a protocol identical to that described above.
Pinacidil, diltiazem, Bay K 8644, and ibuprofen were obtained from Research Biochemicals International; Ang II, from Sigma Chemical Co; and glibenclamide, from Hoechst-Roussel Pharmaceuticals Inc. All other reagents were obtained from GIBCO.
Analysis of Data
Video images were digitized (model IVG-128, Datacube) for on-line analysis. Custom software was used to measure vessel diameter as described previously.9 Vessel segments (10 to 20 μm in length) were scanned at 0.5-second intervals. The mean-diameter measurements obtained during the plateau of the response were then averaged. Typically, one diameter determination was derived from the mean of 30 to 60 individual measurements, each in turn representing the mean diameter over the length of the arteriolar segment. Efferent arteriolar diameters were measured within 50 μm of the glomerulus. Afferent arteriolar diameters were measured in the most proximal regions, just after branching from the interlobular artery.
Throughout the text, data are expressed as the mean±SEM, as an index of dispersion. The number of replicates refers to the number of afferent and/or efferent arterioles examined. Only one vessel (either afferent or efferent arteriole) or pair of vessels (afferent and efferent arterioles) was studied in each kidney preparation. Differences between means were evaluated by ANOVA followed by Student’s t test (paired or unpaired). Values of P<.05 were considered statistically significant for single comparisons. The Bonferroni correction was used for multiple comparisons. In such cases, values of P<.05/n were considered significant, where n indicates the number of comparisons.
Treatment with 0.1 μmol/L Bay K 8644 elicited strong oscillations in the afferent arteriole in all preparations (eg, Fig 1⇓, top). Mean afferent arteriolar diameters were reduced from 17.7±1.0 μm (basal) to 12.0±1.0 μm (P<.005, n=5). Pinacidil at concentrations of 0.001, 0.01, 0.1, 1.0, and 10 μmol/L increased afferent arteriolar diameter to 12.2±1.0, 12.8±1.3, 16.6±1.0 (P<.005), 16.9±1.0 (P<.005), and 17.0±0.8 (P<.025) μm, respectively. Subsequent treatment with 10 μmol/L glibenclamide completely restored the Bay K 8644–induced vasoconstriction (9.8±1.4 μm; P>.2 versus Bay K 8644 alone; eg, Fig 1⇓). The pinacidil-induced inhibition of Bay K 8644–induced afferent arteriolar vasoconstriction is summarized in Fig 2⇓. The approximate IC50 (extrapolated from the concentration-response curve) was 54 nmol/L.
In contrast to its effects on Bay K 8644–induced vasoconstriction, pinacidil had no significant effect on afferent arteriolar vasoconstriction when L-type Ca2+ channels were activated by KCl-induced depolarization. A typical tracing is shown in Fig 1⇑, bottom. KCl reduced the mean afferent arteriolar diameter from 16.7±1.0 to 8.7±0.9 μm (P<.01). The subsequent addition of 0.001, 0.01, 0.1, 1.0, and 10 μmol/L pinacidil did not significantly alter the mean arteriolar diameter (ie, 8.8±0.7, 8.0±0.5, 8.1±0.5, 8.9±0.7, and 9.6±0.9 μm, respectively; P>.5 versus KCl alone). The data are plotted in Fig 2⇑ as the percent inhibition of KCl-induced vasoconstriction.
In order to investigate the actions of pinacidil on both afferent and efferent vasoconstriction, Ang II was used as the vasoconstrictor stimulus. In contrast to Bay K 8644 and KCl, which act exclusively on the afferent arteriole, Ang II constricts both vessels but does so through different mechanisms. Fig 3⇓ depicts original tracings illustrating the response of an afferent (top) and efferent (bottom) arteriole to 0.1 nmol/L Ang II. In these tracings, Ang II decreased afferent arteriolar diameter from 15.7 to 4.2 μm and efferent arteriolar diameter from 10.5 to 3.0 μm. The addition of 1.0 μmol/L pinacidil caused a prompt vasodilation of the afferent arteriole (Fig 3⇓, top) but had little effect on the efferent arteriole (Fig 3⇓, bottom). In contrast, 10 μmol/L pinacidil dilated both vessels to preangiotensin levels. The subsequent addition of 10 μmol/L glibenclamide restored the Ang II–induced vasoconstriction in the continued presence of pinacidil.
To further compare the effects of pinacidil on the afferent and efferent arterioles, paired vessels from the same glomerulus were exposed to repeated applications of 0.1 nmol/L Ang II. The effects of increasing concentrations of pinacidil (1.0 nmol/L to 10 μmol/L) on basal diameters and on Ang II–induced vasoconstriction were assessed for each vessel. Table 1⇓ and Fig 4⇓ summarize these data. Over this concentration range, pinacidil had no effect on basal diameter of either vessel (P>.8, Table 1⇓). Pinacidil produced a concentration-dependent inhibition of the Ang II–induced vasoconstriction of the afferent arteriole, significantly increasing the diameters of Ang II–treated vessels at both 1 and 10 μmol/L (P=.006 and P=.0002 versus control, respectively; Table 1⇓). When the data were normalized by calculating the Ang II–induced change in afferent arteriolar diameter, a significant effect of pinacidil was observed at concentrations of 0.1 μmol/L (41.5±4.5% decrease versus 61.1±6.0% in the absence of pinacidil, P<.005) and higher. In the efferent arteriole, pinacidil significantly increased diameters during Ang II treatment (Table 1⇓) and inhibited the Ang II–induced change in diameter only at 10 μmol/L (P<.005). These data are plotted as the percent inhibition of the Ang II–induced change in diameter in Fig 4⇓. Pinacidil produced a greater inhibition of the afferent arteriolar response at concentrations of 0.1 μmol/L (31±6%, afferent; −3±14%, efferent; P<.05) and 1.0 μmol/L (59±13%, afferent; 15±9%, efferent; P<.05). The IC50s (extrapolated from Fig 4⇓) were 0.5 and 4.6 μmol/L for the afferent and efferent arteriole, respectively. Nevertheless, the maximal inhibition produced by 10 μmol/L was similar in both vessels (84±10% and 71±9% for afferent and efferent arterioles, respectively; P=.35).
Glibenclamide reversed the effects of pinacidil on both afferent and efferent arterioles, suggesting that each of these actions involves activation of KATP (Fig 5⇓). Basal diameters were not affected by 10 μmol/L pinacidil or 10 μmol/L pinacidil plus 10 μmol/L glibenclamide in either afferent (P=.3) or efferent (P>.8) arterioles (n=5 in each case). In the absence of pinacidil (control), Ang II reduced afferent arteriolar diameter from 15.9±0.7 to 6.9±1.5 μm (P=.002). Pinacidil at 10 μmol/L completely inhibited the response to Ang II (basal diameter, 15.4±0.5 μm; after Ang II, 13.5±2.1 μm; P=.35), whereas glibenclamide restored normal afferent arteriolar responsiveness (basal diameter, 14.0±1.1 μm; after Ang II, 6.9±1.2 μm; P<.0001). In the efferent arteriole, the corresponding Ang II–induced changes were from 10.1±2.1 to 4.3±0.3 μm for the control condition (P=.03), from 10.5±1.8 to 8.8±1.9 μm in the presence of pinacidil (P=.16), and from 10.4±1.8 to 5.2±0.6 μm in the presence of pinacidil plus glibenclamide (P=.04).
Additional studies were conducted to further define the mechanisms underlying the effects of pinacidil on the reactivity of the efferent arteriole. Previous investigations have demonstrated that the efferent arteriolar response to Ang II is not affected by Ca2+ antagonists.11 12 Similarly, in the present study, 10 μmol/L diltiazem had no effect on the vasoconstrictor response of this vessel to Ang II. In paired experiments (n=5), Ang II reduced efferent arteriolar diameters from 12.3±1.3 to 6.3±1.0 μm (P=.06) during the control condition and from 12.0±1.1 to 6.9±1.2 μm (P=.003) in the presence of diltiazem (Fig 6⇓). The effects of pinacidil on Ang II–induced changes in efferent arteriolar diameters in vessels pretreated with diltiazem are summarized in Table 2⇓. Fig 7⇓ compares the percent inhibition of Ang II responses by pinacidil in the presence and absence of 10 μmol/L diltiazem (data from Tables 1⇑ and 2⇓). Identical concentration-response curves to pinacidil were obtained under these two conditions (P>.15 for all points).
Since the above results suggested that the efferent arteriolar actions of pinacidil might involve KATP (reversed by glibenclamide) but did not involve modulation of L-type Ca2+ channels (not affected by diltiazem), we next examined the dependence of the actions of pinacidil on the K+ gradient. If the effects of pinacidil on the efferent arteriole are mediated exclusively by K+ channel activation, elevation of external K+ would be anticipated to eliminate the inhibition. Therefore, we determined whether 45 mmol/L KCl reversed and/or prevented the inhibitory actions of pinacidil. In order to eliminate effects of KCl on renal perfusate flow and afferent tone, these studies were conducted in the presence of 10 μmol/L diltiazem. The protocol used in this series of experiments is illustrated by the representative tracing in Fig 8⇓. As depicted, the inhibitory effects of pinacidil were completely reversed by the elevation of external K+ (from 5 to 45 mmol/L KCl). Fig 9⇓ summarizes our findings when using this protocol (n=10). Neither pinacidil nor KCl altered basal diameter in the presence of diltiazem (12.4±0.9, 12.8±0.8, and 12.5±0.7 μm for diltiazem alone, diltiazem plus pinacidil, and diltiazem plus pinacidil and KCl, respectively; P>.8 versus diltiazem alone). In the absence of pinacidil, Ang II reduced efferent arteriolar diameter from 12.4±0.9 to 8.1±0.7 μm (P<.0001). Pinacidil attenuated the Ang II–induced vasoconstriction (from 12.8±0.8 to 11.4±0.8 μm, P=.0012 versus diltiazem alone). Subsequent treatment with 45 mmol/L KCl restored original reactivity to Ang II in the continued presence of pinacidil (from 12.5±0.7 to 9.0±0.8 μm, P=.012 versus pinacidil/diltiazem and P=.31 versus diltiazem alone).
To further examine the effects of KCl on the inhibitory actions of pinacidil and to ensure that KCl had no potentiating action on Ang II responsiveness on its own, additional studies were conducted in which the order of KCl and pinacidil addition was reversed. As depicted by the tracing in Fig 10⇓, when the KCl was added before treatment with pinacidil, the pinacidil-induced inhibition of Ang II vasoconstriction was prevented. Mean results obtained from three replicate studies were as follows: under control conditions, Ang II reduced diameters from 11.8±1.7 to 7.5±1.5 μm; in the presence of 10 μmol/L diltiazem, from 11.1±1.8 to 6.4±1.6 μm; in the presence of 45 mmol/L KCl (plus diltiazem), from 11.0±1.7 to 6.1±1.7 μm; and in the presence of 10 μmol/L pinacidil (plus 45 mmol/L KCl and 10 μmol/L diltiazem), from 11.1±1.6 to 6.4±1.8 μm.
The present study is the first to compare the effects of KATP activation on renal afferent and efferent arterioles. Our findings indicate that KATP-induced hyperpolarization preferentially attenuates afferent arteriolar reactivity, in that pinacidil was approximately ninefold more potent in inhibiting Ang II responses of afferent versus efferent arterioles. This preferential action most likely reflects the greater dependence of the afferent arteriolar vasoconstriction on L-type Ca2+ channel activation.6 11 12 13 14 Consistent with this interpretation, we found that pinacidil potently inhibited the afferent arteriolar response to L-type Ca2+ channels activated by Bay K 8644. In contrast, pinacidil had no effect on KCl-induced activation of L-type Ca2+ channels, presumably reflecting the dependence of K+ channel–induced hyperpolarization on a normal transplasmalemmal K+ gradient and K+ equilibrium potential.
Although pinacidil exhibited a greater potency on the afferent arteriole, maximal concentrations of pinacidil produced similar inhibitory effects on both afferent and efferent responses to Ang II. Both the afferent and efferent arteriolar actions of pinacidil were reversed by glibenclamide and blocked by KCl, suggesting that pinacidil acts via KATP-induced membrane hyperpolarization in both vessels. These findings were somewhat surprising, since it is well documented that the renal efferent arteriole is insensitive to vasodilators acting exclusively on L-type Ca2+ channels (for review see Reference 66 ). Fleming et al11 first demonstrated that nitrendipine and diltiazem preferentially dilate the afferent arteriole in the in vivo hydronephrotic kidney model. Similarly, Carmines and Navar12 and Conger and colleagues13 14 found diltiazem to prevent Ang II–induced vasoconstriction and Ca2+ signaling in afferent arterioles, without affecting either parameter in efferent arterioles. Studies using KCl-induced depolarization also indicate a lack of L-type Ca2+ channels in the efferent arteriole.7 8 In agreement with these previous observations, diltiazem had no effect on the efferent arteriolar response to Ang II in the present study. More important, diltiazem did not alter the pinacidil-induced inhibition of this response. The possibility that hyperpolarization alters voltage-sensitive Ca2+ entry through non–L-type Ca2+ channels is unlikely, as 45 mmol/L KCl had no effect on efferent arteriolar diameters in the presence of diltiazem (eg, Fig 10⇑). Thus, our findings indicate that the efferent arteriolar actions of pinacidil are mediated by KATP-induced hyperpolarization but clearly do not involve alterations in L-type or other voltage-dependent Ca2+ channels. To our knowledge, this is the first study to directly demonstrate PCO-induced vasodilation of a resistance arteriole under physiological conditions through a mechanism that is completely independent of modulation of voltage-gated Ca2+ entry.
Although it is generally acknowledged that PCO-induced hyperpolarization can elicit vasodilation by inhibiting the activity of voltage-gated Ca2+ channels, a number of studies suggest additional mechanisms. Cook et al15 and Bray et al16 noted that cromakalim inhibited dihydropyridine-insensitive contractile responses of rabbit aorta and suggested that in addition to its indirect effects on L-type Ca2+ channel activity, this agent specifically affects receptor-mediated Ca2+ entry or some other mechanism specific to agonist-induced vasoconstriction. Okada et al17 reported that levcromakalim reduced Ca2+ sensitivity in canine coronary artery in the presence of 30 mmol/L KCl. In contrast, Yamagishi et al18 found cromakalim to have no effect on the enhanced Ca2+ sensitivity induced by thromboxane in this preparation. It is unlikely that the alterations in Ca2+ sensitivity reported by Okada et al are involved in the efferent arteriolar actions of pinacidil observed in the present study, since these effects of pinacidil were abolished by KCl.
A number of studies suggest that PCO-induced hyperpolarization may influence phospholipase C activation. Quast and Baumlin19 reported that cromakalim inhibits isradipine-insensitive phasic responses to norepinephrine in the perfused rat mesenteric bed. Since cromakalim had no effect on the phasic vasoconstriction induced by caffeine, these authors suggested that cromakalim interferes with norepinephrine-induced Ca2+ mobilization. Similarly, Ito et al20 found that lemakalim blocked norepinephrine-induced contraction and Ca2+ signaling in Ca2+-free medium and inhibited norepinephrine-stimulated IP3 formation in isolated mesenteric arteries. These actions of lemakalim were abolished in chemically skinned arteries. Ito et al suggested that hyperpolarization directly alters phospholipase C activity, thereby inhibiting agonist-induced intracellular Ca2+ release and protein kinase C activation. Itoh et al21 reported that pinacidil also inhibits norepinephrine-induced Ca2+ signaling and IP3 formation in intact but not chemically skinned smooth muscle. These actions of pinacidil were accompanied by membrane hyperpolarization and were prevented by glibenclamide. Similarly, Yamagishi et al22 reported that PCOs inhibit thromboxane-induced intracellular Ca2+ release and IP3 formation, but not caffeine-induced Ca2+ release, in isolated canine coronary arteries. Finally, Ganitkevich and Isenberg23 directly demonstrated that depolarization stimulates and hyperpolarization attenuates IP3-dependent Ca2+ transients in voltage-clamped coronary myocytes, suggesting a direct modulation of phospholipase C activity by membrane potential. Hyperpolarization-induced inhibition of phospholipase C could certainly contribute to the efferent arteriolar actions of pinacidil that we observed in the present study. Conger et al13 suggested that Ang II–induced contractions of the efferent arteriole may be dependent on Ca2+ release from intracellular stores, because this response is resistant to removal of extracellular Ca2+ but is prevented by dantrolene-induced depletion of intracellular Ca2+ stores. Studies directly examining the effects of PCOs on efferent arteriolar membrane potential, Ca2+ signaling, and inositol metabolism are required to resolve this issue.
The results of the present investigation and previous studies from our laboratory9 indicate that KATP may play an important role in the regulation of the renal microvasculature. The present findings suggest that activation of these channels at least at intermediate levels would preferentially attenuate afferent arteriolar reactivity. As illustrated in the present study, Ang II constricts both afferent and efferent arterioles in vitro. However, in a number of in vivo settings (eg, renal arterial stenosis), the preglomerular actions of Ang II appear to be diminished. The mechanisms responsible for the preferential efferent actions of Ang II in such settings are unknown. The present results suggest that an augmentation of K+ channel activity is one potential mechanism for selectively attenuating the preglomerular actions of Ang II. A number of endogenous vasodilators, including adenosine,24 vasoactive intestinal peptide,3 and calcitonin gene-related peptide,25 activate KATP in other vascular beds. The role of KATP in the renal actions of these agents or in in vivo settings in which the afferent arteriolar actions of Ang II are attenuated have not been determined.
In conclusion, the present study demonstrates that KATP activation elicits vasodilation of both afferent and efferent arterioles but does so through different mechanisms. Pinacidil potently inhibits L-type Ca2+ channel activity in the afferent arteriole, and this mechanism likely accounts for the preferential afferent arteriolar actions of KATP activation. The ability of high concentrations of pinacidil to reduce the reactivity of the efferent arteriole clearly does not involve modulation of voltage-gated Ca2+ entry but appears to be mediated by KATP-induced hyperpolarization in that these effects of pinacidil are blocked by glibenclamide and elevated K+. The present findings are the first direct evidence that under physiological conditions, K+ channel–induced hyperpolarization modulates the reactivity of resistance arterioles by L-type Ca2+ channel–dependent and –independent mechanisms.
Selected Abbreviations and Acronyms
|Ang II||=||angiotensin II|
|KATP||=||ATP-sensitive K+ channel|
|PCO||=||K+ channel opener|
This study was supported by grants from the Medical Research Council of Canada, the Alberta Heritage Foundation for Medical Research, and the Alberta Chapter of the Kidney Foundation of Canada. Dr Loutzenhiser is an Established Investigator of the American Heart Association and an Alberta Heritage Foundation Medical Scholar.
- Received May 11, 1995.
- Accepted August 10, 1995.
- © 1995 American Heart Association, Inc.
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