(Hypertension. 2001;38:353.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Enhanced Interaction Between Renovascular 
2-Adrenoceptors and Angiotensin II Receptors in Genetic Hypertension
Center for Clinical Pharmacology, Departments of Pharmacology (E.K.J., C.K.K.) and Medicine (E.K.J., W.A.H., C.K.K., S.J.V.), University of Pittsburgh Medical Center, Pa.
Correspondence to Edwin K. Jackson, PhD, Center for Clinical Pharmacology, Department of Medicine, 623 Scaife Hall, 3550 Terrace St, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. E-mail edj+{at}pitt.edu
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Abstract |
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Abstract—— In spontaneously hypertensive rats (SHR), hypertension is mediated in part by an enhanced renovascular response to angiotensin (Ang) II. Pertussis toxin normalizes renovascular responses to Ang II and lowers blood pressure in SHR, suggesting a role for altered Gi signaling in the enhanced renovascular response to Ang II in SHR. To further investigate this hypothesis, we measured reductions in renal blood flow and increases in renovascular resistance in response to intrarenal infusions of Ang II in the presence and absence of coactivation of
2-adrenoceptors (ie, receptors selectively coupled to Gi) with UK 14,304 in adrenalectomized, renal-denervated, captopril-pretreated SHR and normotensive Wistar-Kyoto rats. In SHR, but not Wistar-Kyoto rats, UK 14,304 markedly enhanced renovascular responses to Ang II and vasopressin. However, UK 14,304 did not enhance renovascular responses to methoxamine (1-adrenoceptor agonist) in either strain. In uninephrectomized, normotensive Sprague-Dawley animals and in Sprague-Dawley rats with nongenetic hypertension induced by uninephrectomy, chronic administration of deoxycorticosterone acetate, and 1% saline as drinking water, UK 14,304 had little or no effect on renovascular responses to Ang II. In SHR, intrarenal infusions of U73122, a phospholipase C/D inhibitor, blocked the enhancement of renovascular responses to Ang II by UK 14,304. We conclude that activation of 2-adrenoceptors selectively enhances renovascular responses to Ang II and vasopressin in vivo in animals with genetic hypertensive but not in normotensive animals or animals with acquired hypertension. These results suggest that in SHR, there is a genetically mediated enhanced cross talk between the Gi signal transduction pathway and signal transduction pathways activated by Ang II and vasopressin, but not methoxamine, and involving phospholipase C and/or D.
Key Words: hypertension, genetic • angiotensin II • vasopressin • kidney • G protein • receptors, adrenergic, alpha
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Introduction |
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Transplantation studies1 implicate a renal defect as the cause of hypertension in spontaneously hypertensive rats (SHR), a well-studied model of genetic hypertension. Additionally, the development and maintenance of hypertension in SHR require an intact renin-angiotensin system.2–4 However, SHR do not have elevated plasma renin activity,5 and circulating6 and kidney7 levels of angiotensin (Ang) II are not increased in SHR. These facts support the hypothesis that hypertension in SHR is caused in part by an enhanced renal responsiveness to normal levels of Ang II.8 Indeed, Ang II exerts a greater effect on renal vascular resistance (RVR) in SHR than in Wistar-Kyoto rats (WKY).8–12
It is important to elucidate the mechanism of the enhanced RVR response to Ang II in SHR. In this regard, a number of studies demonstrate that activation of Gs-coupled receptors attenuates RVR responses to Ang II in WKY, but not SHR, kidneys,13–15 suggesting an involvement of renovascular adenylyl cyclase in the enhanced renovascular response to Ang II in SHR. Although these experiments are open to several non–mutually exclusive interpretations, one possibility is that excessive Gi pathway–induced inhibition of adenylyl cyclase limits the ability of adenylyl cyclase agonists to increase cAMP in the presence of Ang II. Consistent with the hypothesis of increased Gi pathway–mediated effects in SHR kidneys are the observations that pertussis toxin normalizes the enhanced renovascular response to Ang II in SHR,16,17 normalizes the increased basal renovascular tone in SHR,18 and normalizes the reduced preglomerular vascular smooth muscle cell cAMP levels in SHR.19 In addition, pertussis toxin causes a prolonged antihypertensive effect in SHR.18
The purpose of the present investigation was to test further the hypothesis of increased Gi pathway-mediated renovascular effects in SHR kidneys. In this regard, our experimental strategy was to activate the Gi pathway as selectively as possible and then to determine the effects of such activation on the renovascular responses to Ang II and, for comparison, vasopressin and methoxamine. Although no method exists for activating the Gi pathway with 100% selectivity in vivo, 2-adrenoceptors are considered classic Gi-coupled receptors.20,21 In reconstituted phospholipid vesicles, 2A-adrenoceptors and 2-C4-adrenoceptors couple to Gi more than to Go and do not couple to Gs.22 In HEK 293 cells coexpressing 2A-adrenoceptors and G proteins, 2A-adrenoceptors selectively couple to Gi rather than Gq or Gs.23 Indeed, coupling of 2-adrenoceptors to Gs requires marked overexpression of receptors and high concentrations of agonist.24 For these reasons, we chose to activate the Gi pathway in vivo with UK 14,304, a highly selective 2-adrenoceptor agonist.21,25
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Animals
Studies used either male SHR (n=57) and WKY (n=43) (Taconic Farms, Germantown, NY) or male Sprague-Dawley rats (n=28) (Charles River Laboratories, Wilmington, Mass). At 12 weeks of age, Sprague-Dawley rats were subjected to a right nephrectomy and randomized to either deoxycorticosterone acetate (DOCA) suspended in olive oil (30 mg/kg SC twice weekly) plus 1% saline as drinking water or olive oil (1 mL/kg SC twice weekly) plus tap water as drinking water. Animals were used for acute experiments at
16 weeks of age. The Institutional Animal Care and Use Committee approved all procedures.
Surgical Preparation
Rats were anesthetized (thiobutabarbital; 90 mg/kg IP) and placed on an isothermal pad. Temperature was monitored with a rectal probe thermometer and kept at 37°C with a heat lamp. The trachea was cannulated (polyethylene [PE]-240), and a PE-50 cannula was placed in the left jugular vein. A left carotid artery cannula (PE-50) was inserted and connected to a digital blood pressure analyzer for continuous measurement of mean arterial blood pressure (MABP).
To remove the influence of endogenous catecholamines on 2-adrenoceptors, both adrenal glands were removed, and the left kidney was denervated by stripping away all visible renal nerves and by painting the renal artery with 10% phenol in ethanol. To replace the loss of adrenal steroids, an infusion of 0.9% saline containing aldosterone (20 ng/min) and hydrocortisone (20 µg/min) was initiated at 50 µL/min via the jugular vein catheter.
A transit-time flow probe was positioned around the left renal artery and connected to a transit-time flowmeter to monitor renal blood flow (RBF). A 32-gauge needle connected to a PE-10 catheter was placed into the renal artery. The PE-10 catheter was inserted into a connector, and 2 or 3 PE-10 lines linked the connector to 2 or 3 separate infusion pumps. An intrarenal infusion of 0.9% saline was initiated into 2 intrarenal infusion lines at 25 µL/min. Some animals received 3 concomitant intrarenal infusions. In these animals, the third intrarenal infusion was U73122, a widely used phospholipase C inhibitor26 that also inhibits phospholipase D.27 U73122 was infused at 5 µL/min and was dissolved in dimethyl sulfoxide. After surgery, animals were given a bolus injection of captopril (30 mg/kg) to remove the influence of endogenous Ang II and a bolus of 0.9% saline (20 mL/kg) to improve hemodynamic stability. After a 1-hour stabilization period, the protocols were conducted.
Protocol 1
RBF and MABP were recorded just before and during the last minute of a 5-minute intrarenal infusion of Ang II (10 ng/kg per minute infused in 0.9% saline at 25 µL/min). Next, half of the SHR (n=7) and WKY (n=7) received an intrarenal infusion of UK 14,304, a highly selective 2-adrenoceptor agonist,21,25 at 3 µg/kg per minute. These groups are referred to as the UK 14,304 groups. The other half of the SHR (n=7) and WKY (n=7) received an intrarenal infusion of the vehicle for UK 14,304 (0.9% saline infused at 25 µL/min). These groups are referred to as the time-control groups. The time-control groups were included to make certain that any apparent changes induced by UK 14, 304 were indeed mediated by UK 14,304 and were not due to time and/or vehicle effects. After 20 minutes, RBF and MABP again were recorded just before and during the last minute of a 5-minute intrarenal infusion of Ang II. RVR was calculated by dividing RBF per gram kidney weight into the MABP. The percent changes in RBF and RVR induced by Ang II were calculated by subtracting the baseline RBF or RVR from the RBF or RVR during the last minute of each Ang II infusion, dividing this difference by the baseline RBF or RVR, and multiplying the calculated ratio by 100. In each strain, MABP, RBF, and RVR before and during Ang II and the Ang II–induced percent changes in RBF and RVR were analyzed with a 2-factor ANOVA with repeated measures on 1 factor. In this analysis, 1 factor was experimental group (2 levels, either time-control group or UK 14,304 group), and the other factor was experimental period (2 levels, either period 1 or period 2, repeated factor). If the ANOVA indicated a significant groupxperiod interaction, a Fisher’s least significant difference test was used to compare the values between period 2 of the time-control group and period 2 of the UK 14,304 group and between period 1 and period 2 of the UK 14,304 group. Additional statistical analyses were conducted with unpaired or paired 2-tailed Student’s t tests. The criterion of significance was P<0.05. All values in text and tables are mean±SEM.
Protocol 2
Protocol 2 was the same as protocol 1 except that RVR responses were elicited with intrarenal infusions of arginine vasopressin (AVP; 2 ng/kg per minute) rather than Ang II.
Protocol 3
Protocol 3 was the same as protocol 1 except that RVR responses were elicited with intrarenal infusions of methoxamine (1.5 µg/kg per minute; selective 1-adrenoceptor agonist) rather than Ang II.
Protocol 4
Protocol 4 was the same as protocol 1 except that animals with DOCA/salt-induced hypertension (n=14) substituted for SHR and uninephrectomized Sprague-Dawley rats (n=14) substituted for WKY.
Protocol 5
Protocol 5 was conducted as described for protocol 1 except that only SHR were used and animals received an intrarenal infusion of U73122 (3 µg/kg per minute) beginning 1 hour before the protocol was conducted and continuing for the duration of the protocol.
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Results |
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Before adrenalectomy and administration of captopril, MABP in SHR (194±3 mm Hg) was significantly (P<10-6) greater than MABP in WKY (128±2 mm Hg), and MABP in DOCA/salt rats (171±4 mm Hg) was significantly (P<10-6) greater than MABP in uninephrectomized Sprague-Dawley rats (129±2 mm Hg). Adrenalectomy plus captopril lowered MABP in all animals, but more so in hypertensive animals, such that MABP was similar in normotensive versus "hypertensive" animals (see Tables 1 through 5 for MABPs after adrenalectomy and captopril). In most groups, UK 14,304 slightly or modestly reduced MABP and RBF but did not change RVR, and Ang II slightly increased MABP and markedly decreased RBF and increased RVR (see Tables 1 through 5 for specific values and comparisons).
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Protocol 1
In the time-control group of WKY, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of Ang II reduced RBF by -20±2.2% and -18±2.2%, respectively, and increased RVR by 32±5.2% and 30±4.2%, respectively (Table 1). In the UK 14,304 group of WKY, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of Ang II reduced RBF by -15±5.3% and -15±8.0%, respectively, and increased RVR by 27±7.8% and 29±14%, respectively. In WKY, the groupxperiod interactions for both percent change in RBF and percent change in RVR were not significant, indicating no evidence of an effect of UK 14,304 on renovascular responses to Ang II.
In the time-control group of SHR, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of Ang II reduced RBF by -31±4.4% and -22±3.1%, respectively, and increased RVR by 51±12% and 32±5.4%, respectively. In the UK 14,304 group of SHR, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of Ang II reduced RBF by -23±4.5% and -40±4.8%, respectively, and increased RVR by 37±10% and 71±13%, respectively. In SHR, the groupxperiod interactions for both percent change in RBF and percent change in RVR were significant (P=0.0006 and P=0.0036, respectively), indicating potentiation by UK 14,304 of renovascular responses to Ang II.
Protocol 2
In the time-control group of WKY, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of AVP reduced RBF by -20±5.6% and -15±1.6%, respectively, and increased RVR by 51±17% and 29±2.9%, respectively (Table 2). In the UK 14,304 group of WKY, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of AVP reduced RBF by -14±2.2% and -15±2.7%, respectively, and increased RVR by 31±4.9% and 37±5.1%, respectively. In WKY, the groupxperiod interactions for both percent change in RBF and percent change in RVR were not significant, indicating no evidence of an effect of UK 14,304 on renovascular responses to AVP.
In the time-control group of SHR, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of AVP reduced RBF by -22±6.6% and -14±2.9%, respectively, and increased RVR by 51±23% and 24±4.2%, respectively. In the UK 14,304 group of SHR, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of AVP reduced RBF by -14±3.9% and -32±6.0%, respectively, and increased RVR by 25±3.4% and 65±20%, respectively. In SHR, the groupxperiod interactions for both percent change in RBF and percent change in RVR were significant (P=0.0099 and P=0.0423, respectively), indicating potentiation by UK 14,304 of renovascular responses to AVP.
Protocol 3
In the time-control group of WKY, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of methoxamine reduced RBF by -23±3.6% and -15±2.6%, respectively, and increased RVR by 41±7.1% and 26±3.1%, respectively (Table 3). In the UK 14,304 group of WKY, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of methoxamine reduced RBF by -28±5.1% and -8±2.1%, respectively, and increased RVR by 50±12% and 18±5.5%, respectively. In WKY, the groupxperiod interactions for both percent change in RBF and percent change in RVR were not significant, indicating no evidence of an effect of UK 14,304 on renovascular responses to methoxamine.
In the time-control group of SHR, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of methoxamine reduced RBF by -29±3.4% and -25±5.1%, respectively, and increased RVR by 54±7.9% and 44±11%, respectively. In the UK 14,304 group of SHR, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of methoxamine reduced RBF by -18±3.9% and -9.5±2.7%, respectively, and increased RVR by 31±7.0% and 9.7±1.9%, respectively. In SHR, the groupxperiod interactions for both percent change in RBF and percent change in RVR were not significant, indicating no evidence of an effect of UK 14,304 on renovascular responses to methoxamine.
Protocol 4
In the time-control group of uninephrectomized Sprague-Dawley rats, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of Ang II reduced RBF by -9.0±1.1% and -9.0±1.3%, respectively, and increased RVR by 14±2.2% and 15±1.9%, respectively (Table 4). In the UK 14,304 group of uninephrectomized Sprague-Dawley rats, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of Ang II reduced RBF by -16±2.7% and -24±2.1%, respectively, and increased RVR by 24±5.2% and 30±4.3%, respectively. In uninephrectomized Sprague-Dawley rats, the groupxperiod interaction for percent change in RBF was significant (P=0.0183), whereas the groupxperiod interaction for percent change in RVR was not significant, indicating little evidence of an effect of UK 14,304 on renovascular responses to Ang II.
In the time-control group of DOCA/salt hypertensive rats, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of Ang II reduced RBF by -15±3.0% and -13±1.9%, respectively, and increased RVR by 21±4.8% and 17±2.8%, respectively. In the UK 14,304 group of DOCA/salt hypertensive rats, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of Ang II reduced RBF by -15±1.9% and -22±2.7%, respectively, and increased RVR by 24±4.2% and 29±1.4%, respectively. In DOCA/salt hypertensive rats, the groupxperiod interaction for percent change in RBF was significant (P=0.0143), whereas the groupxperiod interaction for percent change in RVR was not significant, indicating little evidence of an effect of UK 14,304 on renovascular responses to Ang II.
Protocol 5
In the time-control group of SHR pretreated with U73122, the first (no UK 14,304) and second (no UK 14,304) intrarenal infusions of Ang II reduced RBF by -23±3.8% and -20±3.3%, respectively, and increased RVR by 41±8.2% and 33±6.4%, respectively (Table 5). In the UK 14,304 group of SHR pretreated with U73122, the first (no UK 14,304) and second (+UK 14,304) intrarenal infusions of Ang II reduced RBF by -22±3.1% and -27±6.3%, respectively, and increased RVR by 36±6.7% and 40±11%, respectively. In SHR pretreated with U73122, the groupxperiod interactions for both percent change in RBF and percent change in RVR were not significant, indicating no evidence of an effect of UK 14,304 on renovascular responses to Ang II.
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Discussion |
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The present study demonstrates that, in SHR, administration of UK 14,304, a selective
2-adrenoceptor agonist, augments renovascular responses to both Ang II and AVP but not methoxamine. Our results also establish that in contrast to SHR, UK 14,304 has little or no effect on renovascular responses to Ang II in normotensive WKY, in normotensive Sprague-Dawley rats, or in Sprague-Dawley rats with acquired hypertension. Finally, we demonstrate that UK 14,304–induced potentiation of Ang II–mediated renal vasoconstriction is blocked by U73122, a phospholipase C/D inhibitor. These results suggest that in SHR, there is a genetically mediated enhanced cross talk between the Gi signal transduction pathway and signal transduction pathways activated by Ang II and vasopressin, but not methoxamine, and involving phospholipase C and/or D.
The focus of the present study was the ability of 2-adrenoceptor activation to enhance the renovascular responses to Ang II and AVP. Bohmann et al28 report that vasoconstrictor doses of Ang II unmask vasoconstrictor 2-adrenoceptors in isolated perfused SHR and WKY kidneys, but more so in SHR kidneys. The results of our study and the study by Bohmann et al are consistent and are indeed different perspectives on the same underlying phenomenon, ie, an enhanced interaction between 2-adrenoceptors and Ang II receptors.
What is the mechanism of the enhanced interaction between 2-adrenoceptors and Ang II/AVP in SHR? As noted above, 2-adrenoceptors selectively activate the Gi pathway20–23; therefore, it is highly likely that in SHR, there is an enhanced interaction between the Gi pathway and signal transduction pathways shared by Ang II and AVP. Both AT1 receptors29 and V1 receptors30 are Gq-coupled receptors, albeit nonselectively, and Ang II and AVP cause renal vasoconstriction by activating AT111 and V1 receptors,31 respectively. Therefore, one interpretation of the present findings is that the ability of UK 14,304 to potentiate RVR responses to Ang II and AVP in SHR is evidence for an enhanced ability of Gi-coupled receptors to augment RVR responses to Gq-coupled receptors in SHR. Indeed, it is well established that even though ß
subunits per se have no effect on phospholipase C-ß, the ability of q to activate phospholipase C-ß is markedly enhanced by ß subunits released from Gi proteins.32 Although ß subunits are also released from Gs and Gq, the mRNA expression of Gs and Gq in the renal microcirculation is only a small fraction of the expression of Gi,33 and therefore ß subunits released from Gs and Gq are quantitatively less important than ß subunits released from Gi. These considerations suggest that the mechanism by which Gi-coupled receptors enhance the renovascular response to Ang II and AVP could involved enhanced "coincident signaling" between q and ß at the level of phospholipase C-ß. Consistent with this hypothesis is our observation that U73122, a potent phospholipase C inhibitor, abolished the ability of UK 14,304 to enhance RVR responses to Ang II in SHR.
The hypothesis that coincident signaling through phospholipase C-ß mediates the enhanced cross talk between the Gi pathway and Ang II/AVP in the SHR kidney is also consistent with previous findings13,14 that cAMP production in the SHR kidney is dysregulated. Studies by Ali et al34 demonstrate that cAMP via protein kinase A increases phosphorylation of phospholipase C-ß and that phosphorylation of phospholipase C-ß inhibits the ability of ß subunits to activate phospholipase C-ß. Thus, it is conceivable that the primary defect in the SHR kidney is reduced production of cAMP in the renal vasculature, perhaps Gi mediated, leading to decreased phosphorylation of phospholipase C-ß, increased ability of ß subunits to enhance the effects of q on phospholipase C-ß activity, and finally enhanced renovascular responses to Ang II and AVP.
Although the aforementioned hypothesis reconciles a large base of experimental results and explains the involvement of Gs, Gi, and Gq in the pathophysiology of enhanced renovascular responses to Ang II in SHR, the results with methoxamine are at odds with the simple concept of enhanced coincident signaling between q and ß at the level of phospholipase C-ß. Since 1-adrenoceptors are also coupled to Gq,21 the hypothesis of increased coincident signaling between q and ß at the level of phospholipase C-ß would predict that UK 14,304 should also potentiate the renovascular response to methoxamine. However, in the present study UK 14,304 did not potentiate renovascular responses to methoxamine. There are several possibilities to explain the methoxamine data: (1) the hypothesis of increased coincident signaling between q and ß at the level of phospholipase C-ß is incorrect; (2) the hypothesis is correct, but stimulation of 1-adrenoceptors activates additional signal transduction mechanisms that inactivate coincident signaling of phospholipase C-ß; and (3) the hypothesis is correct, but stimulation of 1-adrenoceptors fails to activate additional signal transduction pathways required for the effect of enhanced coincident signaling via phospholipase C-ß to be manifested as increased renovascular responses.
We have recently shown that phospholipase D2 is activated by Ang II in preglomerular microvascular smooth muscle cells, and this response is markedly enhanced in SHR versus WKY cells and is mediated by RhoA.35 Inasmuch as U73122 also inhibits phospholipase D,27 it is possible that coincident signaling via RhoA and/or phospholipase D mediates in part the interaction between the Gi pathway and Ang II and AVP.
It is unlikely that the enhanced coincident signaling between UK 14,304 and Ang II/AVP in SHR kidneys is mediated by changes in receptor characteristics. The ability of UK 14,304 to potentiate the effects of both Ang II and AVP in SHR is suggestive of a common-pathway intracellular signaling defect rather than widespread changes in receptor characteristics. Moreover, we have performed Western blots for the AT1 receptor and the 2A-adrenoceptor in proteins extracted from freshly isolated preglomerular microvessels from SHR and WKY. Our results in this regard indicate that the expression of neither of these receptors is elevated in SHR.
Our experimental strategy was to remove the interaction between endogenous ligands of 2-adrenoceptors and AT1 receptors to reveal the nature of the interaction with exogenous ligands. An added benefit of this approach was that MABP in SHR and WKY was equalized. Thus, the enhanced interaction between UK 14,304 and Ang II/AVP observed in SHR was not due to an elevated MABP at the time of study. Although UK 14,304 slightly enhanced the percent reduction in RBF induced by Ang II in DOCA/salt-induced hypertension, this effect was quantitatively small and also observed in uninephrectomized normotensive rats. Moreover, when analyzed as percent change in RVR, UK 14,304 had no effect on Ang II–induced renovascular responses. The little or no interaction between UK 14,304 and Ang II in animals with DOCA/salt-induced hypertension ruled out the possibility that the enhanced interaction in SHR was secondary to long-standing hypertension. Thus, the enhanced interaction between UK 14,304 and Ang II/AVP in the SHR kidney is most likely genetically determined. Whether the genetic determinism is direct or indirect, however, cannot be deduced from the present study.
Ang II at 10 ng/kg per minute only slightly increased MABP, and it is unlikely that this small systemic effect of Ang II confounded the results. UK 14,304 caused a reduction in MABP, most likely mediated by central inhibition of sympathetic tone via agonism of central nervous system 2-adrenoceptors. It is unlikely that this systemic effect of UK 14,304 was involved in the renal effects of UK 14,304. The kidney was denervated so that changes in sympathetic tone would not have been transmitted to the renal vasculature. UK 14,304 decreased MABP in animals with DOCA/salt-induced hypertension, yet UK 14,304 had little or no effect on RVR responses to Ang II in this model of acquired hypertension. This ruled out the possibility that UK 14,304–induced changes in MABP mediated the enhancement of RVR responses to Ang II in SHR.
In summary, the present findings support the conclusion that in SHR there is a genetically mediated enhanced cross talk between the Gi signal transduction pathway and signal transduction pathways activated by Ang II and vasopressin, but not methoxamine, and involving phospholipase C and/or D.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (HL-55314 and HL-35909).
Received October 5, 2000; first decision November 28, 2000; accepted February 21, 2001.
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