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The endothelin ETB receptor (ETBR) agonist sarafotoxin 6c (S6c) causes sustained hypertension in rats. Because S6c produces natriuresis and relaxation of most arteries, but constricts most veins, we've proposed that S6c-induced hypertension is due to venoconstriction. However, S6c also activates ETBRs in sympathetic ganglia to increase superoxide formation. This could increase sympathetic activity and blood pressure. The "rescued" ETBR-deficient rat expresses functional ETBRs in sympathetic neurons, but not in blood vessels or renal tubules. Therefore, they were used to test where S6c acts to cause hypertension. Female ETBR-deficient (-/-) and wild type (+/+) rats were instrumented with a radiotelemetry transmitter. After 3 control days, rats were given tempol (an antioxidant, 1 mmol/L in drinking water) for 3 days. S6c was then infused continuously (30 pmol/kg/min, sc) for 7 days. After 5 days of S6c-infusion, tempol was removed. Following S6c infusion, rats were allowed a 4-day recovery. Mean arterial pressure (MAP) was significantly higher in -/- than in +/+ rats (132 ± 3 vs 101 ± 3 mmHg) during the control period. $6c infusion increased MAP by 37 ± 2 mmHg in +/+ rats but only 7 ± 2 mmHg in -/-. Tempol had no effect on resting MAP or the response to S6c. The data indicate that S6c-induced hypertension is not sympathetically mediated and support an important contribution by ETBR on venous smooth muscle. (NIH P01HL70687) [ABSTRACT FROM AUTHOR]

Cardiac sympathetic innervation originates in the stellate ganglia. Norepinephrine (NE) reuptake via NE transporter (NET), and release of NE from sympathetic nerve terminals are regulated by the endothelin-I (ET1) receptors, ETA and ETB, respectively. Regulation of NET by ET1 in the stellate ganglia is unknown. ETB receptor deficient rats (ETB -/-) lack functional ETB receptors in all tissues except those expressing dopamine beta hyrdoxylase (DBH). Since functional ETB expression is coupled to DBH promoter (DBH-ETB) in this model, it is possible that sympathetic neurons overexpress ETB. The purpose of this study was to examine ETB and NET in the stellate ganglia of ETB -/- rats using histology and PCR. Histology revealed that there was a significant elevation of ETB receptor protein in both the nuclear (n=4, p<0.0001) and cytoplasmic compartments (n=4, p<0.0001) in bilateral stellate ganglia from ETB -/- rats. In all stellate ganglion neurons from ETB -/- rats, NET protein was significantly increased (n=3, p<0.05), while NET mRNA was unchanged (n=3-6, p>0.05), suggesting that ET1 modulation of NET is post-transcriptional. In summary, the ETB -/- rat overexpresses ETB and NET protein in the stellate ganglia revealing an important feature of this animal model that is otherwise devoid of functional ETB receptors. This supports the notion that altered ET1 signaling can regulate NET in ganglia. [ABSTRACT FROM AUTHOR]

ET-1 is more potent in contracting veins than arteries. We hypothesized that ET-1 contracts veins, but not arteries, by acting at ETA (ETAR) and ETB receptors (ETBR). Using ETBR deficient (-/-), +/+ and +/- rats, we studied ET-1 constrictions of mesenteric arteries and veins (150-300 µm) in vitro. Veins were more sensitive than arteries to ET-1 in +/- and +/+ rats, but not in -/- rats. The ETBR agonist, S6c, constricted veins, but not arteries, from +/+ and +/- rats. S6c did not constrict -/- veins. An ETAR antagonist, (ABT627), but not BQ-788 (ETBR antagonist) blocked arterial ET-1 responses. ABT627 reduced ET-1 responses in +/+ and +/- veins and blocked responses in -/- veins. BQ-788 did not affect ET-1 responses in any vein. Antagonist co-application blocked ET-1 responses in +/+ and +/- veins suggesting an ETAR and ETBR interaction. ET-1 responses desensitized in all arteries and in -/- veins. Veins from +/+ and +/- rats were resistant to desensitization. Immunocytochemistry revealed that ETAR localized to the membrane of arterial and venous smooth muscle cells (VSMCs), while ETBRs were intracellular in arteries. ETBRs localized to the membrane of +/+ and +/- VSMCs. In -/- VSMCs, ETARs, but not ETBRs, were in the membrane. We conclude that membrane expression of ETBR in VSMCs accounts for: 1) increased sensitivity of veins to ET-1 compared to arteries; 2) venous resistance to ET-1 desensitization. [ABSTRACT FROM AUTHOR]

We previously observed functional ETA and ETB receptor cross-talk in rat vena cava. We hypothesized that ETA and ETB receptor interaction would not occur in vena cava from ETB receptor deficient rats (sl/sl) compared to their wild-type counterparts (+/+). We compared isometric contraction to ET-1 during ETA receptor blockade, ETB receptor blockade and ETAETB receptor blockade in rings of thoracic aorta and vena cava from +/+ and sl/sl rats. Vena cava from sl/sl rats did not contract to the ETB receptor agonist sarafotoxin 6c (S6c, 100 nM), while vena cava from +/+ rats contracted to S6c [73±10 % norepinephrine (10 µM) contraction]. In vena cava from sl/sl rats, ETB receptor blockade did not alter ETA receptor sensitivity to receptor blockade, while in vena cava from +/+ rats, ETB receptor blockade increased ETA receptor sensitivity to receptor blockade (Table 1). Our data demonstrate that vena cava from sl/sl rats express dysfunctional ETB receptors that do not functionally interact with ETA receptors, similar to aortic ETB receptors. These results suggest that a contractile ETB receptor is key to functional ETA and ETB receptor interaction. [ABSTRACT FROM AUTHOR]