Vascular smooth muscle cells of human IMA, IMV, and PCA contain both ETA and ETB receptors, whereas the endothelium of IMA and PCA does not express functional ETB receptors linked to nitric oxide and/or prostacyclin production. Hence, inhibition of endothelin-induced contraction in patients requires the use of combined ETA/ETB antagonists.

T he hallmark of hypertension is an increase in peripheral vascular resistance. 1 This increase is considered to be related to an increase in tone of resistance arteries as well as to structural changes (i.e., vascular remodeling) of these blood vessels. Accordingly, hypertension research has focused on identifying the mediator or mediators responsible for this phenomenon. Although several possible candidates have been extensively studied, in particular the renin-angiotensin system and catecholamines, no definite answer has been found. Hence, the search for additional mediators or the mediator causing the increase in peripheral vascular resistance in hypertension continues.In addition to the increase in peripheral vascular resistance, hypertension is associated with cardiovascular complications such as myocardial infarction and stroke. In both syndromes, severe ischemia to these vital organs is responsible for the clinical syndrome. Again, structural and functional alterations of the supplying circulation are held responsible. In contrast to the increase in peripheral vascular resistance, however, these changes are primarily seen in certain (i.e., coronary and cerebral) vascular beds rather than in the entire circulation.The question of whether endothelin is involved in hypertension, its complications, or both cannot be solved at this point; however, several aspects can be addressed. Can Endothelin Induce Hypertension?When infused intravenously, endothelin causes a rapid and transient vasodilation followed by a profound and long-lasting increase in blood pressure.2 " 4 This increase in blood pressure is dose dependent, occurs at much lower concentrations than with any other vasoconstrictor hormone, and also is remarkably long-lasting. In vitro experiments have demonstrated that this increase in blood pressure is related to profound vasoconstriction of resistance arteries of different vascular beds of the circulation. -6 Although the vasodilator effects of endothelin are related to activation of endothelin B-receptors 7 -8 linked to the formation of prosta-

We characterized vascular endothelin receptors of the renal artery from adult (12 to 16 weeks of age) and old (72 to 76 weeks) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Vessels were suspended in organ chambers (37 degrees C, aerated with 95% O2/5% CO2), and isometric tension was recorded. The endothelin-A (ETA) receptor antagonist FR139317, the combined ETA/ETB receptor antagonist bosentan, and the ETB-selective agonist sarafotoxin S6c were used. In old (and less so in adult) SHR, cumulative concentration-contraction curves to endothelin-1 showed a small contraction resistant to FR139317 (10(-5) mol/L) at 3 x 10(-9) to 10(-8) mol/L endothelin-1, which was completely inhibited by bosentan (10(-5) mol/L). This FR139317-resistant contraction to endothelin-1 was not present in WKY. Furthermore, in the presence of FR139317 (10(-5) mol/L), sarafotoxin S6c induced a stronger contraction in old SHR than in WKY (P < .05). In rings contracted with norepinephrine, sarafotoxin S6c caused endothelium-dependent relaxations in both strains; these relaxations were blocked by N omega-nitro-L-arginine methyl ester, indicating that nitric oxide is the mediator. In WKY but not SHR, release of nitric oxide by sarafotoxin S6c increased with age (P < .05). Thus, both ETA and ETB receptors mediate contraction to endothelin-1 in the renal artery from SHR but not WKY. ETB receptors on vascular smooth muscle seem to be unmasked with age in SHR, whereas those on endothelium (mediating nitric oxide release) exhibit more efficient responses with age in WKY.

The favorable effects of estrogen on cardiovascular diseases can be explained by several mechanisms such as changes in serum lipid profiles and thrombogenecity. Estrogen also affects the vascular tone, but there has been no report in which the effect of estrogen was tested comprehensively for several vasoactive substances, especially after long-term administration. Two weeks after bilateral ovariectomy in 8-week old female Sprague-Dawley rats, placebo or 17 beta-estradiol (E2) pellets (0.5 mg; released over 3 weeks) were implanted subcutaneously. Two weeks after pellet implantation, organ chamber experiments were performed using aortae. Compared with control, E2-treated vessels showed impaired endothelium-dependent relaxation to acetylcholine. E2 enhanced the contraction to norepinephrine and U46619 and had no effect on endothelin-1-induced contraction. In contrast, the contraction to angiotensin (AT)-II was inhibited by E2. Northern blot analysis for AT1 receptor expression using cultured aortic smooth muscle cells showed no difference between control and E2-treated cells, suggesting that AT1 receptor downregulation is not the likely mechanism. These results suggest that E2 affects the vascular tone variably according to vasoactive substances.

Background Although postmenopausal estrogen replacement therapy is known to reduce cardiovascular mortality, the mechanism is not clear yet. Furthermore, the effect of estrogen on vascular tonus is reportedly variable according to the animal models, vascular beds and agonists used. Materials and Method Bilateral ovariectomies were performed in 12 week-old, 18 spontaneously hypertensive rats SHR and 18 normotensive Wistar-Kyoto rats WKY . Rats were divided into three groups according to the dose of 17 -estradiol E 2 pellets implanted subcutaneously two weeks after ovariectomy control no implantation , lowdose 0.5 mg and high-dose 5 mg E 2 replacement group. Two weeks after pellet implantation, organ bath experiments were performed using descending thoracic aortae. For endothelium-dependent relaxation, acetylcholine 10 9 3 10 6 M was cumulatively added into the vessels precontracted with 10 7 M norepinephrine NE . For vasoconstrictor responses, cumulative concentration-contraction curves were constructed in quiescent vessels using NE 10 9 10 5 M , U46619 10 9 3 10 6 M , endothelin-1 10 10 10 7 M . In addition, contraction to angiotensin 10 7 M was also obtained. Serum 17 -estradiol levels were measured by radioimmunoassay. Blood pressure was measured by tail-cuff method in some SHRs before ovariectomy and after placebo/E 2 replacement. Results Endothelium-dependent relaxation to acetylcholine was impaired in WKY treated with 5 mg E 2 pIC 50 control vs 5 mg E 2 7.75 0.13 vs 7.27 0.16 n 6 p 0.05 . No significant effect was noted in SHR. Contraction to angiotensin was inhibited by low-dose E 2 in WKY and high-dose E 2 in SHR % of the contraction to 60 mM KCl WKY control vs 0.5 mg E 2 39 5 vs 25 2 SHR control vs 5 mg E 2 34 4 vs 22 2 n 6 and p 0.05 in WKY and SHR . In contrast, NEinduced contraction was enhanced by E 2 replacement both low-and high-dose in WKY and SHR WKY control vs 0.5 mg E 2 vs 5 mg E 2 AUC 280 24 vs 387 26 vs 374 25 maximal contraction 137 8 vs 166 8 vs 162 3 pD 2 7.63 0.11 vs 8.17 0.13 vs 8.13 0.13 SHR control vs 0.5 mg E 2 vs 5 mg E 2 AUC 265 17 vs 349 16 vs 406 19 maximal contraction 152 6 vs 181 9 vs 203 16 pD 2 7.45 0.13 vs 7.91 0.08 vs 8.04 0.04 n 6 and p 0.05 between control and treated groups in WKY and SHR for all parameters . Contraction to U46619 was enhanced by E 2 replacement in SHR control vs 0.5 mg E 2