s6c-sarafotoxin and Hypercholesterolemia

Vasoconstriction in response to endothelin-1 has been shown to be primarily related to its effects on the endothelin-A receptor. Experimental hypercholesterolemia is associated with an increase in coronary vasoconstrictor response to endothelin-1 in vivo, although the relative contributions of subtypes of endothelin receptor in this model remain unknown.. To test the hypothesis that there is an increase in coronary vasoconstriction in response to stimulation of endothelin-B receptor in hypercholesterolemia, which might be related to attenuation of activity of endothelin-derived relaxing factor.. We infused 5 ng/kg/min sarafotoxin, a specific endothelin-B receptor agonist, or 50 micrograms/kg/min NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase, into the left anterior descending coronary arteries of pigs before and after feeding them a cholesterol-rich diet for 10 weeks.. There was a significant increase in serum level of cholesterol. After 10 weeks, infusion of sarafotoxin resulted in an accentuated decrease in coronary blood flow (CBF) compared with baseline (decreases by 60 +/- 7 versus 34 +/- 6%, P < 0.05). There was no significant difference between the effects on diameter of coronary arteries for the two time periods. The effect of L-NMMA on CBF was attenuated after 10 weeks (by 5 +/- 10.1 versus 45.6 +/- 4.7%, P < 0.05). Endothelin-receptor status of epicardial coronary arteries remained unchanged. Sarafotoxin and L-NMMA were co-infused at the above-mentioned doses into normolipidemic animals; the decrease in CBF in response to this co-infusion was comparable to the decrease observed with sarafotoxin alone in hypercholesterolemic animals (decreases of 67 +/- 5 versus 60 +/- 7, NS).. The present results demonstrate that selective stimulation of the endothelin-B receptor increases coronary vasoconstriction in experimental hypercholesterolemia, primarily at the level of the microvasculature. These findings may be related to the attenuation of activity of endothelin-derived relaxing factor in this model, and support the hypothesis that endothelin-B receptor plays a role in the regulation of coronary vascular tone in pathophysiologic states.

Topics: Animals; Coronary Vessels; Female; Hypercholesterolemia; Nitric Oxide; omega-N-Methylarginine; Receptor, Endothelin B; Receptors, Endothelin; Swine; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia. We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, n=5; 5 ng x kg[-1] x min[-1]) and acetylcholine (group III, n=7; 10[-6] to 10[-4] mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 microg x kg[-1] x min[-1]; group II, n=6; group IV, n=6). Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg x kg[-1] x h[-1], group V, n=5). The ETB-receptor agonist sarafotoxin 6c (5 ng x kg[-1] x min[-1]; n=4) was also infused. The percentage change in coronary artery diameter (%deltaCAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %deltaCAD at baseline and 10 weeks (-10+/-2% and -12+/-3%, respectively). FR-139317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%deltaCAD -18+/-8% for group I versus -12+/-6% for group II; P=NS) but did at 10 weeks (%deltaCAD -77+/-14% for group I versus -14+/-6% for group II; P<.05). FR-139317 did not affect the response to acetylcholine at baseline (%deltaCAD 5+/-2% for group III versus 7+/-3% for group IV, P=NS) or at 10 weeks (%deltaCAD -23+/-12% for group III versus -19+/-7% for group IV; P=NS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. Short-term ET-receptor inhibition in experimental hypercholesterolemia attenuated the enhanced coronary epicardial vasoconstrictor effects of ET-1 but not acetylcholine-induced coronary epicardial vasoconstriction, suggesting that acetylcholine-induced coronary epicardial vasoconstriction may not be mediated by ET receptors.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Azepines; Blood Pressure; Bosentan; Cholesterol; Coronary Vessels; Diet, Atherogenic; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypercholesterolemia; Indoles; Receptors, Endothelin; Sulfonamides; Swine; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (< 481 +/- 25 microns in diameter) to cumulative concentrations (10(-10) to 10(-6) mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86 +/- 7% versus 47 +/- 7%, P = .001) and hypercholesterolemic (77 +/- 6% versus 37 +/- 7%, P < .001) pigs. At 10(-10) mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23 +/- 6% versus 8 +/- 3%, P = .02) and S6c (17 +/- 5% versus 4 +/- 2%, P = .02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR-139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10(-10) mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Azepines; Cholesterol, Dietary; Coronary Vessels; Diet, Atherogenic; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Hypercholesterolemia; Indoles; Lipids; Oligopeptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Swine; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms