Identification of adrenoceptors and dopamine receptors mediating vascular responses in the superior mesenteric arterial bed of the rat

1 The effect of local administration of the dopamine2 (DA2)-receptor agonist quinpirole and of the DA,-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat.2 Local infusion of quinpirole (30 pg kg-'min-' for 5min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 ± 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline.3 The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 pg kg-') but not by the selective DA,-receptor antagonist SCH 23390 (50 pg kg-'). 4 Local infusion of fenoldopam (30 pg kg-' min-' for 5 min) reduced baseline perfusion pressure to 89.9 ± 1.9%, increased the pressor response to electrical stimulation (4Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 ± 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 ± 8.2%. Similar pressor responses induced by the selective a,-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 ± 6.4%), but responses to locally administered angiotensin II were not modified.5 Pretreatment with SCH 23390 (50 pg kg-') antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline.6 Pretreatment with the selective az-adrenoceptor antagonist rauwolscine (100 pg kg-') had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation.7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2-receptors while fenoldopam stimulates postsynaptic vasodilatory DA,-receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic a,-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic oi2-adrenoceptors.

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed

Dupont

Lefebvre

Vanderniepen

1987

“…Of the range of vascular beds thus studied, uncertainty still exists about the precise nature of the receptors mediating vasoconstriction of the rat superior mesenteric arterial bed. Considerable evidence from studies of the isolated vasculature suggests that the vasoconstriction seen here is mediated entirely by means of al-adrenoceptors (Eikenburg, 1984;Yamamoto et al, 1984;Hogestatt & Andersson, 1984;Agrawal & Daniel, 1985: Nichols & Hiley, 1985. Despite this, there is evidence for a mixed population of pharmacologically functional a,-and a2-adrenoceptors in this tissue; decreases in cardiac output distribution to this bed occur after administration ofeither methoxamine (an a1-adrenoceptor agonist) or UK 14,304 (an M2-adrenoceptor agonist) to the pithed rat (Hicks & Waldron, 1983;Waldron & Hicks, 1985).…”

Section: Introductionmentioning

confidence: 93%

Effects of α‐adrenoceptor agonists on cardiac output and its regional distribution in the pithed rat

Thomas

1987

ICardiac output, its distribution and tissue blood flows were determined with tracer microspheres in pithed rats during pressor responses elicited by either x,-adrenoceptor agonists (tirazoline, phenylephrine) or a2-adrenoceptor agonists (xylaxine, B-HT 933). Two doses were used for each of cirazoline and B-HT 933 and phenylephrine was investigated in the presence of propranolol (3 mg kg-'). The rats were pithed under halothane anaesthesia. 2 Cardiac output was increased by xylazine, the higher dose of B-HT 933 and phenylephrine. Heart rate was increased by phenylephrine and the higher doses of both cirazoline and B-HT 933. Stroke volume was greater in those groups given xylazine, phenylephrine and the higher dose of B-HT 933 but was decreased in those animals given the higher dose of cirazoline. 3 Both M2-adrenoceptor agonists increased the number of microspheres trapped in the lungs and the proportion ofthe cardiac output passing through the hepatic artery but decreased that flowing through the spleen and gastrointestinal tract. The higher dose of B-HT 933 also decreased the fraction of cardiac output fiowing to the kidneys but kidney blood flow was maintained as a result of the increased cardiac output. Also, this treatment reduced blood flow in the epididimal fat pads. 4 Both a,-adrenoceptor agonists increased the fraction of cardiac output received by the coronary vasculature but the only other effect on distribution common to these agents was an increase in the percentage of the cardiac output passing to the hepatic artery. Cirazoline decreased the proportion of cardiac output distributed to the gastrointestinal tract and spleen but the total fraction of cardiac output passing to the hepatosplanchnic region was maintained as a result of the increase to the hepatic artery.5 Cirazoline markedly reduced the proportion of the cardiac output received by the kidneys and absolute flow in these organs was only 1.4% of control after the higher dose of this agonist but flow at the lower dose was maintained by the higher cardiac output. 6 It is concluded that there is a significant contribution to the pressor responses elicited by x-agonists resulting from an oc-adrenoceptor-mediated increase in cardiac output that may result from greater heart rates or stroke volumes. Also, there is a differential distribution of cx-receptor subtypes throughout the vasculature which is especially noticeable in the kidneys.

“…The responses were stable for up to 2 h in vivo and 5 h in vitro and have previously been shown to be mediated by al-adrenoceptors since they can be blocked with selective doses of prazosin (lOgg kg-') (Nichols & Hiley, 1985;Nichols, 1985).…”

Section: Resultsmentioning

confidence: 86%

“…; Sagatal, May & Baker). The animals were prepared for the in situ blood perfusion of the superior mesenteric arterial bed as described previously by Nichols & Hiley (1985). Briefly, the trachea was cannulated as were the jugular vein, for the administration of drugs and saline, and the right carotid artery, for measurement of systemic arterial blood pressure (Bell & Howell pressure transducer Type 4-422-0001) and heart rate (Grass 7P44 tachograph using the pressure trace as the trigger).…”

Section: In Vivo Preparationsmentioning

confidence: 99%

Interactions between noradrenaline and α₂‐adrenoceptor agonists in the superior mesenteric arterial bed of the rat

Thomas

1986

Interactions between α2‐agonists and noradrenaline vasoconstrictor responses were studied in the superior mesenteric arterial bed of the rat by use of perfusion both in situ with blood and in vitro with Krebs‐Henseleit solution. Xylazine (1.9 × 10−6 mol) administered into the perfusion circuit reduced the maxium response to noradrenaline in the in situ preparation by 35% and decreased the pD50 for noradrenaline from 8.5 ±0.01 to 7.9 ±0.13 (n = 7). Yohimbine (1 mg kg−1, i.v.) gave a small parallel shift in the noradrenaline log dose‐response curve and prevented the reduction in the maximum response by subsequent administration of xylazine. In vitro, xylazine (1.9 × 10−6 mol) also gave a long‐lasting reduction of 37% in the maximum response but did not affect the mid‐point sensitivity to noradrenaline. Yohimbine (10−6 M) did not change either of these effects. Clonidine (1.9 × 10−6 mol) did not affect the maximum response to noradrenaline in vitro but did reduce the pD50 from 7.72 ± 0.17 to 6.9 ± 0.17 (n = 6). Yohimbine did not change these effects. Guanfacine (1.8 × 10−6 mol) had no effect on the sensitivity of the in vitro preparation to noradrenaline but did reduce the maximum response by 20%. Yohimbine (10−6 M) prevented the depression of the maximum response. It is concluded xylazine and clonidine interfere with noradrenaline induced vasoconstriction only to a limited extent through their interaction with α2‐adrenoceptors and that some other, as yet uncharacterised mechanism which may be activated by their aryl amidine structure, is responsible for their in vitro effects.