Cardiovascular Characterization of DA-1 and DA-2 Dopamine Receptor Agonists in Anesthetized Rats

Abstract

This report summarizes studies aimed to characterize pharmacologically, hemodynamically and biochemically DA-1 (fenoldopam) and DA-2 (quinpirole) dopamine receptor agonists in anesthetized rats. Fenoldopam (20 micrograms/kg/min i.v. over 15 min) and quinpirole (10 micrograms/kg/min i.v. over 15 min) share the common property of decreasing mean carotid artery blood pressure by lowering peripheral vascular resistance. Fenoldopam increased mesenteric and renal blood flows whereas quinpirole decreased the former blood flow, but enhanced the latter. These effects of quinpirole were antagonized selectively by S-sulpiride, but not SCH 23390; however, with fenoldopam the reverse was found. In chlorisondamine-pretreated rats with blood pressure supported by vasopressin, fenoldopam, but not quinpirole, caused hypotension. In nephrectomized rats, the blood pressure effects of fenoldopam (assessed as area under the infusion time-response curve) were more pronounced than in sham-operated controls. The hypotensive effects due to an i.v. bolus injection of fenoldopam, but not to acetylcholine, histamine, salbutamol or quinpirole, were significantly inhibited in rats pretreated with an infusion of fenoldopam. In pithed rats, quinpirole reduced the pressor responses to electrical stimulation of the spinal cord without affecting those to exogenous norepinephrine, angiotensin II or 5-hydroxytryptamine which, on the contrary, were inhibited by fenoldopam. The plasma renin activity (in intact rats) was reduced by quinpirole, but elevated by fenoldopam. The latter effect also occurred in pithed rats and was blocked by SCH 23390. Quinpirole lowered heart rate, whilst fenoldopam produced tachycardia. These effects of quinpirole and fenoldopam were significantly inhibited by S-sulpiride and SCH 23390, respectively. In chlorisondamine-pretreated rats quinpirole failed to change heart rate whereas fenoldopam still increased it. In conclusion, these results indicate that DA-1 and DA-2 dopamine receptor agonists can be easily discriminated on the basis of their cardiovascular profiles.

Blockade of Spinal Dopamine D2 Receptors Enhances the Pressor Effect of Intravenous Quinpirole in Normotensive, Conscious Rats

“…Blockade of peripheral dopamine D 2 receptors by intravenous domperidone enhances the maximal pressor response to quinpirole, as previously reported in normotensive, conscious rats (Nagahama et al 1986a(Nagahama et al & 1987. This agrees with previous reports that the peripheral dopamine D 2 receptor-mediated depressor effect, which is manifested in anaesthetized rats (Nagahama et al 1986b;Cavero et al 1987;Lahlou 1998), is masked by the central pressor effect of quinpirole in conscious rats (Nagahama et al 1986a).…”

“…The site of action of quinpirole in the brain has been suggested to be the nucleus tractus solitarius (Yang et al 1990). In anaesthetized rats, quinpirole decreased blood pressure, an effect that is mediated partly by peripheral (Nagahama et al 1986b;Sengupta & Lokhandwala 1985;Lefevre-Borg et al 1987;Cavero et al 1987;Lahlou 1998) and partly by spinal dopamine D 2 receptor stimulation (Lahlou 1998). In conscious rats, the central influence of quinpirole predominates and masks the peripheral depressor effect.…”

Lack of effect of lithium on the renal response to DA1‐dopamine receptor stimulation by fenoldopam in normal man [see comments]

“…However, no significant changes occurred in this study with seven volunteers. In the study of Jeffrey et al (1988) Cavero et al (1987) demonstrated a rise of PRA by direct DA1 stimulation. The extent of increase in PRA during fenoldopam infusion was influenced by the presence of lithium and suggests that lithium enhances the effects of DA1-dopamine stimulation.…”

Facile One Pot Microwave Induced Solvent-Free Synthesis and Antifungal, Antitubercular Screening of Spiro [1,5]-Benzothiazepin-2,3'[3'H]indol-2[1'H]-ones

“…to the mankind and those in which the fused benzene ring is substituted at various positions have been found to be more potent.1) The research on the chemistry of indoles has continued unabated due to their wide spread occurrence in nature and biological activities [2][3][4] and the compounds in which the bio-active indole nucleus is spiro fused with another heterocycle at the C-3 position shows immense pharmaceutical applications.5-7) Further, spiro-3-indole derivatives, incorporating five and six membered heterocycles have been extensively reviewed [8][9][10][11][12] but few reports are available regarding those incorporating a seven membered thiazepine moiety. Also, 3-aroyl-2H-indol-2-ones (4a, b) have been found as the essential synthetic building block [13][14][15] for the synthesis of a wide variety of 3-spiro indolines and condensed indole derivatives.…”