Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists

Abstract

Background and purpose: Partial agonists of the nociceptin opioid peptide (NOP) receptor have potential therapeutic use as antihypertensive and water diuretics (aquaretics). To date, peptide NOP receptor ligands have failed to progress in clinical trials due to poor pharmacokinetics and adverse effects. Nonpeptide, small-molecule NOP receptor ligands may be more suitable as therapeutic agents. This study investigated the cardiovascular and renal responses produced by the novel nonpeptide NOP agonists AT-403, AT-090, AT-127, and AT-039.

Experimental approach: Changes in mean arterial pressure (MAP), heart rate (HR), renal excretory function and occurrence of sedation and hyperphagia were determined before and after i.v. bolus injection or infusion of the NOP agonists in conscious Sprague-Dawley rats. Additional studies involving (i) measurement of renal sympathetic nerve activity (RSNA) and (ii) renal denervation were conducted to investigate the role of the renal nerves in the cardiorenal responses to AT-039.

Key results: Bolus i.v. injection of AT-403, AT-090, AT-127 and AT-039 produced significant decreases in MAP and HR and a sodium-sparing diuresis. AT-403, AT-090, and AT-127, but not AT-039, induced sedation and hyperphagia at all doses tested. Infusion i.v. of AT-039 produced hypotension and aquaresis without adverse central nervous system effects or change in HR, responses that were also observed in renal denervated rats.

Conclusions and implications: Nonpeptide NOP agonists decrease blood pressure and produce aquaresis in conscious rodents. Due to lack of sedation and hyperphagia, AT-039 represents a novel NOP agonist that may be useful for treatment of hypertension and/or volume overload/hyponatraemic states.

Figure 1:. Chemical structure of non-peptide NOP selective ligands

Figure 2:. Cardiovascular and renal responses produced by 100 nmol kg⁻¹ i.v. bolus administration of AT-403, AT-090, AT-127, AT-039, or vehicle.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), mean arterial pressure (MAP), urine flow rate (V), urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbols *, †, ‡, § denote a significant change (p<0.05) from respective baseline control (C) values within each group.

Figure 3:. Cardiovascular and renal responses produced by 30 nmol kg⁻¹ i.v. bolus administration of AT-090, AT-403, or vehicle.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), mean arterial pressure (MAP), urine flow rate, urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbols *, †, ‡, § denote a significant change (p<0.05) from respective baseline control (C) values within each group.

Figure 4:. Cardiovascular and renal responses produced by 300 nmol kg⁻¹ i.v. bolus administration of AT-127, AT-039, or vehicle.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), mean arterial pressure (MAP), urine flow rate, urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbols *, †, ‡, § denote a significant change (p<0.05) from respective baseline control (C) values within each group.

Figure 5:. Cardiovascular and renal responses produced by 1, 3, 10 nmol kg⁻¹min⁻¹ i.v. infusion administration of AT-039 or vehicle.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), mean arterial pressure (MAP), urine flow rate, urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbols *, †, ‡ denote a significant change (p<0.05) from respective baseline control (C) values within each group.

Figure 6:. Cardiovascular and renal responses produced by 10 nmol kg⁻¹min⁻¹ i.v. infusion administration of AT-039, or vehicle in surgically denervated rats.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), mean arterial pressure (MAP), urine flow rate, urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbol *, denotes a significant change (p<0.05) from respective baseline control (C) values within each group.

Figure 7:. Cardiovascular, renal, and renal sympathetic nerve activity responses produced by 10 nmol kg⁻¹min⁻¹ i.v. infusion administration of AT-039 or vehicle.

The values are means ± S.E. and illustrate the effects of AT compounds on heart rate (HR), renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), urine flow rate, urinary sodium excretion (UNaV), and urinary potassium excretion (UKV). Statistical significance within each group was determined by two-way analysis of variance with Dunnett’s multiple comparisons test. Symbol *, denotes a significant change (p<0.05) from respective baseline control (C) values within each group.