Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats.

INTRODUCTION: Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats. METHODS: An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured. RESULTS: Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats. CONCLUSIONS: The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

Interaction of morphine with a new alpha2-adrenoceptor agonist in mice.

UNLABELLED: Finding new chemicals or adjuvants with analgesic effects in the central nervous system is clinically relevant due to the limited number of drugs with these properties. Here, we present PT-31, which is chemically related to 3-benzyl-imidazolidine, with an analgesic profile that results from alpha(2)-adrenoceptor activation. Intraperitoneal administration of PT-31 dose-dependently produced antinociception in the hot plate test, and interacted synergistically with morphine. This effect was completely reversed by yohimbine, a non-selective antagonist of alpha(2)-adrenoceptors, and by BRL 44408, a selective alpha(2A)-adrenoceptor antagonist. The combination of morphine and PT-31 produced greater antinociceptive activity than either alone, and isobolographic analysis revealed a synergistic interaction between these compounds. Docking results confirm the high affinity of the PT-31 ligand at the alpha(2A)-adrenoceptor. PERSPECTIVE: This study introduces a new analgesic compound (PT-31) that acts via alpha(2A)-adrenoceptor activation. A significant increase in analgesia was observed when co-administered with morphine. PT-31 is an interesting new substance for pain therapy.

Dexmedetomidine prolongs spinal anaesthesia induced by levobupivacaine 0.5% in guinea-pigs.

Alpha-2 adrenoceptor agonists have been used in association with local anaesthetic to increase the duration of spinal anaesthesia. Intrathecal administration of clonidine prolonged motor blockade induced by local anaesthetic. Since the affinity of dexmedetomidine (DEX) to alpha-2 adrenoceptors is eight-times greater than clonidine, it is expected that DEX could be advantageous in clinical anaesthesia. We investigated the duration of motor nerve block induced by spinal injection of 0.5% levobupivacaine (LVB) associated with intrathecal or intraperitoneal administration of DEX. Seventy-two guinea-pigs were randomly divided in 12 groups, which were all treated with intrathecal injection of 50 microL of LVB. DEX was injected intrathecally with LVB in 6 groups or injected intraperitoneally after LVB in another 6 groups. Intrathecal DEX (0.1, 0.2 and 0.4 microg) increased the LVB-induced motor anaesthesia from 48 (41-66) min to 84.5 (52-91) min (P < 0.05), 101.5 (83-115) min (P < 0.05) and 105 (97-114) min (P < 0.05), respectively. Similarly, intraperitoneal DEX (20 and 40 microg kg(-1)) increased the motor blockade from 48.5 (33-59) min to 88 (71-114) min (P < 0.05) and 114.5 (103-156) min (P < 0.05), respectively. Pre-treatment with yohimbine reduced the duration of motor block from 101.5 (83-115) to 76.5 (68-86) min (P < 0.05) or from 114.5 (103-156) to 90 (83-93) min (P < 0.05) when DEX was administered by the intrathecal or intraperitoneal routes. Motor block induced by spinal injection of LVB was prolonged by intrathecal and systemic administration of DEX, which was partially dependent on activation of alpha-2 adrenoceptors.