Pharmacogenomic Strain Differences in Cardiovascular Sensitivity to Propofol

Abstract

Introduction A pharmacogenomic approach was used to further localize the genetic region responsible for previously observed enhanced cardiovascular sensitivity to propofol in Dahl Salt Sensitive (SS) vs. control Brown Norway (BN) rats. Methods Propofol infusion levels that decreased blood pressure by 50% were measured in BN.13SS rats (substitution of SS chromosome 13 into BN) and in 5 congenic (partial substitution) strains of SS.13BN. The effect of superfused 2,6 diisopropylphenol on small mesenteric arterial vascular smooth muscle transmembrane potential was measured in congenic strains before and during superfusion with Rp-cAMPS and Rp-8-pCPT-cGMPS, inhibitors of protein kinase A and G respectively. The genetic locus and potential role of the renin gene in mediating VSM sensitivity to propofol were determined in three selected sub-congenic SS.BN13 strains. Results A 30 – 32% smaller propofol infusion rate reduced blood pressure by 50% in BN.13SS compared to BN and the SS.13BN congenic containing a 80 BN gene substitution. Compared to the latter, SS exhibited greater protein kinase A dependent vascular smooth muscle hyperpolarization in response to propofol. Using sub-congenics, the increased propofol-induced cardiovascular sensitivity and hyperpolarization was further localized to an 8-gene region (containing the BN renin gene). Blockade of angiotensin (AT1) receptors with losartan in this sub-congenic, elevated propofol-induced hyperpolarization by 3 fold, to that observed in SS. Conclusions Enhanced cardiovascular sensitivity to propofol in SS (compared to BN) is caused by an altered renin gene. Through modified second messenger function, this differentially regulates VSM contractile state and reduces vascular tone exacerbating cardiovascular depression by propofol.

Propofol attenuates inflammatory damage on neurons following cerebral infarction by inhibiting excessive activation of microglia

“…Finally, the rats in the experimental group were treated with propofol (100 mg/kg; Sigma-Aldrich; Merck KGaA), while the rats without any surgery in the sham group and rats subjected to tMCAO in control group were only treated with saline (100 mg/kg; Sigma-Aldrich; Merck KGaA) (25,26). A total of 10 animals were used for each group.…”

Reduced neural activity during volatile anesthesia compared to TIVA: evidence from a novel EEG signal processing analysis

“…Patients in the TIVA group received 2-4 ng/mL remifentanil (46) and 2-4 µg/mL propofol (46, 47) for maintenance. The titration of both drugs was done according to TCI regulations, and the exact concentrations were affected by physiological parameters (clinical assessment) and BIS (47)(48)(49)(50)(51). For those drugs' administration, we used the B Braun Perfusor Space Target Controlled Infusion Pump (B Braun Medical Ltd., UK).…”

“…Nevertheless, the cardio-depressive effects of propofol can be controlled by careful titration and with drug interaction with short-acting opiates such as remifentanil. In general, low-dose opiates induce minimal cardiovascular effects, and their main use is to induce analgesia (together with anesthetic drugs) to improve anesthesia (21). Therefore, different brain activity under TIVA, compared to volatile anesthesia, should not stem from cardiovascular effects, due to signi cant cerebral perfusion autoregulation.…”

Rapid Enkephalin Delivery Using Exosomes to Promote Neurons Recovery in Ischemic Stroke by Inhibiting Neuronal p53/Caspase-3

“…Animals were housed at 22-25°C with a humidity of 65±5%, 0.03% CO2, and 12 h light/dark cycle, with free access to water and food. A transient middle cerebral artery occlusion (tMCAO) model was established in rats as previously described [ 20 – 22 ]. In brief, the common, internal, and external carotid arteries were exposed by blunt dissection after 2.5% sodium pentobarbital injection (36 mg/kg; Sigma-Aldrich; Merck KGaA) into the rats' abdominal cavity.…”