Magister Scientiae (Medical Bioscience) - MSc(MBS) / Conclusion of this study: These data suggest that 6 weeks of high-fat feeding induces hypertension but does not produce obesity, dyslipidemia and insulin resistance. However, this model may be useful in studying vascular reactivity in hypertension in the absence of insulin resistance. / South Africa

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Background: It is well known that some genetic factors and dietary factors, such as excessive salt intake and excessive caloric intake (resulting in obesity) are risk factors for hypertension. Fifty percent of all hypertensive patients are also insulin resistant. Both hypertension and insulin resistance are again risk factors for other cardiovascular diseases such as atherosclerosis and heart failure. The nature of the association between hypertension and insulin resistance has not been clearly elucidated. Spontaneously hypertensive rats are the ideal models to study the aspects of the relationships between hypertension and insulin resistance. Models of high-fat feeding induce obesity,hypertension and insulin resistance and are thus used extensively to study hypertension because these models closely mimic some of the renal and cardiovascular changes found in human hypertensive patients. The present study was initiated to evaluate if insulin resistance will develop within 6 weeks in a model of high-fat diet induced hypertension and if so, to determine whether captopril will affect the presence of insulin resistance.This model should in future be used to study vascular reactivity to phenylephrine (PHE),acetylcholine (ACH) and sodium nitroprusside (SNP) in hypertensive animals in theabsence or presence of insulin resistance and in normotensive insulin resistant animals. Methods: In a series of experiments, rats were divided into four groups that received different treatments: (i) laboratory pellets, (ii) high-fat diet, (iii) high-fat diet plus captopril and (iv) high-fat diet plus vehicle. Body weight was measured weekly for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured every week during the 6-weeks feeding period by the tail cuff method using a two channel computerized non-invasive system from Kent Scientific Corporation, USA.m Intraperitonealy glucose tolerance tests (IPGTTs) were performed at week 3 and week 6.After 6 weeks, and after an overnight fast, the plasma lipid profile was determined using a portable CardiochekTM blood test system. Fasting plasma insulin was determined using an immunoenzymatic assay for the in vitro quantitative measurement of rat insulin (INS) in serum and plasma. Insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) using the fasting plasma insulin and fasting glucose levels. After week 6 on the high-fat diet, thoracic aortae from the control and high-fat fed(HFD) animals were excised and vascular response to PHE, ACH and SNP were assessed in intact and denuded endothelium.Result: High-fat feeding did not cause a significant increase in body weight. High-fat feeding significantly increased systolic blood pressure from 125±2.1 mmHg in control animals to 155±5.9 mmHg in the HFD group (P < 0.05) and 158±5.6 mmHg in the HFDV group (P < 0.05). Diastolic blood pressure was increased from 86±2.8 mmHg in the control group to 117±2.5 mmHg in the HFD group (P < 0.05) and 113±3.4 mmHg in the HFDV group (P < 0.05). Visceral fat was increased from 0.8±0.1g in the control group to 3.1±0.6 g in the HFD group and 3.8±0.6 g in the HFDV group. IPGTTs performed at weeks 3 and 6 respectively did not differ significantly from the control group as evidenced from the AUC’s at weeks 3 and 6 respectively. High-fat feeding had no significant effects on blood cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) values or and fasting plasma insulin levels. The KCl induced contraction in both aortic rings with intact and denuded endothelium did not differ significantly between the control and HFD groups (P= 0.4 and 0.8) respectively. The contraction mediated by KCl in aortic rings with intact and denuded endothelium from the control or HFD groups also did not differ significantly(control: intact vs denuded, P = 0.2; HFD: intact vs denuded, P = 1). Dose responsecurves(1-10 μM) to PHE indicated slightly stronger contractions in the high-fat fed animals at submaximal doses tested. The maximum contraction achieved was however the same (94±19% and 99±2.6% relative to KCl induced contraction, in the control and HFD group respectively, P<0.05). Relaxation responses to ACH and SNP represent preliminary data.Conclusion: These data suggest that 6 weeks of high-fat feeding induces hypertension but does not produce obesity, dyslipidemia and insulin resistance. However, this model may be useful in studying vascular reactivity in hypertension in the absence of insulin resistance.

Neonatal quinpirole treatment to rats produces long-term increases in D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon referred to as D(2) priming. Male and female Sprague-dawley rats were administered quinpirole (1 mg kg(-1)) or saline from postnatal days (P)1-11. At P60, all animals were given an injection of quinpirole (100 microg kg(-1)), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D(2) receptor priming because yawning is a D(2) receptor mediated event. Beginning 1-3 days later, locomotor sensitization was tested through administration of d-amphetamine (1 mg kg(-1)) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed. Findings indicated that D(2)-priming enhanced horizontal activity in response to amphetamine in females compared to males at Days 1 and 4 of locomotor sensitization testing, and D(2)-priming enhanced turning in response to amphetamine. Seven to ten days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1-3.0 mg kg(-1)). D(2)-primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine. Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D(2) priming. These results indicate that D(2) receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D(2) receptor sensitivity is a hallmark.

Neonatal quinpirole treatment in rats produces increased sensitivity of dopamine D2-like receptors throughout the animal's lifetime, referred to D2 priming. There is little information on the effects of nicotine in adolescent rats, especially in a model that has clinical relevance to psychosis where increased D2 receptor sensitivity is common. Male and female rats were treated with quinpirole (1 mg/kg) or saline from postnatal (P) day P21, given nicotine (0.5 mg/kg) or saline from P33 through P49, and placed into a locomotor arena for behavioral testing. Nicotine or saline treatment was preceded by the D2-like receptor antagonist eticlopride, D3 antagonist nafadotride, or saline. Conditioned hyperactivity was analyzed on P50 in the same context in a drug-free test. In females, D2 priming increased the locomotor response to acute nicotine, but did not affect subsequent nicotine sensitization, and only non–D2-primed females demonstrated conditioned hyperactivity. Eticlopride and nafadotride blocked behavioral sensitization, although nafadotride was more effective at blocking nicotine-conditioned hyperactivity in females. In males, D₂ priming enhanced sensitization to nicotine and produced conditioned hyperactivity, which were blocked by eticlopride and nafadotride. These results have implications for psychosis and comorbidity of nicotine abuse in adolescence.

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The designer proline-rich antimicrobial peptide (PrAMP) Chex1-Arg20 amide (ARV-1502) is active against Gram-negative and Gram-positive pathogens in differentmurine infection models when administered parenterally and possesses a wide therapeutic index. Here we studied the pharmacokinetics of ARV-1502 for the first time when administered intramuscularly or intravenously (IV) in Sprague Dawley rats and Beagle dogs. First, a specific and robust quantitation method relying on parallel reaction monitoring (PRM) using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer coupled on-line to reversed-phase uHPLC was established and validated. The limit of detection was 2 ng/mL and the limit of quantitation was 4 ng/mL when spiked to pooled rat and dog plasma. When ARV-1502 was administered IV at doses of 75 and 250 μg/kg in dogs and rats, the plasma concentrations were 0.7 and 3.4μg/mL 2min post-administration, respectively. ARV-1502 plasma concentrations declined exponentially reaching levels between 2 and 4 ng/mL after 2 h. Intramuscular administration of 0.75 mg/kg in dogs and 2.5 mg/kg in rats resulted in a different pharmacokinetics profile. The plasma concentrations peaked at 15min post-injection at 1μg/mL (dogs) and 12μg/mL (rats) and decreased exponentially within 3 h to 4 and 16 ng/mL, respectively. The initial plasma concentrations of ARV-1502 and the decay timing afterwards indicated that the peptide circulated in the blood stream for several hours, at some point above the minimal inhibitory concentration against multidrug-resistant Enterobacteriaceae, with blood concentrations sufficient to suppress bacterial growth and to modulate the immune system.

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