Narcotic antagonist-induced hypotension in the spontaneously hypertensive rat

Intravenous naloxone or naltrexone produced transient, dose-related reductions in the mean arterial pressure (MAP) and heart rate (HR) of urethane-anesthetized spontaneously hypertensive rats (SHRs). Yet these same doses of narcotic antagonists reduced HR but not MAP of normotensive Wistar-Kyoto rats (WKYs). Such effects were not observed upon administration to SHRs of increasing doses of methylnaltrexone, which possesses no central activity. (+)-Naloxone, which does not block opiate receptors, reduced HR but not MAP of both SHRs and WKYs. These findings indicate that SHRs and WKYs differ in their MAP and HR responses to narcotic antagonists. The high doses required for effect plus the brevity of the responses suggest that these drug effects are perhaps not mu-opiate receptor-mediated; however, the methylnaltrexone and (+)-naloxone findings clearly implicate a central specificity of action. We conclude that narcotic antagonist-induced changes in MAP and HR in SHRs are possibly specific and central in origin yet not mediated by mu-opiate receptors.     

Intensified mouse killing in the spontaneously hypertensive rat

After one week in isolation spontaneously hypertensive male rats killed mice more frequently than did normal Wistar Controls, 70 vs 20%. Hypertensive killers had a somewhat lower blood pressure than did hypertensive non-killers. Retest after one hour demonstrated slower recognition time, decreased killing and increased kill time for normotensive killer rats. Mouse killing increased among hypertensive rats, and they became more proficient as evidenced by decreased kill time.     

Metallothioneins in spontaneously hypertensive rat liver.

The metallothionein (MT) synthesis was induced in the liver of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats through sc injections of CdCl2 for 3 and 6 days. The MT contents of the liver of these animals and of untreated rats from both groups were determined by gel filtration, HPLC, SDS/PAGE and amino acid analysis. The isoforms MT1 and MT2 were identified and their Cd, Zn and SH-group contents were determined. The SHR showed significantly higher values of MT than WKY rats in the untreated animals and on the 3rd day of the induction. On the 6th day, the MT levels in both groups were equal. The Cd and Zn contents followed the MT concentration in the homogenates. The possible relation between the arterial hypertension and the zinc and copper homeostasis is discussed.     

Skin blood flow in the Wistar-Kyoto rat and the spontaneously hypertensive rat

• 1.1. Using laser Doppler techniques in man, we have previously demonstrated differences in skin blood flow properties at sites with primarily nutritive (NUTR) perfusion, such as the elbow or knee, as compared to sites such as the finger pulp, with predominantly arteriovenous anastomotic (AVA) perfusion.
• 2.2. Basal and heat stimulated flow is greater at AVA sites. In man, blood pressure changes are reflected primarily by changes at AVA rather than NUTR sites.
• 3.3. These blood pressure induced changes affect the red blood cell velocity (VEL) component at AVA sites more than microvascular volume (VOL).
• 4.4. Given these findings in man, we decided to compare skin blood flow properties in a suitable animal model.
• 5.5. We chose the Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rat (SHR) strains, in view of the marked difference in systemic blood pressure in these two related strains.
• 6.6. Skin blood flow varied considerably at different skin sites in the rats. Skin sites with hair covering, on the back and at the base of the tail, showed low basal and heat stimulated blood flow.
• 7.7. In contrast, the plantar surface of the paw behaved similarly to the finger or toe pulps in man, with 3–4-fold higher basal flow than the hair covered areas and a 7–8-fold rise with local heating to 44°C.
• 8.8. Furthermore, there was a 25% greater blood flow at the plantar paw surface in the SHR rats as compared to the WKY rats, corresponding to the 25% higher systemic blood pressure in these animals.
• 9.9. The heat induced increase in flow at the plantar surface of the paw was primarily a result of a marked increase in VEL rather than VOL.
• 10.10. The higher flow at this site in SHR as compared to WKY rats was likewise ascribable to an increase in VEL, VOL being equivalent in the two strains.

     

Glucose oxidation in skeletal muscle from the spontaneously hypertensive rat

The metabolic activity of the cremaster muscle, as measured by glucose oxidation, was lower (16.7%) in the spontaneously hypertensive rat (SHR) than in the normotensive Wistar-Kyoto rat (WKY). This alteration in metabolic activity was accompanied by a reduction of the respiratory rate (12.5%) in the SHR rats when compared to WKY animals. The decreased respiratory rate and the lowered metabolic activity of the cremaster muscle occured at a time when blood pressure is increasing in SHR animals.     

Acute antihypertensive action of nitroxides in the spontaneously hypertensive rat

Tempol is an amphipathic radical nitroxide (N) that acutely reduces blood pressure (BP) and heart rate (HR) in the spontaneously hypertensive rat (SHR). We investigated the hypothesis that the response to nitroxides is determined by SOD mimetic activity or lipophilicity. Groups (n = 6-10) of anesthetized SHRs received graded intravenous doses of Ns: tempol (T), 4-amino-tempo (AT), 4-oxo-tempo (OT), 4-trimethylammonium-2,2,6,6-tetramethylpiperidine-1-oxyl iodide (CAT-1), 3-carbamoyl-proxyl (3-CP), or 3-carboxy-proxyl (3-CTPY). Others received native or liposomal (L) Cu/Zn SOD. T and OT are uncharged, AT is positively charged and cell-permeable, and CAT-1 is positively charged and cell-impermeable. 3-CP and 3-CTPY have five-member pyrrolidine rings, whereas T, AT, OT, and CAT-1 have six-member piperidine rings. T and AT reduced mean arterial pressure (MAP) similarly (-48 +/- 2 mmHg and -55 +/- 8 mmHg) but more (P < 0.05) than OT and CAT-1. 3-CP and 3-CTPY were ineffective. The group mean change in MAP with piperidine Ns correlated with SOD activity (r = -0.94), whereas their ED(50) correlated with lipophilicity (r = 0.89). SOD and L-SOD did not lower BP acutely but reduced it after 90 min (-32 +/- 5 and -31 +/- 6 mmHg; P < 0.05 vs. vehicle). Pyrrolidine nitroxides are ineffective antihypertensive agents. The antihypertensive response to piperidine Ns is predicted by SOD mimetic action, and the sensitivity of response is by hydrophilicity. SOD exerts a delayed hypotensive action that is not enhanced by liposome encapsulation, suggesting it must diffuse to an extravascular site.     

Age-related changes in serum proteins of the spontaneously hypertensive rat

Urinary protein excretion and composition in spontaneously hypertensive rats (SHR) change dramatically with age and sex. In this study, serum proteins were analyzed by electrophoresis in male and female SHR and Wistar-Kyoto (WKY) normotensive controls aged 5 to 80 weeks. Serum albumin concentrations of SHR were significantly higher than those of WKY at 5 (4.02 +/- 0.24 vs 3.60 +/- 0.25 g/dl) and 20 weeks (4.30 +/- 0.30 vs 3.77 +/- 0.31 g/dl) and significantly lower at 73-80 weeks (2.73 +/- 0.33 vs 3.45 +/- 0.34 g/dl). In addition, male SHR had significantly lower albumin levels than female SHR after 40 weeks of age. These differences may contribute to the development of hypertension and reflect the appearance of pathologic proteinuria in SHR. In spite of their differences in albumin concentrations, the fractional composition of serum protein from SHR and WKY were undistinguishable. All animals, regardless of strain or sex, manifested a significant decline in the relative amounts of albumin and low molecular weight protein and a significant increase in the relative amount of high molecular weight protein with increasing age. The etiology and significance of these age related changes in the fractional composition of serum protein are unknown, but they differ from the normal developmental pattern in humans.     

Acute antihypertensive action of Tempol in the spontaneously hypertensive rat

Acute intravenous Tempol reduces mean arterial pressure (MAP) and heart rate (HR) in spontaneously hypertensive rats. We investigated the hypothesis that the antihypertensive action depends on generation of hydrogen peroxide, activation of heme oxygenase, glutathione peroxidase or potassium conductances, nitric oxide synthase, and/or the peripheral or central sympathetic nervous systems (SNSs). Tempol caused dose-dependent reductions in MAP and HR (at 174 micromol/kg; DeltaMAP, -57+/- 3 mmHg; and DeltaHR, -50 +/- 4 beats/min). The antihypertensive response was unaffected by the infusion of a pegylated catalase or by the inhibition of catalase with 3-aminotriazole, inhibition of glutathione peroxidase with buthionine sulfoximine, inhibition of heme oxygenase with tin mesoporphyrin, or inhibition of large-conductance Ca(2+)-activated potassium channels with iberiotoxin. However, the antihypertensive response was significantly (P < 0.01) blunted by 48% by the activation of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channels with cromakalim during maintenance of blood pressure with norepinephrine and by 31% by the blockade of these channels with glibenclamide, by 40% by the blockade of nitric oxide synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME), and by 40% by the blockade of ganglionic autonomic neurotransmission with hexamethonium. L-NAME and hexamethonium were additive, but glibenclamide and hexamethonium were less than additive. The central administration of Tempol was ineffective. The acute antihypertensive action of Tempol depends on the independent effects of potentiation of nitric oxide and inhibition of the peripheral SNS that involves the activation of K(ATP) channels.     

A-type natriuretic peptide receptor in the spontaneously hypertensive rat kidney

Renal NPR-A binding characteristics was examined in SHR. Renal ANP binding sites of NPR-A showed a lower maximal binding capacity and higher affinity in SHR than in WKY at all intrarenal sites. Despite the lower B(max) in SHR, both ANP(1-28) and ANP(5-25) stimulate similar or greater cGMP production in isolated glomeruli. Studies on guanylate cyclase from glomerular and papillary membranes have reported an increased basal and stimulated guanylate cyclase activity in SHR. The present study provides further evidences for altered NPR-A receptors in SHR kidney, which might act as a negative feedback in response to hypertension.     

Genetic analysis of metabolic defects in the spontaneously hypertensive rat

Abnormalities in carbohydrate and lipid metabolism are common in patients with essential hypertension and in the spontaneously hypertensive rat (SHR). To identify chromosome regions contributing to this clustering of cardiovascular risk factors in the SHR, we searched for quantitative trait loci (QTL) associated with insulin resistance, glucose intolerance, and dyslipidemia by using the HXB/BXH recombinant inbred (RI) strains. Analysis of variance in RI strains suggested significant effects of genetic factors. A genome screening of the RI strains with more than 700 markers revealed QTL significantly associated with insulin resistance on Chromosomes (Chrs) 3 and 19. The Chr 19 QTL was confirmed by testing a previously derived SHR-19 congenic strain: transfer of a Chr 19 segment delineated by markers D19Rat57 and D19Mit7 from the Brown Norway (BN/Cr) strain onto the genetic background of the SHR/Ola was associated with decreased insulin and glucose concentrations and ameliorated insulin resistance at the tissue level. These findings suggest that closely linked genes on Chr 19, or perhaps even a single gene with pleiotropic effects, influence the clustering of metabolic disturbances in the SHR-BN model.     

Pharmacological characterization of apomorphine-induced hypothermia in the spontaneously hypertensive rat

The dopamine agonist apomorphine was more potent in eliciting hypothermia in spontaneously hypertensive rats (SHRs) than in normotensive Wistar rats (NWRs), while normotensive Wistar-Kyoto rats (WKYs) were intermediate in response. Various drug interventions were attempted in an effort to explain the greater sensitivity of SHRs to apomorphine. Haloperidol produced abolition of apomorphine-induced hypothermia in SHRs but at greater doses than required for antagonism of the drug effect in WKYs and NWRs. Chronic hydralazine treatment that reduced the high blood pressure of SHRs failed to appreciably influence the magnitude of apomorphine-induced hypothermia, compared to the response in control SHRs that received no hydralazine. These findings suggested to us that the enhanced hypothermic effect of apomorphine in SHRs was entirely dopamine receptor-mediated and that it was also independent of the high blood pressure. We also found that chronic lithium treatment that had no influence upon apomorphine-induced hypothermia in WKYs and NWRs significantly reduced the drug effect in SHRs. Based on this finding, we suggest that the greater hypothermic effect induced by apomorphine in SHRs might be due to a supersensitivity of hypothermia-mediating dopamine receptors in the hypertensive strain.     

Mapping of the rat glypican genes

The glypicans compose a family of glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycans that play a role in the control of cell division and growth regulation. So far, six members (GPC1-6) of this family are known in vertebrates. The rat glypican gene 3 (Gpc3) was previously assigned to chromosome Xq36 (Shen et al., 1997). Using standard and radiation cell hybrids, we localized the five other rat glypican genes.     

Alterations in a hypothalamic GABA system in the spontaneously hypertensive rat

The density (Bmax) of muscimol and clonazepam binding to hypothalamic membranes from spontaneously hypertensive rats (SHR) was reduced compared to age-matched Wistar Kyoto (WKY) animals in the period 80 – 120 days. There were no significant differences in dissociation constant (Kd) for either ligand at this time. At 30 – 36 days, prior to development of pronounced hypertension, there were no differences in Kd or Bmax for either ligand in SHR and WKY animals. There were also deficits in endogenous hypothalamic GABA concentrations in SHR at 75 and 120 days as compared to WKY. The hypothesis is advanced, that there may be a dysfunction of a hypothalamic GABA system in the SHR rat as hypertension develops.     

Reduced serotonin uptake by spontaneously hypertensive rat platelets

Platelets of Spontaneous Hypertensive (SH) rats show a significant reduction in serotonin uptake, compared with that of rats with normal blood pressure. The difference was due to the V_max, which was about 40% of normals, while the K_m values were almost constant. The possible analogy between blood platelets and serotonergic nerve terminals in SH rats is considered in the evaluation of the results.     

A possible explanation of genetic hypertension in the spontaneously hypertensive rat

Converting enzyme inhibitors prevent the development of hypertension and normalize arterial blood pressure in spontaneously hypertensive rats (SHR), suggesting a critical role for angiotensin II in genetic hypertension. We hypothesized that the SHR is hyperresponsive to the slow-pressor effect of angiotensin II. To test this hypothesis, 14 SHR and 14 normotensive Wistar Kyoto rats (WKY) were treated chronically with captopril (100 mg X kg-1 X day-1 in drinking water) beginning at 5 weeks of age. At 9 weeks of age, either angiotensin II (125 ng/min; 7 SHR and 7 WKY) or vehicle (7 SHR and 7 WKY) was infused for 2 weeks via an osmotic minipump implanted into the peritoneal cavity. Captopril treatment was maintained and systolic blood pressure was monitored 3 times weekly. Although systolic blood pressure was similar in SHR and WKY infused with vehicle (101 +/- 2 versus 103 +/- 5 mmHg, respectively during the second week), systolic blood pressure in SHR treated with angiotensin II was much greater than systolic blood pressure in WKY treated with angiotensin II (193 +/- 9 versus 132 +/- 11 mmHg, respectively during the second week, p less than 0.001). These results indicate that compared to WKY, SHR are remarkably more sensitive to the slow-pressor effect of chronic, low-dose infusions of angiotensin II. Our results support the hypothesis that the critical genetic defect in SHR is a change in the sensitivity to the slow-pressor effect of angiotensin II.