Blood Pressure In Spontaneously Hypertensive Research Articles

Selective Phosphodiesterase 1 Inhibitor LY1 Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats

Regulation of the peripheral vascular resistance via modulating the vessel diameter has been considered as a main determinant of the arterial blood pressure. Phosphodiesterase enzymes (PDE1‐11) hydrolyse cyclic nucleotides, which are key players controlling the vessel diameter and thus peripheral resistance, aiming at achieving and maintaining a homeostatic balance between their production and destruction. On the contrary, pathological shift in the balance to words the destruction leads to depletion of the cyclic nucleotides and dysregulation of the blood pressure. Here, we have tested and reported the effects of a novel selective PDE1 inhibitor (LY1) on the cardiovascular system. In vitro experiments have been conducted to determine the IC50 of LY1 using phosphodiesterase radiometric enzyme assay. We used rat mesenteric artery to conduct myogrphy study to determine the effect of the drug on the vessel diameter. Also, short as well as long term telemetric studies were done on normal Sprague Dawley (SD), spontaneously hypertensive (SHR), and Dahl salt sensitive (SS) rats to document the in vivo efficacy of the compound. LY1 inhibited all three isoforms of PDE1 in nanomolar concentration (1.74 nM, 2.44 nM and 1.20 nM for PDE1A, PDE1B and PDE1C, respectively), while micromolar concentrations were needed to induce effective inhibition for other PDEs. The myography study revealed a potent vasodilatory effect of the drug, which was confirmed in vivo by an increase in the blood flow in the rat ear arteriole reflected by the rise in the temperature. LY1 proved a high efficacy in lowering the blood pressure in two animal models for hypertension i.e. SHR and SS rats. 3 mg/kg of LY1 twice daily through oral gavage could efficiently reduce the blood pressure in both SHR and SS rats approximately 40 mmHg compared to the untreated control group. Therefore, LY1 induced an efficient vasodilation that was accompanied by a significant reduction of blood pressure in different hypertensive rat models. Thus, PDE1 appears to be a tempting therapeutic target for treatment of resistant hypertension.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension. The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n=9) or sham CSD (n=9) 5weeks after renal artery clipping, in comparison with normal Wistar rats (n=5). After 21days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98±4mmHg vs. 2K1C: 147±8mmHg; P<0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P<0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14±2mmHg by week 3 (P<0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension.

Diesel exhaust induced pulmonary and cardiovascular impairment: The role of hypertension intervention

Exposure to diesel exhaust (DE) and associated gases is linked to cardiovascular impairments; however, the susceptibility of hypertensive individuals is poorly understood. The objectives of this study were (1) to determine cardiopulmonary effects of gas-phase versus whole-DE and (2) to examine the contribution of systemic hypertension in pulmonary and cardiovascular effects. Male Wistar Kyoto (WKY) rats were treated with hydralazine to reduce blood pressure (BP) or l-NAME to increase BP. Spontaneously hypertensive (SH) rats were treated with hydralazine to reduce BP. Control and drug-pretreated rats were exposed to air, particle-filtered exhaust (gas), or whole DE (1500μg/m3), 4h/day for 2days or 5days/week for 4weeks. Acute and 4-week gas and DE exposures increased neutrophils and γ-glutamyl transferase (γ-GT) activity in lavage fluid of WKY and SH rats. DE (4weeks) caused pulmonary albumin leakage and inflammation in SH rats. Two-day DE increased serum fatty acid binding protein-3 (FABP-3) in WKY. Marked increases occurred in aortic mRNA after 4-week DE in SH (eNOS, TF, tPA, TNF-α, MMP-2, RAGE, and HMGB-1). Hydralazine decreased BP in SH while l-NAME tended to increase BP in WKY; however, neither changed inflammation nor BALF γ-GT. DE-induced and baseline BALF albumin leakage was reduced by hydralazine in SH rats and increased by l-NAME in WKY rats. Hydralazine pretreatment reversed DE-induced TF, tPA, TNF-α, and MMP-2 expression but not eNOS, RAGE, and HMGB-1. ET-1 was decreased by HYD. In conclusion, antihypertensive drug treatment reduces gas and DE-induced pulmonary protein leakage and expression of vascular atherogenic markers.

P68 Role of endothelial H2S in the pathogenesis of hypertension in spontaneously hypertensive (SHR) rats

Hypertension (HTN) increases the risk for cardiac disease and stroke. Endogenous hydrogen sulfide (H 2 S), which plays a prominent role in a multitude of pathologies like inflammation/sepsis, hypertension, peripheral and cerebro-vascular, and coronary artery disease, is now well characterized as a physiologic vasodilator [1] . H 2 S is produced by cystathionine- γ -lyase (CSE) in vascular endothelium. It caters to relaxation through sulfhydration (posttranslational modification) of IK, SK and K ATP channels, resulting in vascular smooth muscle cell hyperpolarization. This effect is independent of the Nitric Oxide (NO)/cGMP/PKG axis [2] . Tang et al. studied H 2 S in spontaneously hypertensive (SHR) rats and demonstrated a loss of CSE/H 2 S in HTN and a decrease in BP (blood pressure) on substitution of H 2 S [3] . Aim To elicit if loss of endogenous H 2 S contributes to the pathogenesis of hypertension. Results Tail cuff was used to measure BP in SHR and control Wistar Kyoto (WKY) rats starting at age 4 weeks (w) up until SHRs became hypertensive. Infusion of glybenclamide (20 mg/kg) a K ATP channel blocker, revealed a significant increase in systolic BP (SBP) in 4-week-old SHR (ΔSBP = 43.16 ± 24.24%, n = 5) and 4 w WKY (ΔSBP = 89.97 ± 41.40%, n = 4), while little change was demonstrated in hypertensive 90 w SHR (ΔSBP = 24.07 ± 21.99%, n = 4), measured invasively via aortic catheterization.In a separate experiments, aortic rings isolated from age matched SHRs ( n = 5) and WKYs ( n = 5), were mounted on a myograph, prepared in physiologic buffer at 37 °C, and constricted with phenylephrine (1 μM), for assessment of endothelial function. Acetylcholine (ACH) dependent maximum relaxation on treatment with L-Name (eNOS inhibitor) was modestly attenuated in aortas of 4 w WKY (92.79 ± 2.64–83.26 ± 3.35%), 4 w SHR (83.50 ± 4.47–59.48 ± 8.75%) and 90-week-old WKYs (71.39 ± 15.06–15.77 ± 5.16%). Contrary to that, this response was completely blocked in 90 w SHRs (35.32 ± 5.16–0.24 ± 3.17%). Treatment with propargylglycine (CSE blocker) did not affect ACH mediated maximum relaxation in 90 w SHR (35.32 ± 5.16–29.40 ± 5.86%), but it significantly attenuated the responses in 4 w WKYs (92.79 ± 2.64–56.30 ± 4.55), 4 w SHRs (83.50 ± 4.47–71.63 ± 12.25) and 90 w SHRs (71.39 ± 15.06–8.13 ± 4.61%). Strikingly, rings from normotensive 16 w SHR had a complete L-Name sensitive attenuation of endothelial relaxation (63.25 ± 5.15–2.74 ± 1.75%). Conclusion There appears to be a NO independent component of endothelial relaxation in normotensive blood vessels, which is sensitive to CSE inhibitors and blockage of K ATP channels. This NO independent component of relaxation is absent in HTN and pre-HTN vessels; hence implying that loss of the CSE/H 2 S/K ATP axis could be a mechanism preceding HTN. We aims to measure CSE activity and sulfhydration of Kir 6.1-Cysteine 43 and GAPDH in normotensive/pre and post HTN blood vessels in different animal models of HTN to elicit if CSE/H 2 S/K ATP axis is a potential target for the treatment of hypertension.

The Role of Macrophage Migration Inhibitory Factor (MIF) in the Paraventricular Nucleus (PVN) During Acute Stress

We previously demonstrated that MIF is upregulated by angiotensin II (AngII) in the PVN of normotensive animals and counteracts the pressor action of AngII. In contrast, AngII fails to upregulate MIF in spontaneously hypertensive (SHR) rats, but overexpression of MIF reduces blood pressure (BP) in SHRs. Here, we investigated whether MIF is involved in BP regulation in normotensive Sprague‐Dawley (SD) rats during acute stress and under resting conditions. BP was measured with telemetry and AAV2‐GFP (n=8) or AAV2‐MIF (n=8) was injected bilaterally into the PVN. Responses to 1hr restraint stress (RS) and 15 min water stress (WS, 1cm deep, 25 °C) were evaluated. Unlike in SHRs, MIF overexpression had no effect on baseline BP in SD rats, and did not influence the amplitude of BP and HR responses to RS or WS. However, recovery time following WS was shorter in MIF‐ vs GFP‐treated rats (24±2 vs 30±3 min). In addition, spontaneous baroreflex sensitivity (sBRS) analyzed by the sequence method tended to increase following MIF treatment (from 1.74±0.14 to 1.94±0.15 ms/mmHg, P=0.07), while power in the LF range of BP variability spectrum indicating sympathetic nervous system influence on vasculature tended to decrease (from 2.83±0.32 to 2.48±0.24 mmHg2; P=0.06). In conclusion, in normotensive animals, MIF overexpression has only subtle effects on BP regulatory mechanisms. Supported by NIH #HL93186 (MPI).

Chronically inhaled ambient particles cause cardiac inflammation in normal, diseased, and elderly rat hearts

Exposure to ambient particulate matter (PM) is linked to increases in cardiovascular morbidity and mortality. The exact mechanism by which PM induces cardiovascular toxicity is not completely understood. We sought to study histopathological changes in the heart muscle in young healthy (Wistar–Kyoto, WKY) and spontaneously hypertensive (SHR) rats and old (22-month-old) Sprague–Dawley rats (SD) chronically exposed to PM. WKY rats and SHR were exposed for 3 months to ultrafine particles (UFP) or filtered air (FA). SD rats were exposed for 9 months to coarse (CP), fine (FP), and ultrafine particles or FA. In addition, we studied effects of PM on mean arterial blood pressure (MABP) and echocardiograms in WKY rats and SHR. Chronic exposure to PM caused histopathological changes in the hearts of all studied strains. The effects ranged from cardiac inflammation caused by 3 months of exposure to UFP in WKY rats and SHR to more severe changes in SD rats exposed to PM for 9 months. Changes in SD rats were inflammation, intracellular edema, and vacuolization in hearts exposed to FP and UFP and vacuolization and collagen accumulation in CP-exposed hearts. In addition, evidence of only mild inflammation was seen in the respiratory tract. We did not observe any statistically significant changes in the MABP (constantly recorded over the entire period of exposure by implanted telemetric devices) and in the echocardiograms in WKY rats and SHR exposed to UFP or FA. MABP at the end of 3 months exposure comprised 153.3 ± 13.9 and 160.3 ± 14.7 mmHg in the SHR-FA and SHR-UFP, respectively, and 124.4 ± 11.2 and 107.9 ± 9.2 mmHg in the WKY-FA and WKY-UFP, respectively (mean ± SD). Our data indicate that chronic exposure to particulate air pollutants causes histopathological changes in healthy (WKY), diseased (SHR), and old SD rat hearts.

LVV-hemorphin-7 lowers blood pressure in spontaneously hypertensive rats: radiotelemetry study.

Cardiovascular effects of LVV-hemorphin-7, a member of the family of fragments from beta-chain of human or bovine hemoglobin, were studied in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by radiotelemetry. Intraperitoneal injection of hemorphin in a dose of 100 microg/kg significantly decreased blood pressure in SHR, whereas negligible effect was seen in normotensive WKY rats. Blood pressure changes were accompanied by reduction of heart rate. In conclusion, a direct effect of LVV-hemorphin-7 on blood pressure was demonstrated in SHR. These biologically active peptides could be involved in blood pressure regulation especially in hypertensive rats, but the precise mechanism should be elucidated.

Quinapril effects on resistance artery structure and function in hypertension

The effects of chronic treatment with quinapril on blood pressure, vascular reactivity and structure of resistance arteries were examined in adult, male spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. SHR and WKY at 15 weeks of age were treated with quinapril (10 mg/kg per day) for 10 weeks. Structural changes in the mesenteric arteries were measured by optical sectioning with confocal microscopy and in renal arteries by light microscopic measurements. Apoptotic cells in the mesenteric vessel wall were identified using the terminal deoxynucleotide transferase-mediated dUTP-nick end-labelling (TUNEL) method. The response of mesenteric arteries to noradrenaline, electrical stimulation, acetylcholine and sodium nitroprusside was studied using a pressure myograph system. Treatment with quinapril significantly lowered systolic blood pressure and ventricular weight in both SHR and WKY. It reduced wall thickness and medial volume in mesenteric arteries from SHR and WKY and media-to-lumen ratio in interlobular arteries of SHR. It also decreased the number of smooth muscle layers in SHR and increased the number of apoptotic smooth muscle cells in both SHR and WKY. In addition, treatment normalized the augmented contractile responses and improved the impaired relaxation response of SHR mesenteric arteries to the level of WKY. We conclude that treatment with quinapril lowered blood pressure and improved cardiac and vessel structure and vessel function. An increase in apoptotic process of medial smooth muscle cells is one of the mechanisms underlying the vascular structural improvement.

Contractile Responses of Aortae from WKY and SHR to Vasoconstrictors

Aortae taken from spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats aged 4, 8 and 16 weeks were prepared as rings and used to measure the effects of five vasoconstrictors. The endothelium was removed in order to measure selectively the contractile responses induced by potassium chloride (KCl), phenylephrine (PHE), angiotensin‐II (Ang II), endothelin‐1 (ET‐1) and human urotensin‐II (U‐II). These responses were assumed to derive from the activation of specific receptors (namely α1, AT1, ETA and UT‐II) or from depolarization of the smooth muscle fibers by KCl. Specific antagonists prazosin, losartan, BQ‐123 and [Orn8]‐UII were used at various concentrations for a pharmacological characterization of these latter receptor systems. The primary purpose of the study was to explore mechanisms or factors that may intervene in the development and maintenance of high blood pressure in SHR. Results indicate that isolated aortae of SHR and WKY contain contractile sites (receptors) whose pharmacological profiles (pEC50 for agonists, pA2 for antagonists) are very similar to those of other biological systems and should be considered as typical for the α1, AT1, ETA and UT‐II receptor types. Aortae taken from SHR 4 (non hypertensive), 8 and 16 weeks old (hypertensive) responded to the vasoconstrictors with reduced maximal contractions compared to those of age‐matched WKY. These unexpected reduced responses of aortae, observed with the five vasoconstrictors, may be attributed to a non specific lesions. Maximal contraction of aortae from SHR increased from 4 to 16 weeks for KCl, PHE and U‐II, decreased for Ang II, and remained stable for ET‐1. There was also an age‐dependent increase of maximal contraction induced by U‐II in WKY. It is suggested that aortae from SHR undergo early remodelling that leads to reduced contractility in vitro and possibly to vessel rigidity in vivo. The factors involved in this process appear to be of genetic origin since they are present before hypertension: they may contribute to modify aortic compliance and perhaps vascular resistance in hypertensive animals and thus being the cause and not the consequence of high blood pressure.

Sympathetic Activation in Adipose Tissue and Skeletal Muscle of Hypertensive Rats

The activation of the sympathetic nervous system is a common feature of arterial hypertension and other cardiovascular diseases. This activation might be dependent on an altered baroreflex control of vascular resistance of which the inhibitory response on sympathetic activity appears impaired. The aim of the study was to monitor during the natural course of arterial hypertension in spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats (5, 16, 30, and 54 weeks of age) the peripheral sympathetic activity expressed as interstitial norepinephrine (NE) release and as tyrosine hydroxylase (TH) activity, the rate-limiting enzyme of NE synthesis, in the differently baroreflex-controlled subcutaneous adipose tissues and skeletal muscles. Blood pressure and plasma NE in SHR were similar to WKY at 5 weeks of age but increased at all other ages. Body weight was similar in both 5-week-old rats but reduced in SHR at all other ages. The interstitial NE levels were greater in both SHR tissues at all ages as compared with WKY. In adipose tissue of SHR, TH activity was higher at all ages as compared with WKY, whereas TH activity in skeletal muscle was higher only after the development of hypertension. These data show that in both SHR tissues, an increase of interstitial NE release is always present during its lifespan. This suggests that increased sympathetic activation in the SHR model is not specific to baroreflex-controlled tissues such as skeletal muscle but involves also subcutaneous adipose tissue, the sympathetic efferents of which are independent from baroreflexes.

Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats.

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.

Plasma and lipoprotein lipid composition and hepatic antioxidant status in spontaneously hypertensive (SHR) and normotensive (WKY) rats

Plasma and lipoprotein lipid composition and endogenous hepatic antioxidant status were investigated in hypertensive, 14-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats fed a standard commercial rat chow. Total plasma calcium and magnesium concentrations were similar between both rat strains; however, systolic blood pressure in SHR was greater than in WKY at 13 weeks of age (197 +/- 12 vs. 132 +/- 14 mmHg; p < or = 0.05), confirming hypertension in SHR. Total plasma cholesterol and triacylglycerol concentrations were lower (p < or = 0.05) in SHR compared with WKY. A lower (p < 0.05) HDL cholesterol level in SHR plasma resulted in a higher LDL to HDL cholesterol ratio compared with WKY counterparts. No significant differences in the relative proportion of HDL apolipoprotein A-I fraction were observed between SHR and WKY. Both SHR VLDL and HDL triacylglycerol fractions were lower (p < 0.05) in SHR than WKY. Analysis of liver antioxidant enzyme activities showed no differences in rat liver superoxide dismutase (SOD), but lower (p < 0.05) liver glutathione peroxidase (GSH-Px) activity in SHR. However, liver glutathione (GSH) levels were similar in SHR and WKY counterparts. A possible compensatory effect to the oxidative status of SHR was suggested by the significant (p < 0.05) increase in both liver catalase (CAT) and glutathione reductase (GSSG-Red) activities. Despite these results, in vitro oxidative challenge studies with H2O2 demonstrated a greater susceptibility of liver to GSH depletion in the SHR, although no parallel change in thiobarbituric acid reactive substances (TBARS) production was observed. The comparatively lower plasma cholesterol observed in hypertensive SHR paralleled specific differences in liver catalase and glutathione redox antioxidant enzyme activities.

Alteration of Cytochrome P-450 Isozymes by Captopril and Idrapril in Hepatic and Renal Microsomes of Normotensive and Spontaneously Hypertensive Rats

To examine the effects of angiotensin-converting enzyme (ACE)inhibitors such as captopril and idrapril on the P-450 system, these compounds were administered 100 mg/kg i.p. for 4 days to spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats; thereafter, the principal hepatic and renal microsomal monooxygenase activities were determined. In all the rat strains used, both captopril and idrapril decreased only the P-450 2C11, (as determined by immunoblotting) and its linked activities such as 16alpha-, 2alpha- and 17-testosterone hydroxylases. These changes were accompanied by a significant decrease of blood testosterone levels both in normotensive and, more markedly, in hypertensive rats and by a reduction of systolic blood pressure, but only in SHRs. Only in SHRs as well, the renal immunodetectable P-450 4A content and the P-450 4A-dependent activities, such as the (omega)-lauric acid hydroxylase, diminished after captopril or idrapril treatment. These data suggest that the decrease of increased blood pressure in hypertensive SHRs by the ACE inhibitors may be linked to the downregulation of the circulating testosterone level, the renal P-450 4A expression, and the related formation of the potent vasoconstrictor (omega)-hydroxy arachidonic acid.

Role of angiotensin II and catecholamines in blood pressure variability responses to stress in SHR.

The contribution of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) to blood pressure (BP) and heart rate (HR) variability responses to air-jet stress was assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Activity of the encogenous RAS was suppressed by chronic treatment by a nonpeptide angiotensin II receptor antagonist (Iosartan). The role of alpha 1-adrenoceptor activity was evaluated in rats by acute administration of prazosin. In untreated animals, an air jet induced an increase in systolic BP (SBP; 9 +/- 2 mmHg for WKY and 8 +/- 2 mmHg for SHR) and in HR (56 +/- 19 beats/min for WKY and 76 +/- 8 beats/min for SHR), followed by an increase of the midfrequency (MF; 0.2-0.6 Hz) component of HR in WKY (183%) and by an increase of the MF component of SBP and diastolic BP in SHR (65%). Prazosin prevented BP rises as well as the MF component of BP and HR increases associated with air-jet stress. Chronic suppression of the RAS by losartan did not alter the BP response to the air jet in WKY and slightly reduced it in SHR but abolished all the BP and HR variability changes in both strains. These results indicate that the SNS but not RAS is essential for the BP rise induced by stress and demonstrate that RAS in conjunction with SNS is involved in BP and HR variability changes associated with stress.

Comparative effects of 6-week nicotine treatment on blood pressure and components of the antioxidant system in male spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats

Hypertension, cigarette smoking, and nicotine augment the clinical significance of other risk factors associated with cardiovascular diseases by mechanisms which are poorly understood. Since altered trace element metabolism and antioxidant status have also been implicated in these diseases, the present study investigated the interaction of nicotine treatment and hypertension on tissue trace element concentrations and select indices of antioxidant status. Spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats were treated with nicotine, via a time release tablet at an average rate of 75 μg/h for 6 weeks. Systolic blood pressure in nicotine-treated SHRs was significantly higher at weeks 3 and 6 of treatment than in the SHR-controls. Blood pressure in WKY rats was not affected by nicotine. Plasma and liver iron concentrations in the nicotine-treated SHR were higher than the SHR-controls and the WKY groups. Nicotine treatment did not affect plasma and liver zinc and copper concentrations or liver manganese (Mn) concentrations. Plasma ceruloplasmin activity was increased by nicotine treatment in the SHRs. Liver Mn superoxide dismutase (MnSOD) activities and glutathione concentrations, and liver and heart glutathione reductase activities, were higher in both groups of SHRs than in the WKY groups. Red cell SOD activity in the nicotine-treated SHR was lower than in the SHR-controls. In summary, blood pressure increased more rapidly in the nicotine-treated SHRs compared to the controls. The marked effects on antioxidant status observed were attributable more to hypertension than to the nicotine treatment.

Effect of inhibition of nitric oxide synthesis on the uptake of LDL and fibrinogen by arterial walls and other organs of the rat

1. The effects of administering 3 mg ml-1 NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO), on the uptake of low density lipoprotein (LDL), fibrinogen and blood pressure were determined in conscious, unrestrained, cannulated normotensive and spontaneously hypertensive (SHR) Wistar rats. 2. The uptake of LDL and fibrinogen, labelled respectively with 125I or 131I via the adduct tyramine cellobiose ([125I]TC-LDL and [131I]TC-fibrinogen), were compared in aortic walls, heart, skeletal muscle, lung, liver, kidney and adrenal during the final 24 h of 6 days' administration of L-NAME in the drinking water. 3. In control normotensive rats, the systolic blood pressure did not change significantly over 6 days, while administration of L-NAME in normotensive rats increased the blood pressure progressively and significantly to about 170 mmHg over the same period. 4. In normotensive rats L-NAME increased significantly the uptake of both LDL and fibrinogen by aortic walls and heart, but not by muscle, lung, liver, kidney and adrenal. 5. The blood pressure in SHR was about 170 mmHg before administration of L-NAME and did not increase significantly after 6 days of treatment. In these rats the uptake of LDL or of fibrinogen was increased only in the heart but not in aortic walls nor in any of the other organs. 6. In normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increases in the uptake of the atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart but not by the skeletal muscle, lung, liver, kidney and adrenal. The slightly higher blood pressure of SHR treated with L-NAME was not associated with increased uptake of LDL or fibrinogen by aorta nor by any organ except heart. Thus, while in normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increase in the uptake of atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart, in SHR which showed uptakes similar to the normotensive animals, the non-significant increase in blood pressure induced by inhibition of NO generation was not associated with increased uptake of LDL or fibrinogen in any organ except the heart.7. These results are consistent with effects, demonstrated earlier, of infusing the pressor agents noradrenaline, adrenaline and angiotensin II, which produce increases in uptake of LDL and fibrinogen by aortic wall, whereas this is not so in spontaneously hypertensive rats.

Timing of preweanling maternal effects on development of hypertension in SHR rats

Cross-fostering of litters was used to determine the timing of preweanling maternal influences on the development of high blood pressure in spontaneously hypertensive (SHR) rats. The SHR litters were either reared by their natural mothers or reciprocally cross-fostered to normotensive Wistar-Kyoto (WKY) mothers for postnatal days 1–7, 1–14, 1–21, 8–21, or 15–21. All SHR litters were weaned at 21 days of age and males were housed in groups of two to three per cage until physiological measures were obtained at 100 days of age. At 100 days of age, all rats were surgically prepared with tail artery catheters and, on the day after surgery, direct measures of mean arterial pressure (MAP, mmHg) and heart rate (HR, bpm) were obtained while rats were resting and undisturbed in their individual home cages. Our findings indicate that cross-fostering SHR pups to WKY foster mothers was attended by significant effects on body weights at weaning and on adult MAPs. Compared to control SHRs, cross-fostered SHRs, with the exception of the 15–21-day group, were significantly heavier at weaning. By 100 days of age, body weights of SHRs were similar across treatment groups. Basal MAPs of SHRs cross-fostered for days 1–7, 1–14, 1–21, and 8–21, but not days 15–21, were reduced significantly compared to SHR controls reared by their natural mothers. In contrast, basal HRs were not affected in any of the cross-fostered SHR groups. These data indicate that maternal environmental influences on the development of high blood pressure in SHRs are limited to the first 2 weeks of postnatal life. This corresponds to the time prior to weaning when rat pups receive all of their nourishment from their mothers.

Effects of β1 and β2-Adrenoceptor Agonists Applied into the Hypothalamic Paraventricular Nuclei of Spontaneously Hypertensive Rats on Urine Production

We investigated effects of beta-adrenoceptor agonists (beta 1-selective: T-1583 and dobutamine, beta 2-selective: fenoterol, non-selective: isoproterenol) on urine outflow rate, blood pressure, heart rate, respiratory rate and rectal temperature. The drugs were applied into the paraventricular nuclei (PVN) of spontaneously hypertensive (SHR), Wistar-Kyoto (WKY) and Wistar rats. Fenoterol and isoproterenol markedly decreased the urine outflow rate, compared with T-1583 and dobutamine in the rats. There was no marked difference among the three strains in responsiveness to fenoterol and isoproterenol. The antidiuretic effects of fenoterol were inhibited by a beta 2-selective antagonist, butoxamine, more markedly than a beta 1-selective antagonist, atenolol, in SHR; and the inhibitory effects of these drugs were partial in WKY. In Wistar rats, the effect of fenoterol was inhibited by a non-selective beta-antagonist, timolol, but not by atenolol or butoxamine. A vasopressin antagonist (i.v.) did not diminish the antidiuretic effect of fenoterol. Fenoterol reduced the blood pressure in SHR and WKY, but not in Wistar rats. It was suggested that there were predominantly beta 2-adrenoceptors mediating antidiuresis in SHR. In WKY and Wistar rats, however, the beta-adrenoceptor subtypes mediating antidiuresis have yet to be determined. The ability of beta-adrenoceptor agonists to decrease urine outflow rates in SHR was not altered as compared to that in the control rats. beta-Adrenoceptor-mediated antidiuresis was not due to vasopressin release.

Depressor effect of intraventricular administration of calcium on spontaneously hypertensive rats

The role of central Ca 2+ in the regulation of blood pressure (BP) was investigated in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Ten μl of a high Ca 2+ solution (Ca 2+: 32.6 mM) administered intracerebroventricularly (i.c.v.) decreased the mean arterial pressure (MAP) for more than 20 min in SHR ( n = 7, P < 0.005), while no change of MAP was observed in the WKY ( n = 6). This depressor response to Ca 2+ i.c.v. was dose-dependent at Ca 2+ concentrations between 16.3 and 65.2 mM. We also investigated the effect of high Ca 2+ i.c.v. in SHR after pretreatment with Ca 2+ channel blockers, diltiazem (60 μg/10 μl) or nisoldipine (4, 8, 16 and 32 μg/10 μl), administered i.c.v., the autonomic ganglion, hexamethonium (50 mg/kg), administered i.v. and α-methyl- p-tyrosine (100 and 400 μg/10 μl) delivered i.c.v. Pretreatment with i.c.v. diltiazem (=8) or nisolipine ( n=5 for 8 μg, n=6 for 4,16,32 μg) abolished and/or blunted the decrease of MAP due to high Ca 2+. Hexamethonium administered i.v. ( n=6) also canceled the depressor action of i.c.v. Ca 2+. Pretreatment with 100 μg of i.c.v. α-methyl- p-tyrosine could not prevent the depressor action of i.c.v. Ca 2+; however, 400 μg of α-ethyl- p-tyrosine administered i.c.v. abolished the effect of i.c.v. Ca 2+. Furthermore Ca 2+ channel blockers administered i.c.v. in themselves increased MAP in SHR ( P < 0.05). These results suggest that central Ca 2+ is involved in the central regulation of BP in SHR. This effect may be mediated through changes in sympathetic activity.

Dietary gamma-linolenic acid lowers blood pressure and alters aortic reactivity and cholesterol metabolism in hypertension.

To determine the effects of dietary gamma-linolenic acid upon blood pressure, aortic reactivity and cholesterol metabolism in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Randomized parallel-group study. SHR and WKY rats were fed a purified diet containing either sesame or borage oil rich in gamma-linolenic acid for 7 weeks. Blood pressure measured by the tail-cuff method and weight were monitored weekly. At the end of the study, intra-arterial pressor responses to norepinephrine and angiotensin II, and reactivity of isolated aortic rings to norepinephrine, angiotensin II, KCl and acetylcholine were determined. Serum cholesterol and triglycerides were measured. Hepatic and intestinal enzymes and receptors of cholesterol metabolism were also measured. Dietary borage oil significantly decreased blood pressure in SHR and WKY rats compared with sesame oil-fed rats. Pressor responses to norepinephrine and angiotensin II, and aortic reactivity to norepinephrine, angiotensin II, KCl and acetylcholine were not significantly different. The borage oil diet increased serum cholesterol levels in WKY rats and hepatic B-hydroxy-3-methylglutaryl coenzyme A reductase in SHR. These data indicate that dietary borage oil has a blood pressure lowering effect in hypertensive and normotensive rats. However, the effect cannot be explained by altered sensitivity to humoral and neural vasoconstrictors or changes in cholesterol metabolism. Other mechanisms should be investigated.