Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.     

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats.

Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo.     

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats during development of hypertension

Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats (SHR) during development of hypertension were investigated using in vivo and in vitro methods. Plasma ACTH responses to hemorrhage and ether stress were significantly smaller in 7-week-old SHR than in age-matched Wistar-Kyoto rats (WKY), while plasma corticosterone baseline levels and its response to stress were greater in SHR than in WKY. There was no significant difference in the plasma ACTH response to ether stress between bilaterally adrenalectomized SHR and WKY replaced with a 25% corticosterone pellet for 6 days. Adrenalectomy prevented the development of hypertension in SHR; however, corticosterone replacement restored hypertension. Plasma ACTH showed a smaller response to iv CRH injection in SHR than in WKY, while the ACTH response to arginine vasopressin was not different between SHR and WKY. CRH concentrations in the median eminence, posterior pituitary, and cerebral cortex were lower in SHR than in WKY, while the CRH concentration in the median eminence was not different in SHR and WKY when they were adrenalectomized with or without corticosterone replacement. Basal in vitro CRH release from hypothalamic tissue was reduced in SHR, while CRH release in response to 56 mM KCl was not different in SHR and WKY. These results suggest that adrenocortical function is enhanced in young SHR, that reduced ACTH response to stress and exogenous CRH in SHR may be ascribed to higher plasma corticosterone levels, and that corticosterone is essential for the development of hypertension in SHR.     

Renal xanthine oxidoreductase activity during development of hypertension in spontaneously hypertensive rats

BACKGROUND: Hyperuricaemia and reactive oxygen species have recently been associated with essential hypertension. Xanthine oxidoreductase (XOR) produces urate and, in its oxidase isoform, reactive oxygen species also. Our previous studies indicated that hypertension-prone rat strains have greater renal XOR activity than their normotensive counterparts, and that dietary sodium modifies renal XOR activity. OBJECTIVE: To clarify whether renal XOR induction precedes or follows the development of hypertension. METHODS: Five-week-old spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were kept for 3-8 weeks on low sodium (0.3% salt w/w) or high sodium (6.0% salt w/w) intakes, with or without allopurinol, an inhibitor of XOR, to study the possible pathogenetic role of XOR in hypertension. Systolic blood pressure (SBP), renal XOR activity and mRNA expression were measured. RESULTS: Regardless of sodium intake, renal XOR activity increased twofold during growth in SHRs, but not in WKY rats. SBP increased from 122 +/- 4 to 241 +/- 13 mmHg in SHRs kept on the high-sodium diet and to 204 +/- 11 mmHg in those on the low-sodium diet. At the end of the experiment, renal XOR activity correlated with SBP in SHRs. Allopurinol prevented hypertension-induced left ventricular and renal hypertrophy in SHRs, but had negligible effect on blood pressure. CONCLUSION: Renal XOR induction in SHRs does not precede the development of hypertension, but progress concomitantly with an increase in SBP. The results indicate a role for locally synthesized XOR in the development of hypertension-associated end-organ damage, but no major role in the development of hypertension.     

Impaired collateral artery development in spontaneously hypertensive rats

OBJECTIVE: To determine whether collateral artery development is impaired in spontaneously hypertensive (SHR) relative to normotensive (WKY) rats. METHODS: Sequential mesenteric arteries were ligated to create a collateral pathway responsible for the perfusion of approximately 50 first-order arterioles. Collateral development was assessed by measurement of in vivo arterial diameter before and 1 week after ligation. Histological and morphometric measurements were made from cross-sectional preparations of these arteries to evaluate intimal and medial cell numbers and medial area. eNOS expression was evaluated with Western blotting. RESULTS: One week after arterial ligation, collateral diameter was increased more in WKY than SHR both absolutely (137 +/- 9.1 versus 99 +/- 8.6 microm) and relative to same-animal controls (38 +/- 5.5% versus 13 +/- 7.1%). At the time of model creation, blood flow was elevated to comparable levels in both WKY and SHR, and wall shear rate in the SHR collateral was greater than both the SHR control and WKY collateral arteries. Endothelial cell number in arterial cross-section was increased in collaterals by 80% in WKY and only 22% in the SHR. eNOS expression was increased in the WKY (128%) but not in the SHR collateral. CONCLUSIONS: For equivalent arterial occlusion, the data demonstrate that collateral development is suppressed in the SHR as indicated by luminal expansion. This impairment of luminal expansion is associated with a decreased endothelial proliferation and the lack of an increase in eNOS expression.     

Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension

OBJECTIVES: Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats. METHOD: NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner. RESULTS: NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity. CONCLUSION: Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.     

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

Summary 1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4,10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.     

Inhibitors of Na+/Mg2+ exchange activity attenuate the development of hypertension in angiotensin II-induced hypertensive rats

OBJECTIVES: To investigate whether imipramine and quinidine, inhibitors of the Na /Mg exchanger, influence development of hypertension in rats infused with angiotensin (Ang) II. METHODS: Sprague-Dawley rats were divided into six groups: (1) control (vehicle); (2) Ang II (150 ng/kg per min subcutaneously); (3) imipramine alone (5 mg/kg per day in drinking water); (4) quinidine alone (5 mg/kg per day in drinking water); (5) Ang II plus imipramine; (6) Ang II plus quinidine. Rats were studied for 3 weeks. To verify that Ang II directly influences Na -dependent Mg exchange, in-vitro studies were performed in vascular smooth muscle cells (VSMCs) derived from mesenteric arteries. RESULTS: Ang II increased systolic blood pressure (SBP) in all groups. The magnitude of the increase was lower ( 0.01) in Ang II groups treated with imipramine (151 +/- 7.4 mmHg) or quinidine (163 +/- 4 mmHg) than in the Ang II only group (205 +/- 4 mmHg). Neither imipramine nor quinidine influenced SBP in vehicle-treated rats. Plasma concentrations of Mg and K were decreased in Ang II rats compared with controls (P < 0.05). Platelet intracellular free Mg concentration was reduced and platelet intracellular free Na concentration was increased in the Ang II group compared with control and treated groups (P < 0.01). These effects were normalized by imipramine and quinidine. Ang II stimulated Na -dependent Mg transport in VSMCs. These actions were abrogated by imipramine and quinidine and in Na -free conditions. CONCLUSIONS: Our data demonstrate that inhibitors of Na -dependent Mg transport attenuate development of hypertension in rats infused with Ang II. These findings suggest a possible role for Na /Mg exchange activity in the pathogenesis of Ang II-dependent hypertension.     

Thymectomy delays the development of hypertension in Okamoto spontaneously hypertensive rats

Previous studies in rats have demonstrated that immune system dysfunction contributes to the aetiology of spontaneous hypertension. Chronic immunosuppression with cyclophosphamide attenuated the level of hypertension in Okamoto spontaneously hypertensive rats (SHR) by approximately 50%. Also, neonatal thymic implants delayed the development of spontaneous hypertension and significantly attenuated its level at the age of 22 weeks in SHR. In the present study, the effect of thymectomy at the age of 4 weeks on blood pressure was investigated in SHR and Wistar-Kyoto (WKY) rats. The removal of the thymus gland in 4-week-old SHR produced a significant reduction in systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and mean arterial pressure (MAP) when rats were 16-19 weeks old, while no pressure reduction was observed in WKY rats. The decrease in arterial pressure of 16-week-old SHR was associated with a significant reduction in lymphocyte count at this age as compared with the control group. In 1-year-old SHR, thymectomized at the age of 4 weeks, there was no significant difference in arterial pressure or lymphocyte count compared with controls. These data support the hypothesis that an immune imbalance may be important in the development of spontaneous hypertension. We conclude that thymectomy at a young age (4 weeks) delays the development of hypertension in SHR.     

Proximal tubular fluid angiotensin II levels in angiotensin II-induced hypertensive rats

BACKGROUND: It has been shown that infusions of low-dose angiotensin II (Ang II) for 2 weeks lead to impaired pressure natriuresis and autoregulatory capability. Although intrarenal renin content and renin mRNA levels are markedly reduced, whole-kidney Ang II content has been shown to be increased. However, the intrarenal distribution of the increased intrarenal Ang II has not been established. OBJECTIVE: To determine the concentrations of Ang II in the proximal tubule fluid achieved in hypertensive rats (n = 16) infused with Ang II, previously prepared by infusion with Ang II at 60 ng/min via osmotic minipump for 13 days. METHODS: Rats were anesthetized with pentobarbital sodium and prepared for micropuncture, and then several free-flow proximal tubular fluid collections were obtained and pooled for each rat. At the end of each experiment, a blood sample was collected and the micropunctured kidney was excised and homogenized in chilled methanol. All samples were extracted immediately after collection and stored at 20 degrees C until the day of Ang II radioimmunoassay. RESULTS: Mean arterial blood pressure averaged 179 +/- 3 mmHg, renal plasma flow was 1.89 +/- 0.15 ml/min per g, and glomerular filtration rate averaged 0.58 +/- 0.04 ml/min per g. The Ang II concentration in proximal tubular fluid averaged 4.5 +/- 1.1 pmol/ml, a value substantially greater than the Ang II concentrations in plasma (0.17 +/- 0.03 pmol/ml), urine (0.06 +/- 0.01 pmol/ml), or total kidney tissue (0.40 +/- 0.10 pmol/g). Plasma renin activity (1.0 +/- 0.21 ng Ang I/ml per h) was markedly suppressed, as observed previously.CONCLUSIONS These findings indicate that Ang II concentrations in proximal tubular fluid collected from kidneys of anesthetized hypertensive rats infused with Ang II are in the nanomolar range, similar to those observed in normotensive rats. The inappropriate maintenance of nanomolar concentrations of Ang II in proximal tubular fluid of Ang II-infused hypertensive rats, even at markedly increased arterial pressures, may contribute to the impaired pressure natriuresis capability previously reported and, thereby, to the development and maintenance of hypertension in this model.     

Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats

In order to determine whether the morphological modifications observed in arterial media of spontaneously hypertensive rats (SHR) could be induced by an abnormal response of the smooth muscle cells to vasoactive agents, we studied the action of angiotensin (Ang) II on cultured aortic smooth muscle cells from both SHR and Wistar-Kyoto rats (WKY). Under our experimental conditions, Ang II exerts a mitogenic action on SHR cells, whereas its effect is very weak on WKY cells. Phospholipase C activation and c-fos and c-myc proto-oncogene expressions induced by Ang II are considerably enhanced in SHR cells, and these abnormalities may be linked to an increased number of Ang II receptors.     

Altered responsiveness of proximal tubule fluid reabsorption of peritubular angiotensin II in spontaneously hypertensive rats

Stimulation of proximal tubular fluid reabsorption by peritubular angiotensin II (Ang II) was examined by split-drop micropuncture in 5- and 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). In WKY, the maximum stimulation occurred at 10(-11) mol/l and the response did not vary with age. In 5-week-old SHR, the dose-response relationship was similar in shape and in the extent of the maximum response but was shifted one half-logarithmic step to the right, indicating decreased sensitivity to Ang II. In contrast, the dose-response relationship was shifted one half-logarithmic step to the left in 12-week-old SHR compared with WKY. Alterations in the responsiveness of the proximal tubule to Ang II in young SHR could contribute to sodium retention observed during development of hypertension in these rats.     

Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.     

The effect of thymectomy on the development of hypertension in spontaneously hypertensive rats

We studied the effect of thymectomy on the development of hypertension in spontaneously hypertensive rats (SHR). There were no significant differences between thymectomized and sham thymectomized SHR during either the initial or chronic phase of spontaneous hypertension. Similarly, administration of anti-Thyl. 1 or anti-T sera did not influence the blood pressure in SHR during the chronic phase. The results suggest that the thymus does not play a direct role in the development and maintenance of blood pressure in SHR.     

Immunisation of spontaneously hypertensive rats against angiotensin I

Immunization against angiotensin I has been considered in comparison with the immunization against renin, in the spontaneously hypertensive rat (SHR). Among 6 different methods of immunization, two (AI-gluta-LPH and AI-Carbo-LPH coupling) permitted to obtain high levels of antibodies against angiotensin I (higher than 1/10,000), after four injections of 50 micrograms AI at three weeks interval. The titration of the antibodies was realized in radio-immuno-assay (RIA), with the determination of the cross-reactivity with AII by the same method. Characterization of the isotypes and the affinity calculation were realized with the ELISA method. The average level of antibodies is about 1/10,000 to 1/100,000, and the cross reactivity of the antibodies for AII is about 0.1 p. 100 in RIA. In ELISA, the study of the different isotypes shows a good maturation of the immune system with a sharp elevation of the IgG1 and IgG2 alpha isotypes, after 2 or 3 injections. The affinity of the antibodies purified by affinity chromatography is about 10.3 10(-9) M. The weekly measure of the arterial pressure during 6 months does not reveal at any moment a fall of pressure during the immunizations. The average pressure of the immunized group (209.4 +/- 23.8 mmHg, n = 40) is non significantly different from the average pressure of the mock group (208.5 +/- 22.6 mmHg, n = 10).     

Impairment of atypical beta-adrenergic-mediated relaxation in spontaneously hypertensive rats before and during the development of arterial hypertension

The aims of this study was to characterize the functional response of atypical beta-adrenoceptors (beta-AR) in rat aorta and to investigate whether this relaxation was altered before and during the development of hypertension. Aortic rings from 4 or 12 weeks old Wistar Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta-AR agonists were constructed. In intact aortic rings from 12 weeks old WKY rats, CGP 12,177 (CGP) and cyanopindolol (partial beta 3-AR agonists and atypical beta-AR agonists with beta 1/beta 2-AR antagonist properties) produced concentration-dependent relaxation (pD2 = 5.09 +/- 0.03; Emax = 60.4 +/- 2.5%; n = 9; pD2 = 6.17 +/- 0.05; Emax = 95.9 +/- 1%; n = 5 respectively). The endothelium removal did not modify this relaxation. In 12 weeks old WKY rats, the endothelium-independent relaxation to CGP was not modified in the presence of nadolol (beta 1/beta 2-AR antagonist) or L-748 337 (beta 3-AR antagonist) excluding the participation of beta 1, beta 2 et beta 3-AR in this effect. By contrast, this relaxation was significantly inhibited by CGP 20712A or bupranolol, atypical beta-AR antagonists at high concentrations. In 12 weeks old SHR, endothelium-independent relaxation to CGP or cyanopindolol was greatly inhibited. In order to sought out whether impairment of atypical beta-AR-mediated relaxation was due to hypertension, experiments were performed in 4 weeks old SHR. At this age, CGP-induced relaxation was greatly inhibited compared to that obtained in age-matched WKY rats. In 12 weeks old SHR pretreated with pertussis toxin (10 micrograms/kg i.p./3 days), the relaxant effect to CGP was partly restored. We conclude that the atypical beta-AR were functionally expressed in aortic vascular smooth muscle cells of rat aorta. In 4 or 12 weeks old SHR rats, atypical beta-AR-mediated relaxation was impaired, suggesting that this dysfunction occurs before the establishment of hypertension. Gi proteins may be one of the factors that contributes to this impairment.     

Baroreceptor denervation prevents sympathoinhibition during angiotensin II-induced hypertension

Arterial baroreflexes are well established to provide the basis for short-term control of arterial pressure; however, their role in long-term pressure control is more controversial. We proposed that if the sustained decrease in renal sympathetic nerve activity (RSNA) we observed previously in response to angiotensin II-induced hypertension is baroreflex mediated, then the decrease in RSNA in response to angiotensin II would not occur in sinoaortic-denervated (SAD) animals. Arterial pressure and RSNA were recorded continuously via telemetry in sham and SAD rabbits living in their home cages before, during, and after a 7-day infusion of angiotensin II (50 ng . kg(-1) . min(-1)). The arterial pressure responses in the 2 groups of rabbits were not significantly different (82+/-3 mm Hg sham versus 83+/-3 mm Hg SAD before angiotensin II infusion, and 101+/-6 mm Hg sham versus 100+/-4 mm Hg SAD day 6 of angiotensin II). In sham rabbits, there was a significant sustained decrease in RSNA (53+/-7% of baseline on day 2 and 65+/-7% on day 6 of the angiotensin II). On ceasing the angiotensin II, all variables recovered to baseline. In contrast, RSNA did not change in SAD rabbits with the angiotensin II infusion (RSNA was 98+/-8% of baseline on day 2 and 98+/-8% on day 6 of the angiotensin II infusion). These results support our hypothesis that the reduction in RSNA in response to a pressor dose of angiotensin II is dependent on an intact arterial baroreflex pathway.     

Cyclic GMP formation of resistance vessel in the development of hypertension in spontaneously hypertensive rats.

We investigated the basal levels and responses of cyclic GMP (cGMP) derived from perfused mesenteric arteries to acetylcholine (ACh) and sodium nitroprusside (SNP) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) at different ages, in order to evaluate the basal and stimulated release of endothelium-derived relaxing factor (EDRF) from the resistance vessel during the development of hypertension. The mesenteric arteries were removed from 8-, 12- and 20-week-old WKY and SHR, and were perfused with Krebs-Henseleit solution containing 0.2 mM isobutyl methyl xanthine. The effluents from the perfused arteries were corrected before and after infusions of graded doses of ACh or SNP, and the levels of cGMP were measured. The basal levels of cGMP from the mesenteric arteries in the 12- and 20-week-old SHR were significantly lower than those in age-matched WKY. A negative correlation was observed between the basal levels of cGMP and the systolic blood pressure in SHR, but not in WKY, among all ages. On the other hand, there were no differences in the responses of cGMP to infusion of ACh between the WKY and SHR at each age. Moreover, the responsiveness of cGMP to infusion of SNP in the 12-week-old SHR was much higher than that in age-matched WKY. These data suggest that the basal cGMP formation in the arteries which may reflect the basal release of EDRF is reduced in older SHR and is associated with the development of hypertension, and that the stimulated release of EDRF is not associated with the development of hypertension.