Comparison of angiotensin II-induced blood pressure and structural changes in Fischer 344 and Wistar Kyoto rats

1. The purpose of the present study was to evaluate the blood pressure (BP) response, the BP and heart rate (HR) components of the startle reaction and the structure of the carotid artery and the aorta during chronic infusion of angiotensin (Ang) II in Fischer 344 (F344) compared with Wistar Kyoto (WKY) rats, two in-bred normotensive contrasted strains. 2. Osmotic mini-pumps filled with saline vehicle or AngII (120 ng/kg per min) were implanted subcutaneously in 8-week-old normotensive rats and infused for 4 weeks in F344 rats (saline, n = 10; AngII, n = 10) and WKY rats (saline, n = 10; AngII, n = 9). Basal BP, HR and the responses to an acoustic startle stimulus (duration 0.7 s, 115 dB) were recorded in conscious rats. The structure of the carotid artery and aorta was determined in 4% formaldehyde-fixed arteries. 3. Compared with WKY rats, vehicle-treated F344 rats had lower bodyweight (BW; 266 +/- 7 vs 299 +/- 9 g; P < 0.05) and heart weight (0.80 +/- 0.02 vs 0.98 +/- 0.04 g; P < 0.05) and higher aortic systolic BP (SBP; 131 +/- 1 vs 123 +/- 5 mmHg; P < 0.001) and diastolic BP (98 +/- 3 vs 89 +/- 2 mmHg; P < 0.001). In F344 rats, compared with the WKY rats, the wall thickness/BW ratio was increased in the carotid artery (156 +/- 9 vs 131 +/- 6 nm/g; P < 0.05) and abdominal aorta (264 +/- 13 vs 217 +/- 12 nm/g; P < 0.05) and decreased in the thoracic aorta (246 +/- 13 vs 275 +/- 8 nm/g; P < 0.05). There was no difference in elastin and collagen density. Angiotensin II differentially enhanced BP in both strains: (SBP: 163 +/- 5 and 132 +/- 4 mmHg in F344 and WKY rats, respectively; P(strain x treatment) < 0.05). Circumferential wall stress was increased in the aorta of F344 rats compared with WKY rats (1176 +/- 39 vs 956 +/- 12 kPa (P < 0.001) and 1107 +/- 42 vs 813 +/- 12 kPa (P < 0.001) in thoracic and abdominal aortas, respectively). The startle response was amplified in F344 rats, with enhanced increases in SBP and pulse pressure (PP) and bradycardia compared with responses of WKY rats (+44 +/- 9 mmHg, +10 +/- 2 mmHg and -40 +/- 17 b.p.m., respectively, in F344 rats vs+28 +/- 4 mmHg, + 4 +/- 2 mmHg and -19 +/- 10 b.p.m. in WKY rats, respectively; P(strain) < 0.05 for BP and PP). The startle response was not affected by AngII. 4. These results indicate a higher BP producing an increase in wall thickness in F344 rats compared with WKY rats. We propose that an increase in sympathetic nervous activity causes these haemodynamic differences, as suggested by the excessive increase in BP during an acoustic startle stimulus. Angiotensin II increased BP in F344 rats, but did not exaggerate the increase in BP during the startle reaction.     

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.     

Sex differences in physical dependence on pentobarbital in four inbred strains of rats.

1. In Lewis (LEW), Fischer 344 (F344), Spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, pentobarbital (PB)-induced sleep time was much longer in female than in male rats. 2. At the time of awakening, brain levels of PB were significantly higher in the female F344 than in the male rats, but there was no sex differences in other strains. 3. Each strain of rats was treated with PB-admixed food for 47 days. There were significant sex differences in mean drug intake of the SHR and LEW strains, but not the WKY and F344 strains during the final concentration. 4. Only female rats exhibited moderate to severe motor impairment by PB. 5. After PB treatment ended, various signs of PB withdrawal occurred in female, but not male, rats. These marked sex differences were observed in all four inbred strains. 6. The sex differences in physical dependence on PB may be due mainly to differences in rates of drug metabolism for the LEW, SHR and WKY rats, and to differences in CNS sensitivity for the F344 rats.     

Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats

Fischer 344 (F344), Lewis (LEW), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were chronically fed food containing pentobarbital on an escalating drug dosage schedule over a period of 47 days. During treatment, the growth curve in LEW, SHR and WKY rats was suppressed as compared with the respective controls. Motor incoordination was evaluated by a rotarod performance test. The ranking of the motor incoordination was as follows: WKY much greater than LEW greater than SHR greater than F344. After substitution of normal food for the pentobarbital-admixed food, various signs of pentobarbital withdrawal occurred. The withdrawal signs from pentobarbital in F344, LEW and SHR rats were mild as compared with those in WKY rats. The order of the severity of withdrawal signs in four inbred strains was parallel to that for motor incoordination. These results suggest that the differences between strains in withdrawal can be attributed to differences in the degree of chronic CNS depression produced by pentobarbital.     

Changes in autonomic activity and baroreflex sensitivity with the hypertension process and age in rats

1. Autonomic activity and baroreflex sensitivity (BRS) were compared in age-matched conscious groups of Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. Male WKY rats, SHR and SHRSP aged 4-30 weeks were used. Autonomic activity and BRS were estimated by power spectral and cross-spectral analysis of systolic blood pressure (SBP) and SBP-SBP (SS) interval fluctuations, respectively. 3. The time-course of heart rate (HR), SBP, the amplitude of the low-frequency component of SBP fluctuation (SBP-LF; prazosin-sensitive index) and the amplitude of the high-frequency component of the SS interval fluctuation (SS-HF; atropine-sensitive index) consisted of two periods. In the first period (up to 10 or 15 weeks of age), BP, SBP-LF and SS-HF increased with age. The order of SBP-LF was SHRSP > SHR > WKY rats throughout this period. During the second period, BP was sustained at certain levels in all strains, but changes in SBP-LF and SS-HF with age were different among strains. In particular, in SHRSP, SBP-LF markedly decreased with age after 10 weeks. Baroreflex sensitivity in WKY rats increased gradually with age, whereas the BRS in SHR and SHRSP decreased before 6 weeks of age and remained lower than that in WKY rats. 4. In conclusion, the present study shows that both prazosin-sensitive and atropine-sensitive indices are associated with the elevation of BP in all strains studied. However, hypertension after 15 weeks of age in SHRSP is sustained despite a paradoxical reduction in sympathetic activity with an abnormal control of BRS. Therefore, the contribution of autonomic activity to hypertension may be discussed separately as a developmental period and a sustained period.     

Nitric oxide inhibition accelerates hypertension and induces perivascular inflammation in rats

1. Inflammatory changes in peripheral arteries have been reported in animal models of hypertension. Whether they occur in cerebral arteries (CA) with hypertension induced by deprivation of endogenous nitric oxide (NO) remains unknown. 2. In the present study, we compared the arteriolar injury score (AIS) and perivascular inflammation in CA between hypertensive and normotensive rats following NO deprivation with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Five-week-old male spontaneously hypertensive rats (SHR) and Wistar -Kyoto (WKY) rats were fed with L-NAME (1 mg/mL) for 4 weeks. 3. Nitric oxide deprivation resulted in time-dependent elevations in tail-cuff pressure (representing systolic blood pressure (SBP)) in both SHR and WKY rats. The magnitude of increase in SBP was larger in SHR (+81.0 +/- 3.2 vs+25.0 +/- 2.2 mmHg; P < 0.01). Arteriolar hyalinosis and AIS in various segments of the CA were assessed with periodic acid-Schiff staining and inflammatory cells were immunostained with the antibody against macrophage/monocyte marker (ED1). The ED1+ cells appeared in the middle CA of L-NAME-treated SHR as early as 2 weeks after treatment. These cells were not observed in L-NAME-treated WKY rats and untreated SHR. More ED1+ cells were found in L-NAME-treated SHR than L-NAME-treated WKY rats after 4 weeks treatment. 4. The AIS and number of ED1+ cells around the perivascular area of the internal carotid artery were significantly higher in L-NAME-treated compared with untreated rats (AIS: 137 +/- 28 vs 46 +/- 10 for WKY rats, respectively; 169 +/- 18 vs 53 +/- 6 for SHR, respectively (P < 0.01); ED1+ cells: 7.9 +/- 0.6 vs 1.3 +/- 0.9 for WKY rats, respectively; 13.6 +/- 2.7 vs 2.1 +/- 0.9 for SHR, respectively (P < 0.01)), although SBP was higher in untreated SHR than in L-NAME-treated WKY rats (170 +/- 4 vs 137 +/- 4 mmHg, respectively; P < 0.05). 5. These findings suggest that ED1+ cells appeared in the middle CA of L-NAME-SHR as early as 2 weeks after treatment. Chronic inhibition of NO accelerates hypertension and induces perivascular inflammation.     

Centrally produced neuronal nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and spontaneously hypertensive rats

We studied the effect of chronic nitric oxide synthase (NOS) blockade in the brain on mean arterial pressure [MAP (mmHg)], heart rate [HR (bpm)] and baroreceptor reflex sensitivity [BRS (mean slope: bpm/mmHg)] in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Intracerebroventricular (i.c.v.) infusion of the nonselective NOS inhibitor N-Nitro-L-arginine-methylester (L-NAME) (50 microg/kg per day, 11-12 days) increased MAP in WKY and SHR (125+/-2.1 vs 118+/-1.1 controls, P<0.01 and 179+/-3.59 vs 156+/-4.0 controls, P<0.001, respectively) without affecting HR. In L-NAME-treated WKY, BRS to bradycardia was suppressed (-0.79+/-0.09 vs -1.76+/-0.17 controls, P=0.001), whereas in SHR, L-NAME did not affect BRS to bradycardia. BRS to tachycardia remained unaffected in either strain. In WKY, 7-nitroindazole (7-NI x Na+) (34 microg i.c.v./kg per day, 11-12 days), a selective nNOS inhibitor, did not affect MAP or HR, but BRS to bradycardia and tachycardia was decreased (-0.37+/-0.20 vs -0.97+/-0.41 controls, P<0.01 and -1.78+/-0.20 vs -2.52+/-0.40 controls, P=0.05, respectively). In SHR, the same dose of 7-NI x Na+ increased resting MAP (171+/-5.00 vs 150+/-7.00 controls, P<0.05) without affecting HR or BRS to bradycardia or tachycardia. Thus in WKY, BRS to acute changes in systemic blood pressure (BP) is regulated by NO produced by nNOS in the brain, serving as a neurotransmitter in sympathetic and parasympathetic efferent pathways. In SHR, systemic BP is regulated in part by NO released by the type I NOS isoenzyme in the brain.     

Dissociation of blood pressure and sympathetic activation of renin release in sinoaortic-denervated rats

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.     

Differential amino acid transmission in the locus coeruleus of Wistar Kyoto and spontaneously hypertensive rats

In addition to differences in their blood pressure, Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are known to differ in their emotional behaviour. The neurochemistry underlying these differences is not well understood. In the present study the release rates of the two main regulatory amino acids in the locus coeruleus, glutamate and gamma-aminobutyric acid (GABA), were monitored in WKY rats and SHR to investigate whether basal and/or challenged neurotransmission differs between these strains. The strains differed in their basal blood pressure (WKY 102±2 mmHg, SHR 140±4 mmHg), as well as in their emotional behaviour, since WKY rats displayed enhanced anxiety-related behaviour in the open field test (time in centre: WKY 197±40 s/30 min, SHR 741±93 s/30 min). Basal glutamate and GABA release rates did not differ between WKY rats and SHR. A rise in blood pressure induced by intravenous infusion of noradrenaline for 10 min enhanced GABA release in WKY rats by 60%, while no effect was observed in SHR. Glutamate release did not respond to experimental hypertension in both strains. Intravenous infusion of sodium nitroprusside led to a fall in blood pressure, which was less pronounced and was of shorter duration in WKY rats than in SHR. The depressor response had no effect on amino acid release in the locus coeruleus of both strains. Mild stress induced by noise or tail pinch led to slight rises in arterial blood pressure (10 mmHg and 20 mmHg respectively), which were similar in WKY rats and SHR. Tail pinch enhanced the release rates of glutamate and GABA in the locus coeruleus of WKY rats and SHR; however, no strain differences were noted. Noise stress did not significantly influence amino acid release. These findings demonstrate that SHR and WKY rats differ in GABAergic neurotransmission, which is revealed in response to specific cardiovascular challenges, but not to mild stressors. The observed lack of GABA response to blood pressure elevation in SHR may reflect a disturbed mechanism counteracting high blood pressure, possibly contributing to hypertension in this strain.     

Reactivity and sensitivity of mesenteric vascular beds and aortic rings of spontaneously hypertensive rats to endothelin: effects of calcium entry blockers.

1. The vasoconstrictor effects of endothelin-1 were studied in perfused mesenteric vascular beds (MVB) and aortic rings of 14-16 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). 2. Reactivity to endothelin-1 was increased in MVBs of SHR, as indicated by the maximum perfusion pressure obtained (264 +/- 8 and 141 +/- 9 mmHg respectively) (P less than 0.001), whereas sensitivity was not significantly different between the two strains (EC50 171 +/- 21 and 102 +/- 19, respectively). 3. In aortic rings, in contrast, reactivity to endothelin-1 was reduced in SHR as compared to WKY, whereas sensitivity was similar (EC50 0.78 +/- 0.08 and 0.87 +/- 0.09 nM). 4. As with endothelin-1, reactivity to noradrenaline and potassium chloride was increased in MVBs, but not in aortic rings of SHR. Endothelin-1 was 30 times more potent than noradrenaline in MVBs of SHR, and 15 times more potent than noradrenaline in aortic rings. 5. In both strains, nifedipine and nitrendipine almost completely blocked potassium-induced contractions in MVB and aortic rings, respectively, whereas contractions induced by endothelin-1 or noradrenaline were only partially inhibited. 6. It is concluded that calcium influx via the voltage-operated calcium channel is only partially responsible for the vasoconstrictor action of endothelin-1 in MVBs and aortic rings of SHR and WKY rats. The increased reactivity of the MVB of SHR to endothelin-1 at this stage of the hypertensive process is most likely to be the result of a change in vascular structure rather than due to a primary hypertensive mechanism.     

Withdrawal reveals lack of effect of prolonged antihypertensive treatment on intrinsic aortic wall stiffness in senescent spontaneously hypertensive rats

1. Chronic antihypertensive treatment lowers cardiovascular morbidity and mortality. The beneficial effect on the blood vessel wall may be due to the lowering of blood pressure (BP) and, hence, wall stress (WS), or to a treatment-induced change in wall structure. 2. We have previously shown that, when evaluated at the same level of BP and WS, the stiffness of the aortic wall of old spontaneously hypertensive rats (SHR) is higher than that of young and adult SHR and that of age-matched Wistar-Kyoto (WKY) rats. In the present study, we tested the hypothesis that the intrinsic changes in wall composition and mechanics in old SHR can be modulated by long-term treatment with an angiotensin I-converting enzyme inhibitor (captopril; 40 mg/kg per day) combined with a diuretic (hydrochlorothiazide; 20 mg/kg per day) and that treatment withdrawal would reveal whether such changes are maintained when BP and WS return to pretreatment levels. 3. We evaluated aortic structure and mechanics in SHR following 1 week withdrawal of oral antihypertensive treatment from 3 to 15 months of age (n = 8). Results were compared with age-matched SHR that were maintained on treatment (n = 12) or were not treated (n = 13) and with WKY rats (no treatment n = 11; maintained n = 11; withdrawn n = 10). 4. Isobaric aortic wall stiffness was estimated from the ratio of baseline aortic pulse wave velocity (PWV) to BP and the slope relating aortic PWV to BP following sodium nitroprusside-induced hypotension. Relative wall stiffening was estimated as the ratio of elastic modulus (EM) to WS. We argued that if treatment produced a change in wall elastin or collagen content, with a subsequent decrease in isobaric wall stiffness, then this would be maintained when BP increased following withdrawal of treatment. 5. In old SHR, treatment lowered isobaric wall stiffness (baseline PWV/BP 4.6 +/- 0.3 cm/s per mmHg; slope relating PWV to BP 6.7 +/- 0.4 x 10-3 cm/s per mmHg and EM/WS 4.1 +/- 0.4 vs 6.1 +/- 0.4 cm/s per mmHg, 9.7 +/- 0.9 x 10-3 cm/s per mmHg and 8.9 +/- 1.1, respectively, without treatment; all P < 0.05). After 1 weeks treatment withdrawal, the indices (5.7 +/- 0.2 cm/s per mmHg, 9.1 +/- 0.2 x 10-3 cm/s per mmHg and 7.2 +/- 0.6) increased in parallel with the increase in WS to levels similar to those observed in untreated SHR. There were no significant differences among the WKY rat groups. 6. Treatment increased the elastin and collagen contents of the aortic wall in both SHR (196 +/- 13 and 128 +/- 5 vs 111 +/- 9 and 86 +/- 4 mg/g wet weight, respectively, in untreated; P < 0.05) and WKY rats (190 +/- 19 and 135 +/- 4 vs 115 +/- 7 and 114 +/- 5 mg/g wet weight, respectively, in untreated; P < 0.05). This increase remained following withdrawal (213 +/- 26 and 118 +/- 4 vs 161 +/- 14 and 127 +/- 4 mg/g wet weight in SHR and WKY rats, respectively). 7. In summary, 1 year of treatment with captopril plus hydrochlorothiazide increases wall elastin content and reduces WS and stiffness in old SHR. Following withdrawal, elastin content remains high, but wall stiffness parallels WS in a manner similar to that in untreated SHR.     

22Na+ and 86Rb+ transport in vascular smooth muscle of SHR, Wistar Kyoto, and Wistar rats

To gain further insight into differences in cellular Na+ and K+ regulation between the spontaneously hypertensive rat (SHR), Wistar Kyoto (WKY), and American Wistar (W) rats, 22Na+ and 86Rb+ washouts were performed under steady-state conditions in cultured vascular smooth muscle cells from the three rat strains. SHR vascular smooth muscle cells showed significantly higher bumetanide sensitive 86Rb+ washout rate constant (x 10(-4)/min; mean +/- SEM) than WKY cells (-38.6 +/- 2.84 and -23.8 +/- 3.58, respectively; p less than 0.005). SHR vascular smooth muscle cells also exhibited significantly higher values than WKY cells in the total 22Na+ washout rate constant (x 10(-2)/min) (-61.0 +/- 1.57 vs. -53.8 +/- 1.24; p less than 0.005). The amiloride sensitive component of the 22Na+ washout rate constant accounted for these differences (-18.6 +/- 1.04 for SHR and -12.1 +/- 2.00 for WKY; p less than 0.05). There were no apparent differences in cellular Na+ concentrations between WKY and SHR cells. In general, the 86Rb+ and 22Na+ washout parameters of W rat cells were quite similar to those of cells from SHR. We conclude that the bumetanide-sensitive 86Rb+ washout (the Na+ K+-cotransport), the overall, and the amiloride-sensitive 22Na+ washout (the latter primarily represents the Na+/H+ antiport) are higher in SHR than WKY rat vascular smooth muscle cells. These findings indicate innate differences in cellular Na+ and K+ transport in vascular smooth muscle cells of the SHR and WKY rat. The mechanisms responsible for these differences are yet to be determined.     

Delayed hypotensive effect of the thromboxane A2/prostaglandin H2 receptor antagonist S-1452 in spontaneously hypertensive rats

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.     

PERTUSSIS TOXIN-SENSITIVE G-PROTEINS AND REGULATION OF BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Increased Gi-protein-mediated receptor-effector coupling in the vasculature of the spontaneously hypertensive rat (SHR) has been proposed as a contributing factor in the maintenance of elevated blood pressure. If increased Gi-protein-mediated activity plays an important role in hypertension in SHR, then inhibition of Gi-proteins by pertussis toxin would be expected to decrease blood pressure in this genetic hypertensive model. To address this hypothesis, studies were undertaken comparing the cardiovascular effects of pertussis toxin in SHR and normotensive Wistar-Kyoto (WKY) rats. 2. Spontaneously hypertensive and WKY rats were instrumented with radiotelemetry devices and blood pressure measurements were recorded in conscious rats. Following a single injection of pertussis toxin (10 micrograms/kg, i.v.), mean arterial blood pressure fell from 161 +/- 3 to 146 +/- 1 mmHg in the SHR and the effect was sustained for more than 2 weeks. In contrast, 10 micrograms/kg, i.v., pertussis toxin produced no significant effect on blood pressure in WKY rats (103 +/- 4 vs 101 +/- 5 mmHg). 3. In a separate study, SHR and WKY rats were administered 30 micrograms/kg, i.v., pertussis toxin or 150 microL/kg, i.v., saline and, 3-5 days later, rats were anaesthetized and instrumented to permit measurement of blood pressure and renal function. At this higher dose, pertussis toxin reduced blood pressure in both strains of rat, although the effect was markedly greater in SHR (approximately 40 mmHg decrease) compared with WKY rats (approximately 15 mmHg decrease). In SHR, pertussis toxin increased renal blood flow (from 5.7 +/- 0.3 to 7.5 +/- 0.8 mL/min per g kidney) and decreased renal vascular resistance (from 31 +/- 2 to 19 +/- 2 mmHg/mL per min per g kidney). In WKY rats, pertussis toxin had no significant effect on renal parameters. 4. Results from these studies indicate that a pertussis toxin-sensitive Gi-protein-mediated pathway contributes to the maintenance of hypertension and elevated renal vascular tone in the SHR.     

The effect of medetomidine, an alpha 2-adrenoceptor agonist, on plasma atrial natriuretic peptide levels, haemodynamics and renal excretory function in spontaneously hypertensive and Wistar-Kyoto rats.

1. The effects of the selective alpha 2-adrenoceptor agonist, medetomidine, were assessed on plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP), haemodynamics and on urine water and solute excretion in conscious, chronically cannulated, 7 month-old spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats, in order to examine the role of alpha 2-adrenoceptors in the control of ANP secretion. 2. A 60 min i.v. infusion of medetomidine (0.2 or 0.6 microgram kg-1 min-1) decreased heart rate dose-dependently in both strains. Medetomidine infusion (0.6 microgram kg-1 min-1) resulted in an increase in mean arterial pressure in WKY, whereas both doses decreased blood pressure in SHR. There was a slight increase in the right atrial pressure in both strains (WKY: +1.18 +/- 0.26 mmHg; SHR: +1.64 +/- 0.64 mmHg, NS) in response to infusion of 0.6 microgram kg-1 min-1 of medetomidine. 3. No differences were found in resting plasma IR-ANP levels between WKY (114 +/- 8 pg ml-1, n = 19) and SHR (117 +/- 10 pg ml-1, n = 21). Infusion of equibradycardic doses of medetomidine increased dose-dependently plasma IR-ANP levels in WKY, but did not affect the plasma IR-ANP concentration in SHR rats. 4. Despite the different effect of medetomidine on ANP release in WKY and SHR rats, i.v. administration of medetomidine affected renal excretory functions similarly in both strains; urine flow and sodium excretion increased and urine osmolality decreased significantly, while there was no consistent change in urinary potassium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes of brain endothelin levels and peripheral endothelin receptors by chronic cigarette smoke in spontaneously hypertensive rats

The present study was conducted to evaluate the contribution of endothelin (ET) to the pharmacodynamic response to chronic cigarette smoke in spontaneously hypertensive rats (SHR). The contribution of ET was studied consequent to the hemodynamic response following 8 weeks of cigarette smoke by determining the changes in tissue ET-1 content and ET receptors. The blood pressure (BP) at the early phase of smoking and the heart rate (HR) 24 h later were apparently reduced in SHR, while the HR at the early phase was transiently elevated in normotensive Wistar Kyoto (WKY) rats. Tissue ET-1 levels in the hypothalamus, striatum, and cortex of SHR were higher than those in WKY rats, and these higher levels in SHR were reduced by exposure to chronic cigarette smoke. The ET-1 contents in the medulla oblongata and midbrain of both strains were clearly increased by smoke exposure, although the levels of SHR and WKY rats were not different. In addition, the immunoreactivity of the ET type A receptor in the adrenal glands and type B receptor in the kidneys of SHR showed a different response to smoke exposure as compared to WKY rats. Our present findings suggest that the changes of ETs may relate to the pharmacodynamic effects of chronic cigarette smoke.     

Upregulated function of phosphatidylinositol-3-kinase in genetically hypertensive rats: a moderator of arterial hypercontractility

1. The growth enzyme phosphatidylinositol 3-kinase (PI3K) was recently implicated in the mediation of arterial spontaneous tone, an event observed in arteries from hypertensive, but not normotensive, subjects that contributes to changes in total peripheral resistance in the hypertensive state. We have shown this occurrence in experimentally induced models of hypertension. However, because the majority of hypertension is genetically based, it is important to demonstrate a similar change in genetically hypertensive animals. 2. Aorta from spontaneously hypertensive rats (SHR; systolic blood pressure = 183 +/- 4 mmHg) and Wistar Kyoto (WKY) rats (115 +/- 2 mmHg) were isolated for the measurement of isometric contractile force. Aorta from SHR displayed small increases (approximately 5% maximum phenylephrine (PE)-induced contraction) in spontaneous tone, whereas aorta from WKY rats displayed none. The non-selective PI3K inhibitor LY294002 (20 micromol/L) and the selective inhibitor of the p110delta catalytic subunit of PI3K IC87114 (20 micromol/L) caused a fall of basal tone in SHR aorta (20 +/- 7 and 24 +/- 6% of the initial PE contraction, respectively), but did not alter tone in arteries from WKY rats. LY294002, but not IC87114, normalized the increased potency of noradrenaline (NA) observed in aorta from SHR (-log EC50 values for NA in the presence of vehicle in WKY rats and SHR 7.5 +/- 0.1 and 7.8 +/- 0.1, respectively (P < 0.05); -log EC(50) values for NA in the presence of LY294002 in WKY rats and SHR 7.0 +/- 0.1 and 7.0 +/- 0.1, respectively). 3. Biochemical expression of the p110 catalytic and p85 regulator subunits of PI3K in western analyses revealed no difference in expression of the regulatory p85alpha or p110alpha protein subunits between WKY rats and SHR; p110gamma was not detected. In contrast, p110delta expression was increased greater than 30% in aorta from SHR compared with WKY rats (827.6 +/- 88.5 vs 576.8 +/- 53.4 arbitrary densitometry units, respectively). Immunohistochemical analyses revealed expression of the p110delta isoform in the smooth muscle of arteries. 4. These data underscore the relevance of an enzyme historically classified as one committed to growth/anti-apoptosis in modifying contractility and supports involvement of PI3K in genetically based hypertension.     

Tyrosine kinase inhibition attenuates vasopressin-induced contraction of mesenteric resistance arteries: alterations in spontaneously hypertensive rats

This study examined the role of tyrosine kinase-dependent signaling pathways in arginine vasopressin (AVP)-induced contractile responses in resistance arteries from spontaneously hypertensive rats (SHR). Systolic blood pressure was measured in conscious 6- and 21-week old SHR and Wistar Kyoto rats (WKY) by tail cuff measurements. Segments of third-order mesenteric arteries (about 200 microm in diameter, 2mm in length) were mounted in a pressurized chamber with the intraluminal pressure maintained at 45 mmHg. Contractile effects of AVP (10-12 to 10-7 mol/l) were determined in the absence and presence of the selective tyrosine kinase inhibitor tyrphostin A23 (10-5 mol/l) and the inactive analogue, tyrphostin A1 (10-5 mol/l). Systolic blood pressure was significantly higher in SHR compared with age-matched WKY (p < 0.01). AVP increased contraction in a dose-dependent manner with significantly greater responses in adult SHR (pD2 = 10.3 +/- 0.06) than age-matched WKY (pD2 = 9.4 +/- 0.04). Tyrphostin A23 shifted the AVP dose response curve to the right in 6- and 21-week WKY and 6-week SHR, but had little effect on AVP-induced responses in 21-week-old SHR. Tyrphostin A1 did not influence contraction in any groups. Protein tyrosine phosphorylation in VSMCs and mesenteric arteries was increased 2-3 fold in 21-week SHR compared with WKY counterparts. AVP significantly increased tyrosine phosphorylation in VSMCs, with enhanced effects in SHR compared with WKY (p < 0.05). These effects were inhibited by tyrphostin A23. Our findings demonstrate that protein tyrosine kinases contribute to AVP-induced contraction of resistance arteries from WKY and SHR during the phase of developing hypertension. These processes do not seem to play an important role in AVP-induced hypercontractility in SHR with established hypertension.     

Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder

The validity of the Spontaneously Hypertensive rat (SHR) as a model for Attention Deficit Hyperactivity Disorder (ADHD) is explored by comparing the SHR with Wistar-Kyoto (WKY) and Wistar rats in a number of different tests. In the open field, SHR are hyperactive compared to both Wistar and WKY, but only at specific ages. At those ages, methylphenidate (1mg/kg) did not attenuate hyperactivity. Subsequently, a dose response study of methylphenidate (0.1-10mg/kg) was conducted in the Differential Reinforcement of Low-rate responding (DRL)-72s and five-choice serial reaction time tests (5-CSRTT). Compared to WKY but not Wistar rats, SHR performed worse on the DRL-72s. Performance was not improved by methylphenidate (0.1-1.0mg/kg). In the 5-CSRTT, attentional performance was similar for all rat strains, but Wistar rats made more impulsive responses than both the SHR and the WKY. Methylphenidate only attenuated impulsivity in Wistar rats. Because SHR do not consistently display symptoms of ADHD across the different tests, and methylphenidate effects were observed in both WKY and Wistar rats, but not in SHR, we conclude that SHR is not a representative animal model for ADHD.