1 We employed the technique of impedance spectral analysis to investigate the role of endogenous nitric oxide (NO) in the regulation of steady and pulsatile haemodynamics in Wistar Kyoto rat (WKY). 2 A total of 12 WKYs was anaesthetized with pentobarbitol sodium (40 mg kg 71 , i.p.) and arti®cially ventilated with an animal respirator. The aortic pressure wave was monitored with a high ®delity Millar sensor, and aortic¯ow wave with an electromagnetic¯ow probe. The pressure and¯ow waves were subjected to Fourier transform for the analysis of impedance spectra. 3 The baseline cardiovascular parameters were mean arterial pressure (APm) 95+9 mmHg, heart rate (HR) 338+9 b.p.m., stroke volume (SV) 0.23+0.01 ml, cardiac output (CO) 77.8+1.6 ml min 71 , total peripheral resistance (TPR) 98+11 (610 3 ) dyne s cm 75 , characteristic impedance (Zc) 2046+141 dyne s cm 75 , arterial compliance at mean AP (Cm) 3.78+0.22 ml mmHg 71 and backward pulse wave (P b ) 12.9+0.6 mmHg. 4 An NO synthase inhibitor, N G -nitro-L-arginine monomethyl ester (L-NAME) was administered at graded intravenous doses. This agent caused dose-dependent increases in AP and TPR with decreases in HR. At an accumulative dose of 10 mg kg 71 , APm was increased by 29+3 mmHg (+31%) and TPR by 49+6 (610 3 ) dyne s cm 75 (+50%), while HR was reduced by 37+5 b.p.m. (711%) and CO by 10.4+0.8 ml min 71 (714%). The pulsatile haemodynamics including Zc and P b were slightly increased by 14 ± 15%. Cm was decreased by 1.09 ml mmHg 71 (729%). L-NAME also did not signi®cantly a ect the ventricular work including the steady, oscillatory and total work. 5 Aminoguanidine, a speci®c inhibitor for inducible NO synthase (iNOS), in dose 10 ± 60 mg kg 71 i.v. did not alter the AP, HR and other parameters. The result indicated that blockade of constitutive NOS, but not iNOS is involved in these changes. 6 Angiotensin II (Ang) in various infusion doses was used to produce a pro®le of AP increase similar to that caused by L-NAME. Ang remarkably increased Zc, while TPR was moderately elevated. The pattern of haemodynamic changes was di erent from that following L-NAME. 7 The results suggest that blockade of the endogenous NO a ects predominantly the arterial pressure and peripheral resistance. The Windkessel functions such as arterial impedance and pulse wave re¯ection are slightly increased. Ventricular works are not signi®cantly altered.
In hypertensive animals and humans, cardiac hypertrophy may occur as a consequence of an external load on the heart. Several studies have suggested that the non-pulsatile components of arterial haemodynamics, such as arterial pressure and vascular resistance, do not adequately represent the ventricular afterload and are not well correlated with the degree of cardiac hypertrophy (CH). The present study was undertaken to analyse the correlation between the degree of CH and various haemodynamic parameters in the spontaneously hypertensive rat (SHR) with established hypertension. A total of 36 SHRs (6-8 months) with a tail-cuff pressure above 190 mm Hg were used. Control data were obtained from 32 age-matched normotensive Wistar Kyoto rats (WKY). Animals were anaesthetized with pentobarbitone sodium (40 mg/kg i.p.) and artificially ventilated with a respirator. A Millar catheter with a high-fidelity pressure sensor was used to record the aortic pressure and an electromagnetic flow transducer to monitor the aortic flow. The pressure and flow signals were subjected to Fourier transformation for the analysis of the arterial impedance spectrum. The left ventricular weight-to-body weight ratio (LVW/BW) was taken as a measure of the degree of CH. The measured haemodynamic parameters in these anaesthetized, open-chest SHRs were systolic pressure (SP) (mean +/- SE) 172 +/- 4 mm Hg, diastolic pressure (DP), 120 +/- 3 mm Hg, pulse pressure (PP) 52 +/- 2 mm Hg, peripheral resistance (Rp) 344,032 +/- 8,012 dyne.s.cm-5, characteristic impedance (Zc) 6,442 +/- 313 dyne.s.cm-5, the impedance modulus at the first harmonic (Z1) 26,611 +/- 1,061 dyne.s.cm-5, mean arterial compliance (Cm) 0.87 +/- 0.04 microliter/mm Hg and LVW/BW 3.092 +/- 0.026 mg/g.(ABSTRACT TRUNCATED AT 250 WORDS)
The baroreflex function has been assessed with logistic function analysis, a mathematical model suitable for function curves of sigmoid shape. The nonlinear (sigmoid) relationship between carotid sinus pressure (CSP) and systemic arterial pressure (SAP) reflects threshold and saturation of the SAP responses to CSP changes. The threshold and saturation pressures (TP and SP) are often determined by gross inspection from the experimental recordings. Objective and accurate determination of TP and SP may be achieved by mathematical analysis. Kent et al. (Cardiology, Vol. 57, pp. 295-310, 1972) provided equations that estimated SP and TP to be +/- 1.317/k from the midrange CSP (k, the slope coefficient of a curve). Tan et al. (Circ. Res., Vol. 65, pp. 63-70, 1989) recently used an equation to calculate TP based on the consideration that it is about 95% of the maximal SAP. In this report, we elaborated new equations for the estimation of SP and TP, which approximate midrange pressure +/- 2/k. The accuracy of these new equations compared to other equations was tested using various sets of simulation data. In addition, experiments were conducted in anesthetized dogs with isolated carotid sinus. The open-loop CSP-SAP curves were obtained following various holding pressure (HPs) to demonstrate the phenomenon of baroreflex acute resetting. The effects of using different equations on the values of TP, SP, and delta TP/delta HP (extent of resetting) were analyzed. Both simulation and experimental data revealed that the equations of Kent et al. gave rise to values of TP and SP far different from the realistic values. The values of TP calculated by equation of Tan et al. were dependent on the maximal SAP and the slope of the function curve. The TP and SP (+/- 2/k from the midrange pressure of the sigmoid curve) obtained by our new equations were not significantly affected by the maximal SAP and the curve slope. The mathematical analysis may be particularly useful for comparison among various baroreflex curves with different maximal SAP and/or curve slope.
1 The formation of advanced glycation endproducts (AGEs) on collagen within the arterial wall may be responsible for the development of diabetic vascular injury. This study was to examine the role of aminoguanidine (AG), an inhibitor of AGEs formation, in the prevention of arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) induced diabetes in rats. 2 Diabetes was induced in animals by a single tail vein injection with 65 mg kg À1 STZ. After confirmation of the development of hyperglycemia (2 days later), rats were treated for 8 weeks with AG (daily peritoneal injections of 50 mg kg À1 ) and compared with the age-matched untreated diabetic controls.3 After exposure to AG, the STZ-diabetic rats showed no alterations in cardiac output, aortic pressure profiles, total peripheral resistance, and aortic characteristic impedance. 4 By contrast, treatment of this experimental diabetes with AG resulted in a significant increase in wave transit time (t), from 20.470.6 to 24.770.5 ms (Po0.05) and a decrease in wave reflection factor (R f ), from 0.7870.04 to 0.5370.02 (Po0.05). The decreased R f associated with the increased t suggest that AG may retard the diabetes-induced augmentation in systolic load of the left ventricle coupled to its arterial system. 5 Meanwhile, the diminished ratio of left ventricular weight to body weight suggests that prevention of the diabetes-related cardiac hypertrophy by AG may correspond to the drug-induced decline in aortic stiffening. 6 Glycation-derived modification on aortic collagen was also found to be enhanced in rats with diabetes ( þ 65.3%, Po0.05) and the advanced glycation process was retarded by AG treatment. 7 We conclude that long-term administration of AG to the STZ-treated rats imparts significant protection against the diabetes-derived deterioration in vascular dynamics, at least partly through inhibition of the AGEs accumulation on collagen in the arterial wall. Abbreviations: AG, aminoguanidine; AGEs, advanced glycation endproducts; BW, body weight (g); C, systemic arterial compliance (ml kg À1 mmHg À1 ); CO, cardiac output (ml kg À1 min À1 ); HR, basal heart rate (beats min À1 ); iNOS, inducible isoform of nitric oxide syntheses; LVW, left ventricular weight (g); NO, nitric oxide; P b , magnitude of the forward pressure (mmHg); P d , diastolic aortic pressure (mmHg); P f , magnitude of the forward pressure (mmHg); P m , mean aortic pressure (mmHg); P s , systolic aortic pressure (mmHg); R f , wave reflection factor; R p , total peripheral resistance (mmHg min kg ml À1 ); SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; STZ, streptozotocin; SV, stroke volume (ml kg À1 beat À1 ); Z c , aortic characteristic impedance (mmHg min kg ml À1 ); Z i , aortic input impedance spectra (mmHg min kg ml À1 ); t, wave transit time (ms)
Long-term administration of AG to the STZ-NA diabetic rats imparts significant protection against the NIDDM-derived impairment in vascular dynamics, at least partly through inhibition of the AGE accumulation on collagen in the arterial wall.
The heavy intensity with early return of the pulse wave reflection may augment systolic load of the left ventricle coupled to the arterial system, leading to cardiac hypertrophy in the rats at 8 weeks after following STZ and NA administration.
Background and purpose: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been shown to prevent arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) and nicotinamide (NA)-induced type 2 diabetes in rats. Our aims were to examine whether AG produced benefits on cardiac pumping mechanics in the STZ and NA-treated animals in terms of maximal systolic elastance (E max ) and theoretical maximum flow (Q max ). Experimental approach: After induction of type 2 diabetes, rats received daily injections of AG (50 mg kg À1 , i.p.) for 8 weeks and were compared with age-matched, untreated, diabetic controls. Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E max and Q max , using the elastance-resistance model. Physically, E max reflects the contractility of the myocardium as an intact heart, whereas Q max has an inverse relationship with the LV internal resistance. Key results: Both type 2 diabetes and AG affected E max and Q max , and there was an interaction between diabetes and AG for these two variables. The E max and Q max were reduced in rats with type 2 diabetes, but showed a significant rise after administration of AG to these diabetic rats. Moreover, the increase in Q max corresponded to a decrease in total peripheral resistance of the systemic circulation when the STZ and NA-induced diabetic rats were treated with AG. Conclusions and implications: AG therapy prevented not only the contractile dysfunction of the heart, but also the augmentation in LV internal resistance in rats with STZ and NA-induced type 2 diabetes. (2008) 154, 758-764; doi:10.1038/bjp.2008 published online 31 March 2008 Keywords: advanced glycation end products; aminoguanidine; maximal systolic elastance; theoretical maximum flow; streptozotocin-nicotinamide diabetic rats Abbreviations: AG, aminoguanidine; AGEs, advanced glycation end products; E max , maximal systolic elastance; NA, nicotinamide; P isomax , peak isovolumic pressure of the left ventricle; Q max , theoretical maximum flow; R, internal resistance of the left ventricle; R p , total peripheral vascular resistance; STZ, streptozotocin; V eed , effective end-diastolic volume of the left ventricle British Journal of Pharmacology
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