Histamine attenuates the arrhythmogenic effects of norepinephrine in hearts of spontaneously hypertensive rats

A potential physiological role for cardiac histamine and its interaction with norepinephrine were investigated in isolated left ventricles from spontaneously hypertensive rats (SHR). Prior to drug administration, left ventricle-to-body weight ratios and spontaneous firing rates (beats per min) were significantly increased in SHR ventricles vs. age- and sex-matched controls (WKY). Also, action potential duration was significantly prolonged in SHR at all levels of repolarization. In all hearts, norepinephrine (10(-7)-10(-4) M) increased spontaneous rate and the percent incidence of arrhythmias. The H2-receptor antagonist cimetidine (10(-5) M) potentiated the rate and arrhythmogenic effects of norepinephrine in SHR and, to a lesser extent, in WKY preparations; propranolol (10(-6) M) reduced them. Histamine (10(-7) M) also inhibited the norepinephrine-induced increase in arrhythmias in SHR, but not in WKY. The attenuation of adrenergically induced rhythm disturbances by histamine and their potentiation by cimetidine in hypertensive hearts support the hypothesis that histamine plays a role as a postjunctional modulator of adrenoceptor function in a setting of hypertension and myocardial hypertrophy.     

Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats

The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at < or = 3 x 10(-5) M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10(-6) to 3 x 10(-5) M relaxed the KCl-contracted aorta. Dofetilide at 10(-9)-10(-7) M augmented the force of contraction of leftventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17-21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12- and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10(-7)-10(-5) M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.     

Effects of BDF 9198 on left ventricular contractility in advanced spontaneously hypertensive rats with heart failure

In the first part of this study, we characterized 24-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), their heart weights, and the responses of the isolated left ventricles to electrical stimulation. In the main part of the study, we tested whether the positive inotropic effects of BDF 9198, which prevents the closure of the cardiac sodium channel, were present in senescence and heart failure. Thus, we studied the effects of BDF 9198 on the left ventricle strips of 24-month-old WKy rats (senescence) and SHRs using contractility methods. In comparison with WKY rats, the left ventricles of 24-month-old SHRs were hypertrophied and had prolonged times to peak contraction. BDF 9198 (10(-8) to 10(-6) M) was a positive inotrope on the left ventricles of WKY rats, with a maximum augmenting effect of 122% with BDF 9198 at 10(-7) M. The magnitude of the augmenting effects of BDF 9198 were reduced in SHR heart failure, with a maximum augmenting effect of 26% at 10(-7) M. BDF 9198 at 10(-6) M attenuated the responses of the SHR left ventricle to electrical stimulation. In conclusion, the potential of drugs that prevent closure of the sodium channel as positive inotropes in the treatment of heart failure should be further considered.     

The effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.     

Release of atrial natriuretic peptide from rat myocardium in vitro: effect of minoxidil-induced hypertrophy.

1. Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive-ANP (IR-ANP) as well as ANP messenger RNA (mRNA), and the release of IR-ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil-treated Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. IR-ANP levels in the ventricles of untreated, 12 month-old SHR with severe ventricular hypertrophy were increased when compared to age-matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR-ANP concentrations (in WKY from 133 +/- 20 to 281 +/- 34 pg ml-1, P less than 0.01; in SHR from 184 +/- 38 to 339 +/- 61 pg ml-1, P less than 0.05), and in ventricular IR-ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR-ANP content and ventricular weight to body weight ratio (r = 0.59, P less than 0.001, n = 26). 3. When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil-treated SHR, control SHR, minoxidil-treated WKY and control WKY, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of clofilium on cardiovascular tissues from normo- and hypertensive rats

1. The overall aim was to test whether clofilium has some potential as a positive inotrope for heart failure. We used Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) and studied the effects of clofilium on isolated blood vessels, left ventricular action potentials and left ventricular contractility. 2. Clofilium at < or = 10(-6) M had no effect on WKY portal vein contractions and at < or = 3 x 10(-4) M had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries. 3. Clofilium at 10(7) - 10(-5) M prolonged the WKY left ventricular action potentials and with 10(-6) and 10(-5)M this included after-depolarizations. 4. Clofilium at < or = 3 x 10(-5) M augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12-month-old WKY. 5. The 12-month-old SHR has hypertrophy of the left ventricle with reduced peak force and prolongation of relaxation. The effects of clofilium on 12-month-old SHR left ventricle contractility were similar to those in the age-matched WKY. 6 In summary, clofilium has positive inotropic effects on the rat left ventricle that are maintained in hypertrophy. Clofilium does not have effects on blood vessels that would be detrimental in heart failure. Clofilium prolongs the rat left ventricle action potential and causes after-depolarizations. The pro-arrhythmic potential of clofilium, however, makes it unlikely that it could be used as a positive inotrope in the treatment of heart failure.     

EFFECTS OF VERATRIDINE ON THE ACTION POTENTIALS AND CONTRACTILITY OF RIGHT AND LEFT VENTRICLES FROM NORMO- AND HYPERTENSIVE RATS

1. We have studied the effects of prolonging the opening of sodium channels with veratridine on the action potentials (AP) and contractility of isolated right and left ventricles of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). It was examined whether the effects of veratridine were altered in the SHR right ventricle in the absence of hypertrophy. The main aim of the present study was to test the hypothesis that the effects of veratridine were altered in the SHR left ventricle in the presence of hypertrophy. 2. The tail-cuff pressures of 14- and 22-week-old, but not 5-week-old, SHR were greater than those of the WKY rat. At 14 weeks of age the SHR left, but not right, ventricle had developed hypertension-associated hypertrophy. 3. The AP and contractions and the ability of veratridine to prolong the AP and act as a positive inotrope were similar in the right ventricles from 22-week-old WKY rats and SHR. The effects of veratridine and the AP and contractions of left ventricles of 5-, 14- and 22-week-old WKY rats and of 5- and 14-week-old SHR were also similar. 4. The AP of the left ventricles of 22-week-old SHR were prolonged by 3 ms at the action potential duration (APD)₅₀ and APD₉₀ levels. The contractions to cardiac stimulation and the maximum combined force responses to cardiac stimulation and isoprenaline were reduced in the left ventricles of 22-week-old SHR compared with WKY rats and younger SHR. 5. The effectiveness of veratridine in prolonging the AP and augmenting the contractions to cardiac stimulation was reduced in the hypertrophied left ventricle of 22-week-old, but not 14-week-old, SHR. 6. In summary, the response to prolonging the opening of sodium channels with veratridine is not altered in the SHR right ventricle. However, in left ventricles of the hypertrophied 22-week-old, but not 14-week-old, SHR the effects of veratridine are reduced and this demonstrates that the response to prolonging the opening of sodium channels is changed in persistent hypertension-associated hypertrophy.     

Decreased responsiveness of the aortae of hypertensive rats to acetylcholine, histamine and noradrenaline.

The responses to noradrenaline (NA) of the aortae of various hypertensive rats, namely the spontaneously hypertensive rat (SHR), the low blood pressure SHR (LBP-SHR), and the left renal artery stenosed LBP-SHR (LRAS-LBR-SHR), were compared to those of the normotensive Wistar-Kyoto rats (WKY). The aortae of the hypertensive rats were significantly more responsive (P less than 0.05) to 10(-8) M NA. However, the reverse was true for higher doses of NA. The ED50 values for the aortae of WKY, LBP-SHR, SHR and LRAS-LBP-SHR were 20, 8.5, 7.8 and 8 nM respectively. The NA-contracted aortae of the LRAS-LBP-SHR were significantly less responsive (P less than 0.05) to the relaxant action of histamine and acetylcholine (ACh) compared to those of the WKY. This observation was not made in the aortae of the LBP-SHR. The maximal relaxation (% of the maximal contraction induced by 10(-8) M NA) observed in the aortae of WKY, LBP-SHR and LRAS-LBP-SHR were, respectively, 72 +/- 2, 66 +/- 6, 39 +/- 7 for ACh and 50 +/- 3, 36 +/- 4, 27 +/- 3 for histamine. In aortae where the endothelium had been removed by collagenase treatment, histamine induced a dose-related contraction. The rank order of this dose-related contraction was WKY greater than LBP-SHR greater than SHR greater than LRAS-LBP-SHR with the corresponding maximal tension (g) 0.89 +/- 0.04, 0.59 +/- 0.04, 0.36 +/- 0.04, 0.19 +/- 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

NERVE GROWTH FACTOR mRNA CONTENT PARALLELS ALTERED SYMPATHETIC INNERVATION IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. In order to explore the mechanisms responsible for the hypernoradrenergic innervation of the vasculature in the spontaneously hypertensive rat (SHR) the tissue content of nerve growth factor messenger ribonucleic acid (NGFmRNA) was examined. 2. The concentration of NGFmRNA was markedly elevated in mesenteric veins obtained from SHR when compared with the contents of NGFmRNA in veins from Wistar Kyoto rats (WKY). 3. The NGFmRNA content of kidneys was greater in SHR when compared with the levels present in WKY rats for 10- and 43-day-old animals. 4. In contrast to the pattern observed for veins and kidneys, the NGFmRNA content of SHR hearts was smaller than those present in hearts from WKY rats for 2, 10 and 43-day-old animals. 5. The results demonstrate that tissues with enhanced innervation (the kidney and mesenteric vasculature) in SHR are associated with an enhanced expression of NGFmRNA. In contrast, the heart, which does not display an enhanced sympathetic innervation in the SHR, does not have an increased expression of NGFmRNA. 6. It is suggested that in the SHR there is a tight relationship between hypernoradrenergic innervation in the vasculature and gene expression for NGFmRNA.     

Neuropeptide Y (NPY) reduces field stimulation-evoked release of noradrenaline and enhances force of contraction in the rat portal vein

The effect of neuropeptide Y (NPY) on fractional tritium-noradrenaline (3H-NA) release and contractile activity was studied in the isolated portal vein of SHR and WKY rats. NPY (5 X 10(-7) M) enhanced the force of the spontaneous contractile activity by about 40%. The fractional 3H-release elicited by transmural nerve stimulation (TNS), which mainly reflects 3H-NA, was reduced by about 40% after preincubation with 5 X 10(-7) M NPY in portal veins from both SHR and WKY rats. The inhibitory effect of NPY on TNS-evoked 3H-release was more slowly reversed by washout than the facilitatory action on spontaneous contractile force. The contractile response to field stimulation was not reduced by NPY, but rather tended to be increased. It is concluded that NPY exerts a dual action in the SHR and WKY portal vein, thus enhancing the smooth muscle contractions and inhibiting sympathetic neurotransmission. The inhibitory effect of NPY on TNS-evoked NA efflux, which is present in both SHR and WKY rats, is most likely due to a presynaptic site of action.     

Effect of phorbol ester on the release of atrial natriuretic peptide from the hypertrophied rat myocardium.

1. To determine the cellular mechanisms of atrial natriuretic peptide (ANP) release from ventricular cardiomyocytes, the secretory and the cardiac effects of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate protein kinase C activity in heart cells, were studied in isolated, perfused heart preparations from 2- and 21-month-old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. TPA was added to the perfusion fluid for 30 min at a concentration of 46 nM after removal of atrial tissue. Additionally, atrial and ventricular levels of immunoreactive ANP (IR-ANP) and ANP mRNA, the distribution of ANP within ventricles as well as the relative contribution of atria and ventricles in the release of ANP were studied. 2. Ventricular hypertrophy that gradually developed in hypertensive rats resulted in remarkable augmentation of ANP gene expression, as reflected by elevated levels of immunoreactive ANP and ANP mRNA. The total amount of IR-ANP in the ventricles of the SHR rats increased 41 fold and ANP mRNA levels 12.9 fold from the age of 2 to 21 months. At the age of 21 months, levels of IR-ANP and ANP mRNA in the ventricles of SHR rats were 5.4 fold and 3.7 fold higher, respectively, than in the normotensive WKY rats. Immunohistochemical studies demonstrated ANP granules within the hypertrophic ventricles of the old SHR rats, but not within normal ventricular tissue. 3. In isolated perfused heart preparations, the severely hypertrophied ventricular tissue of SHR rats after atrialectomy secreted more ANP into the perfusate than did the control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular tissues from normo- and hypertensive rats.

Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)-10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or = 10(-5) M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or = 3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery. In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.     

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.     

Histamine,histidine decarboxylase and histamine-N-methyltransferase in brain areas of spontaneously hypertensive rats

Summary Histamine levels, histidine decarboxylase and histamine-N-methyltransferase activities were determined in various brain areas of young (9-week old) and adult (18-week old) normotensive rats (WKY) and hypertensive rats (SHR). When compared with WKY, histamine levels were increased in the anterior and posterior hypothalamus of young and adult SHR, as well as in the brainstem of young SHR. Histidine decarboxylase activity was unchanged in the posterior hypothalamus and in the medulla oblongata of young and adult SHR as well as in the anterior hypothalamus of young SHR, but it was slightly decreased in the anterior hypothalamus of adult SHR. Histidine decarboxylase activity was enhanced in the cortex-midbrain of young, as well as adult SHR, histamine-N-methyltransferase in the cortex-midbrain of young SHR. The following differences were found between young and adult rats: histamine levels were elevated in the cortex-midbrain of adult WKY and SHR. In the cortex-midbrain and brainstem of adult WKY and SHR histidine decarboxylase activity was also increased, while histamine-N-methyltransferase activity was elevated in the cortex-midbrain of adult WKY. The findings show changes in histamine levels, histidine decarboxylase and histamine-N-methyltransferase activities in SHR and suggest involvement of histaminergic neurons in hypertension. The activity of histaminergic neurons of adult rats seems to be higher than that of young animals.This work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung (P5750) Send offprint requests to H. Prast at the above address     

高血压性左心室肥厚与心肌原癌基因c-fos表达

采用自发性高血压大鼠(SHR)和两肾一夹型(2K1C)肾血管性高血压大鼠模型，研究细胞核内原癌基因c-fos在高血压性左心室肥厚(LVH)发生，发展过程中的作用. 结果表明：SHR在8-10周龄时已有明显的高血压和LVH，其收缩压(SBP)与左室重/体重比(LVW/BW)均显著高于同龄的WKY大鼠. 20-22周龄与40-42周龄时，SHR的SBP，LVW/BW及左心室c-fos基因表达水平均明显高于同龄对照组WKY大鼠. 2K1C大鼠左肾动脉缩窄1周后发生明显的LVH，同时伴左心室c fos基因的高表达，至术后3和10周仍保持较高水平. 钙拮抗剂尼群地平(10 mg·kg^-1 ig，每日2次，连续10周)或血管紧张素AT₁受体阻断剂洛沙坦(30 mg·kg^-1·d^-1 ig，连续10周)治疗均可逆转2K1C大鼠SBP的增高和LVH的发生与发展，同时左心室c-fos基因表达水平降低. 结果提示心肌原癌基因c-fos的高表达参与高血压性LVH的发生，发展过程.     

Effects of azimilide on cardiovascular tissues from normo- and hypertensive rats

We tested whether azimilide has potential for use in the treatment of heart failure. Azimilide, > or =3 x 10(-5) M, had no effect on the quiescent Wistar-Kyoto (WKY) rat aorta, or mesenteric and intralobar pulmonary arteries. Azimilide > or =3 x 10(-5) M relaxed the KCl-contracted aorta and portal vein. Azimilide, 10(-7)-10(-5) M, prolonged the WKY left ventricular action potential and augmented the force of contraction of left ventricle strips from 12- and 22-month-old WKY rats. Spontaneously hypertensive rats (SHRs), at ages 12 and 22 months, are models of cardiac hypertrophy and failure, respectively. The augmentation of force with azimilide was similar on 12- and 22-month-old WKY rats and 12-month-old SHRs but reduced on the 22-month-old SHR left ventricle. Azimilide, 3 x 10(-6) and 10(-5) M, augmented the force responses of the 22-month-old SHR left ventricle by 40 and 50%, respectively. As azimilide is a vasodilator and positive inotrope in the rat, and the positive inotropic effect is present in heart failure, azimilide should undergo further testing as a positive inotrope for the treatment of heart failure.     

Antagonism of alpha 1-adrenoceptor-mediated vascular contraction by urapidil in isolated arterial strips of spontaneously hypertensive rats

Antagonism of alpha 1-adrenoceptor-mediated vascular contraction by urapidil was examined in helical strips of femoral and mesenteric arteries isolated from 13-week-old Aoki spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats, since this agent has antihypertensive effect through antagonizing peripheral alpha-adrenoceptors. Schild plot analyses clearly demonstrated the existence of only alpha 1-adrenoceptors in these arteries from both strains. Therefore, it is possible to demonstrate alpha 1-adrenoceptor blocking effects of nonselective alpha-adrenoceptor antagonists as well as selective alpha 1-adrenoceptor antagonists. Urapidil antagonized the alpha 1-adrenoceptor-mediated vascular contraction in a competitive fashion. The pA2 value for urapidil against alpha 1-adrenoceptors was not significantly different between SHR and WKY rats. The addition of 10(-5) M norepinephrine (NE) produced a sustained contraction in a SHR femoral artery, whereas in a WKY rat femoral artery this agonist produced a transient contraction followed by a sustained relaxation. Urapidil elicited a dose-dependent relaxation with a IC50 value of 6.50 in the SHR femoral artery precontracted with NE. In the presence of 3 x 10(-7) M timolol, a beta-adrenoceptor antagonist, femoral arteries from both strains exhibited similar magnitude of contraction in response to the stimulation with 10(-5) M NE. Under these conditions, urapidil elicited a similar extent of relaxation between SHR and WKY rats. On the other hand, the addition of 10(-5) M NE produced a sustained contraction in mesenteric arteries from both SHR and WKY rats. The contraction expressed as a ratio to the maximum developed by KCl depolarization was significantly greater in SHR than in WKY rats. In these arteries, the relaxing effect of urapidil was more evident in SHR than in WKY rats. Contractile responses to NE and relaxing effects of urapidil were not affected by timolol. These results suggest that urapidil effectively antagonized enhanced alpha 1-adrenoceptor responses seen in SHR arteries.     

Cardiac adenylate cyclase, cyclic nucleotide phosphodiesterase and lactate dehydrogenase in normotensive and spontaneously hypertensive rats.

To understand altered physiological responses of hypertrophied spontaneously hypertensive rat (SHR) myocardium to beta-adrenergic receptor stimulation in vivo, myocardial tissues from SHR, normotensive Wistar (NR) and normotensive Wistar-Kyoto (WKY) rats were analyzed for adenylate cyclase, phosphodiesterase and lactic dehydrogenase. While WKY left ventricular adenylate cyclase activity exceeded that of SHR at low (1 and 5 μM) norepinephrine concentrations, there were no further differences. Norepinephrine stimulation of NR and SHR left ventricular adenylate cyclase was the same. In all rat strains similar responses of adenylate cyclase to glucagon were observed. Cyclic AMP phosphodiesterase activity of whole left ventricular homogenates were not significantly different in NR, WKY or SHR when assayed at either 1 mM or μM cyclic AMP. While it was not possible to entirely explain previous hemodynamic findings in vivo on the basis of abnormal cAMP-related enzyme activities, certain other interstrain enzymatic differences were observed. The hypertrophied SHR left ventricle contained higher levels of lactate dehydrogenase (LDH) and an altered isozymic composition as compared to both normotensive strains. These changes may indicate a shift in glycolytic enzyme needs as also seen with artificially produced cardiac hypertrophy. In all rat strains the right ventricular wall has less norepinephrine-stimulatable adenylate cyclase activity and more cyclic AMP phosphodiesterase activity than the left ventricle. These results demonstrate differences in cyclic AMP-related activities between the ventricles and increased LDH activity in the hypertrophied SHR left ventricle.     

Effects of BDF 9148 on the action potentials and contractions of left ventricles from normo- and hypertensive rats

1. The aim of the present study was to test the hypothesis that responses to BDF 9148, which prolongs the opening of sodium channels, are reduced in the spontaneously hypertensive rat (SHR) left ventricle in the presence of hypertrophy and failure. 2. We studied the effects of BDF 9148 on the action potentials and contractions of left ventricles from 5-week-old prehypertensive, 14-week-old hypertensive, 6- and 12-month-old hypertension-associated hypertrophy and 18-month-old hypertension-induced heart failure SHR and age-matched Wistar-Kyoto normotensive (WKY) rats. 3. Action potentials and left ventricular contractions did not alter in the early stages of hypertension (14-week-old SHR). The diastolic membrane potential did not change with hypertension-associated hypertrophy, but there was a reduction in amplitude and a prolongation of action potentials in the left ventricles of 6-18-month-old SHR. Cardiac stimulation responses and maximum contractions to 10(-6) mol/L isoprenaline were reduced at 6 months, whereas the maximum contractions to 10(-2) mol/L CaCl2 were only reduced in left ventricles of 18-month-old SHR. 4. At concentrations ranging from 10(-7) to 3 x 10(-6) mol/L, BDF 9148 increased the amplitude and prolonged the duration of action potentials and augmented the force in WKY rat left ventricles. The augmenting effects of BDF 9148 at 3 x 10(-6) mol/L were smaller than at 10(-6) mol/L, possibly because the high concentration of BDF 9148 was also blocking calcium channels. Similar effects were observed with BDF 9148 in the early stages of hypertension (14-week-old SHR). 5. In the presence of persistent hypertension-associated hypertrophy of the SHR left ventricle at > or = 6 months, the effects of BDF 9148 on action potentials and contractions were significantly reduced to a small extent. This impairment of the response to BDF 9148 may reflect the reduced contractility of the SHR left ventricle and/or it may indicate that the response to the opening of sodium channels is altered from 6 months of age. 6. In summary, most of the response of BDF 9148 is maintained in the presence of hypertrophy and failure. Thus, BDF 9148 may have some potential for the treatment of heart failure.     

Alpha 1-adrenoceptor reserve and effects of a Ca2+ entry blocker (Ro 18-3981) on aorta of spontaneously hypertensive rats

The relationship between alpha 1-adrenoceptor reserve and the sensitivity of vasoconstrictor responses to Ca2+ entry blockade was investigated in isolated aortas from age-matched (13-15 weeks) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Noradrenaline (NA) elicited contractile responses with a greater potency (log EC50) in aorta from WKY (-8.7) than in those from SHR (-8.05). The dihydropyridine Ca2+ entry blocker, Ro 18-3981 (10(-6) M), suppressed the maximal NA responses more in aorta of SHR (-54%) than WKY (-14%). The dissociation constant (KA) of NA was similar in aortas of both strains. However, the difference between KA and EC50 values was greater in aorta of WKY (7.2 X) than in those from SHR (1.4 X). Pretreatment of WKY aorta with the irreversible alpha-blocker phenoxybenzamine (10(-9) M) enhanced the inhibitory effect of Ro 18-3981 (10(-6) M) against NA-induced contractions (-14 to -47%). Thus, a smaller alpha 1-adrenoceptor reserve could explain the greater sensitivity of NA-induced contractions in SHR aorta to Ca2+ entry blockade.