Biomedical subjects

I Pörsti

Publications and source records attributed to I Pörsti.

At least 19 recordsLinked to original sources

PubMed2002

Mechanism of the prorelaxing effect of thyroxine on the sphincter of Oddi.

BACKGROUND: Disturbances in the function of sphincter of Oddi (SO) may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. Previously, we have shown increased prevalence of hypothyroidism in CBDS patients. METHODS: In animal (pig) experiments, thyroxine (T4) and triiodothyronine have a specific inhibitory effect on SO contractility, which raises the possibility that the lack of this prorelaxing effect in hypothyroidism could, at least in part, explain the increased prevalence of CBDS. The aims of the present study were to investigate, whether human SO reacts similarly to T4, and to study the mechanisms of the T4 prorelaxing effect. RESULTS: We found that T4 had similar inhibitory effects on both human and pig SO contractions. The T4 effect was dose-dependent, and maximum was observed in 30 min. The maximal prorelaxing effect was achieved with 0.1 nM T4 concentration, the effect of the physiological T4 concentration (0.01 nM) being about half of the maximal effect. Addition of alpha-adrenoceptor antagonist phentolamine, beta-adrenoceptor antagonist propranolol, nitric oxide (NO)-synthesis inhibitor L-NAME, nerve conductance blocker tetrodotoxin, or cyclooxygenase inhibitor diclofenac did not affect the T4-induced inhibition of contraction. Addition of transcription inhibitor actinomycin D or translation inhibitor cyclophosphamide partially reversed the T4-induced inhibition of contraction. Addition of K+ channel blocker glibenclamide totally reversed the T4-induced inhibition of contraction. In Western blotting, the thyroid hormone receptor (TR) antibody recognized 53 kDa and 58 kDa proteins, corresponding to beta1 and beta2 isoforms of TR, in the human SO tissue. CONCLUSIONS: We conclude that T4 has a direct prorelaxing effect on human SO that expresses TR beta1 and beta2. This effect is mediated through a transcriptional mechanism that requires new mRNA and protein synthesis and subsequently leads to the activation of K+ channels.

Acetylcholine↗

PubMed2001

Direct effect of thyroxine on pig sphincter of Oddi contractility.

Sphincter of Oddi (SO) motility has an important role in the regulation of bile flow. SO function disturbances (stenosis or dyskinesia) may prevent normal bile flow and thus enhance the probability of common bile duct (CBD) stone formation. Previously we have shown that there is an increased prevalence of diagnosed hypothyroidism in CBD stone patients, compared with gallbladder stone patients or age-, sex-, and hospital-admission-adjusted controls. The present study was done to test the hypothesis that thyroxine directly effects the SO. The specificity of the effects of thyroxine were studied by comparing with triiodothyronine (T3), progesterone, cortisone, estrogen, and testosterone. For ex vivo studies three or four successive 1 to 1.5-mm SO rings were prepared from each pig and placed between two hooks in oxygenated physiologic salt solution at 37 degrees C. SO contraction was measured with isometric force displacement transducers and registered on a polygraph. Each SO ring was stimulated with KCl (125 mM), acetylcholine (ACh; 10 or 100 microM) and histamine (Hist; 10 or 100 microM) with and without thyroxine (10(-10) or 10(-8) M), T3 (10(-9) or 10(-7) M), progesterone (1 microM), cortisone (1 microM), estrogen (1 microM), or testosterone (1 nM) in the medium. KCI, ACh, and Hist induced strong contractions in the SO rings. The addition of thyroxine did not influence significantly the KCl-induced contractions, but the ACh- and Hist-induced contractions decreased by a mean of 37-44% (P < 0.001) and 54-56% (P < 0.001), respectively, as compared to the contractions without thyroxine. Triiodothyronine had a similar inhibitory effect to thyroxine, whereas cortisone, estrogen, and testosterone had no effect. Progesterone decreased the KCl-, ACh-, and Hist-induced SO contractions. In conclusion, physiological concentrations of thyroxine have an inhibitory effect on receptor-mediated ACh and Hist, but not on the nonspecific KCl-induced SO contraction ex vivo. The inhibitory effect is similar in thyroxine and triiodothyronine. Of the steroid hormones, only progesterone nonspecifically ameliorates SO contractions ex vivo. Because the effect of thyroxine on the SO is prorelaxing, the lack of thyroxine may result in an increased tension of the SO.

Acetylcholine↗

PubMed2000

Arterial responses in vitro and plasma digoxin immunoreactivity after losartan and enalapril treatments in experimental hypertension.

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating sodium pump inhibitor concentration.

Angiotensin Receptor Antagonists↗

PubMed2000

Histamine in the control of porcine and human sphincter of Oddi activity.

Histamine decreases sphincter of Oddi (SO) contractility in vivo in opossum, but increases contractility in vitro in guinea-pig. In resistor-like SO, such as in pig and man, the histamine effect is poorly known. We investigated the effect of histamine on pig SO in vivo and in vitro and on human SO in vitro. Perfusion manometry catheter and two silver electrodes for simultaneous pressure and electromyography registration were inserted into the SO transduodenally by laparotomy in six anaesthetized pigs weighing for 25-28 kg. Histamine (5-10 microgram kg-1) was infused intra-arterially (i.a.) into the pancreaticoduodenal artery with and without diphenhydramine (75 microgram kg-1) i.a. premedication. Acetylcholine (4 microgram kg-1) i.a., a potent SO stimulator, was used as positive control. After these experiments, the SO was removed and, together with seven human SO from Whipple specimens, were cut into 1.0-1.5 mm thick transverse sections (rings). The rings were placed between two hooks in oxygenated organ bath solution at 37 degrees C. The SO contraction force was measured with isometric force-displacement transducers and registered on a polygraph. SO rings were incubated with histamine (10-100 micromol L-1) and acetylcholine (100 micromol L-1) with or without diphenhydramine (10 micromol L-1), cimetidine (10 micromol L-1), or atropine (1 micromol L-1). Acetylcholine induced huge electrical bursts, and basal SO pressure increased by 20 +/- 10 mmHg. Histamine (10 microgram kg-1) induced strong SO contraction and the SO remained oedematous for over 10 min. Histamine (5 microgram kg-1) resulted in electromyographic burst activity with phasic SO contractions and increase in basal SO pressure by 34 +/- 19 mmHg for over 15 min. Diphenhydramine did not alter acetylcholine-induced SO motility, but significantly decreased histamine-induced contractions and almost abolished electrical activity. In vitro, acetylcholine induced SO contractions in pig (335 +/- 111 mg) and in man (323 +/- 54 mg). Histamine did not change SO tone in man, but in pig it induced dose-dependent contractions in the same way as acetylcholine. These contractions could be inhibited by diphenhydramine, but not by cimetidine or atropine. We conclude that histamine has a stimulatory effect, mediated by H1-receptor, on the pig SO motility. The SO response to histamine is different in adult humans from that observed in young pigs.

Acetylcholine↗

PubMed2000

High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension.

Because the effects of calcium supplementation on arterial tone in nitric oxide-deficient hypertension are unknown, we investigated the influence of elevating dietary calcium from 1.1 to 3.0% in Wistar rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg. kg(-1). day(-1)) for 8 wk. A high-calcium diet attenuated the development of hypertension induced by L-NAME and abrogated the associated impairments of endothelium-independent mesenteric arterial relaxations to nitroprusside, isoproterenol, and cromakalim. Endothelium-dependent relaxations to acetylcholine during nitric oxide synthase inhibition in vitro were decreased in L-NAME rats and improved by calcium supplementation. The inhibition of cyclooxygenase by diclofenac augmented the responses to acetylcholine in L-NAME rats but not in calcium + L-NAME rats. When hyperpolarization of smooth muscle was prevented by KCl precontraction, the responses to acetylcholine during combined nitric oxide synthase and cyclooxygenase inhibition were similar in all groups. Furthermore, superoxide dismutase enhanced the acetylcholine-induced relaxations in L-NAME rats but not in calcium + L-NAME rats. In conclusion, calcium supplementation reduced blood pressure during chronic nitric oxide synthase inhibition and abrogated the associated impairments in endothelium-dependent and -independent arterial relaxation. The augmented vasorelaxation after increased calcium intake in L-NAME hypertension may be explained by enhanced hyperpolarization and increased sensitivity to nitric oxide in arterial smooth muscle and decreased vascular production of superoxide and vasoconstrictor prostanoids.

Adrenergic beta-Agonists↗

PubMed1999

Losartan and enalapril therapies enhance vasodilatation in the mesenteric artery of spontaneously hypertensive rats.

We studied the effects of 10-week long enalapril and losartan treatments (4 and 15 mg kg(-1) day(-1), respectively) on mesenteric arterial function in vitro in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The relaxations of noradrenaline-precontracted rings to acetylcholine, nitroprusside and cromakalim were similar in WKY and enalapril- and losartan-treated SHR, and more pronounced than in untreated SHR. The responses to acetylcholine were attenuated by N(G)-nitro-L-arginine methyl ester in WKY and drug-treated SHR, but were completely inhibited in untreated SHR. When hyperpolarization of smooth muscle was prevented by KCl-induced precontractions, no differences were found in the relaxations to acetylcholine and nitroprusside between the groups, and the dilatations to cromakalim were abolished. Moreover, in noradrenaline-precontracted rings of drug-treated SHR, the addition of tetraethylammonium attenuated the nitric oxide synthase and cyclooxygenase-resistant relaxations to acetylcholine and abolished the enhanced dilatations to nitroprusside. In conclusion, since the enhancement of vasorelaxation in enalapril- and losartan-treated SHR was abolished by conditions preventing hyperpolarization, the improved vasodilatation following these therapies could be attributed to enhanced vasodilatation via K+ channels in this model of hypertension.

Animals↗

PubMed1999

Control of mesenteric arterial tone in vitro in humans and rats.

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75-1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. However, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the beta-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2(+)-induced contractions in human arteries.

Acetylcholine↗

PubMed1999

Interleukin-1beta-induced nitric oxide synthesis in aortic rings from normal and hyperinsulinaemic rats: effect of physical exercise.

Insulin has been suggested to prevent the induction of nitric oxide synthase (NOS) in vitro in arterial smooth muscle, but whether such a mechanism is operative in vivo is not known. Therefore, we evaluated the sensitivity of smooth muscle NOS to induction by interleukin-1beta (IL-1beta) in aortic rings of lean and obese Zucker rats, a model of experimental hyperinsulinaemia. In order to modulate the insulin and glucose balance of the rats, a 22-week-long treadmill exercise was included in the study. The training attenuated weight gain and reduced blood glucose in the obese and lean rats, whereas the abnormally high plasma insulin of the obese rats remained unaffected. A 6-h incubation of aortic rings with IL-1beta (10 ng/ml) increased cyclic GMP in smooth muscle by approximately threefold in all groups, and this effect was prevented by methylene blue. The contractile sensitivity of endothelium-denuded aortic rings to phenylephrine was reduced by incubation with IL-1beta (1 ng/ml and 10 ng/ml) in the exercised obese and lean rats, whereas no significant change was observed in the sedentary groups. The aortic maximal contractile force induced by phenylephrine was reduced in sedentary and exercised obese rats by incubation with IL-1beta, while no change was detected in the lean rats. The aortic relaxation to exogenous L-arginine was augmented by IL-1beta in all groups, while the relaxation sensitivity to L-arginine after induction by IL-1beta was enhanced by exercise in the obese but not in the lean rats. Finally, the relaxation to nitroprusside was not significantly affected by IL-1beta in any of the study groups. In conclusion, since maximal contractile force generation to phenylephrine was reduced by IL-1beta in the obese but not in the lean rats, the sensitivity of NOS to induction by IL-1beta was higher in arterial smooth muscle of the obese than the lean Zucker rats. Thus, this model of hyperinsulinaemia was not associated with reduced sensitivity of smooth muscle NOS to induction by IL-1beta. Regular exercise did not change plasma insulin concentrations, but it enhanced the action of insulin in both strains as reflected by reduced blood glucose, and increased the sensitivity of smooth muscle NOS to induction by IL-1beta.

Animals↗

PubMed1999

Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism.

OBJECTIVE: Since the effects of angiotensin II receptor antagonism on arterial function in nitric oxide (NO)-deficient hypertension are unknown, we investigated the influence of losartan therapy (20 mg kg-1 day-1) on the control of arterial tone in NG-nitro-L-arginine methyl ester (L-NAME; 20 mg kg-1 day-1)-induced hypertension. METHODS: Forty Wistar rats were divided into four groups: control, losartan, L-NAME, and losartan + L-NAME. The responses of isolated mesenteric arterial rings were examined in standard organ chambers after 8 treatment weeks. RESULTS: Losartan therapy prevented the development of L-NAME-induced hypertension and the associated impairments of endothelium-independent relaxations to nitroprusside, isoprenaline, and cromakalim, vasodilators acting via the formation of NO, activation of beta-adrenoceptors and opening of K+ channels, respectively. In addition, endothelium-dependent relaxations of noradrenaline-precontracted rings to acetylcholine during NO synthase inhibition in vitro were decreased in L-NAME rats, and clearly improved by losartan therapy. The inhibition of cyclooxygenase by diclofenac improved the responses to acetylcholine more effectively in L-NAME than losartan + L-NAME rats, but the relaxations remained decreased in L-NAME rats when compared with losartan + L-NAME rats. When hyperpolarization of smooth muscle was prevented by precontractions induced by high concentration of KCl, the responses to acetylcholine during combined NO synthase and cyclooxygenase inhibition were similar and almost abolished in all groups. Furthermore, superoxide dismutase, a scavenger of superoxide anions, enhanced the acetylcholine-induced relaxations more effectively in L-NAME than losartan + L-NAME rats, although plasma antioxidant capacity was similar in all study groups. CONCLUSION: Chronic L-NAME-induced hypertension was associated with attenuated arterial relaxation via endothelium-dependent and -independent mechanisms, both of which were improved by the losartan treatment. The mechanisms whereby losartan enhanced arterial relaxation in this model of experimental hypertension may have included enhanced hyperpolarization and increased sensitivity to NO in smooth muscle, and decreased vascular production of superoxide and vasoconstrictor prostanoids.

Angiotensin II↗

PubMed1999

Exercise enhances vasorelaxation in experimental obesity associated hypertension.

OBJECTIVE: Regular exercise is recommended for the non-pharmacological treatment of hypertension, but the mechanisms underlying the lowering of blood pressure remain controversial. Therefore, we studied the effects of 22-week-long training on blood pressure, arterial reactivity, and metabolic abnormalities in a model of genetic obesity and moderate hypertension. METHODS: Obese and lean Zucker rats were subjected to treadmill exercise from 8 to 30 weeks of age. Blood pressures were measured by the tail-cuff method, and urine was collected in metabolic cages. At the end of the study, the samples for biochemical determinations were taken, and reactivity of isolated mesenteric and carotid arterial rings was examined in standard organ chambers. RESULTS: The exercise prevented the elevation of blood pressure which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. The relaxations of norepinephrine-preconstricted mesenteric and carotid arterial rings to acetylcholine and nitroprusside were clearly improved by exercise in the obese rats. In the lean rats exercise enhanced vasorelaxation to nitroprusside in the mesenteric and carotid rings, and to acetylcholine in the carotid preparations. The exercise-induced improvement of endothelium-mediated dilatation to acetylcholine was abolished by nitric oxide synthesis inhibition with NG nitro-L-arginine methyl ester, but not by cyclooxygenase inhibition with diclofenac or functional inhibition of endothelium-dependent hyperpolarization by precontractions with KCl. The urinary excretion of the systemic prostacyclin metabolite (2,3-dinor-6-ketoprostaglandin F1 alpha) was increased two-fold by exercise in the obese and lean rats, whereas that of the thromboxane A2 metabolite (11-dehydrothromboxane B2) remained unaffected. Treadmill training reduced blood glucose, cholesterol, and triglycerides, but did not affect the high levels of insulin in obese Zucker rats. CONCLUSIONS: These results suggest that the antihypertensive effect of long-term exercise in experimental obesity related hypertension is associated with improved vasodilatation. This is expressed as enhanced relaxation via endogenous and exogenous nitric oxide, and increased endothelial prostacyclin production. The improved control of arterial tone after training could be attributed to the alleviation of hyperlipidemia and insulin resistance, whereas hyperinsulinaemia per se remained unaffected.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Coenzyme Q10 supplementation and recovery from ischemia in senescent rat myocardium.

Many studies have suggested that parenteral administration of coenzyme Q10 (Q10) protects the myocardium of young experimental animals from post-ischemic reperfusion injury. Although parenteral administration, in contrast to per os supplementation, seems to elevate coenzyme Q concentrations in heart tissue, it is not suitable for prophylactic use. In addition, the incidence of ischemic events is greatest in older age. We studied the effect of Q10 supplementation on myocardial postischemic recovery in 18-month-old Wistar rats. The treated group (n=9) received 10 mg/kg/day of Q10 for 8 weeks in their chow while the normal chow of the control group (n=9) contained less than 0.5 mg/kg/day of Q10. The treatment clearly elevated plasma Q10 concentration (286 +/- 25 micromol/l and 48 +/- 30 micromol/l, treated and controls, respectively, p<0.0001) but neither Q9 nor Q10 concentrations in heart tissue were affected by the supplementation. The isolated perfused hearts were subjected to 20 minutes of ischemia and 30 minutes of reperfusion. The preischemic values of developed pressure (DP) but not contractility (+DP/delta t) and relaxation (-DP/delta t) were improved by Q10 supplementation (p=0.034, p=0.057 and p=0.13, respectively) while in postischemic recovery no differences were observed between the groups (p>0.05 at all time points). Also, in myocardial flow, myocardial oxygen consumption (MVO2) and myocardial aerobic efficiency (DP/MVO2) the groups did not differ at any time points. Although dietary Q10 supplementation clearly elevated plasma Q10 concentrations in senescent rats, the coenzyme Q contents in heart tissue and myocardial recovery from ischemia were not affected. However, it is possible that the site of action for the reported beneficial effects of Q10 is in the coronary endothelium rather than myocardium itself.

Aging↗

PubMed1999

Control of vascular tone in isolated mesenteric arterial segments from hypertensive patients.

1. Experimental hypertension is associated with several functional alterations of vascular endothelium and smooth muscle, but relatively few studies have examined the control of arterial tone in isolated vascular preparations from patients with essential hypertension. Therefore, we compared functional characteristics in vitro of distal ring segments of the mesenteric artery from 17 hypertensive and 22 normotensive humans. 2. Arterial constrictor responses induced by cumulative addition of Ca(2+) in the presence of noradrenaline (NA) were more effectively inhibited by the Ca(2+) entry blocker nifedipine (0.5 nM) in hypertensive than normotensive subjects (by 55.4+/-4.9, n=17 and 35.0+/(-5.2%), n=22, respectively). Also the contractions elicited by high concentrations of KCl were more effectively inhibited by nifedipine in arterial rings from hypertensive than normotensive patients (by 38.9+/(-3.7), n=17 and 20. 2+/(-4.6%), n=22, respectively). However, the concentration-response curves of contractions to NA, serotonin and KCl in the absence of nifedipine were similar between the study groups. 3. The concentration-response curves of endothelium-dependent relaxations to acetylcholine and Ca(2+) ionophore A23187, as well as of endothelium-independent relaxations to the nitric oxide donor nitroprusside, beta-adrenoceptor agonist isoprenaline and K+ channel opener cromakalim did not show any differences between the groups. Moreover, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (0.1 mM) almost abolished the relaxations to acetylcholine and Ca(2+) ionophore in both groups, indicating that these responses were largely mediated by nitric oxide. The function of arterial sodium pump was evaluated by relaxations elicited by the return of K+ upon contractions induced by K+-free solution. The rate of K+-relaxation was similar in hypertensive and normotensive arteries (for all these responses n=20 - 22 in the normotensive and 15 - 17 in the hypertensive group). 4. These results suggest abnormal function of voltage-dependent Ca(2+) channels in arterial smooth muscle of hypertensive patients, whereas vascular responses to endothelium-dependent and -independent vasodilators and classical contractile agents were similar between hypertensive and normotensive subjects. The present findings support the view that blockade of voltage-dependent Ca(2+) channels is an effective means of reducing arterial tone in essential hypertension.

Adult↗

PubMed1999

Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats.

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.

Adrenomedullin↗

PubMed1999

Effects of continuous versus intermittent ethanol exposure on rat sympathetic neurons.

BACKGROUND: Binge ethanol exposure is known to induce degeneration of central nervous system (CNS) neurons. Sympathetic hyperactivity has been related to ethanol withdrawal symptoms, but the effects of repeated withdrawals on peripheral sympathetic neurons have not been studied previously. METHODS: The effects of continuous versus intermittent ethanol consumption on sympathetic neurons of the superior cervical ganglion (SCG) were studied in male Wistar rats. Two-month-old rats were divided into three groups: one group with ethanol (10% v/v) as the drinking fluid throughout the 51/2-month experiment (continuous, n = 9), one group drinking ethanol on 4 days/week and water on 3 days/week (intermittent, n = 9), and a control group (n = 9) with water as the only available fluid. All groups had food ad libitum. SCG volume, neuron density, and total number of neurons were measured by using unbiased morphometric methods. RESULTS: As the mean daily ethanol consumption did not differ between the two ethanol-exposed groups (continuous 5.7 g/kg/day versus intermittent 5.8 g/kg/day), the total dose of ethanol consumed was 42% smaller in the intermittent group. The total number of SCG neurons decreased by 28%, and neuron density by 23%, in the intermittent group compared with the control group, whereas no significant neuron loss was observed in the continuous group. The volume of the SCG was similar in all study groups. The results suggest that repeated ethanol withdrawals, rather than ethanol exposure per se, are deleterious to sympathetic neurons. CONCLUSIONS: Ethanol-induced degeneration of neurons is not only related to the amount of ethanol consumed, but also to the patterns of drinking.

Adrenergic Fibers↗

PubMed1999

Influence of chronic ethanol consumption on arterial tone in young and aged rats.

The aim of this work was to evaluate the effects of long-term ethanol consumption on arterial responses in vitro in young and aged rats. Therefore, Wistar rats (ages 3 and 29 mo, respectively) were allocated to six groups: control-young, sucrose-young, ethanol-young, control-aged, sucrose-aged, and ethanol-aged. The ethanol-fed groups were given 25% ethanol by intragastric gavage three times a day 4 days a week. Responses of mesenteric arterial rings were examined in standard organ chambers after 5 treatment weeks. In norepinephrine-precontracted arterial rings, endothelium-dependent relaxations to acetylcholine, as well as endothelium-independent relaxations to isoproterenol, were attenuated in aged rats when compared with young controls. Relaxation responses to isoproterenol, but not to acetylcholine and nitroprusside, were clearly improved by ethanol treatment in both young and aged rats. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilating and constricting prostanoids, enhanced the relaxation to acetylcholine in all three aged rat groups but was without significant effect in the young rats. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester the relaxation to acetylcholine in control and sucrose-fed aged rats was markedly reduced compared with control rats, whereas in the young controls and in both young and aged ethanol-exposed groups, distinct relaxations to higher concentrations of acetylcholine were still present. The endothelium-independent relaxations to cromakalim, a hyperpolarizing vasodilator acting via ATP-sensitive potassium channels, were also markedly augmented by ethanol feeding in both young and aged rats. In conclusion, ethanol consumption in both young and aged rats was associated with markedly improved arterial relaxations to isoproterenol and cromakalim, as well as clearly augmented relaxation to acetylcholine during inhibition of cyclooxygenase and nitric oxide synthase. These findings suggest that especially the potassium channel-related component of arterial relaxation was augmented by long-term ethanol exposure.

Acetylcholine↗

PubMed1999

Potassium channel-mediated vasorelaxation is impaired in experimental renal failure.

Chronic renal failure is associated with increased cardiovascular morbidity and abnormal arterial tone, but the underlying pathophysiological mechanisms are poorly understood. Therefore, we studied the responses of isolated mesenteric arterial rings from Wistar-Kyoto rats in standard organ chambers 6 wk after subtotal (5/6) nephrectomy or sham operation. Subtotal nephrectomy resulted in a 1.7-fold elevation of plasma urea nitrogen, whereas blood pressure was not significantly affected. Endothelium-mediated relaxations of norepinephrine-precontracted rings to ACh were impaired in renal failure rats. The nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester inhibited relaxations to ACh more effectively in the renal failure group, whereas the cyclooxygenase inhibitor diclofenac did not significantly affect the response in either group. Inhibition of Ca(2+)-activated K(+) channels by charybdotoxin and apamin attenuated NO synthase- and cyclooxygenase-resistant relaxations to ACh in control but not renal failure rats and abolished the difference between these groups. Endothelium-independent relaxations to isoproterenol and cromakalim, vasodilators acting via beta-adrenoceptors and ATP-sensitive K(+) channels, respectively, were impaired in the renal failure group, whereas relaxations to the NO donor nitroprusside were similar in both groups. In conclusion, endothelium-mediated relaxation in renal failure rats was impaired in the absence and presence of NO synthase and cyclooxygenase inhibition but not with prevented smooth muscle hyperpolarization. Endothelium-independent relaxations to isoproterenol and cromakalim were also attenuated after 5/6 nephrectomy. These results suggest that impaired vasodilatation in experimental renal failure could be attributed to reduced relaxation via arterial K(+) channels.

Animals↗

PubMed1998

Comparison of the effects of supplementation with whey mineral and potassium on arterial tone in experimental hypertension.

OBJECTIVE: The aim of this work was to compare the effects of supplementation of rat chow diet with potassium (K+) and whey mineral concentrate (Whey), a diet rich in milk minerals, on blood pressure and arterial responses in vitro in spontaneously hypertensive rats (SHR). METHODS: Thirty young SHR and twenty Wistar-Kyoto rats (WKY) were allocated into five groups: SHR, Whey-SHR, K(+)-SHR, WKY and Whey-WKY. Whey-supplementation was performed by adding 25% whey mineral concentrate to the chow, which in particular increased the intake of potassium (from 1.0% to 3.6%) and also that of calcium (from 1.0% to 1.3%) and magnesium (from 0.2% to 0.3%) in the rats. The K(+)-SHR were given extra potassium chloride (KCl) so that the final potassium content in the chow was 3.6%. Blood pressures were measured indirectly by the tail-cuff method. Responses of mesenteric arterial rings were examined in standard organ chambers after 12 study weeks. RESULTS: During the 12-week study systolic blood pressures in control SHR increased steadily from 160 to about 230 mmHg, while supplementation with either Whey or potassium had a clear antihypertensive effect of about 50 mmHg in the hypertensive rats. Blood pressures in the WKY and Whey-WKY groups remained comparable during the whole study. In noradrenaline-precontracted arterial rings, endothelium-dependent relaxation to acetylcholine (ACh), as well as endothelium-independent relaxations to nitroprusside and isoprenaline were attenuated in untreated SHR, while all these dilatory responses were similarly improved by Whey and potassium supplementation. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilatory and constricting prostanoids, clearly enhanced the relaxation to ACh in untreated SHR, but was without effect in the other groups. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester the relaxation to ACh was markedly reduced in all SHR groups, whereas in the two WKY groups, distinct relaxations to ACh were still present. The remaining responses were partially prevented by tetraethylammonium, an inhibitor of calcium-activated potassium channels, and the difference between untreated and potassium-supplemented SHR was abolished. When endothelium-mediated hyperpolarization of smooth muscle was prevented by precontracting the preparations with 50 mM KCl, only marginal differences were observed in relaxations to ACh between untreated SHR and the other groups. Interestingly, the impaired endothelium-independent relaxations to cromakalim, a hyperpolarizing vasodilator acting via ATP-sensitive potassium channels, were normalized by Whey mineral and potassium diets. CONCLUSION: Supplementation with Whey mineral and a comparable dose of potassium similarly opposed the development of experimental genetic hypertension, an effect which was associated with improved arterial dilatory properties. Both supplements augmented the hyperpolarization-related component of arterial relaxation, increased the sensitivity of smooth muscle to nitric oxide, and decreased the production of vasoconstrictor prostanoids. Therefore, the beneficial effects of the Whey diet could be attributed to increased intake of potassium in SHR.

Acetylcholine↗

PubMed1998

Effects of calcium and potassium supplements on arterial tone in vitro in spontaneously hypertensive rats.

1. Calcium and potassium intakes inversely correlate with blood pressure in experimental hypertension. Therefore, we examined the effects of calcium and potassium supplements alone and in combination on arterial tone in spontaneously hypertensive rats (SHR). Wistar-Kyoto (WKY) rats served as normotensive controls. Calcium and potassium contents in the control diet were both 1%, while those in supplemented chows were 3% and 3.5%, respectively. The sodium content of all diets was moderately elevated to 1.1%. 2. After 12 weeks of the study systolic blood pressures in SHR on high calcium and on high potassium diets were markedly lower (about 53 and 58 mmHg, respectively) than in hypertensive controls, while combined supplementation of these cations reduced blood pressure even further (about 69 mmHg). 3. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Both high calcium and high potassium diets improved the impaired relaxation to acetylcholine (ACh) in SHR, while the combination of these supplements completely normalized this response. Cyclo-oxygenase inhibition by diclofenac augmented the relaxation to ACh in hypertensive controls but not in the other groups. Nevertheless, enhanced endothelium-mediated dilatation was still observed in the presence of diclofenac and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in all supplemented groups. Interestingly, additional blockade of Ca2+-activated K+ channels by tetraethylammonium abolished the improved relaxation to ACh in SHR on high calcium and on high potassium, but distinct responses were still observed in WKY rats and SHR on the combined supplement. 4. When hyperpolarization of smooth muscle was prevented by precontraction of the preparations with 50 mM KCl, only marginal differences were observed in the diclofenac and L-NAME-resistant relaxations to ACh between the study groups. Finally, endothelium-independent vasorelaxations of noradrenaline-precontracted rings to nitroprusside, isoprenaline and cromakalim were comparably augmented by all supplements. 5. In conclusion, the vascular mechanisms underlying the antihypertensive effect of high calcium and high potassium diets during moderately elevated sodium intake in SHR may involve enhanced arterial hyperpolarization, increased smooth muscle sensitivity to nitric oxide and decreased production of vasoconstrictor prostanoids. The administration of these cations in combination was more effective than either of them alone in reducing blood pressure and restoring arterial tone.

Animals↗