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Effect of long-term intake of isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), or a sour milk product containing these peptides on development of hypertension was investigated in spontaneously hypertensive rats (SHR). Six-week-old SHR were given: 1) water (control group), 2) IPP and VPP dissolved in water (peptide group) or 3) sour milk containing IPP and VPP (sour milk group) for 12 weeks. Systolic blood pressure (SBP) was measured by tail-cuff method. Development of hypertension was attenuated in the groups receiving tripeptides or sour milk as compared to the control group. At the end of treatment period, SBP was 176 +/- 1 mmHg in sour milk group, 181 +/- 2 mmHg in peptide group, and 193 +/- 1 mmHg in control group (P < 0.001). After treatment withdrawal, SBP rose gradually reaching the level of control group within four weeks' follow-up. In functional bioassay of ACE inhibitory activity, effect of the tripeptides on angiotensin I or angiotensin II-induced contraction in rat mesenteric arteries was evaluated. IPP inhibited the angiotensin I-induced contraction, whereas the angiotensin II-induced contraction remained unaltered. In conclusion, long-term intake of IPP and VPP, or a sour milk containing these tripeptides attenuated the development of hypertension in SHR. One possible mechanism underlying this effect is ACE inhibition.

Background: The introduction of cyclosporine (CsA) has led to an improvement in the prognosis of solid organ transplantation. However, drug-induced hypertension and nephrotoxicity, associated with the development of atherosclerosis and coronary heart disease, still worsen the long-term outcome of CsA-treated patients. Whether the CsA-induced myocardial changes are associated with the induction of connective tissue growth factor (CTGF), a recently found polypeptide implicated in extracellular matrix synthesis, is not known., Methods: Spontaneously hypertensive rats (8-9 weeks old) were treated with CsA (5 mg x kg(-1) x d(-1) subcutaneously) for 6 weeks. The influence of angiotensin-converting enzyme inhibition (enalapril 30 mg x kg(-1) x d(-1) orally) and angiotensin-1 receptor blockade (valsartan 3 and 30 mg x kg(-1) x d(-1) orally) on CsA toxicity was also investigated. Myocardial morphology was examined, and vascular lesions were scored. Localization and the quantitative expression of CTGF, as well as collagen I and collagen III, mRNA were evaluated by in situ hybridization and Northern blot., Results: CsA-induced hypertension and nephrotoxicity were associated with myocardial infarcts and vasculopathy of the coronary arteries. CsA increased myocardial CTGF, collagen I, and collagen III mRNA expressions by 91%, 198%, and 151%, respectively. CTGF mRNA expression colocalized with the myocardial lesions. Blockade of the renin-angiotensin system prevented vascular damage and the CsA-induced CTGF, collagen I, and collagen III mRNA overexpressions in the heart., Conclusions: CsA increases CTGF, collagen I, and collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.

Functional and morphological changes of blood vessels in cyclosporine A (CsA)-induced hypertension and nephrotoxicity were studied in spontaneously hypertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1) d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitantly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicity. CsA also impaired mesenteric and renal arterial function and caused structural damage to intrarenal and extrarenal small arteries and arterioles. Medial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arterial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excretion or endothelial or inducible NO synthase expression in kidney, aorta or heart) or oxidative stress (urinary excretion of 8-isoprostaglandin F2alpha, plasma urate concentration or total radical trapping capacity). Concomitant L-arginine treatment did not affect CsA-induced changes in blood pressure or histological findings but tended to alleviate the arterial dysfunction. The renal and cardiovascular toxicity of CsA was associated with arterial dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidative stress or a defect in the L-arginine-NO pathway.

1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

Cyclosporine A causes hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). In the present study, arterial function was investigated using in vitro vascular preparations after long-term treatment with cyclosporine A. SHR received cyclosporine A (5 mg kg(-1) day(-1) s.c.) and high-Na(+) diet for 6 weeks during the developmental phase of hypertension. Part of the rats were treated concomitantly either with the angiotensin converting enzyme inhibitor enalapril (30 mg kg(-1) day(-1) p.o.) or with an angiotensin AT(1) receptor antagonist valsartan (3 or 30 mg kg(-1) day(-1) p.o.). In renal arteries, contractile responses to noradrenaline and angiotensin II, as well as relaxation responses to acetylcholine (endothelium-dependent) and to sodium nitroprusside (endothelium-independent), were severely impaired by cyclosporine A-treatment. There was also a trend for the dysfunction of the mesenteric arteries, but the impairment did not reach statistical difference. Enalapril and valsartan improved the impaired renal arterial functions. Cyclosporine A-induced hypertension and nephrotoxicity seem to be associated with renal arterial dysfunction in SHR on high-Na(+) diet. Antagonism of the renin-angiotensin system protects from vascular toxicity of cyclosporine A.

A short review on the role of endothelium and nitric oxide (NO) in experimental hypertension is presented in the light of the literature and our own recent findings. Based on these data, it is concluded that even though there is a lot of evidence in favor of the primary and causal association of endothelial dysfunction and NO in experimental hypertension, it seems still more plausible that they are causative in some types of hypertension only. Our own experience rather speaks for a secondary but still an important participation of endothelium in the maintenance and further elevation of high blood pressure. Endothelium plays a key role in the development of organ damages in hypertension.

Cardiovascular effects of subcutaneous administration of synthetic alpha-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk alpha-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. Alpha-lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 microg/kg, and the maximal reductions in systolic and diastolic BP (by 23+/-4 and 17+/-4 mm Hg, respectively) were observed at 100 microg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to alpha-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the alpha-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.

Objective: We review the published data relating to intake of coffee and caffeine on blood pressure in man. We also refer to studies on the possible mechanisms of actions of these effects of caffeine., Design: The MEDLINE and Current Contents databases were searched from 1966 to April 1999 using the text words 'coffee or caffeine' and 'blood pressure or hypertension'. Controlled clinical and epidemiologic studies on the blood pressure effects of coffee or caffeine are reviewed. We also refer to studies on the possible mechanisms of action of these effects of caffeine., Results: Acute intake of coffee and caffeine increases blood pressure. Caffeine is probably the main active component in coffee. The pressor response is strongest in hypertensive subjects. Some studies with repeated administration of caffeine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not increase blood pressure. Epidemiologic studies have produced contradictory findings regarding the association between blood pressure and coffee consumption. During regular use tolerance to the cardiovascular responses develops in some people, and therefore no systematic elevation of blood pressure in long-term and in population studies can be shown., Conclusions: We conclude that regular coffee may be harmful to some hypertension-prone subjects. The hemodynamic effects of chronic coffee and caffeine consumption have not been sufficiently studied. The possible mechanisms of the cardiovascular effects of caffeine include the blocking of adenosine receptors and the inhibition of phosphodiesterases.

The effects of moxonidine on blood pressure, heart rate and sympathetic tone were studied in conscious spontaneously hypertensive rats. Intravenous moxonidine (80 nmol) transiently increased blood pressure without affecting heart rate or splanchnic nerve activity. Moxonidine (20-80 nmol) given into the fourth cerebral ventricle dose-dependently lowered mean arterial pressure, heart rate and sympathetic outflow (maximally by 60 +/- 3 mm Hg, 148 +/- 10 beats min(-1) and 15 +/- 3 microV). Moxonidine was more effective by this route than after the injection into the lateral ventricle. Clonidine (20-80 nmol) produced an initial pressor response after both intracerebroventricular routes of administration. A decrease in blood pressure was observed only when clonidine was given into the fourth ventricle. Clonidine decreased heart rate and splanchnic nerve activity similarly like moxonidine when the substances were given into the fourth ventricle. The data imply that the hypotensive effect of moxonidine is related to central sympathoinhibition. The main site of this action appears to be in the brainstem region.

Data accumulated from epidemiological observations, intervention trials and studies on experimental animals provide a growing body of evidence of the influence of various dietary components on blood pressure. Dietary sodium, usually taken in the form of sodium chloride (common salt), is positively associated with blood pressure, and in many hypertensive patients reduction in sodium intake lowers blood pressure. On the other hand, in certain patients potassium, calcium and magnesium may be protective electrolytes against hypertension. Dietary fats, especially n-3 polyunsaturated fatty acids, may also influence blood pressure, whereas the possible role of other macronutrients, such as proteins and carbohydrates, or vitamins in the regulation of blood pressure is less well understood. Occasional ingestion of coffee transiently increases blood pressure, but the effects of habitual coffee consumption are controversial. Excessive use of alcohol on a regular basis has been associated with elevated blood pressure. It has also been shown in case reports that large amounts of liquorice lead to the development of hypertension. Thus, with appropriate dietary modifications, it is possible to prevent the development of high blood pressure and to treat hypertensive patients with fewer drugs and with lower doses. In some patients antihypertensive medication may not be at all necessary.

Centrally administered thyrotropin-releasing hormone exerts a well documented hypertensive effect. In this study, the possible physiological role of thyrotropin-releasing hormone in the central cardiovascular regulation was evaluated in spontaneously hypertensive rats receiving long-term (8-14 days) intracerebroventricular infusion of a heterologous antiserum to thyrotropin-releasing hormone. The effect of this passive immunization on the blood pressure was monitored from conscious animals by the tail-cuff method. Thyrotropin-releasing hormone antiserum significantly decreased the systolic arterial pressure in adult rats with established hypertension. No alterations in serum thyroid hormone status were observed indicating that the antihypertensive effect of immunological blockade of thyrotropin-releasing hormone was not due to changes in the serum thyroid hormone levels. These results provide evidence for a role of endogenous brain thyrotropin-releasing hormone in the maintenance of hypertension in spontaneously hypertensive rats.

A hypertensive patient with left cardiac enlargement developed marked hypertension under general anaesthesia, during which time a tourniquet was applied around his thigh. When the tourniquet was released, severe hypotension ensued which responded to therapy. The patient, however, died 16 h later of a myocardial infarction. Because of this incident, the anaesthetic and haemodynamic data of 699 patients who underwent limb surgery with a pneumatic tourniquet inflated for at least an hour were retrospectively examined using multivariate analysis. A 30% increase in systolic and/or diastolic arterial blood pressure occurred in 27% of the total patient material and in 67% of those who had had a general anaesthetic. There was a higher frequency of the occurrence of "tourniquet hypertension" with older age, longer operations and the operation site being the lower rather than the upper limb. Tourniquet hypertension rarely occurred in patients with spinal anaesthesia (2.7%) and brachial plexus blockade (2.5%), while those with intravenous regional anesthesia had a higher incidence (19%) of hypertension.

Risk function analysis was performed in order to clarify the relationship between coronary heart disease death rate and occupational carbon disulfide exposure along with two other important risk factors, elevated diastolic blood pressure and older age, in a data set obtained from a 10-year prospective follow-up of coronary mortality in two cohorts of over 340 male industrial workers in Finland. The sole effect of carbon disulfide on the coronary mortality was statistically significant (relative risk = 2.3), and it was largely independent of the level of the other two risk factors. Log-linear models were fitted to predict coronary heart disease deaths. The analysis identified the dual role of raised blood pressure in the potential mechanism of coronary death. Relative risks ranging up to 48 were obtained for the joint non-synergistic effect of these three factors in the exposed group compared to a subgroup of nonexposed, 40-year-old normotensive men. The effect of carbon disulfide exposure on the risk of coronary death, while clearly distinguishable from the effect of hypertension and aging, stayed subordinate to them, but nevertheless remained an important risk element in the work environment.