Terttu-Liisa Teräväinen

Effects of Dietary Sodium and Magnesium on Cyclosporin A–Induced Hypertension and Nephrotoxicity in Spontaneously Hypertensive Rats

Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.

Cardiovascular effects of a low-dose combination of ramipril and felodipine in spontaneously hypertensive rats

Cardiovascular effects of submaximal antihypertensive doses of the angiotensin converting enzyme inhibitor, ramipril (0.25 mg kg−1 day−1 in the food), and the calcium channel blocker, felodipine (0.4 mg kg−1 day−1 subcutaneously by osmotic minipump), both alone and in combination, were examined in spontaneously hypertensive rats (SHR) in a four‐week study. Both ramipril and felodipine as monotherapy decreased systolic blood pressure. The antihypertensive effect of the drug combination was more than that of ramipril treatment alone, but not significantly better than that of felodipine monotherapy. Ramipril or felodipine treatments did not significantly affect the heart rate, either alone or in combination. The beneficial effect of ramipril monotherapy on left ventricular hypertrophy was more prominent than that of felodipine. The cardioprotective effect of felodipine was improved when combined to ramipril. The systolic blood pressure at the end of the experimental period correlated only weakly with left ventricular hypertrophy. Responses of mesenteric arterial rings in vitro were examined at the end of the four‐week study. Ramipril and felodipine monotherapies as well as their combination markedly improved the endothelium‐dependent vascular relaxation responses to acetylcholine. The combination of ramipril and felodipine slightly enhanced the endothelium‐independent vascular relaxation responses to sodium nitroprusside. Ramipril treatment alone slightly diminished the vascular contractile responses to noradrenaline. Neither ramipril nor felodipine alone or in combination affected the vascular contractile responses to potassium chloride. Ramipril treatment, both alone and in combination with felodipine, caused a three fold increase in plasma renin activity. Serum aldosterone, fasting blood glucose level, serum insulin and the 24 hour urinary excretions of sodium, potassium, magnesium, calcium, phosphorus or protein were not significantly affected by the drug treatments. Our findings suggest that a better overall control of hypertension and end‐organ damages, without an increase in adverse effects, can be achieved by the combination of submaximal antihypertensive doses of felodipine and ramipril than by monotherapy with either drug alone.

Influence of different dietary salts on the cardiovascular and renal effects of moxonidine in spontaneously hypertensive rats

Abstract The influence of common salt (NaCl) and a novel potassium-, magnesium-, and L-lysine-enriched mineral salt on the cardiovascular and renal effects of the selective imidazoline I1-receptor agonist moxonidine was examined in spontaneously hypertensive rats (SHR). Common salt was added at the level of 6% of the dry weight of the chow, and mineral salt at a 75% higher level of 10.5% thereof to produce the same NaCl concentration of 6% as in the common salt group. During the control diet an 8-week oral treatment with moxonidine (117mg/1000g of the dry weight of the chow producing an approximate daily dose of 10mg/kg), lowered blood pressure by 13mmHg. The common salt diet alone raised blood pressure by 27mmHg. Moxonidine lowered blood pressure by 21mmHg during the common salt diet, but the blood pressure remained 19mmHg higher than in the moxonidine-treated SHR receiving the control diet (P<0.05). Unlike common salt, mineral salt alone did not raise blood pressure nor did it interfere with the antihypertensive effect of moxonidine. Moxonidine showed a kidney-protective effect during the control diet measured as decreased urinary protein excretion, but it did not affect the development of left ventricular hypertrophy. Moxonidine increased plasma renin activity during the control diet and it raised the serum aldosterone level both during the control and mineral salt diets. The vascular relaxation responses of the mesenteric arterial rings to both acetylcholine (an indicator of endothelium-dependent vascular relaxation) and nitroprusside and nitroprusside (an indicator of endothelium-independent vascular relaxation) were attenuated by the common salt diet alone but maintained during the moxonidine treatment.Our findings are consistent with the concept that moxonidine is able to improve the excretion of sodium. This effect might explain the maintenance of normal vascular relaxation during a high intake of common salt. These effects may partly account for the antihypertensive effect of moxonidine.

Influence of dietary salts on the cardiovascular effects of low‐dose combination of ramipril and felodipine in spontaneously hypertensive rats

In spontaneously hypertensive rat (SHR) we examined over a 4‐week period the influence of control low sodium diet, common salt‐enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt‐enriched diet (potassium‐, magnesium‐, and l‐lysine‐enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low‐dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg−1 day−1 in the food) and a calcium channel blocker felodipine (0.4 mg kg−1 day−1 subcutaneously via an osmotic minipump). Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. Responses of endothelium‐intact mesenteric arterial rings in vitro were examined at the end of the four‐week study. The combination of ramipril and felodipine markedly improved the endothelium‐dependent vascular relaxation responses to acetylcholine and enhanced the endothelium‐independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium‐dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the α‐adrenoceptor‐mediated vascular contractile responses to noradrenaline during the common salt diet. Ramipril and felodipine in combination increased plasma renin activity by 1.9–3.2 fold without affecting serum aldosterone levels. Our findings suggest that the cardiovascular effect of the low‐dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium‐ and magnesium‐enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium‐dependent and endothelium‐independent vascular relaxation responses and attenuated α‐adrenoceptor‐mediated vascular contractile responses.

Influence of age on cardiovascular effects of increased dietary sodium and angiotensin-converting enzyme inhibiton in normotensive Wistar rats

Recent studies have shown that increased intake of dietary sodium chloride produces blood pressure‐independent increase in cardiac and renal mass even in young normotensive rats. With advancing age the harmful cardiovascular effects of increased dietary sodium are not so well known. In the present study the influence of advancing age on the cardiovascular effects of increased intake of sodium (control diet, 0.3% and high‐sodium diet, 2.6% sodium in the chow) were examined in young and aged (3 and 18 months old, respectively, at the beginning of the experiment) male normotensive Wistar rats in a six‐week study. Moreover, the potential role of renin‐angiotensin system in ageing during normal and a high‐sodium intake was studied using a pharmacological tool, angiotensin converting enzyme (ACE) inhibitor ramipril.

Cardiovascular Effects of Dietary Salts and Isosorbide-5-Mononitrate in Spontaneously Hypertensive Rats

The influence of isosorbide-5-mononitrate (IS-5-MN) on the cardiovascular effects of high dietary salt intake (NaCl, 6.6% of dry weight of food) and that of a potassium, magnesium and l-lysine-enriched salt alternative (Pansalt 10.5%, producing a 6.6% content of NaCl) was studied in spontaneously hypertensive rats in an 8-week experiment. Common salt produced a marked rise in blood pressure and induced cardiac and renal hypertrophy, while the salt alternative, although containing the same amount of NaCl, neither increased blood pressure nor caused any significant cardiac hypertrophy. IS-5-MN treatment at a daily dose of approximately 60-70 mg/kg (mixed with food) attenuated the rise in blood pressure induced by common salt, but did not prevent the cardiac or renal hypertrophy. IS-5-MN did not offer any additional benefit to the use of the salt alternative diet alone in treatment of high blood pressure. Mesenteric arterial responses in vitro were examined at the end of the study. IS-5-MN treatment during the moderately low-salt (NaCl 0.7%) control diet tended to decrease the contractile response to noradrenaline and increase the relaxation to acetylcholine. Common salt, but not the salt alternative, induced a 50% increase in the 24-h urinary excretion of cyclic GMP. Both salt supplements induced an 8-9-fold increase in the excretion of calcium, and about a 2-fold increase in the excretion of phosphorus. Common salt also increased the excretion of magnesium by 50%. IS-5-MN treatment had no significant effect on the excretion of the mineral elements. Our findings show that increased intake of potassium and magnesium reduces the harmful effects of common salt. Pressure-independent mechanisms are involved in salt-induced left ventricular and renal hypertrophy, since they remained unaffected despite the prevention of the salt-induced rise in blood pressure by IS-5-MN treatment.

Delayed Increase in Blood Pressure Induced by Spontaneously Hypertensive Rat Plasma after High Sodium Intake

Plasma from spontaneously hypertensive rats (SHR) and from patients with essential hypertension has been suggested to contain a substance with a delayed pressor effect, parathyroid hypertensive factor (PHF), associated with salt-sensitive forms of hypertension. In order to study whether high sodium intake would increase plasma levels of PHF-like activity, determined by bioassay, SHR received either a high-sodium (2.6% Na in the chow) or a normal-sodium (0.3% Na) diet for 6 weeks. Intravenous injection of plasma from SHR on a high-sodium diet (6 ml/kg) to urethane-anaesthetized Wistar rats induced a delayed increase in mean arterial blood pressure 70-80 min after bolus injection. No delayed pressor effects could be demonstrated by plasma from SHR or Wistar rats on a normal-sodium diet. It is concluded that a factor with a delayed blood pressure-increasing effect appears to be present in plasma from SHR on a high-sodium diet but not in plasma from normotensive Wistar rats or SHR on a normal-sodium diet. Further studies to characterize this factor and its possible relation to salt-induced hypertension are warranted.