A. Soro

Effect of the HMG-CoA Reductase Inhibitors on Blood Pressure in Patients With Essential Hypertension and Primary Hypercholesterolemia

Certain hydroxymethylglutaryl coenzyme A reductase inhibitors, ie, statins, may cause vasodilation by restoring the endothelial dysfunction that frequently accompanies hypertension and hypercholesterolemia. Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is lacking. After an 8-week placebo and diet run-in period, 30 persons with moderate hypercholesterolemia and untreated hypertension (total cholesterol 6.29+/-0.52 mmol/L, systolic and diastolic blood pressure 149+/-6 and 97+/-2 mm Hg) were randomized in a double-blind manner to placebo or pravastatin (20 to 40 mg/d) in a crossover design. In 25 participants who completed the 32-week trial, pravastatin decreased total and LDL cholesterol (both -1.09 mmol/L, P=0.001), systolic and diastolic blood pressure (-8 and -5 mm Hg, both P=0.001), and pulse pressure (-3 mm Hg, P=0.011) and blunted the blood pressure increase caused by the cold pressor test (-4 mm Hg, P=0.005) compared with placebo. It also reduced the level of circulating endothelin-1 (P=0.001). The blood pressure results were virtually unchanged in stratified analyses according to gender and age and in intention-to-treat analyses that included the 5 patients who dropped out of the study. When the participants were taking either placebo or pravastatin, blood pressure was not significantly correlated with total or LDL cholesterol or with circulating endothelin-1. Pravastatin decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and hypertension. This antihypertensive effect may contribute to the documented health benefits of certain statins.

Effect of endothelin on regional hemodynamics and renal function in awake normotensive rats

Summary: The effects of endothelin on regional hemodynamics and renal function were studied in awake normotensive rats. Intravenous injection of endothelin (700 pmol/kg) transiently lowered mean blood pressure (from 108 ± 2 to 84 ± 2 mm Hg, p < 0.01), due to a reduction in total vascular resistance (38 ± 1%, p < 0.01), and increased stroke volume (29 ± 5%, p < 0.01) and heart rate (from 399 ± 18 to 447 ± 18 bpm, p < 0.05); mesenteric and renal blood flow was reduced (37 ± 13, p < 0.05 and 63 ± 5%, p < 0.01), whereas carotid blood flow was increased (78 ± 5%, p < 0.01). This effect was followed by long-lasting hypertension due to increased total vascular resistance (112 ± 19%, p < 0.01); stroke volume, mesenteric, and renal blood flow were reduced (34 ± 5, 41 ± 4, and 58 ± 4%, respectively, p < 0.05) and carotid blood flow returned to basal levels. Bilateral nephrectomy enhanced the initial hypotensive effect. Pretreatment with nifedipine blocked the hypertensive effect, whereas bilateral nephrectomy did not. A subpressor dose of endothelin (70 pmol/kg) had no effect on stroke volume, mesenteric blood flow, glomerular filtration rate, and plasma renin activity; carotid blood flow was transiently increased (48 ± 16%, p < 0.05), then returned to basal levels; renal blood flow decreased (22 ± 6 and 15 ± 4% at 30 s and 10 min, respectively p < 0.05). Our data show a heterogeneity in the response of regional vascular beds to endothelin, the renal and mesenteric compartments being very sensitive to its vasoconstricting action. Endothelin, acting as paracrine or endocrine hormone, might have an important role in the pathogenesis of high blood pressure.

Interaction of α1-Na,K-ATPase and Na,K,2Cl-Cotransporter Genes in Human Essential Hypertension

Essential hypertension is a common disease the genetic determinants of which have been difficult to unravel because of its clinical heterogeneity and complex, multifactorial, polygenic etiology. Based on our observations that α1-Na,K-ATPase ( ATP1A1 ) and renal-specific, bumetanide-sensitive Na,K,2Cl-cotransporter ( NKCC2 ) genes interactively increase susceptibility to hypertension in the Dahl salt-sensitive hypertensive (Dahl S) rat model, we investigated whether parallel molecular genetic mechanisms might exist in human essential hypertension in a relatively genetic homogeneous cohort in northern Sardinia. Putative ATP1A1-NKCC2 gene interaction was tested by comparing hypertensive patients (blood pressure [BP] >165/95 mm Hg) with normotensive controls age >60 years with BP <140/85 mm Hg. Genotype analysis with microsatellite markers revealed conformation to Hardy-Weinberg proportions for 6 alleles of both ATP1A1 ( D1S453 ) and NKCC2 ( NKCGT7 ) markers, respectively. Two-by-six χ2 analysis of alleles identified overrepresentation of ATP1A1 No. 4 and NKCC2 No. 4 alleles, respectively, in hypertensives compared with controls. With a qualitative trait framework, single-gene analysis detected association of both the ATP1A1 No. 4 allele ( P =0.004, χ2=8.094, df =1) and the NKCC2 No. 4 allele ( P =0.0002, χ2=14.279, df =1) with moderate to severe hypertension. Digenic analysis revealed that ATP1A1 No. 4– NKCC2 No. 4 allele interaction increases susceptibility to hypertension ( P <0.0001, χ2=22.3, df =1) beyond levels obtained in single-gene analysis. Analysis was also performed in a quantitative trait framework with BP as the continuous trait parameter. Digenic analysis of ATP1A1 No. 4– NKCC2 No. 4 allele interaction revealed significant association with systolic (1-way ANOVA, P =0.000076) and diastolic ( P =0.00099) BP. Interaction was corroborated by 2×2 factorial ANOVA for interaction (systolic BP interaction term, P <0.05, diastolic BP interaction term, P =0.035). The data are compelling that ATP1A1 and NKCC2 genes are candidate interacting hypertension-susceptibility loci in human essential hypertension and affirm gene interaction as an important genetic mechanism underlying hypertension susceptibility. Although corroboration in other cohorts and identification of functionally significant mutations are imperative next steps, the data provide a genotype-stratification scheme, with 4-fold predictive value (odds ratio, 4.28; 95% confidence interval, 2.29 to 8.0), which could help decipher the complex genetics of essential hypertension.

Brain kinins are responsible for the pressor effect of intracerebroventricular captopril in spontaneously hypertensive rats.

The role of the brain kallikrein-kinin system in the regulation of arterial blood pressure of normotensive and spontaneously hypertensive rats was evaluated. Intracerebroventricular administration of the kinin antagonist [DArg0]Hyp3-Thi5,8[DPhe7]bradykinin caused no change in mean blood pressure in Wistar-Kyoto, Sprague-Dawley, or spontaneously hypertensive rats. The antagonist proved to be very potent in blocking the pressor effect of intracerebroventricular bradykinin (32 +/- 3 vs. 3 +/- 1 mm Hg, p less than 0.01). It was specific, as the pressor effect induced by other unrelated peptides was similar during the infusion of either vehicle or kinin antagonist (angiotensin II, 25 +/- 4 vs. 26 +/- 2 mm Hg; prostaglandin E2, 48 +/- 3 vs. 47 +/- 8 mm Hg; norepinephrine, 17 +/- 2 vs. 18 +/- 2 mm Hg; leucine-enkephaline, 15 +/- 2 vs. 16 +/- 1 mm Hg; neurotensin, 18 +/- 2 vs. 19 +/- 1 mm Hg; substance P, 19 +/- 2 vs. 19 +/- 2 mm Hg). Intracerebroventricular administration of 1 mg captopril, an inhibitor of kininase II (one of the enzymes responsible for kinin degradation), caused no change in mean blood pressure in normotensive rats, whereas it increased mean blood pressure by 44 +/- 9 mm Hg (p less than 0.01) in spontaneously hypertensive rats. This increase in mean blood pressure was blocked and then reversed into a hypotensive effect (22 +/- 6 mm Hg, p less than 0.05) during the infusion of kinin antagonist. Our data suggest that the pressor effect induced by intracerebroventricular captopril is due to a transient elevation in endogenous brain kinin levels, supporting the hypothesis that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure in spontaneously hypertensive rats.

Recognition of markers of response to potassium-canrenoate in essential hypertension

Potassium canrenoate (K-Can) prevents hypertension in Milan hypertensive strain (MHS) but not in spontaneously hypertensive rats (SHR). Essential hypertensive patients (HT) may have differential sensitivity to diuretics, since a subgroup of HT insensitive to hydrochlorothiazide (HCTZ) but sensitive to K-Can has previously been found. The aims of this study were: 1) to seek markers of response in essential hypertensive patients selectively sensitive to K-Can: and 2) to test whether selective sensitivity to furosemide may also be demonstrated. After 2 weeks of placebo (P) 50 uncomplicated, mild to moderate HT (46 +/- 9 yrs, mean +/- SD) received K-Can (50 mg/day) for 4 weeks. After 2 more weeks of P, patients received HCTZ (25 mg) and furosemide (25 mg) for 4 weeks each in a single blind crossover design, with 2 weeks P between each treatment. Dosages were doubled after 2 weeks if diastolic blood pressure (DBP) was > 90 mmHg. Responders (R) were those HT whose DBP was < or = 90 mmHg and/or at least 10 mmHg lower than before treatment. Systolic blood pressure (SBP)/DBP was measured every 2 weeks with plasma renin activity (PRA), red blood cell Na(+)-K(+)-Cl- cotransport (COT) and Na(+)-K+ ATPase pump activity measured at the end of the first P period, and serum electrolytes at the end of each period. Four HT dropped out because of low compliance, 6 because of reversible side effects, and 1 because blood pressure was not back to pre-treatment value after the second placebo period.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives.

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.

Effect of angiotensin converting enzyme inhibition on the menstrual cycle of hypertensive women.

Angiotensin II was reported to play a key role in ovulation in rats and it seems also to be involved in the regulation of LH release. Thus, we studied the effect of chronic ACE inhibition on the menstrual cycle, measuring daily plasma estradiol, progesterone, LH and FSH, and renin and prorenin before and during the third month of treatment with enalapril (10 mg b.i.d.) in 10 mild essential hypertensive women. Blood pressure was normalized by treatment. The cyclical changes of steroids and gonadotrophins were unaffected in their temporal relationships and in the magnitude of their variation during the experimental cycle compared with the basal cycle. A synchronization of plasma prorenin with the other hormones was seen both before, as previously reported, and during enalapril treatment. Our data show that peripheral blockade of angiotensin I conversion does not affect the pituitary guidance of the ovarian hormonal response or the ovarian prorenin release during the menstrual cycle. Our data are in agreement with the hypothesis that circulating angiotensin II does not play a key role in the human fertility process and that hydrophilic ACE inhibitors can be safely used in the treatment of hypertensive women of reproductive age.

Natriuretic effect of acute nifedipine administration is not mediated by the renal kallikrein-kinin system

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 x 106 KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at - 10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume ( + 47|X%), Na+ ( + 54|X%) and C1- ( + 58|X%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ ( + 38|X%) and K+ ( + 29|X%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans.

Angiotensin converting enzyme inhibition reduces ACTH release due to hypoglycaemia.

To investigate the role of Angiotensin II in the release of ACTH, the response of adrenocorticotrophic hormone to hypoglycaemia was studied before and during treatment with an angiotensin converting enzyme inhibitor, enalapril, in 15 male patients with essential hypertension. Plasma levels of ACTH were measured before and 60, 90 and 120 min after an i.v. bolus of normal saline, as placebo, and, 3 days later, after an i.v. bolus of regular insulin (0.15 U/Kg b.w.). Enalapril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH plasma levels were observed after acute normal saline either before or during enalapril treatment. On the contrary, hypoglycaemia induced a sharp increase of ACTH before enalapril (from 19.5 +/- 4.1 to 74.4 +/- 13.0 pg/ml, p less than 0.01 60 min after insulin) but not during ACE inhibition (from 26.1 +/- 6.2 to 34.6 +/- 5.9 pg/ml, NS, at min 60 of the study). The present data confirm our previous observation on the reduction of the hypoglycaemic-induced ACTH release during ACE inhibition with captopril and support the hypothesis that circulating Ang II may exert a facilitating role on adrenocorticotrophic hormone release.

Correlates of atrial natriuretic factor in chronic renal failure

Plasma atrial natriuretic factor (ANF), blood pressure, age, plasma renin activity and creatinine were measured in 50 normal volunteers, 141 essential hypertensives, 35 patients with chronic renal failure who had never been dialysed and 27 patients with end-stage renal failure on constant haemodialysis. Plasma ANF was correlated positively with age in the normal group (r = 0.52, P less than 0.01) and with blood pressure in the essential hypertensives (r = 0.50, P less than 0.001), and negatively with renin in the normal and end-stage renal failure patients (r = -0.47, r = -0.34; P less than 0.01, P less than 0.05, respectively). When patients without left ventricular hypertrophy were matched for age and blood pressure, plasma ANF was significantly different between the essential hypertensives and the normal and end-stage renal failure patients (16 +/- 1, 38 +/- 6 and 148 +/- 24 pmol/l, respectively; P less than 0.001). Cardiac factors are therefore not the only determinant of circulating plasma ANF in humans with chronic renal failure.