Maria G. Melis

Association of Trp64arg β3-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population

OBJECTIVE To evaluate the possible association of three candidate gene polymorphisms with essential hypertension in the genetically homogeneous Sardinian population. SUBJECTS AND METHODS We studied 494 unrelated, nondiabetic subjects, 213 (43.2%) with essential hypertension. All subjects underwent a 75 g oral glucose tolerance test with determination of glycemia and insulinemia and serum lipids. The polymorphisms evaluated comprised Trp64Arg of the beta 3-adrenergic receptor, Gly40Ser of the glucagon receptor gene and the insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene. RESULTS Among the overall population studied, 48 (9.7%) were heterozygous carriers of the Trp64Arg polymorphism. The frequency of the Trp64Arg variant was significantly higher in hypertensives (13.6%) than normotensives (6.8%; chi 2 5.73, P = 0.017). The 48 subjects with the Trp64Arg variant had significantly higher (P < 0.049) serum triglyceride levels than the 446 with the Trp64Trp variant, while no significant differences were observed, either fasting or during the 75 g oral glucose tolerance test, in glycemia and insulinemia. No differences were found between hypertensive and normotensive subjects for ACE gene insertion/deletion polymorphism nor in the frequency of the Gly40Ser coding change in exon 2 of the glucagon receptor gene. CONCLUSIONS Our results are consistent with the thesis that the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is associated more often with the condition of high blood pressure than with normal blood pressure.

Physiological and genetic characterization of the Gly40Ser mutation in the glucagon receptor gene in the Sardinian population

Summary A Gly40Ser amino acid substitution in the glucagon receptor gene has been associated with non-insulin-dependent diabetes mellitus (NIDDM), but the questions raised about its physiological implications have not been resolved. The aim of this study was to determine the frequency of the Gly40Ser mutation in different regions of Sardinia and to investigate the physiological implications of the mutation in glucose and insulin homeostasis. We studied a population of 691 subjects, selected on the basis of their Sardinian origin. Only heterozygous subjects were found, 21 of 574 (3.6 %) in NIDDM patients and 5 of 117 in non-diabetic subjects (4.2 %). In northern Sardinia 3.4 % of the NIDDM patients were carriers of the Gly40Ser substitution, 1.4 % in central Sardinia, while 7.6 % carried the substitution in the Southern part. No significant differences were found between hypertensive and normotensive subjects with respect to the presence of Gly40Ser. Ten subjects with Gly40Ser were carefully matched for diabetic state, BMI, age, sex, and geographical origin with 10 patients with Gly40, and a glucagon infusion test was performed using 1, 3, 9 and 27 ng glucagon kg–1· min–1 for 30 min. Blood for determination of glucose, glucagon, and insulin concentrations was drawn at 15-min intervals from the Controlateral arm. Plasma glucagon increased dose-dependently during the infusion with no significant difference between the two groups. Carriers of Gly40Ser had a significantly lower (p < 0.02) increase in plasma glucose concentration in response to glucagon infusion compared to Gly40 homozygous subjects at all times, while the plasma insulin increase was not significantly different at any time. In conclusion, our results indicate that the Gly40Ser variation is not associated with NIDDM in the Sardinian population, and that its frequency varies in different parts of Sardinia. Moreover in vivo Gly40Ser plays a physiological role in the glucose homeostasis under glucagon control both in NIDDM and non-diabetic subjects. This latter result suggests that this amino acid substitution in the glucagon receptor may lead to a decreased blood glucose concentration because of the reduced stimulation of liver glucose output via the glucagon receptor. [Diabetologia (1997) 40: 89–94]

Effect of verapamil versus nicardipine on 24-hour blood pressure

Thirty patients with uncomplicated, mild to moderate essential hypertension entered a comparative open study of the efficacy and tolerability of slow-release verapamil versus nicardipine. After a 2-week washout period, patients were randomly allocated to receive either verapamil SR 240 mg once daily or nicardipine 40 mg BID for 6 weeks. Lisinopril 10 mg once daily was added after 3 weeks of treatment if the sitting diastolic blood pressure was >95 mmHg. Twenty-four-hour blood pressure monitoring was performed at week 0 and after 3 and 6 weeks of treatment. Within the first 2 weeks, four patients in the nicardipine group withdrew from the study because of tachycardia (n = 2) or headache (n = 2). Three patients in both groups needed the addition of lisinopril. A significant and comparable reduction in systolic and diastolic blood pressures over 24 hours was obtained after 3 and 6 weeks with both treatments (P < 0.01). We conclude that verapamil SR 240 mg once daily is an effective and well-tolerated antihypertensive drug that does not interfere with the circadian rhythm of blood pressure. Its once-a-day formulation may increase patient compliance with the antihypertensive treatment.

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.

Glucagon receptor Gly40Ser amino acid variant in Sardinian hypertensive non-insulin-dependent diabetic patients

Abstract A significantly different prevalence in the Gly40Ser variant of the glucagon receptor gene in a small group of essential hypertensive patients compared with normotensive probands was described in a Caucasian population. It has been postulated that this variant may exacerbate the antinatriuretic effect of high plasma insulin levels commonly seen in hypertensive subjects, leading to volume expansion and rise in blood pressure level. The aim of this study was to evaluate the prevalence of the Gly40Ser variant in a population of 404 non-insulin-dependent diabetic patients of Sardinian origin. No association of the Gly40Ser variant with hypertension was seen in this large population.

Circulating prorenin and renin in response to intravenous adrenocorticotrophic hormone in essential hypertension.

Plasma prorenin and renin changes after a bolus injection of 25 U intravenous adrenocorticotrophic hormone (ACTH, synacthen) were studied in seven untreated uncomplicated essential hypertensives over a period of 24 h. Plasma prorenin did not change significantly during the study, whereas renin after 24 h was higher than at baseline (4.3 +/- 0.6 versus 2.3 +/- 0.9 ng angiotensin I (Ang I)/ml per h, P less than 0.01). We conclude that endogenous glucocorticoid stimulation induced by exogenous ACTH and ACTH itself seem to induce a secondary or tertiary rather than a primary effect on the human renin gene.