Michael S. Golub

Obesity and hypertension

Substantial evidence from epidemiological data supports a link between obesity and hypertension. However, the relationship between the two disorders is not straightforward and most likely represents an interaction of demographic, genetic, hormonal, renal, and hemodynamic factors. Age, race, and sex also modulate the strength of the association between obesity and hypertension. Hyperinsulinemia, which is characteristic of obesity, can contribute to the probability of developing hypertension by activating the sympathetic nervous system (SNS) and by causing sodium retention. The pressor effect of insulin in obesity may be further enhanced by the observation that its vasodilator action can be blunted in obese subjects. Preliminary data have shown that leptin, whose levels are increased in most obese individuals, can contribute to hypertension in obesity through its effects on insulin, SNS, and sodium excretion. The kidney may also have a role in the pathophysiology of hypertension in obesity. Abnormal renal sodium handling coupled with structural changes in the kidney of an obese patient can raise blood pressure. In addition, obesity is associated with distinct cardiovascular hemodynamic alterations and development of eccentric myocardial hypertrophy. Most of these obesity-associated abnormalities, as well as hypertension itself, can be reversed by weight loss. Furthermore, weight loss can prevent, or at least delay, the development of hypertension in patients with high-normal blood pressure. Weight reduction should be the first-line treatment in every obese hypertensive patient. However, the majority of patients will need pharmacologic intervention in conjunction with weight loss. Selection of antihypertensive agents in the overweight patient should take into account the mechanisms leading to hypertension and the metabolic abnormalities that characterize the obese patient.

Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries

To investigate the long-term influence of insulin resistance and hyperinsulinemia on vascular reactivity, both muscarinic and alpha2-receptor-mediated relaxations and the contribution of nitric oxide to these mechanisms were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n = 6) or normal chow (CNT, n = 6) for 40 weeks. Systolic blood pressure was measured by tail-cuff method. A 3-mm segment of mesenteric artery was excised, cannulated and pressurized, pretreated with prazosin (10(-6) mol/L) and propranolol (3 x 10(-6) mol/L), then precontracted with serotonin (10(-6) mol/L). Endothelium dependent relaxation was induced by addition of acetylcholine (10(-9) to 10(-4) mol/L), or a selective alpha2-agonist B-HT 920 (10(-9) to 10(-5) mol/L), with or without the nitric oxide synthase inhibitor L-NAME (10(-4) mol/L). Systolic blood pressure was significantly higher in FFR at the early period; however, there was no difference at the end of 40 weeks compared to CNT. Fasting plasma insulin was much higher in FFR than in CNT (110+/-62 v 41+/-11 microU/mL, P < .05), whereas plasma glucose was not different. Maximum relaxation to acetylcholine was attained at 10(-6) mol/L in FFR but at 3 x 10(-7) mol/L in CNT. The degree of maximum relaxation attained with acetylcholine was similar in FFR and CNT (89+/-9 and 94+/-4% of precontraction), although attenuated (P < .01) by the addition of L-NAME only in FFR (to 34+/-22%, P < .05) but not in CNT (to 82+/-25%). The half-maximal relaxation dose of acetylcholine was greater in FFR (P < .01) compared with CNT and was significantly increased (P < .05) by L-NAME in both groups. B-HT 920 at 10(-5) mol/L induced a greater relaxation in CNT (36+/-10% of serotonin constriction) than in FFR (19+/-14%, P < .05). These responses were significantly blunted by L-NAME. Thus, muscarinic receptor-mediated vascular relaxation is less sensitive and more nitric oxide dependent in FFR versus CNT. Alpha2-adrenergic-mediated relaxation, predominantly mediated by nitric oxide, is also impaired in FFR. It is possible that prolonged insulin resistance and hyperinsulinemia in FFR could alter endothelial-dependent vasodilatory mechanisms, thereby contributing to the increase in blood pressure seen in this model.

Elevated 12-lipoxygenase activity in the spontaneously hypertensive rat.

We have previously demonstrated that administration of inhibitors of the lipoxygenase (LO) pathway of arachidonic acid metabolism lowers blood pressure in hypertensive rats. In addition, we have shown that LO inhibition attenuates pressor agonist-induced vascular reactivity in vitro and calcium mobilization in cultured vascular smooth muscle cells (VSMC). To further elucidate the relationship between elevated LO activity and hypertension, 4, 8, and 12 week old hypertensive SHR were compared with age-matched Wistar-Kyoto (WKY) rats for plasma 12(S)-hydroxyeicosatetraenoic acid (12-HETE) concentration. 12-HETE levels were significantly elevated in the SHR compared to the WKY (SHR elevated by 154%, 159%, and 272% compared to WKY at 4, 8, and 12 weeks, respectively, P < .01 for all ages). There were no differences in plasma potassium levels between SHR and WKY at any of the ages tested. Plasma aldosterone levels and plasma renin activity were in the normal range at the three ages. At 12 weeks of age, both serum (4.72 +/- 0.23 v 2.18 +/- 0.33 microg/mL, P < .01), and aortic smooth muscle 12-HETE levels (0.94 +/- 0.09 v 0.66 +/- 0.08 microg/mg protein, P < .05) were elevated in SHR compared with WKY. The 12 week old SHR were given a bolus of the LO inhibitor 5,8,11-eicosatriynoic acid (ETI, 7 mg/kg, intravenously) and blood pressure measured after 20 min. ETI reduced mean systolic blood pressure from 175.8 +/- 4.2 to 141.6 +/- 5.9 mm Hg (P < .05). To investigate these effects of HETEs, cultured vascular smooth muscle cells were pretreated for 1 min with 12(S)HETE and then challenged with angiotensin II (AngII). The addition of 12(S)HETE increased AngII-induced intracellular calcium levels in normal cultured rat vascular smooth muscle cells by 78% compared to vehicle (P < .05). Thus, LO products, which are high in SHR, may contribute to vascular tone through alterations in the intracellular calcium signal by potentiating calcium responses to pressors such as Ang II.

Renal Effects of Nitrendipine Monotherapy in Essential Hypertension

Summary Ten male patients with essential hypertension were studied on a constant diet (100 mEq of sodium daily) while on placebo, immediately following a 20-mg oral dose of nitrendipine, and during 1 week of nitrendipine therapy (10 mg twice daily). After 2 weeks of outpatient follow-up on 20–40 mg nitrendipine daily, the patients were readmitted and restudied with the same protocol. Glomerular filtration rate, effective renal blood flow, blood volume, and cardiac output were determined isotopically. Free water clearance and osmolar clearance following a water load were also measured. Twenty-four-hour urinary creatinine and electrolyte excretion were measured during the hospitalization periods. Blood pressure decreased significantly during the acute and chronic periods when compared to placebo. During the first 7 days of nitrendipine treatment, urinary sodium excretion increased significantly from control, and a mean deficit of 148 ± 7 mEq (p < 0.001) was calculated. There was a mean weight loss of 1.0 ± 0.1 kg (p < 0.05) after a week of treatment. Glomerular filtration rate, renal blood flow, blood volume, cardiac output, plasma renin activity, plasma catecholamines, and urinary aldosterone remained unchanged from control in both the acute and chronic periods. Compared to the placebo period, free water clearance (1.8 ± 0.6 versus 2.9 ± 0.5 ml/min; p < 0.05) and osmolar clearance (1.9 ±0.3 versus 2.9 ± 0.5 ml/min; p < 0.05)increased significantly in the chronic period. The natriuresis and diuresis associated with nitrendipine therapy without any changes in renal function may represent a direct renal tubular effect of the drug.

Clonidine, a centrally acting sympathetic inhibitor, as monotherapy for mild to moderate hypertension

Sixteen patients with uncomplicated essential hypertension were treated with 0.2 mg of clonidine three times daily as the sole antihypertensive drug. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 139 +/- 3/89 +/- 2 mm Hg (mean +/- standard error of the mean) after 1 week (p less than 0.001) and remained at 140 +/- 3/90 +/- 2 mm Hg after 3 months of therapy. There were no significant changes in cardiac output, blood volume, renal blood flow or glomerular filtration rate during clonidine therapy. Clonidine significantly decreased plasma catecholamines and there was a linear correlation between the change in blood pressure and decreases in plasma catecholamine concentration (r = 0.61, p less than 0.001). There was also a significant correlation between the decreases in heart rate and blood pressure (r = 0.78, p less than 0.001). It is concluded that clonidine can be used effectively and safely as the sole agent in the treatment of mild to moderate hypertension.

Altered vascular responses in cyclosporine-treated rats

Administration of cyclosporine to allograft recipients and patients with immunologically mediated disorders is associated with a high incidence of the development of hypertension. We studied the effect of CsA on blood pressure and on the in vitro tail artery contractile response to transmural nerve stimulation (TNS) and exogenous norepinephrine (NE) in the spontaneously hypertensive rat (SHR). Fourteen days of p.o. administration of CsA 5 mg/kg/day (CsA5) or CsA 20 mg/kg/day (CsA20) resulted in significant increases in blood pressure. The effective level of TNS that resulted in a 50% of maximal response (ED50) was significantly (P < 0.05) decreased in the CsA5 and CsA20 animals compared to controls. The values for controls (n = 7), CsA5 (n = 10), and CsA20 (n = 9) were 4.3±0.3, 3.2±0.3, and 3.1±0.4 pulses/sec, respectively. In the CsA20 group, the doseresponse curve to NE was significantly shifted to the left, and the ED50 was significantly (P < 0.01) decreased compared to controls (5.7 ± 0.8×10−5 mol/L, n = 11, vs. 8.9±0.6×10−5 mol/L, n = 12). We conclude that the in vitro contractile response to nerve stimulation is augmented by CsA. Some of the increase may be related to an enhancement of NE response, but a direct effect on neurovascular function is also suggested. This effect of CsA may be important in the development of hypertension and the changes in neurovascular tone seen with the clinical administration of this immunosuppressant.

Role of Prolactin and the Renin-Angiotensin System in Mediating Dopaminergic Control of Aldosterone Secretion in the Rat

Blockade of dopaminergic pathways increases aldosterone levels by mechanisms that are not well delineated. Since both prolactin (PRL) and plasma renin activity (PRA) also increase after administration of dopaminergic antagonists, the aldosterone increments may be secondary to these changes. To address these questions, the relationship between plasma aldosterone (PA) and PRL responses to 2 different dopamine receptor antagonists, haloperidol and metoclopramide (MCP) was examined in rats. The PA response to MCP was compared before and after blockade of the renin-angiotensin system with saralasin and after pre-administration of L-dopa. MCP administration produced significant and parallel increments in PA and PRL whereas haloperidol increased PRL without any change in PA or PRA. L-dopa pre-treatment suppressed the early PA response to MCP. Hypophysectomy prior to MCP administration eliminated the PRL response but did not significantly alter the PA response to MCP. Our findings suggest that dopamine has an inhibitory action on the adrenal gland production of aldosterone acting independently of changes in PRL and the renin-angiotensin system.

Hormonal correlates of weight loss associated with blood pressure reduction.

This study investigated changes in plasma norepinephrine and the renin-angiotensin-aldosterone system during weight loss. Subjects were maintained on a hypocaloric and low sodium diet for 12 weeks. During weight loss statistically significant decreases in blood pressure, aldosterone, plasma renin activity, and norepinephrine were evident. Plasma renin substrate was suppressed from week one to eight and returned to control levels by week twelve. The data indicate that a reduction in the activity of the renin-angiotensin-aldosterone system, modulated by circulating norepinephrine and plasma renin substrate, may significantly contribute to the fall in blood pressure associated with weight loss.

Stimulation of Intestinal Mucosal Afferent Nerves Increases Superior Mesenteric Artery and Decreases Mesenteric Adipose Tissue Blood Flow

We tested the hypothesis that stimulation of intestinal mucosal afferent nerves produces an increase in superior mesenteric artery (SMA) but a decrease in mesenteric adipose tissue (MAT) blood flow. In anesthetized rats, blood flow in the SMA (pulsed Doppler flowmetry) and MAT (hydrogen gas clearance) was measured simultaneously before and after administration of 0.9% saline, 640 μM capsaicin, or 5% dextrose into the intestinal lumen. The changes in the SMA were 3.8 ± 3.0, 15.9 ± 4.0, and 18.8 ± 7.6%; and those in the MAT, 4.7 ± 4.0, −11.5 ± 3.4, and −0.07 ± 3.4% of baseline, respectively. The data indicate that exposure of the intestinal lumen to an afferent nerve stimulant or nutrient induced a dichotomous pattern of blood flow changes, an increase in the SMA and a reduction in MAT. The capsaicin-sensitive afferent nerves may be instrumental in mediating these energy responses.

PROSTAGLANDIN AND ANGIOTENSIN CONVERTING ENZYME INHIBITION: EFFECTS ON BLOOD PRESSURE, RENIN ACTIVITY AND RENAL FUNCTION IN HEMORRHAGED CONSCIOUS RABBITS

The interaction of the prostaglandin and renin-angiotensin systems on blood pressure and renal function was studied in conscious rabbits following mild (6 ml/kg) or moderate (15 ml/kg) hemorrhage. One hour following the injection of the prostaglandin synthetase inhibitor indomethacin (Indo) plasma renin activity (PRA) was significantly lower than the values in control animals. Two hours following hemorrhage, the increase in PRA was very similar in the Indo and control animals. Renal plasma flow (RPF) was not affected by Indo. Glomerular filtration rate (GFR) was significantly lower in the Indo group following moderate hemorrhage. Interruption of the renin-angiotensin system with the converting enzyme inhibitor (CEI), captopril, resulted in similar hypotensive responses in the Indo and non-Indo groups. The marked PRA increase induced by this agent also was not influenced by Indo. The CEI increased RPF and decreased renal vascular resistance (RVR) in the mild hemorrhage animals. However, in the moderate hemorrhage group the RPF changes were variable and RVR tended to increase, especially in the Indo group. GFR fell significantly following captopril in both Indo and non-Indo animals after moderate hemorrhage. The results indicate that prostaglandin inhibition lowers basal PRA levels but that the renin response to hemorrhage and captopril are not prevented. Indo also did not alter the hypotensive response to CEI, suggesting that prostaglandins do not play a major role in this effect. The magnitude of the hemorrhagic stress influences the renal responses to inhibition of the prostaglandin or renin-angiotensin systems in the conscious rabbit.