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P J Mulrow

Publications and source records attributed to P J Mulrow.

At least 19 recordsLinked to original sources

Angiotensin II and aldosterone regulation.

The circulating renin-angiotensin system is a major regulator of the secretion of the adrenocortical hormone, aldosterone. This renin-angiotensin aldosterone system is important in the control of salt and water balance and blood pressure. This review describes the historical background leading to the discovery of aldosterone in the 1950s and the recognition in the 1960s that angiotensin II was involved in its control. Although angiotensin II is important in the regulation of aldosterone secretion, its action is influenced by multiple other factors, especially potassium and atrial natriuretic peptide. In addition to the circulating renin-angiotensin system, a local renin-angiotensin system is present in the zona glomerulosa cell. This local system also appears to be involved in the regulation of aldosterone production. The mechanism by which angiotensin II stimulates the adrenal zona glomerulosa cell is described in some detail. Angiotensin II interacts with the angiotensin receptor (AT1) membrane receptor that is coupled to cellular second messengers. Specific AT1 receptor antagonists are now clinically used to block angiotensin II's action on various target organs, including the adrenal gland.

Adrenal Glands↗

Detection and control of hypertension in the population: the United States experience.

Trends in prevalence, awareness, treatment, and control of hypertension in the adult US population are reported. The data are from the National Health and Nutrition Examination Surveys (NHANES), carried out in four separate surveys, the last being NHANES III, 1988-1991. The age-adjusted prevalence of hypertension at > or = 160/95 mm Hg declined from 20% to 14%, and at > 140/90 mm Hg it declined from 36.3% to 20.4% in NHANES III. Hypertension awareness increased significantly to as high as 89% for those with blood pressures > or = 160/95 mm Hg. For all people with blood pressure > or = 160/95 mm Hg, nearly 64% have it controlled below that level, but only 29% have their blood pressure controlled below 140/90 mm Hg. Although the data from these surveys are encouraging, there are still too many people in the United States with uncontrolled hypertension.

Adolescent↗

Secondary hypertension: evaluation and treatment.

Most patients with hypertension in the United States have essential (primary) hypertension (95%), the cause of which is unknown. The remaining 5% of adults with hypertension have the secondary form of hypertension, the cause and pathophysiologic process of which are known. Internists and other primary care physicians refer to this as treatable or curable hypertension, because the hypertension can be managed or even controlled with medications. Similarly, the condition is called surgical hypertension by surgeons in the belief that once the cause is determined and identified, surgical intervention will result in cure of hypertension. Secondary causes of hypertension include renal parenchymal disease, renovascular diseases, coarctation of the aorta, Cushing's syndrome, primary hyperaldosteronism, pheochromocytoma, hyperthyroidism, and hyperparathyroidism. Occasionally included in this category are alcohol- and oral contraceptive-induced hypertension and hypothyroidism, but these conditions are not discussed herein. The evaluation of secondary hypertension is of interest and can bring together different facets of anatomy, physiology, pharmacology, and radiology in the medical and surgical treatment of these disorders. Despite enthusiasm that can be generated in the evaluation of these conditions, evaluation can be expensive and should not be conducted for all patients with hypertension. Features that aid in the diagnosis of secondary hypertension include the following: 1. Onset of hypertension before the age of 20 or after the age of 50 years. The presence of hypertension at a young age may suggest coarctation of the aorta, fibromuscular dysplasia, or an endocrine disorder. Hypertension found for the first time after the age of 50 years may suggest the presence of renovascular hypertension caused by atherosclerosis. 2. Markedly elevated blood pressure or hypertension with severe end-organ damage, as in grade III or IV retinopathy. These findings suggest the presence of renovascular hypertension or pheochromocytoma. 3. Specific body habitus and ancillary physical findings. For example, truncal obesity and purple striae occur with hypercortisolism, and exophthalmos is associated with hyperthyroidism. 4. Resistant or refractory hypertension (poor response to medical therapy usually necessitating use of more than three antihypertensive medications from three different classes). 5. Specific biochemical test that suggest the existence of certain disorders, such as hypercalcemia in hyperparathyroidism, hyperglycemia in Cushing's syndrome and pheochromocytoma, and unprovoked hypokalemia with renin-producing tumors, primary hyperaldosteronism, or renin-mediated renovascular hypertension. 6. Other characteristics that may suggest secondary hypertension such as abdominal diastolic bruits (renovascular hypertension), decreased femoral pulses (coarctation of the aorta), or bitemporal hemianopias (Cushing's disease). A combination of a good history and physical examination, astute observation, and accurate interpretation of available data usually are helpful in the diagnosis of a specific causation.

Adult↗

Reversal of the suppressed kidney renin level in the hypertensive transgenic rat TGR(mRen-2)27 by angiotensin converting enzyme inhibition.

The transgenic rat TGR(mRen-2)27 develops severe hypertension with high adrenal renin and low kidney renin. The mechanism of suppressed kidney renin in these animals is still unclear. We investigated the effect of the angiotensin converting enzyme (ACE) inhibitor, perindopril on the renin-angiotensin system in plasma and tissues (adrenal gland and kidney), and the effect of mouse renin antibody on plasma and tissue renin activity before and after perindopril administration. Perindopril lowered blood pressure in the TGR(mRen-2)27 rats from 254.5 +/- 7.4 mm Hg to 154 +/- 7.8 mm hg (n = 8, P < .0001), while blood pressure in the untreated TGR (mRen-2)27 rats increased from 253.7 +/- 8.1 to 276.1 +/- 14.3 mm Hg during the study period. Perindopril significantly suppressed plasma angiotensin II (Ang II) from 19.4 +/- 2.5 pg/mL to 2.6 +/- 0.4 pg/mL, P < .0001, while markedly increasing plasma renin concentration (PRC) from 15.5 +/- 1.8 ng AngI/mL/h to 148.2 +/- 35.5 ng AngI/mL/h, P < .005 and kidney renin from 56.7 +/- 18.1 micrograms AngI/g/h to 827.4 +/- 79.1 micrograms AngI/g/h, P < .0001. However, adrenal renin was not increased. A mouse Ren-2 renin antibody at a 1:1000 dilution that suppresses purified mouse Ren-2 renin activity by 62.6 +/- 3.6% (n = 3, P < .0001) and does not suppress renin activity in plasma and kidney of the Sprague-Dawley rats, suppressed PRC in the untreated TGR(mRen-2)27 rats by 52.3 +/- 3.5% (n = 6, P < .0001). However, it only suppressed PRC in the perindopril treated TGR(mRen-2)27 rats by 7.0 +/- 2.4% (n = 6, P < .05). The antibody suppressed adrenal renin in both untreated and perindopril treated TGR(mREN-2)27 rats by 57.3 +/- 5.4% (n = 5, P < .0001) and 49.7 +/- 2.2% (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < NS). The pH profile of renin activity in plasma confirmed the results of the antibody study. We conclude that in the TGR(mRen-2)27 rats adrenal renin is mainly mouse renin and kidney renin is mainly rat renin. The main sources of circulating renin in the TGR(mRen-2)27 rats are extra-renal tissues, including the adrenal glands, where mouse Ren-2 renin transcripts are highly expressed. The increased circulating renin in perindopril treated TGR(mRen-2)27 rats is rat renin derived from the kidney. The failure of adrenal renin to increase with perindopril suggests that at least in the basal state there is no feedback inhibition as there is in the kidney. The low kidney renin appears to be due to physiological rather than genetic factors.

Adrenal Glands↗

Locally generated angiotensin II in the adrenal gland regulates basal, corticotropin-, and potassium-stimulated aldosterone secretion.

The zona glomerulosa cells of the adrenal gland have an intrinsic renin-angiotensin system that appears to modulate the aldosterone response to potassium and corticotropin. The actions of circulating angiotensin II (Ang II) are mediated by the activation of the Ang II type 1 (AT1) receptor on the adrenal cortex. In this study we examined the effects of the AT1 receptor antagonist DuP 753 and other antagonists on aldosterone secretion in cultured bovine zona glomerulosa cells. Zona glomerulosa cells were cultured in PFMR-4 medium containing 10% fetal calf serum for 72 hours, and the medium was replaced with serum-free medium for the next 24-hour experimental period. DuP 753 (10 mumol/L) inhibited basal aldosterone secretion (from 88.6 +/- 7.1 to 54.8 +/- 9.6 pg/10(6) cells per hour; 38% inhibition). EXP 3174, an active metabolite of DuP 753, also inhibited aldosterone dose dependently (from 88.6 +/- 7.1 to 55.9 +/- 8.4 at 1 mumol/L and 88.6 +/- 7.1 to 21.7 +/- 3.3 at 100 mumol/L; 37% and 75% inhibition, respectively). Another and more potent AT1 receptor antagonist, L158,809, showed significant inhibition at 100 nmol/L, and at 10 mumol/L it inhibited basal aldosterone secretion (from 144.7 +/- 18.2 to 83.4 +/- 17.1 pg/10(6) cells per hour; 42% inhibition). DuP 753 inhibited Ang II (100 nmol/L)-stimulated aldosterone production in a dose-dependent fashion, with a 30% reduction at 100 nmol/L and complete inhibition at 100 mumol/L. DuP 753 also inhibited potassium (12 nmol/L) and corticotropin (1 nmol/L) stimulation of aldosterone in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

Role of the tissue renin-angiotensin system in the action of angiotensin-converting enzyme inhibitors.

The mechanism of the blood pressure-lowering action of chronic administration of angiotensin-converting enzyme (ACE) inhibitors is still controversial. We investigated the effects of the ACE inhibitors, captopril and perindopril, on the renin-angiotensin system (RAS) in plasma and tissues (adrenal gland and kidney) in the rat. Captopril or perindopril was infused intraperitoneally into rats via a mini-osmotic pump for 6 days at a rate of 0.5 or 0.25 mg/kg/hr, respectively. Perindopril markedly increased plasma renin concentration (PRC) from 12.7 +/- 1.1 to 867 +/- 59 ng Ang I/ml/hr and significantly inhibited plasma angiotensin II (Ang II) from 17.5 +/- 3.5 to 7.8 +/- 0.6 pg/ml and plasma ACE activity from 31.6 +/- 1.7 to 1.7 +/- 0.3 U/liter. Captopril also increased PRC from 12.1 +/- 2.1 to 147 +/- 17 ng Ang I/ml/hr. However, it did not inhibit plasma Ang II (20.6 +/- 1.9 vs 22.0 +/- 2.1 pg/ml, N.S.) and increased plasma ACE activity from 35.9 +/- 1.8 to 65.0 +/- 4.8 U/liter. Perindopril increased kidney renin from 625.3 +/- 84.6 to 2152.3 +/- 233.4 micrograms/g/hr, while captopril produced a modest but insignificant rise in kidney renin (708.0 +/- 107.1 vs 1083.3 +/- 155.5 micrograms Ang I/g/hr, N.S.). On the other hand, both captopril and perindopril decreased adrenal Ang II significantly (from 21.1 +/- 2.7 to 9.2 +/- 0.5 pg/capsule and from 15.5 +/- 2.9 to 2.0 +/- 0.6 pg/capsule, respectively). Adrenal renin was not altered by either treatment. In spite of no inhibition of plasma Ang II, the pressor response to intravenous Ang I was still suppressed after captopril treatment. Both captopril and perindopril lowered the blood pressure of the rats significantly. Our results support the hypothesis that inhibition of tissue RAS is important for the hypotensive action of ACE inhibition.

Adrenal Glands↗

Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.

The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4 +/- 37.3 ng angiotensin I/mL, n = 4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4 +/- 66.7 to 225,000 +/- 48,000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 microL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7 +/- 4.7 and 61.8 +/- 2.7 mmHg, respectively, whereas injection of 200 microL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensinogen↗

Effects of nephrectomy and adrenalectomy on the renin-angiotensin system of transgenic rats TGR(mRen2)27.

The transgenic rat TGR(mRen2) develops severe hypertension with high renin activity in the adrenal and low renin activity in the kidney. To clarify the role of the adrenal gland as a source of circulating renin in TGR rats, we investigated the effects of nephrectomy (NEPEX) and adrenalectomy (ADX) on the adrenal and plasma renin-angiotensin system. TGR rats had a high basal plasma renin concentration (PRC; 18.2 +/- 1.0 ng angiotensin-I (AngI)/ml.h) compared with Harlan Sprague-Dawley (SD) rats (7.4 +/- 0.5 ng AngI/ml.h; P < 0.01) and SD rats of the Hannover strain from which the TGR rat was derived (5.3 +/- 0.6 ng AngI/ml.h, P < 0.01); TGR rats also had high adrenal renin (83.3 +/- 8.9) compared with Harlan SD rats (5.5 +/- 0.7; P < 0.01) and Hanover SD rats (6.1 +/- 0.6 ng AngI/ml.h). NEPEX markedly increased PRC (82.4 +/- 18.8 ng AngI/ml.h, P < 0.01) and adrenal renin levels (386.3 +/- 43.9 ng AngI/adrenal.h; P < 0.01) in TGR rats. ADX significantly lowered control levels of PRC and plasma AngII in the TGR rats (19.0 +/- 1.2 to 7.7 +/- 1.2 ng AngI/ml.h and 33.5 +/- 5.6 to 12.8 +/- 2.1 pg/ml, respectively) and suppressed the increases in PRC (119.4 +/- 20.2 to 61.8 +/- 4.0 ng AngI/ml.h) and plasma AngII (95.8 +/- 9.8 to 55.1 +/- 4.3 pg/ml; P < 0.01) caused by NEPEX in TGR rats. However, the levels of PRC and plasma AngII remained high after NEPEX/ADX in TGR rats. Our results suggest that the adrenal gland is one of the main sources of circulating renin in the TGR rat, but other extrarenal sources of plasma renin also exist in these animals.

Adrenal Glands↗

The intrarenal renin-angiotensin system.

The standard concept of the renin-angiotensin system is that renin is secreted by the juxtaglomerular cells of the kidney into the circulation, where it cleaves angiotensin to release angiotensin I. The angiotensin I is converted to angiotensin II by a converting enzyme located on the plasma membrane of the endothelial cell. The released angiotensin II binds to receptors on target cells to initiate a series of intracellular actions that result in a specific cell function. The kidney was conceived to secrete renin with the circulatory angiotensin II returning to the kidney to alter renal function. It is now clear that all the components of the renin-angiotensin system can be synthesized within the kidney. In fact, angiotensin II is formed in very high concentrations in the renal interstitial space. Local angiotensin II production can have profound influences on renal function, ie, alter glomerular hemodynamics, reduce sodium excretion, and constrict small arterioles. In certain disease states, the local action of angiotensin II may have harmful effects on the kidney, and blockade of the renin-angiotensin system can be beneficial to the kidney.

Angiotensin I↗

Transforming growth factor-beta 1 inhibits aldosterone biosynthesis in cultured bovine zona glomerulosa cells.

Transforming growth factors (TGF beta s) are emerging as possible autocrine regulators of steroidogenesis in a variety of steroid hormone-producing cells. Our laboratory has recently shown that TGF beta 1 is a potent inhibitor of basal and ACTH- and (Bu)2cAMP-stimulated aldosterone production. In this study, we investigated the effects of TGF beta 1 on potassium- and angiotensin-II (A-II)-stimulated aldosterone and the mechanisms by which TGF beta 1 inhibits aldosterone biosynthesis. Cultured zona glomerulosa cells were incubated in serum-free PFMR-4 medium in the presence and absence of TGF beta 1. To investigate the effects of TGF beta 1 on the early pathway of aldosterone biosynthesis, we studied the production of pregnenolone in the presence of the cyanoketone derivative WIN 19,578, which blocks the conversion of pregnenolone to progesterone. TGF beta 1 inhibited pregnenolone production from 133.9 +/- 30.1 to 68.7 +/- 25.4 ng/10(6) cells.h, and the ACTH-stimulated production of pregnenolone was inhibited from 764.6 +/- 127.7 to 141.0 +/- 2.2 ng/10(6) cells.h. In contrast, TGF beta 1 did not inhibit 25-hydroxycholesterol-stimulated pregnenolone production. To study the late pathway of aldosterone production, we added the steroid precursors deoxycorticosterone and corticosterone. TGF beta 1 significantly inhibited deoxycorticosterone- and corticosterone-stimulated aldosterone production by over 50%. TGF beta 1 inhibited the AII- and potassium-induced synthesis of aldosterone. These observations show that TGF beta 1 inhibits AII- and potassium-induced aldosterone synthesis and the early pathway of aldosterone biosynthesis by interfering with the transport of cholesterol across the mitochondrial membrane as well as inhibiting the late pathway of aldosterone biosynthesis.

Aldosterone↗

Effect of atrial natriuretic peptide (8-33-Met ANP) in patients with hypertension.

In this pilot study we investigated the effects of a 4-h infusion of atrial natriuretic peptide (8-33 Met ANP) on hemodynamic, renal, and hormonal parameters in 12 patients with hypertension. Either 8-33 ANP in 5% mannitol (0.7 microgram/min [eight patients] and 1.05 micrograms/min [four patients]) or placebo (5% mannitol) was infused for 4 h on 2 consecutive days in a randomized double-blind crossover design. The plasma levels of ANP were not significantly different between the two doses of ANP and therefore the results from the two doses were combined. Plasma ANP increased from 61 +/- 24 pg/mL to 291 +/- 55 pg/mL after 2 h and to 288 +/- 40 pg/mL after 4 h. ANP caused a significant lowering of systolic blood pressure after 2 h of infusion from 148 +/- 5 mm Hg to 142 +/- 5 mm Hg (P less than .05) and to 128 +/- 6 after 4 h (P less than .01). Two hours after discontinuation of the infusion, systolic blood pressure was 126 +/- 6 and 135 +/- 7 mm Hg 4 h after the end of the infusion. Diastolic blood pressure did not change. Heart rate increased from 69 +/- 3 beats/min to 74 +/- 3 beats/min after 4 h and to 78 +/- 4 beats/min 2 h after termination of the infusion. Cardiac output did not change significantly. Urinary sodium and chloride increased significantly but creatinine clearance did not change. Plasma aldosterone decreased after 2 h of ANP infusion from 9.8 +/- 1.7 ng/dL to 6.7 +/- 0.9 ng/dL (P less than .01) and to 6.5 +/- 1.2 ng/dL after 4 h (P less than .05). Plasma renin activity decreased from 0.81 +/- 0.1 ng angiotensin I/mL/h to 0.57 +/- 0.1 after 2 h of infusion (P less than .05). There were no significant changes in plasma catecholamines or arginine vasopressin. Two patients developed severe hypotension and bradycardia and one of them had a sinus pause of 7.4 sec associated with loss of consciousness. Neither of these two patients had a significant increase in plasma catecholamines in response to the severe hypotension, suggesting that ANP may have inhibited their sympathetic response and increased their sensitivity to vagal cardioinhibitory reflexes. In conclusion, infusion of ANP in hypertensive patients causes prolonged lowering of systolic blood pressure with no change in diastolic pressure and cardiac output.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Changes in cholesterol levels after coronary artery bypass surgery.

To determine the factors responsible for the dramatic fall in cholesterol levels after coronary artery bypass surgery (CABG), the authors reviewed, in a retrospective study, the cholesterol levels of 36 patients who underwent CABG surgery during 1987 and compared their levels with those of a control group of 30 patients who underwent cholecystectomies during the same time. In a prospective study, the authors measured the lipids and the hematocrit levels of 15 patients undergoing CABG surgery before the initiation of cardiopulmonary bypass, after 5 minutes of extracorporeal circulation (ECC), and at the end of ECC. In the CABG group, the plasma cholesterol level fell from 211 +/- 63 mg/dl (mean +/- SE) to 70 +/- 48 mg/dl (p less than 0.01), a 77% decrease within 24 hours of surgery. In the cholecystectomy group, the plasma cholesterol fell from 192.3 +/- 8.9 mg/dl to 158 +/- 76 mg/dl (p less than 0.01), an 18% decrease within 24 hours of surgery. To estimate the contribution of hemodilution or blood loss to the fall in cholesterol, changes in hematocrit were recorded. In the CABG group, hematocrit fell from 39.5 +/- 0.7% to 23.5 +/- 0.7% 24 hours after surgery (41% decrease) (p less than 0.01), whereas in the cholecystectomy group hematocrit fell from 39.4 +/- 0.8% to 37.1 +/- 0.9% on the first postoperative day (6% decrease). There was a positive correlation between the fall in cholesterol and the fall in hematocrit in the CABG group (correlation coefficient 0.472), suggesting that hemodilution was a major factor in the decrease in cholesterol levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of angiotensin II on renin production by rat adrenal glomerulosa cells in culture.

Angiotensin II (Ang II) inhibits renin secretion and production from the kidney, but the effect of Ang II on adrenal renin is not clear. Nephrectomy, via elevated plasma adrenocorticotropic hormone (ACTH) and potassium, is a strong stimulator of adrenal renin production in the rat. This stimulation is inhibited by the infusion of Ang II, suggesting a negative feedback between Ang II and adrenal renin. In the present study, we examined the effect of Ang II on adrenal renin using a primary culture of rat glomerulosa cells. Cells were exposed to ACTH (10(-11) M), high potassium (8 and 12 mM), db-cyclic AMP (db-cAMP), (10(-3) M), or Ang II (10(-11) to 10(-5) M) for 24 hours, and active renin and inactive renin were measured. Active renin was predominant in the cells, whereas inactive renin predominated in the medium. Ang II stimulated renin production in a dose-dependent fashion (cell-active renin, 1.21 +/- 0.20 to 2.39 +/- 0.16; medium-inactive renin, 2.59 +/- 0.40 to 6.14 +/- 0.49 ng Ang I/10(6) cells). Both ACTH and db-cAMP significantly stimulated active renin in the cells (ACTH, 1.73 +/- 0.14 to 9.44 +/- 0.98; db-cAMP, 1.45 +/- 0.16 to 3.96 +/- 0.71 ng Ang I/10(6) cells) and inactive renin in the medium (ACTH, 4.98 +/- 0.38 to 43.7 +/- 5.63; db-cAMP, 3.80 +/- 0.32 to 33.55 +/- 5.62 ng Ang I/10(6) cells). The addition of Ang II (10(-7) M) blunted the stimulation of renin production by both ACTH and db-cAMP by 60%. High potassium-stimulated renin production was not inhibited by Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

Regulation of renin gene expression in rat adrenal zona glomerulosa cells.

Our previous studies indicated that the amount of renin present in cultured adrenal zona glomerulosa cells increased after stimulation with adrenocorticotropic hormone or potassium. In the present study, we investigated the effects of adrenocorticotropic hormone or potassium on renin gene expression in cultured rat adrenal zona glomerulosa cells. The amount of rat renin messenger RNA (mRNA) was measured by complementary DNA synthesis and the competitive polymerase chain reaction method. The effects of adrenocorticotropic hormone or potassium on adrenal zona glomerulosa cell renin activity and renin mRNA content were compared with the activity and content of control cells. After 1 and 4 hours of stimulation by adrenocorticotropic hormone or potassium, total renin in the medium increased slightly; at the same time, the percent change in the amount of renin mRNA was 281% and 291%, respectively, in the adrenocorticotropic hormone-stimulated group and 218% and 348%, respectively, in the potassium-stimulated group. Twenty-four hours after adrenocorticotropic hormone or potassium stimulation, total renin in the medium increased significantly, by 689% and 220%, respectively; percent change in the renin mRNA content was 754% and 278%, respectively. These results demonstrate that adrenocorticotropic hormone and potassium increased the activity of adrenal renin through an increase in the level of renin mRNA.

Adrenocorticotropic Hormone↗

Regulation of the adrenal renin angiotensin system in cultured bovine zona glomerulosa cells: effect of catecholamines.

The renin-angiotensin system consists of two main enzymes, renin and angiotensin-converting enzyme, which lead to the formation of angiotensin-II. Angiotensin-II is a potent vasoconstrictor and stimulates the production of aldosterone. In this study we examined the effect of ACTH, potassium, (Bu)2cAMP (dbcAMP), and catecholamines on the adrenal renin-angiotensin system. To study the production of renin and aldosterone in vitro, we developed a monolayer culture of bovine zona glomerulosa cells in serum-free medium. Collagenase-dispersed zona glomerulosa cells were incubated in Pasadena Foundation for Medical Research-4 medium containing 10% fetal calf serum for 72 h, and the medium was replaced with serum-free medium for the next 24 h of the experimental period. The cells during this 24 h were exposed to various doses of ACTH, potassium, dbcAMP, and sympathomimetic agents. ACTH and dbcAMP stimulated aldosterone secretion, and this secretion was associated with an increase in renin activity in cells and medium. Aldosterone was also stimulated by high doses of potassium, and potassium had a stimulatory effect on the secretion of renin in medium. Catecholamines had a weak stimulating effect on aldosterone secretion and were potent stimulators of adrenal renin activity in cells and medium. Dopamine had no significant effect on basal aldosterone secretion or renin activity in cells and medium. In conclusion, these data indicate that adrenal renin is synthesized in bovine zona glomerulosa cells in vitro, and that ACTH and dbcAMP stimulate adrenal renin and aldosterone production. Furthermore, adrenal renin, like renal renin, may be under the control of the sympathetic nervous system.

Adrenocorticotropic Hormone↗

Transforming growth factor-beta 1 inhibits aldosterone and stimulates adrenal renin in cultured bovine zona glomerulosa cells.

Transforming growth factors-beta (TFG beta s) are multifunctional peptides that affect proliferation, differentiation, and many other functions in a variety of cell types. In this study we examined the effect of TGF beta 1 on aldosterone and adrenal renin production using cultured bovine adrenal zona glomerulosa cells. Collagenase-dispersed zona glomerulosa cells were incubated in PFMR-4 medium containing 10% fetal calf serum for 72 h, and the medium was replaced with serum-free medium for the next 24 h. The cells during this 24-h period were exposed to TGF beta 1, ACTH, and (Bu)2cAMP (dbcAMP). It was observed that TGF beta 1 at 1 nM 1) inhibited basal aldosterone secretion from 680.0 +/- 40.0 to 270.0 +/- 10.0 pg/10(6) cells.h, 2) inhibited ACTH- and dbcAMP-stimulated aldosterone production, 3) increased levels of active renin in the cells from 17.8 +/- 2.5 to 70.7 +/- 4.4 pg angiotensin-I/10(6) cells.h and prorenin from 270.0 +/- 5.0 to 970.0 +/- 90 pg angiotensin-I/10(6) cells.h, 4) stimulated prorenin in the medium synergistically in combination with ACTH and dbcAMP, and 5) had no significant effect on basal cAMP production, but significantly inhibited the ACTH-stimulated production of cAMP. These observations show that TGF beta 1 is a potent inhibitor of basal and ACTH- and cAMP-stimulated aldosterone production and inhibits ACTH-stimulated cAMP production. Contrary to its effect on aldosterone, TGF beta 1 stimulates the synthesis and release of adrenal renin and prorenin. TGF beta 1 may act as an autocrine or paracrine regulator of aldosterone production.

Adrenocorticotropic Hormone↗