Kathleen H. Berecek

Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril.

Our purpose was to evaluate whether early treatment of spontaneously hypertensive rats (SHR) with the angiotensin converting enzyme inhibitor captopril could permanently alter the course of hypertension. Mating pairs of SHR were treated with captopril, and their pups were maintained on captopril until experimentation. Some captopril-treated rats were taken off treatment at 2 months of age, and then some of these rats were mated at 3 months of age. The mean arterial pressures of conscious captopril-treated rats, the rats removed from therapy, and the offspring of the rats removed from therapy were significantly smaller than control rats at 4 and 9 months of age. Central administration of angiotensin I or II induced significantly smaller increases in blood pressure and drinking in captopril-treated rats and the rats removed from therapy compared with control rats. The increase in blood pressure in response to intravenous injection of angiotensin I or II was similar among all groups, with the exception that captopril-treated rats showed lesser pressor responses to angiotensin I. Early administration of captopril, even after administration was stopped, prevented the subsequent development of hypertension in SHR and altered the course of development of hypertension in their progeny. This effect was associated with decreased central responses to angiotensin I and II. Our data suggest that captopril may permanently alter the development of hypertension in SHR through an alteration in the central renin-angiotensin system.

Report of the National Heart, Lung, and Blood Institute Working Group on Epigenetics and Hypertension

Hypertension, defined as a condition associated with ≥140-mm Hg systolic blood pressure or ≥90-mm Hg diastolic blood pressure, affects >1 billion people worldwide,1 and in 2009 it cost the US healthcare system more than

Altered vascular reactivity and baroreflex sensitivity induced by chronic central administration of captopril in the spontaneously hypertensive rat.

73 billion.2 Despite the availability of many antihypertensive therapies, individual responses vary, and efficacy remains a concern. Current treatments have yielded only modest reductions in the overall disease risk even in countries where therapeutics are available and affordable. The initiating causes and the pathogenic mechanisms for disease and its comorbidities remain largely unknown, and prognostic markers for adult hypertension that could improve its diagnosis, prevention, and, ultimately, its management are not yet available. As a result, ≈28% of the US population and a similar proportion of the adult Western European and Canadian populations experience what is known as “essential hypertension,”3 which is a primary component of several complex, multifactorial, multigenic conditions that are commonly associated with high levels of morbidity and mortality from diabetes mellitus, cardiovascular disease, and renal disease. If the current rise in the number of hypertension cases is not abated, total annual global healthcare costs resulting from suboptimal blood pressure for those >30 years of age could amount to

Increased PI3-kinase in presympathetic brain areas of the spontaneously hypertensive rat.

3.6 trillion more over the next 10 years.4 The causes of essential hypertension remain poorly understood, although the complex mechanisms for blood pressure (BP) regulation have been extensively characterized in both humans and animal models.5–7 Comprehensive study of >12 inbred rat strains that recapitulate many aspects of hereditary human hypertension has added substantially throughout the years to our understanding of the underlying physiological and molecular pathways, the genetic complexity of risk and treatment responses, and the pathological consequences of hypertension.8 In fact, many interventions that lead to a …

Central role for vasopressin in cardiovascular regulation and the pathogenesis of hypertension

Previous studies from our laboratory have shown that chronic intracerebroventricular administration of captopril attenuates the development of hypertension in the spontaneously hypertensive rat of the Okamoto strain (SHR) without altering sodium and water balance, plasma renin, or sympathoadrenal activities. To determine whether the depressor effect of intracerebroventricular captopril was associated with an alteration in peripheral vascular reactivity and/or baroreflex sensitivity, vascular reactivity to phenylephrine and vasopressin was assessed in renal, mesenteric, and hindquarter vascular beds using pulsed Doppler flow probes. Captopril was infused into the jugular vein or lateral ventricle of male SHR and Wistar-Kyoto (WKY) rats for 4 weeks (osmotic mini pump, 1.25 micrograms/0.5 microliter/hr). Control SHR or WKY received intracerebroventricular infusions of vehicle. Four weeks of captopril decreased arterial pressure in both SHR and WKY. In response to phenylephrine and vasopressin, SHR and WKY treated with intracerebroventricular captopril showed significantly attenuated increases in arterial pressure and vascular resistance in comparison to either vehicle-treated rats or rats receiving intravenous captopril. Reflex decreases in heart rate in response to phenylephrine were also greater in SHR and WKY treated with intracerebroventricular captopril than in the other rat groups. Neither vascular reactivity nor baroreflex sensitivity was altered in rats treated with intravenous captopril. We conclude that the depressor effect of captopril involves a blunting of vascular reactivity to vasoconstrictors and a potentiation of the baroreflex.

Changes in renal Angiotensin II receptors in spontaneously hypertensive rats by early treatment with the angiotensin-converting enzyme inhibitor captopril

Existing evidence led us to hypothesize that increases in p85α, a regulatory subunit of PI3-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85α, p110α, and p110δ mRNA was 1.5- to 2-fold higher in the paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHR) compared with their controls, Wistar Kyoto rats (WKY). The increase in p85α/p110δ was attenuated in SHR treated with captopril, an angiotensin (Ang)-converting enzyme inhibitor, from in utero to 6 months of age. In the rostral ventrolateral medulla (RVLM), p110δ mRNA was ≈2-fold higher in SHR than in WKY. Moreover, the increases in mRNA were associated with higher PI3-kinase activity in both nuclei. The functional relevance was studied in neuronal cultures because SHR neurons reflect the augmented p85α mRNA and PI3-kinase activity. Expression of a p85 dominant-negative mutant decreased norepinephrine (NE) transporter mRNA and [3H]NE uptake by ≈60% selectively in SHR neurons. In summary, increased p85α/p110δ expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PI3-kinase p85α/p110δ expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.

Extracellular ATP and zinc are co-secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta-cells to potentiate insulin secretion

In recent years the role of neuropeptides in the central regulation of arterial pressure and the pathogenesis of hypertension has been the subject of considerable attention. Of all the neuropeptides, vasopressin (AVP) has been one of the most widely studied. The availability of sophisticated immunocytochemical and biochemical methods has permitted localization of AVP in areas of the brain known to be involved in cardiovascular regulation

Baroreflex function in lifetime-captopril-treated spontaneously hypertensive rats.

We tested the hypothesis that in utero treatment with the angiotensin-converting enzyme inhibitor captopril could change the affinity, density, and/or subtypes of angiotensin II (Ang II) receptors in the kidneys of spontaneously hypertensive rats (SHR). Newborn, 7-day-old, and 4-month-old SHR and Wistar-Kyoto (WKY) rats were used. SHR and WKY rat breeders were treated with captopril (0.4 mg/mL, 100 mg/kg per day) in drinking water, and their pups were maintained on captopril treatment until experimentation. Control groups were untreated, age-matched SHR and WKY rats. The density, affinity, and subtypes of renal Ang II receptors were determined using radioligand binding techniques and receptor antagonists specific for Ang II receptor subtypes 1 and 2 (losartan, an AT1-specific antagonist, and CGP 42112B, an AT2-specific antagonist). AT1 receptor density in kidneys was higher than AT2 receptor density in both neonatal and adult rats. AT1 receptor density in kidneys increased approximately twofold from birth to 7 days of age in all groups. Newborn and 7-day-old SHR showed significantly greater Ang II receptor densities in kidneys than other rat groups because of significantly greater densities of both AT1 and AT2 receptors. At 4 months of age, there were no significant differences in Ang II receptor densities in kidneys between captopril-treated and control SHR. Our data indicate that the expression of AT1 and AT2 receptors in kidneys is differentially regulated during development. Enhanced activity of the renal renin-Ang II system in newborn and probably fetal SHR may be involved in the pathogenesis of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Salt-induced hypertension in normotensive spontaneously hypertensive rats.

It is well established that ATP is co-secreted with insulin and zinc from pancreatic beta-cells (β-cells) in response to elevations in extracellular glucose concentration. Despite this knowledge, the physiological roles of extracellular secreted ATP and zinc are ill-defined. We hypothesized that secreted ATP and zinc are autocrine purinergic signaling molecules that activate P2X purinergic receptor (P2XR) channels expressed by β-cells to enhance glucose-stimulated insulin secretion (GSIS). To test this postulate, we performed ELISA assays for secreted insulin at fixed time points within a “real-time” assay and confirmed that the physiological insulin secretagogue glucose stimulates secretion of ATP and zinc into the extracellular milieu along with insulin from primary rat islets. Exogenous ATP and zinc alone or together also induced insulin secretion in this model system. Most importantly, the presence of an extracellular ATP scavenger, a zinc chelator, and P2 receptor antagonists attenuated GSIS. Furthermore, mRNA and protein were expressed in immortalized β-cells and primary islets for a unique subset of P2XR channel subtypes, P2X2, P2X3, P2X4, and P2X6, which are each gated by extracellular ATP and modulated positively by extracellular zinc. On the basis of these results, we propose that, within endocrine pancreatic islets, secreted ATP and zinc have profound autocrine regulatory influence on insulin secretion via ATP-gated and zinc-modulated P2XR channels.

Central vasopressin receptors are upregulated by deoxycorticosterone acetate

The effects of lifetime oral captopril treatment on baroreflex control of heart rate and lumbar sympathetic nerve activity were measured in 19-21-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The sensitivity of baroreflex control of heart rate and lumbar sympathetic nerve activity were determined by the slopes of the relation between the change in mean arterial pressure (MAP) (mm Hg) versus the change in pulse interval (msec/beat) and the change in MAP versus the percent change in nerve activity, respectively. Untreated SHR had significantly higher MAP than WKY (157 +/- 3 vs. 115 +/- 3 mm Hg, p less than 0.001) and exhibited a decreased baroreflex control of heart rate. Lifetime treatment with captopril prevented the development of hypertension in SHR (MAP = 110 +/- 5 mm Hg) and increased the sensitivity of baroreflex function. The gains of the baroreflex control of heart rate for captopril-treated SHR and control SHR when MAP was raised or lowered by phenylephrine or nitroprusside were 2.38 +/- 0.49 vs. 1.10 +/- 0.33 msec/mm Hg (p less than 0.05) and 0.74 +/- 0.20 vs. 0.54 +/- 0.09 (NS) msec/mm Hg, respectively. The sensitivity of the baroreflex control of lumbar sympathetic nerve activity was greater in captopril-treated SHR than in control SHR when MAP was increased or decreased (-1.03 +/- 0.26 vs. -0.38 +/- 0.11, p less than 0.05; -0.84 +/- 0.2 vs. -0.04 +/- 0.58 (NS) mm Hg-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)