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a sweet deal for normal baroreflex function.

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Presentation on theme: "a sweet deal for normal baroreflex function."— Presentation transcript:

1 a sweet deal for normal baroreflex function.
BRAIN INSULIN: a sweet deal for normal baroreflex function.

2 Aortic Depressor Nerve ↓ Vascular Resistance and Blood pressure
Baroreceptor Reflex BRAIN Carotid Sinus Spinal Cord Vagus (PNS) Aortic Depressor Nerve SNS Aortic Baroreceptors ↓ Vascular Resistance and Blood pressure ↑ BP Heart Vasculature ↓ Heart Rate

3 Measuring Baroreflex Function Heart Rate (HR) Lumbar Sympathetic Nerve Activity (LSNA)
1 min BP mmHg Nitroprusside Phenylephrine HR bpm LSNA µV

4 Measuring Baroreflex Function Heart Rate (HR) Lumbar Sympathetic Nerve Activity (LSNA)
BP mmHg Nitroprusside Phenylephrine

5 Measuring baroreflex function Heart Rate (HR) Lumbar Sympathetic Nerve Activity (LSNA)
Nitroprusside Phenylephrine BP mmHg HR bpm LSNA µV 1 min

6 Conditions associated with an impaired baroreflex
Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Congestive Heart Failure Aging Pregnancy

7 Reduced ability to maintain blood pressure: orthostatic hypotension
Impaired baroreflex function: risk factor for cardiovascular complications Reduced ability to maintain blood pressure: orthostatic hypotension hemorrhagic hypotension Increased blood pressure variability, leading to: increased risk for myocardial infarction target organ damage

8 Conditions associated with an impaired baroreflex
Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Congestive Heart Failure Aging Pregnancy .

9 Impaired baroreflex and insulin resistance
Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Congestive Heart Failure Aging Pregnancy

10 baroreflex gain

11 Pregnancy decreases baroreflex gain.

12 Pregnancy impairs the baroreflex.
Cardiac baroreflex: Rabbit Rat Dog Sheep Goats Human Sympathetic baroreflex: Rabbit Rat Human

13 HYPOTHESIS PREGNANCY INSULIN SENSITIVITY BAROREFLEX GAIN

14 Measuring insulin sensitivity: Hyperinsulinemic-euglycemic clamp
High Insulin Sensitivity Low Insulin Sensitivity insulin glucose

15 Decreases in insulin sensitivity and baroreflex gain exhibit the same time course.
Daubert et al. Am.J.Physiol 292: R2188, 2007

16 Baroreflex gain and insulin sensitivity are related.

17 HYPOTHESIS PREGNANCY INSULIN SENSITIVITY BAROREFLEX GAIN

18 HYPOTHESIS PREGNANCY rosiglitazone INSULIN SENSITIVITY BAROREFLEX GAIN

19 HYPOTHESIS PREGNANCY rosiglitazone INSULIN SENSITIVITY BAROREFLEX GAIN

20 HYPOTHESIS PREGNANCY rosiglitazone INSULIN SENSITIVITY BAROREFLEX GAIN

21 Rosiglitazone increases insulin sensitivity
and baroreflex gain Daubert et al. Am.J.Physiol 292: R2188, 2007

22 no effects in non pregnant rabbits.
Rosiglitazone: no effects in non pregnant rabbits. Daubert et al. Am.J.Physiol 292: R2188, 2007

23 HYPOTHESIS PREGNANCY INSULIN SENSITIVITY BAROREFLEX GAIN

24 Conditions associated with an impaired baroreflex
Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Congestive Heart Failure Aging Pregnancy

25 Obesity decreases baroreflex gain
Humans: Grassi et al. Hypertension 25: 560-3, 1995 Arone et al Am.J.Physiol. 269: R222-5, 1995. Zucker Rats: Bunag et al. Am.J.Physiol. 256: H417-21, 1989. Bunag et al. Am.J.Physiol. 259: R842-8, 1990. Schreihofer et al. Am.J.Physiol. 293: H2543-9, 2007

26 Diet-Induced Obesity (DIO): model of
human obesity 250 grams High fat diet Control diet 1/3 OP rats 1/3 OR rats 4-5 weeks

27 Diet-Induced Obesity (DIO): model of
human obesity 250 grams High fat diet Control diet 1/3 OP rats 1/3 OR rats ↓ Baroreflex gain ? 4-5 weeks ↓Insulin Sensitivity

28 OBESITY: INSULIN RESISTANCE
* OP (n=8) OR (n=8) CON (n=8) † * * OP (n=9) OR (n=8) CON (n=8) Ding Zhao * OP (n=8) OR (n=8) CON (n=8) OP (n=9) †

29 OBESITY: decreased baroreflex gain
OP OR CON Ding Zhao

30 OBESITY: decreased baroreflex gain
* * OP OR CON Ding Zhao

31 OBESITY: BRG is related to IS
r2=0.49 P<0.01 Ding Zhao

32 HYPOTHESIS OBESITY rosiglitazone INSULIN SENSITIVITY BAROREFLEX GAIN

33 Impaired baroreflex and insulin resistance
Pregnancy Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Heart Failure Aging Young et al. Insulin enhances the gain of arterial baroreflex control of muscle sympathetic nerve activity in humans. J. Physiol. 588: (2010).

34 How does insulin resistance decrease baroreflex gain?
QUESTION How does insulin resistance decrease baroreflex gain?

35 Aortic Depressor Nerve
Baroreceptor Reflex BRAIN Carotid Sinus Spinal Cord Vagus (PNS) Aortic Depressor Nerve SNS Aortic Baroreceptors Heart Vasculature

36 HYPOTHESIS: BRAIN INSULIN
BLOOD BBB ↓ X INSULIN INSULIN + IR + BRAINSTEM Baroreflex Gain Sympathetic Nervous System

37 Lateral cerebroventricular insulin infusion:
increases baroreflex gain. Pricher et al. Hypertension 51: 1-7 (2008).

38 HYPOTHESIS: BRAIN INSULIN
BLOOD BBB ↓ X INSULIN INSULIN + IR J. Physiol. 588: (2010). + BRAINSTEM Baroreflex Gain Sympathetic Nervous System

39 Pregnancy decreases CSF insulin
Daubert et al. Am.J.Physiol 292: R2188, 2007

40 Baroreflex gain decreases with insulin sensitivity.

41 Obesity decreases brain insulin
Baskin et al. Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci 36: , 1985. Gerozissis et al. A potential role of central insulin in learning and memory related to feeding. Cell Mol Neurobiol 21: , 2001. Kaiyala et al. Obesity induced by a high fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49: , 2000. Shows changes in insulin levels in CSF and plasma. Plasma, no change. CSF decreased by >50% at end at gestation, but not at midgestation.

42 HYPOTHESIS: BRAIN INSULIN
BLOOD BBB ↓ X INSULIN INSULIN + IR + BRAINSTEM Baroreflex Gain Sympathetic Nervous System

43 Pregnancy decreases baroreflex gain in rats
Non-pregnant (n=10) Pregnant (n=7) Shows that in rats, as in rabbits, pregnancy decreases baroreflex gain. The question is whether icv insulin would normalize the baroreflex, look like non-pregnant. Azar and Brooks. Hypertension (2011).

44 ICV insulin infusion in virgin rats
control n=10 insulin virgin Azar and Brooks. Hypertension (2011).

45 ICV insulin infusion in pregnant rats
control n=10 insulin control n=7 insulin virgin pregnant Azar and Brooks. Hypertension (2011).

46 ICV insulin increases baroreflex gain in conscious pregnant rats.
† * Pre- insulin Post-insulin Pre- insulin Post-insulin Virgin Pregnant Azar and Brooks. Hypertension (2011).

47 Conditions associated with an impaired baroreflex
Obesity Type II Diabetes Metabolic syndrome Alzheimer’s Disease Hypertension Congestive Heart Failure Aging Pregnancy

48 ICV insulin infusion increases baroreflex gain and maximum in conscious male obese rats.
OP (n=6) control insulin * MEAN ARTERIAL PRESSURE (mmHg) OR (n=5) insulin control MEAN ARTERIAL PRESSURE (mmHg) HEART RATE (bpm)

49 HYPOTHESIS: BRAIN INSULIN
BLOOD BBB ↓ X INSULIN INSULIN + IR + BRAINSTEM Baroreflex Gain Sympathetic Nervous System

50 ? HYPOTHESIS: BRAIN INSULIN + + BRAIN BLOOD IR BRAINSTEM
BBB INSULIN INSULIN + IR ? + BRAINSTEM Baroreflex Gain Sympathetic Nervous System

51 Where in the brain? insulin Sympathetic Activity PVN Arcuate NTS RVLM
Pricher, M.P., K.L. Freeman, and V.L. Brooks. Hypertension 51: 1-7 (2008).

52 Where in the brain? insulin Sympathetic Activity PVN Arcuate NTS RVLM
Pricher, M.P., K.L. Freeman, and V.L. Brooks. Hypertension 51: 1-7 (2008).

53 Insulin: brain site of action
ArcN PVN RVLM X X PVN inhibition reverses insulin-mediated increases in LSNA and LSNA gain. PVN microinjection of insulin has no effect. ArcN inhibition reverses insulin-mediated increases in LSNA and LSNA gain.

54 ArcN insulin increases LSNA
CON 0.6 6 60 Insulin nU * aCSF 10 sec ArcN insulin increases LSNA Cassaglia et al. J. Physiol. 589: (2011). (n=6)

55 ArcN insulin increases LSNA gain
Control ArcN insulin, 6 nU ArcN insulin, 60 nU MAP (mmHg)

56 ArcN insulin increases LSNA gain
(%/mmHg) CON aCSF 0.6 6 60 Insulin nU LSNA (% control) MAP (mmHg) (n=6) * * Cassaglia et al. J. Physiol. 589: (2011).

57 Insulin acts in the ArcN
PVN RVLM GluR ? Cassaglia et al. J. Physiol. 589: (2011).

58 a master regulator of baroreflex function?
Insulin: a master regulator of baroreflex function? Decreases in baroreflex gain and insulin sensitivity are correlated during pregnancy and obesity. Reversal of insulin resistance (rosiglitazone) normalizes baroreflex gain. Brain insulin levels are reduced during pregnancy and obesity. ICV insulin infusion in conscious pregnant and obese rats normalizes HR gain.

59 HYPOTHESIS: BRAIN INSULIN
BLOOD BBB INSULIN INSULIN ArcN + PVN + RVLM Baroreflex Gain Sympathetic Nervous System

60

61 DAISY DAUBERT KOKO FREEMAN MOLLIE PRICHER SHAREN AZAR THERESA O’DONAUGHY ROBERT GOLDMAN JULIA MULVANEY DING ZHAO BELINDA MCCULLY PRISCILA CASSAGLIA MIKE ANDRESEN

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