Step I Beta Agonists and Renin

[Milotic]

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Maybe I am missing something obvious because I cannot find any info online regarding this, nor have I come across the right Uworld questions regarding this relationship, but I was hoping someone could help me out.

We talk about Dobutamine and Isoproterenol having the Beta1/Beta2 agonist activities (Dobu having more of Beta1). First aid and other sources all talk about there being a decrease in peripheral resistance due to these drugs and that the increase in systolic BP is usually due to the Beta-1 activity from heart etc. First Aid (2016) on page 247 even says that there is unopposed Beta-2 activity on peripheral resistance.

Why doesn't any source mention Beta-1 agonism on JGA (increasing Renin --> increasing ATII --> Vasoconstriction) occurring and even possibly off setting/slightly balancing the Beta-2 vasodilating activity??

Is it just the case that this vasoconstriction activity of JGA (beta-1 agonism) doesn't really occur with these drugs or that it doesn't really turn on until there is DRASTIC hypotension?

Thanks!

TLDR Version: Shouldn't JGA Beta-1 agonism have some effect on the Peripheral resistance when given drugs with both Beta-1/Beta-2 agonism?

 

[dorster]

Thats a really good question.. I'm thinking maybe its b/c the JGA is not just controlled by B1 stimulation but also low Na+ in DCT and low pressure in the afferent arteriole. Also I think the main driver of CO is HR X BP and they don't really focus so much on the role of the JGA in the kidney b/c its secondary and theres lots of other things more directly related to influencing BP and heart rate.

 

[slz1900]

Is there also a time aspect? Maybe since these drugs are typically used acutely there isn't time for raas to be activated and start to exert an effect.

 

[Milotic]

Thats a really good question.. I'm thinking maybe its b/c the JGA is not just controlled by B1 stimulation but also low Na+ in DCT and low pressure in the afferent arteriole. Also I think the main driver of CO is HR X BP and they don't really focus so much on the role of the JGA in the kidney b/c its secondary and theres lots of other things more directly related to influencing BP and heart rate.

Yeah it just sucks when FA uses terms like "unopposed Beta-2" for isoproterenol when talking about peripheral resistance. Also, when I got into my usual rut of researching online for answers, it turns out the Beta-1 response on JGA is VERY strong.... which makes me even more confused.

Sometimes I wish I didn't think about these things when studying. Maybe if a question about nonselective Beta agonism comes up regarding BP, I'll forget the Beta-1 receptors in the JGA exist for that moment haha.

 

[Jabbed]

Maybe I am missing something obvious because I cannot find any info online regarding this, nor have I come across the right Uworld questions regarding this relationship, but I was hoping someone could help me out.

We talk about Dobutamine and Isoproterenol having the Beta1/Beta2 agonist activities (Dobu having more of Beta1). First aid and other sources all talk about there being a decrease in peripheral resistance due to these drugs and that the increase in systolic BP is usually due to the Beta-1 activity from heart etc. First Aid (2016) on page 247 even says that there is unopposed Beta-2 activity on peripheral resistance.

Why doesn't any source mention Beta-1 agonism on JGA (increasing Renin --> increasing ATII --> Vasoconstriction) occurring and even possibly off setting/slightly balancing the Beta-2 vasodilating activity??

Is it just the case that this vasoconstriction activity of JGA (beta-1 agonism) doesn't really occur with these drugs or that it doesn't really turn on until there is DRASTIC hypotension?

Thanks!

TLDR Version: Shouldn't JGA Beta-1 agonism have some effect on the Peripheral resistance when given drugs with both Beta-1/Beta-2 agonism?

ß-adrenergic receptors are a little weird.

So while noreipnephrine/epinephrine are both neurotransmitters and hormones, norepi is more commonly seen as a neurotransmitter and epi is more commonly seen as a hormone. The interesting part is that ß-2 receptors are not innervated by the sympathetic nervous sytem. Essentially, you can only have ß-2 mediates effects (notably, vasodilation) with epinephrine hormonal release and not sympathetic system activation. The flip side is that since ß-1 receptors are directly innervated by the sympathetic nervous system, prolonged stimulation of ß-1 receptors (which would be necessary to sustain the RAAS) tends to only occur with SNS neural stimulation OR when you have a ridiculously high epi load for a reasonably long period of time (think pheo, not a bolus).

The other caveat of course is that RAAS activation takes time (enzymatic rxns) vs pure ß-2 agonism, which is a ligand-gated ion channel. For step 1 purposes, they like to pimp you on CV changes immediately after drug administration, which is several minutes before ß-1 mediated RAAS activation will have a noticeable effect.

 

[Milotic]

Wow thanks so much! That definitely clears it up. I noticed that in Uworld, they even just tend to ignore the JGA actions when it comes to those "Drug X" compared to "pre-admin" stuff. They have made it pretty obvious when they do want us to think about the JGA actions, at least so far.